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VOLUME II
EDITORIAL BOARD
ROGER ADAMS, Editor-in-Chief WERNER E. BACHMANN LOUIS F. FIESER JOHN R. JOHNSON H. R. SNYDER
ASSOCIATE EDITORS
T . A. GEISSMAN CLIFF S. HAMILTON ALBERT L. HENNE A. W. INGERSOLL A. L. WILDS ERNEST L. JACKSON WILLIAM S. JOHNSON NATHAN KORNBLUM D. STANLEY TARBELL
THIRD PRINTING
NEW YORK
JOHN WILEY & SONS, INC.
LONDON: CHAPMAN & HALL, LIMITED
COPYRIGHT, 1944 BY ROGER ADAMS AU Rights Reserved This book or any part thereof must not be reproduced in any form without the wntten permission of the publisher.
Third Printing, December, 1946
PRINTED IN THE UNITED STATES OP AMERICA
PREFACE TO THE SERIES In the course of nearly every program ofresearch in organic chemistry the investigator finds it necessary to use several of the better-known synthetio reactions. To discover the optimum conditions for the application of even the most familiar one to a compound not previously subjected to the reaction often requires an extensive search of the literature; even then a series of experiments may be necessary. When the results of the investigation are published, the synthesis, which may have required months of work, is usually described without comment. The background of knowledge and experience gained in the literature search and experimentation is thus lost to those who subsequently have occasion to apply the general method. The student of preparative organic chemistry faces similar difficulties. The textbooks and laboratory manuals furnish numerous examples of the application of various syntheses, but only rarely do they convey an accurate conception of the scope and usefulness of the processes. For many years American organic chemists have discussed these problems. The plan of compiling critical discussions of the more important reactions thus was evolved. The volumes of Organic Reactions are collections of about twelve chapters, each devoted to a single reaction, or a definite phase of a reaction, of wide applicability. The authors have had experience with the processes surveyed. The subjects are presented from the preparative viewpoint, and particular attention is given to limitations, interfering influences, effects of structure, and the selection of experimental techniques. Each chapter includes several detailed procedures illustrating the significant modifications of the method. Most of these procedures have been found satisfactory by the author or one of the editors, but unlike those in Organic Syntheses they have not been subjected to careful testing in two or more laboratories. When all known examples of the reaction are not mentioned in the text, tables are given to list compounds which have been prepared by or subjected to the reaction. Every effort has been made to include in the tables all such compounds and references; however, because of the very nature of the reactions discussed and their frequent use as one of the several steps of syntheses in which not all of the intermediates have been isolated, some instances may well have been missed. Nevertheless, the
iv
PREFACE TO THE SERIES
investigator will be able to use the tables and their accompanying bibliographies in place of most or all of the literature search so often required. Because of the systematic arrangement of the material in the chapters and the entries in the tables, users of the books will be able to find information desired by reference to the table of contents of the appropriate chapter. In the interest of economy the entries in the indices have been kept to a minimum, and, in particular, the compounds listed in the tables are not repeated in the indices. The success of this publication, which will appear periodically in volumes of about twelve chapters, depends upon the cooperation of organic chemists and their willingness to devote time and effort to the preparation of the chapters. They have manifested their interest already by the almost unanimous acceptance of invitations to contribute to the work. The editors will welcome their continued interest and their suggestions for improvements in Organic Reactions.
CONTENTS
CHAPTER ' PAGE 1 49 94 1. THE CLAISEN REARRANGEMENT—D. Stanley Tarbell 2. THE PREPARATION OP ALIPHATIC FLUOBINM COMPOVNDS—Albert L. Henne . 3. THE CANNIZZARO REACTION—T. A. Geissman . . . .
4. THE FORMATION OP CYCLIC KETONES BY INTRAMOLECULAR ACYLATION—
William S. Johnson
'
114
178
5. REDUCTION WITH ALUMINUM ALKOXIDES (THE MEERWEIN-PONNDORFVERLEY REDUCTION)—A. L. Wilds ' 6. THE PREPARATION OF UNSYMMETRICAL BIARYLS BY THE DIAZO REACTION AND THE NITROSOACETYLAMINE REACTION—Werner E. Bachmann and
Roger A. Hoffman
7. REPLACEMENT OF THE AROMATIC PRIMARY AMINO GROUP BY HYDROGEN—
224
Nathan Kornblum
8. PERIODIC ACID OXIDATION—Ernest L. Jackson 9. THE RESOLUTION OF ALCOHOLS—A. W. Ingersoll 10. THE PREPARATION OF AROMATIC ARSONIC AND ARSINIC ACIDS BY THE BART, BECHAMP, AND ROSENMUND REACTIONS—Cliff S. Hamilton and
262
341 376
Jack F. Morgan
INDEX
415
455
CHAPTER 1
THE CLAISEN REARRANGEMENT
D. STANLEY TAEBBLL
The University of Rochester CONTENTS
INTRODUCTION STRUCTURAL REQUIREMENTS FOR REARRANGEMENT; RELATED REARRANGEMENTS • SCOPE AND LIMITATIONS . . . ./• PAGE 2
4 6
Rearrangement in Open-Chain Compounds Rearrangement of Allyl Aryl Ethers The ortho Rearrangement The para Rearrangement Effect of Substituents in the Allyl Group Effect of Substituents in the Aromatic Nucleus Displacement of Substituents Relation of Bond Structure to Rearrangement Side Reactions Mechanism of the Rearrangement Synthetic Application
OTHER METHODS OF SYNTHESIS OF ALLYLPHENOLS EXPERIMENTAL CONDITIONS AND PROCEDURES
6 8 8 8 9 11 11 13 14 16 17
20 22
Preparation of Allyl Ethers Conditions of Rearrangement 0 Experimental-Procedures Allyl Phenyl Ether Allyl 2,4-Dichlorophenyl Ether 2-Allylphenol 2-Methyldihydrobenzofuran „ Isomerization of 2-Allylphenol to 2-Propenylphenol C-Alkylation. Preparation of 2-Cinnamylphenol
EXAMPLES OF THE REARRANGEMENT
*.
22 23 26 26 26 27 27 27 28
29
Table I. Rearrangement of Open-Chain Compounds A. Ethers of Enols B. Rearrangements' Involving Migration to an Unsaturated Side Chain .
4
29 29 29
2
THE CLAISEN REARRANGEMENT
PAGE
Table II. ortho Rearrangements of Allyl Aryl Ethers A. Benzene Derivatives B. Polycyclic and Heterocyclic Derivatives C. ortho Rearrangements with Displacement of Carbon Monoxide or Carbon Dioxide D. Rearrangements of Ethers Containing Monosubstituted Allyl Groups . 0-Methylallyl Ethers Miscellaneous Ethers, Benzene Derivatives Miscellaneous Ethers, Derivatives of Polycyclic Hydrocarbons . . E. Rearrangements of Ethers Containing Disubstituted Allyl Groups . . Table III. para Rearrangements of Allyl Aryl Ethers A. Allyl Ethers of Phenols and Substituted Phenols B. Ethers Containing Substituted Allyl Groups C. Rearrangements Involving Displacement INTRODUCTION
30 30 35 38 39 39 40 42 43 44 44 45 47
Allyl ethers of enols and phenols undergo rearrangement to C-allyl derivatives when heated to sufficiently high temperatures. The reaction, named after its discoverer (Claisen, 1912), was first observed when ethyl O-allylacetoacetate was subjected to distillation at atmospheric pressure in the presence of ammonium chloride.1'2 OCH2CH=CHj! 0 CH2CH=CH2
CH3C=CHCO2C2HB
-» CH3C—CHCO2C2HB
The allyl ethers of phenols rearrange smoothly at temperatures of about 200°, in the absence of catalysts. If the ether has an unsubstituted ortho position, the product is the o-allylphenol. One of the most interesting features of the rearrangement of allyl phenyl ethers to o-allylphenols OCH2CH=CH2 OH
(ortho rearrangement) is the fact that the carbon atom which becomes attached to the aromatic nucleus is not the one attached to the oxygen atom of the ether, but rather the one in the 7-position with respect to the oxygen atom (p. 9). During the rearrangement the double bond of the allyl group shifts from the /3,7-position to the a,/3-position. T.he inversion of the allyl group is apparent, of course, only when substituents are present on either the a- or 7-carbon atom. Crotyl phenyl ether (I), for example, rearranges to the branched-chain o-methylallylphenol (II).
1 8
Claisen, Ber., 45, 3157 (1912). Claisen, BeHstein, Supplementary Volume III-IV, p. 256.
INTRODUCTION
a 0 y
OCH2C&=CHCH3
OH
y
$
a
—CHCH==CH, CHs Allyl ethers of ortfto-disubstituted phenols rearrange to the corresponding p-allylphenols. It is noteworthy that the para rearrangement is not usually accompanied by inversion of the allyl group.3-4-6- 6>7 For example, cinnamyl 2-carbomethoxy-6-methylphenyl ether (III) rearranges without inversion3 to yield the p-cinnamyl derivative (IV). OCH2CH=CHC6HB OH
CH2CH=CHC6H5 in iv The crotyl ether of the same phenol also rearranges without inversion.8 The only known example of para rearrangement accompanied by inversion is the reaction of a-ethylallyl 2-carbomethoxy-6b-methy]phenyl ether (V), which yields the p-(7-ethylallyl) derivative (VI).6 OCH(C2HB)CH=CH2
v
vi
CH2CH=CHC2H6
This is also the only known example of para rearrangement in which a substituent is present on the a-carbon atom of the allyl group in the ether. Although the number of known para rearrangements in which inversion or non-inversion can be detected hardly justifies a generalization, it does appear that a substituent on the 7-carbon atom of the allyl group prevents inversion, whereas a substituent qn the a-carbon atom favors inversion. In other werds, the para rearrangement appears to operate in such a way that either an a- or 7-substituted allyl group leads to a straight-chain substituent in the product. The occurrence of inversion in the rearrangement of enol ethers appears to be dependent upon, the experimental conditions, at least in some instances. This question is discussed on p. 7.
* Mumm and Moller, Ber., 70, 2214 (1937). 4 Sp&th and Holzer, Ber., 66, 1137 (1933). 8 SpSth and Kuffner, Ber., 72, 1580 (1939). ' Mumm, Hornhardt, and Diederichsen, Ber., 72, 100 (1939). 7 Mumm and Diederichsen, Ber., 72, 1523 (1939).
THE CLAISEN REARRANGEMENT STRUCTURAL REQUIREMENTS FOR REARRANGEMENT; RELATED REARRANGEMENTS The group of atoms which allows rearrangement is
In this group the double bond on the right may be an aliphatic double bond, as in the enol ethers *• 8 - 9 and the allyl vinyl ethers,10 or part of an aromatic ring, as in the phenol ethers. The double bond on the left must, be aliphatic, i.e., must be part of an allyl or substituted allyl group., The position or character of the double bonds in the reactive group cannot be changed without destroying the ability of the compound to rearrange. These generalisations are based (in part) on the following observations. Allyl cyclohexyl ether,11 methyl O-propylacetoacetate,1-12 and n-propyi phenyl ether are stable to heat. Butenyl phenyl ethers of the type C 6 H 6 0CH 3 CH2CH=CH 2 and vinyl phenyl ether, C 6 H 6 OCH=CH 2 , do not rearrange.13 The double bond in the allyl group cannot be r e placed by a triple bond without destroying the ability to rearrange ;1S>14 the phenyl propargyl ethers C 6 H5OCH 2 C=CH do not rearrange on refluxing, although they do give some phenol and other decomposition products. The benzyl phenyl ethers, C6H5CH2OC6H5, contain the requisite group of atoms for rearrangement but do not rearrange under conditions effective for the allyl ethers;13-18 under more drastic conditions rearrangement does take place 16 but a mixture of ortho- and parasubstituted phenols is formed, while the allyl ethers rearrange almost exclusively to the ortho position, if one is free. The double bond of the vinyl (or aryl) portion of the reactive system may be replaced by a carbon-nitrogen double bond, forming the system ~-C=O-—C—0—C=N—, without destroying the tendency toward
M i r
rearrangement. For example, allyl N-phenylbenzimino ether (VII) rearranges to an amide (VIII) when heated to 210-215° for three hours.3
10
Lauer and Kilburn, J. Am. Chem. Soc, 59, 2588 (1937). * Bergmann and Corte, J. Chem. Soc., 1935, 1363. Hurd and Pollack, J. Am. Chem. Soc., 60, 1905 (1938). 11 Claisen, Ann., 418, 97 (1919). 12 Enke, Ann., 266, 208 (1889). " Powell and Adams, J. Am. Chem. Soc , 48, 646 (1920). 14 Hurd and Cohen, J. Am. Chem. Soc, 58, 1068 (1931). 16 Claisen, Kremers, Rqth, and Tietee, Ann., 443, 210 16 Behagel and Freiensehner, Ber., 67, 1368 (1934).
8
Allyl p-tolyl sulfide rearranges (XI — XII) to the extent of 27% > (50% based on sulfide not recovered) when subjected to refluxing at 228-264° for four hours. / .. 1935. CH2==CHCH 2 N=C=S. Soc. Soc.. however. 57. and Heyl.. 63. Chem. 1361. ethyl 1-cyclohexenylallylcyanoacetate (XIII) rearranges quantitatively in ten hours at 170° to ethyl (2-allylcyclohexylidene)-cyanoacetate (XIV). Chem. 23 for example. J. J. 3356 (1930). 1 "I C 6 H 6 6=NC 6 H 5 -» C6H6C—NC6H6 IX x Similar reactions are known of compounds in which the carbon-nitrogen bond is part of a heterocyclic nucleus. Chem. Hofmann. 52. Am... 11 Mumm and Richter. Soc. 462 (1875). 63. 1843 (1941). on distillation rearranges to allyl isothiocyanate. that of the latter is accompanied by inversion. OCH2CH=CHCH3 0 CH(CH3)CH=CH.. Cope. 18 17 . 1158 (1924). M BiUeter. 81 Bergmann.STRUCTURAL REQUIREMENTS FOR REARRANGEMENT OCH. and Hardy. A reaction similar to the Claisen rearrangement but involving the migration of an allyl group from one carbon atom to another has been discovered recently. Bergmann and Heimhold. 1852 (1941). 1935. ibid. yielding cinnamyl isothiocyanate.CH==CH2 C«H B C=NC 6 H6 VII f 5 I O . Ber. CH 2 ==CHCH 2 SC^N. 1365. Ber. some reduction in the tendency toward rearrangement. yielding a-methylallyl isothiocyanate.> C 6 H 6 C—NC 6 H 6 VIII II I CH.CH=CHi! A further resemblance of this rearrangement to the Claisen type is to be observed in the occurrence of inversion when the crotyl ether rearranges (IX->X). 2 0 Cinnaniyl 21 and crotyl 22 thiocyanates also rearrange: the rearrangement of the former occurs without inversion. 28 Cope and Hardy. 441 (1940). 843 (1940). 19 SCH 2 CH=CH 2 Allyl thiocyanate. »• Hurd and Greengard. Am. with. Tschitschibabin and Jeletzsky. 17 ' 18 The oxygen atom of the reactive system may be replaced by a sulfur atom. 73. Hoyle. Chem. 8. Soc.. ibid. J. Ber. 62. Cope..
13 p-Tolyloxyacetone26 does not rearrange. J.23 In all these respects it resembles the Claisen rearrangement (see p.4586 (1930). Tarbell. Chem. although it does form a little p-cresol. with the open-chain systems. it has the group IM I o=c—c—o—c=c—.1-2 the reaction is much more useful and important in the aromatic series. but they do not undergo rearrangement on pyrolysis.1) 'Although the Claisen rearrangement was first observed in the enol allyl ethers.THE CLAISEN REARRANGEMENT . it was found that at 150-200° there is a slow reaction which is more rapid in the presence of ammonium chloride.—C(CN)COOC2H6 CH2CH=CH2 XIII k^—CH2CH=CH2 XIV This type of rearrangement has been shown to take place with inversion. ent in the allyl aryl ethers. The original reports concerned the rearrangement of ethyl O-allylacetoacetate. Am. at temperatures above 275°. it is a first-order reaction and is believed to be intramolecular because the rearrangement of mixtures yields no mixed products. 7. Soc. The following compounds have systems formally similar to that pre&.. 251 (1942). J. SCOPE AND LIMITATIONS Rearrangement in Open-Chain Compounds (Table . 62. 16).24 Phenoxyacetonitrile contains the group N^C—C—0—C=C— but is unchanged by long refluxing. O-allylacetylacetone (XI Vo). Chem. CH3C=CHCOCH3 OC3H5 XIVo XV CH3 Experimental details of the rearrangement of ethyl O-allylacetoacetate were worked out later. instead of rearranging. . Some interesting observations have been made. however. N-Allylaniline has the group —C=C—C—N—C=C— I I I I II but evolves propylene.8 M a Carnahan and Hurd. Org. and O-allyloxymethylenecamphor (XV).
9 There is evidence that. CH3C=CHCO2C2H6 CH3C-CHCO2C2H5 I OCH2CH=CHC«H6 XVI II I O CH(C6H6)CH=€H8 XVII CH3C—CHCO2C2HB 0 CH 2 CH=CHC 6 H 6 XVIII However.26" BrCH2CH(OCH2CH==CH2)2 + KOC4H9(0 -* KBr + <-C4H9OH + [CH 2 =C(OCH 2 CH=CH 2 ) 2 ] Allyl allylacetate is obtained in 43% yield. and Shapiro. when XVI is hydrolyzed with alcoholic alkali. The simplest compounds to undergo the Claisen rearrangement are the vinyl allyl ethers. carried out at 110° in the presence of ammonium chloride. Chem. but the migrating benzyl group appears as an o-tolyl group. 2525 (1942). .9 Apparently the occurrence of inversion here depends on the experimental conditions. Am. the product being benzyl o-tolylacetate. The dibenzylacetal also rearranges. Inversion has been found to accompany the rearrangement of vinyl 7-ethylallyl ether (XXI -»XXII). ' "• MoElvain. it occurs so readily that the ketene acetal cannot be isolated from the products of reaction of diallylbromoacetal with potassium t-butoxide in i-butyl alcohol. rearrangement takes place with inversion.REARRANGEMENT IN OPEN-CHAIN COMPOUNDS 7 In the rearrangement of ethyl O-cinnamylacetoacetate (XVI). 64. CH2==CHOCH2CH=CHC2H6 XXI XXII The rearrangement of ketene diallylacetal is of the Claisen type.10 Vinyl allyl ether itself rearranges cleanly at 255° in the gas phase (XIX .• XX). Anthes. CH2=CHOCH2CH=CH2 -» CH2=CHCH2CH2CHO XIX XX a-Methylvinyl allyl ether and a-phenylvinyl allyl ether behave similarly. J. the substituted allyl group migrates with inversion to give XVII. when the rearrangement is effected by heating at 260° for four hours the product (XVIII) is formed by migration without inversion. Soc.
Helv. Kreis. I. Chim. Soc. 1927. 3144 (1926)]. Claisen and Tietze. M 27 .. 1663. / .8 THE CLAI8EN REARRANGEMENT A different type of rearrangement in which the allyl group migrates to an open-chain carbon atom has been reported. In the rearrangement of allyl (or substituted allyl) ethers of phenolic compounds. Soc.83 are derivatives of polyhydroxybenzenes.. Am. 28 Adams and Rindfusz. the simplest aromatic allyl ether. / . 41. Chem. Phys. ™ Hnrd and Hoffman.26 The reaction is interesting because it is analogous to the rearrangement of allyl phenyl ethers to the para position of the benzene ring. 7. J. 6 1 . A few compounds are known which rearrange with some migration of the allyl group to the para position although a free ortho group is available.. 743 (1922). Rearrangement of Allyl Aryl Ethers The ortho Rearrangement (Table II). complex decomposition ensues. Zentr. and Simonsen. J. 3042 (1939). Soc. and the product is obtained generally in good yield. and Semlt. rearranges almost quantitatively at 200° in an inert atmosphere *•27> 2S-29 to give o-allylphenol. Org. Ada. Chem.. the allyl group usually migrates exclusively to the ortho position if one is free. 12 Perkin and Trikojus. 88 Baker. but the allyl group never goes to the * See p. Sci.. the allyl group migrates to the para position. > " Kawai. 79 of the article cited in reference 11.. Research Tokyo. Am. * Staudinger. 648 (1919). Soc. Chem. 263 (1926) [Chem. If both ortho positions of an allyl aromatic ether are blocked. Chem.26 Allyl ethers of the type XXIII with a prdpenyl group in the ortho position can be rearranged to phenols with the allyl group attached to the side chain.3-methylenedioxyphenyl ether. OH CH 8 XXIV 9116 Two other examples of this type of rearrangement have been reported. If both ortho positions and "the para position are occupied.31-32 and allyl 2. 1939. Ann. Lauer a n d Leekley. Chem. allyl phenyl ether. no detectable amount of the para isomer is formed. 5. The para Rearrangement (Table III). J. 5.30 allyl 2-hydroxyphenyl ether. 3. 212 (1940). Chem. Penfold. Papers Inst. 439. 81 (1926). Thus. 449.7-dimethylallyl 2-methoxyphenyl ether. XXIII yields XXIV in 37% yield when refluxed under diminished pressure at 177° for one hour. It may be significant that all such compounds.
usually the attachment is by the 7-carbon (inversion). Chem. The first example of the abnormal rearrangement (attachment by other than the 7-carbon atom) was found in the rearrangement of 7-ethylallyl phenyl ether (XXVII). Org. rearrange to give products in which the. •* Claisen and Tietze. Am.. J. 88 Lauer and Hansen. 36 Claisen and Tietze.. 275 (1925).EFFECT OF SUBSTITUENTS IN THE ALLYL GROUP 26 34 9 meta position. Soc. a » Hurd and Pollack. 16S6 (1937). 40 Ljiuer and Filbert. Ber. Soc. 2) was first noted35 in the rearrangement of cinnamyl phenyl ether (XXV) to 2-(a-phenylallyl)-phenol (XXVI). with yields sometimes in excess of 85%. / . OCH2CH=CHC6H6 ^ XXV XXVI !H(C 6 HB)CH=CH 2 The structure of XXVI was deduced from the fact that it was different from the 2-cinnamylphenol obtained by direct C-cinnamylation of phenol. Soc.16 Later investigators showed that XXVI is the sole product. ArOCH(R)CH=CH2 or ArOCH2CH=CHR.(or /3-) carbon to the nucleus. 68. This phenomenon of inversion (see p.39'40 The product is 2(a.. / . . Ber. J. 7-carbon atom of the allyl group is attached at the ortho position of the ring. Ethers with the allyl group substituted by alkyl groups in the a. Chem. 1392 (1936). Am. 8T Lauer and Ungnade. Chem. 1388 (1936). Chem. 3. 59. Effect of Substituents in the Allyl Group. OCH 2 CH=CHCH 2 CH 3 OH XXVII XXVIII " Hurd and Yamall. ozonization yielded formaldehyde but not benzaldehyde. 2344 (1926).. 7-Methylallyl phenyl ether also rearranges with inversion. which must be formed as a result of attachment of the 5. 68..The para rearrangement usually is as satisfactory as the ortho rearrangement. Soc. J. Study of many substituted allyl ethers has shown that in no case in rearrangement to the ortho position is the substituted allyl group attached to the nucleus after rearrangement by the same carbon which was attached to the oxygen. yielding 2-(a-methylallyl)-phenol. 61. 550 (1939). 59. Am. 58.or 7-position. . Chem.36 the structure of the rearrangement product has been definitely established 87> 38 by a combination of degradative and synthetic procedures. Am. 3039 (1939).7-dimethylallyl)-phenol (XXVIII)..
inversion does not occur. Another method of proving structures consists in ozonization. Chem. the abnormal product with the side chain —OH(CH3)CH=CHCH2CH3 predominates over the normal product [side chain. When a substituted allyl ether of the type ArOCH2CH=CHR rearranges to the para position. such as ArOCH(CH2CH3)CH==CH2. 41 Lauer and Leekley. 3). No evidence for the formation of abnormal products in the para rearrangement has been reported. A number of j8-methylallyl ethers have been made. the mixture of acids39 (formic. 2-(a-etbylallyl)-phenol (XXIX). The presence of an alkyl group on the (3-carbon of the allyl group. introduces no complications due to inversion. J. . ArOCH2C(CH3)=CH2.39 The allylic isomer of (XXVII). in the rearrangement mixture from XXVII has been demonstrated. acetic. Sometimes the substituted arylacetic acid obtained by oxidation of the rearrangement product (after methylation) has been characterized and/of synthesized. as in the /S-methylallyl ethers.10 THE CLAISEN REARRANGEMENT OH %CH(C2H6)CH=CH2 XXIX The presence of the normal product. The generalizations above apply only to the migration to the ortho position. OCH(C 2 H 6 )CH=CH 2 OH XXX XXXI In the rearrangement of the 7-propylallyl ether derived from ethyl 4-hydroxybenzoate. £he only known para rearrangement of an ether of the type ArOCH(R)CH=CH 2 proceeds with inversion. Soc. however. Am. rearranges normally40 to give only the expected product (XXXI). a-ethylallyl phenyl ether (XXX). —CH(CH2CH2CH3)CH=CH2] by a ratio of two to one. yield only the normal product with 7-attachmeat.41 The corresponding y-ethylallyl ethers behave similarly. followed by oxidation of the aldehydes with silver oxide. As mentioned earlier (p. The 'structures of the rearrangement products in studies on inversion and the abnormal rearrangement are assigned by identification of the aldehyde formed by ozonization. 3043 (1939). and propionic) is analyzed by selective oxidation. 61. and they rearrange in good yield. The a-substituted allyl ethers. because the /S-substituted allyl group is symmetrical.
fluorene. 607 (1942). such as C6H6OCH2CH=CHC1.43 The 7-halogen ethers. nitro. Soc.43 Effect of Substituents in the Aromatic Nucleus. /3-bromoallyl phenyl ether is reported to give 3d% rearrangement after ninety minutes at 215°. 79 (1913). and ft is noteworthy that meta directing groups in the nucleus do not hinder the jreaction. 64. hydrindene. Substituents in the aromatic nucleus do not affect the ease of rearrangement greatly. *' Hurd and Webb. flavone.5. Kuhn. Braun.4* O-AUylsalicylic acid (XXXIV) when heated at 175-180° gives 23% of 2-allylphenol. amino. although they do decompose and yield some phenol. halo. carbethoxyl. Chem. J. and azo. Rearrangements have been reported for allyl aryl ethers with the following substituents in the aromatic nucleus (Table II): hydroxyl. acetyl. phenanthrene. chromone. .5-diallyl-4-allyloxybenzoic acid (XXXVI) OC3H6 OH OC3H6 OH C3H6 XXXIII XXXIV XXXV 42 v. propionyl. No complications are caused by the presence of ester groups in the aromatic nucleus. carboxyl. Am. 2190 (1936). /3-carbomethoxyvinyl. 264 (1926). phenolic resins being the only product observed. formyl. methylenedioxy. 58. and benzothiazole.DISPLACEMENT OF SUBSTITUENTS 11 Allyl aryl ethers with halogen atoms in the allyl group rearrange very poorly. anthracene. 50% being recovered unchanged. Soc. Displacement of Substituents. fluorescein. quinaldine. Am. if a free carboxyl or aldehyde group is present in the position ortho or para to the ether linkage.4. 401.46 A carboxyl group in the para position also is eliminated easily. 44 Claisen and Eideb. methoxyl.. 449.. 46 Tarbell and Wilson. and 64% of 3-allylsalicylic acid (XXXV).-diaIlylsalicylic acid (XXXII) gives a quantitative yield of 2.6-triallylphenok (XXXIII). nor do the strongly ortho-para directing groups seem to favor it greatly. allylbenzene. but. and Weismantel. Ann.48^ Later experiments have not confirmed this.. biphenyl. xylene. 0Allyl-3. toluene. Chem. coumarin.. Section C). do not rearrange. Allyl ethers derived from the following aromatic and heterocyclic nuclei have been rearranged: benzene. thus 3. by rearrangement of the corresponding chloro compound. dibenzofuran. it may be displaced by the allyl group "(Table II. allyloxy (rearrangement involving migration of two allyl groups). J. with loss of carbon dioxide. however. a 24% yield was obtained. the evolution of carbon dioxide starting at 1000. acetamino. 7-hydroxypropyl. naphthalene. Ann.
also. Soc . which is converted to the normal product (XLII. Soc . 64. OCH 2 CH=CH 2 QH OH XLI XLII XLIII Allyl 2. Soc. 1066 (1942). 460 The displacement reactions with the ethers having aldehyde groups in the positions ortho or para to the ether linkage are similar. 4 6 In the rearrangement of the isomer of XXXVII. J. thus the crotyl ether of 3. t See p 115 of the article cited in reference 44. and carbon dioxide is not evolved in appreciable amounts. Am. I t is interesting to note that the benzyl ether corresponding to XXXVII rearranges on heating to give the benzyl ester of 3. although they do not go as smoothly and the temperatures required seem to be higher.* OC3H6 OCH 2 CH=CHCH 3 Clr^HCOOH OH Cl. 60% yield) along with a little (10% yield) of 2-allyl-6-chlorophenol (XLIII).12 THE CLAISEN KEARRANGEMENT rearranges and evolves 99% of the theoretical amount of carbon dioxide. 46 Some hydrogen chloride is evolved. 58.6-dichlorophenyl ether (XLI). in which carbon dioxide is evolved from the para position. J. Chem. J. Thus allyl 2-formyl-4-allyl-6-methoxyphenyl ether (XXXIX) gives X L in 60% yield when heated at 170-285°. Chem. Am.5-dichlorosalicylic acid (XXXVII) gives XXXVIII.46 These results parallel those in the ordinary rearrangement.5diehlorosalicylic acid. 941 (1936). a * TarbeU and Wystrach.f'^r-CHCH=CH2 COOH XXXVI The displacement reaction is accompanied by inversion when migration is to the ortho position.t OC3HB OH u C3H5 XXXIX * u C3H5 XL A displacement of the chlorine atom has been observed in the rearrangement of allyl 2. Tarbell and Wilson. 46 .. Chem.6-dibromophenyl ether behaves similarly. Am. " Hurd and Webb. 2146 (1943). 65. 43 ' 47 * See p 91 of the article cited in reference 44. inversion does not occur.
X but it is reported48 that allyl 2-methoxy-4(7-hydroxypropyl)-phenyl ether rearranges (in unspecified yield). it is clear that the reaction requires the ether oxygen to be attached to a double bond and that after rearrangement the allyl group is attached to the same double bond. with a double bond in the 2. l. 45 and 58 of the article cited in reference 44. J. 49 Fieser and Lothrop. 106 of the article cited in reference 44. 33. Proc. 15. 48 Kawai..7-positions. 40 and 59 of the article cited in reference 44. where rearrangement does not take place although it would be expected if the aromatic nucleus could react in all of the possible Kekule" bond structures. upon the rearrangement is usually small.6-diallyloxynaphthalene (XLVI) does not rearrange in five minutes at 200° and.. f Allyl 2-(hydroxymethyl)-phenyl ether yields formaldehyde and decomposition products when heated. so that a hydroxyl group in a side chain does not necessarily preclude rearrangement.3.3-position. The failure of l-allyl-2-allyloxynaphthalene (XLIV) to rearrange even after long heatingx is explained by assuming C3H6 C3H5 CSHB C3H6 XLIV XLV XLVI that the naphthalene nucleus cannot react in the unsymmetrical form (XLV).. This supports the conclusion that naphthalene does not undergo reactions which would require double bonds in the 2. Acad.5-diallyl-2.. 1459 (1935). poor results have been reported with the following ethers of substituted phenols. t See pp. the 2-nitro compound gives a 73% yield at 180°. Relation of Bond Structure to Rearrangement.RELATION OF BOND STRUCTURE TO REARRANGEMENT 13 Although the effect of ring Bubstituents. Tokyo. Allyl 2allyl-4-methylphenyl ether' and the allyl ether of allyl-m^cresol give poor reactions. probably because of polymerization. From the introductory discussion. and Sugiyama. 45 (1939) [C. Imp. Chem.6-diallyloxynaphthalene49 rearranges smoothly in 85% yield. t See p. While 2.* Allyl 4-nitrophenyl ether rearranges in 30 to 40% yield on refluxing in paraffin oil at 230°.it is probable that further study will disclose satisfactory reaction conditions for at least some of these rearrangements.and 6. Am. * See pp. provided that one or more unsubstituted ortho or para positions are available. decomposes without forming any alkali-soluble material. . 57. A. Nakamura. Numerous examples have been found. other than carboxyl and aldehyde groups. on longer heating. in the allyloxy derivatives of polycyclic aromatic compounds in particular. Soc. 5394 (1939)].
67 Baker and Lothian. 1917 (1931). 61. which stabilizes one Kekule' structure and directs the allyl group to the 3-position (XLVII -> XLVIII). Soc. Proc. the cleavage reaction is favored by increased substitution in the allyl group. 36. Am. Indian Acad.66 and 2methylbenzothiazole. Am. a. Chem. Chem. Chem. Chem. chelation being impossible. 61 hydrindene. 749 (1936). 62 fluorene. 33. Soc . J. 4120 (1931). Chem. 61 Fieser and Young.63 chromone. 2115 (1939)..14 THE CLAISEN^EEAREANGEMENT Similar studies of the relationship between bond structures and the Claisen rearrangement have been made with allyloxy derivatives of other aromatic compounds. A side reaction that often accompanies the rearrangement of substituted allyl ethers is the cleavage of the allyl group from the oxygen with the formation of a phenol and a diene. 2... J. This is attributed to formation of a chelate ring containing a double bond. 132 (1940).. Am Chem. Ber. 11 Lothrop. the allyl group migrates to the 5-position and'L is formed. Soc. A. Am. J. 74. J. Chem. / . J. 1648 (1932).64 fluorenone. 66 Bergmann and Berlin. 68 Hurd and McNamee. J. 68 ' M> 6 0 ' 6 l Thus. Am. Soc. Soc. J Am: Chem. 63. 381 (1937). 1 (1939) [C. Chem. J. Soc . 59. Am. 4244 (1939)]. CH3C=O XLIX Side Reactions.. 60 phenanthrene. Am. 80 Hurd and Sohmerhng. 6Ba The monoallyl ether of resacetophenone 66> 61 rearranges with migration of the allyl group to the 3-position instead of to the 5-position which is usually favored in reactions of substitution. "Rangaswami and Seshadn.A. 1936. 62. 1407 (1941) [C. Chem. 107 (1937). . Soc. 81 Hurd and Cohen. J. 9A.7-dimethylallyl 4-carbethoxyphenyl ether (LI) gives a 59% yield of OCH(CH3)CH=M3HCH3 COOC2H5 LI 60 LII Fieser and Lothrop. 274. 316 (1940) 66 » Ochiai and Nisizawa. Sci. 62. OC3HB C3H CH 3 —C XLVII V H CH. J Org. 63 Lothrop. 54. M Baker and Lothian. 53. Soc . 68 Hurd and Puterbaugh. Soc. there is no stabilization of the bond structure. 64 flavone. 628. With the methyl ether (XLIX) of XLVII. among them anthracene. Soc. 58. 1935. Chem. 5475 (1942)].
7-tetra- LIV methylallyl phenyl ether (LV) undergoes only the cleavage reaction without any rearrangement. 71. 18). in addition to 2-allylphenol. A •33. which is probably produced 0 7 N LVI * See p. J. J. Am.36' M but without experimental details.a.SIDE REACTIONS 62 15 1.3-pentadiene and ethyl 4-hydroxybenzoate. J. 323 (1938) [C. Am. [2] 105.61 It has been reported. Hughes. Recently it has been shown640 that pyrolysis of 7. Soc.7-dimethylallyl phenyl ether yields phenol and isoprene on heating.. 6a Lauer and Ungnade^ J. Wales. Chem. 66 Tarbell and Wilson. 2-Cyclohexenyl phenyl ether (LII) gives a 50-60% yield of phenol and cyclohexadiene. The cleavage of a substituted allyl ether and formation of the phenol have been observed also in an attempted catalytic reduction at low temperature and pressure with a palladium 6 or a platinum catalyst. Chem.63 The very highly substituted ether. 65. prakt. 148 (1939)]. . Chem. that 7. N. Mo Lauer and Moe. ea Cornforth. apparently as the result of an abnormal rearrangement with attachment by the |8-carbon. 3047 (1939). the dihydrobenzofuran derivative (LVb) is produced in small yield. 33% of the diene being obtained after one hour at 160-1700. 61. 79 of the article cited in reference 11. S. Proc. Royal Soc. 289 (1943). but that when heated with sodium carbonate it undergoes rearrangement. The rearrangement of allyl phenyl ether itself yields. M Claisen.* a small amount (4-6%) of the methyldihydrobenzofuran (LVI).66-18 The other side reaction which is sometimes troublesome is illustrated by the formation of LIV (see p. a. followed by ring closure.7dimethylallyl 4-carbethoxyphenyl ether (LVo) gives OCH2CH=C(CH3)2 (CH3)2 HCHS COOC2H5 LVo LV6 mainly the cleavage products. 65 (1922).. Soc. unpublished observation. with 5% of the expected rearrangement product (LIII) and 15% of hexahydrodibenzofuran (LIV). and Lions. isoprene and ethyl 4-hydroxybenzoate.7.
must be the rate-determining step. 3085 (1939). • The rearrangement is intramolecular. 27. September. Tarbell. 1941.. 57. 66 67 . for a more detailed discussion. 371 (1935).60 or cinnamyl 4-methylphenyl ether and allyl 4-aminophenyl ether.. and this step. The cyclic mechanism accounts for the occurrence of inversion. Abstracts of the Atlantic City meeting. Chem. The cyclic mechanism as written does not explain the abnormal rearrangement. Chem. Am. Bartz.. because the 7-methyl group would promote the electronic shifts indicated. and Adams. since rearrangement of mixtures of ethers such as allyl /3-naphthyl ether and cinnamyl phenyl ether. J. Mechanism of the Rearrangement * TheClaisen rearrangement to the ortho position is a first-order reaction. Soc.M-68 thus 2-G8-methylallyl)-phenol*6 forms the corresponding dihydrobenzofuran on heating or even on standing in petroleum ether solution over anhydrous magnesium sulfate. If the latter were the slow step. The mechanism is in agreement with the observation4B that crotyl ethers rearrange more rapidly than allyl ethers. 68 Kincaid and Morse. Soc. Ann. " Watson. Miller. in which the following processes take place. which involves the shift of two hydrogens. J. Am. Revs. 206. 1939. Chem. 495 (1940). 61. the reaction would be speeded up by dimethylaniline. Soc.68 yields none of the cross products which would result from an intermolecular reaction. with the electronic shifts during reaction indicated by the arrows.. Chem. rather than the enolization of the hydrogen.' Kincaid and Tarbell. but this may involve a cyclic intermediate in which the /8-carbon becomes attached to the ortho carbon atom. Repts. The process is best represented by the cyclic mechanism. Compounds with substituted allyl groups seem to form the dihydrobenzofurans more readily than the unsubstituted allyl compounds.16 ' THE CLAISEN REARRANGEMENT by ring closure of the initial product.43.87' 68 and the process does not require catalysis by acids and bases. * Cf. and this is not observed.23-39> 69 H OH / CH2CH=CHi! LVII 1 \ LVIII LIX ' The breaking of the carbon-oxygen bond and the attachment of the ycarbon atom to the ortho position must be simultaneous.
Nature. Chem. 231 (1943). make a cyclic mechanism improbable. J. The allyl aryl ethers. and Subrahmanyam. and this * See p.. 250 (1917). 414.. There^is no evidence for the formation of similar products in the Claisen rearrangement. indicating the intermediate formation of benzyl radicals. 67. Am.* croweacin. with . Chem. and the yield of rearrangement product would be low. 143.. The rearrangement may go through a firstorder dissociation of the allyl ether into either radicals or ions. Jukes. Hickinbottom n isolated benzylquinolines. can be prepared easily in high yields and can be transformed readily in good yields to the 2-allylphenols (LXI). such as phenyl allyl ether (LX). If -allyl radicals (or ions) actually were free during the reaction. 72 Mauthner. Tarbell and Kdneaid.70 The non-occurrence of inversion. / .33 and dill apiole.SYNTHETIC APPLICATION 17 The para rearrangement is also a first-order reaction.72> 73 eugenol. 66. 74 Baker. and toluene. Ber. Synthetic Application The usefulness of the Claisen rearrangement in synthetic work depends on the following facts. 1934. 696 (1934). hydroxyphenylquinolines. Ann. Soc. they should combine with a reactive solvent such as dimethylaniline.. J. before any secondary reactions can take place. 1681.74 The allylphenols serve as easily accessible starting materials for dther synthetic operations. Soc. which must then be assumed to recombine. A study 70° of the decomposition of quaternary ammonium com+ pounds of the type [Me2N(C6H5)C3H5] [OAr]~ indicates that ions are not intermediates in the Claisen rearrangement.the allyl group entering the para position. Among the naturally occurring allylphenols which have been synthesized by this method are elemicin. % Reduction converts them to propyl (or substituted propyl) phenols (LXII). Am. 118 of the article cited in reference 11. 70 7 . °° Tarbell and Vaughan. Soc. and the rate is not greatly affected by acetic acid or dimethylaniline. 728 (1940). which is contrary to the observed facts. Chem. 62. 520 (1939). 78 Hahn and Wassmuth. The reaction thus OCH*CH=CH2 LX LXI LXII furnishes a convenient method of introducing allyl groups into a wide variety of phenolic compounds. 71 Hickinbottom. and the atomic distances involved. From the rearrangement of benzyl phenyl ether in quinoline at 250°.
*'66 hydrobromic acid-acetic acid. and rearrangement of the ethers followed by reduction has been employed as a convenient method of introducing the isobutyl group into phenols. Chem. fieiia. /3-Methylallyl ethers are not subject to this disadvantage. " Hahn and Stenner. t This problem of ring closure of allylphenols is of i*iportanoe in the chemistry of vitamin E and has been discussed in detail by Smith (reference 78). Because of the occurrence of inversion. which is obtained by rearrangement of the allyl ether of hydroquinone monoOH OH LXIV u LXV OCH3 CH2CHO benzoate followed by benzoylation. compounds of the structure HOArCH2CH=CHR cannot be prepared by rearrangement of ethers containing substituted allyl radicals such as farnesyl and phytyl groups. Z. because inversion does not change the structure of the group. 287 (1940).. or forniic acid 36 form 2-methyldihydrobenzofurans (coumarans) such as LXVI. '• Schopf and co-workers.18 THE CLAISEN REARRANGEMENT provides a convenient method of introducing a propyl group into a phenol.5-trimethoxyphenylacetaldehyde (LXV) from the corresponding allyl compound. after protecting the hydroxyl group. prakt. In the presC(CH3)2 O CHCH3 0 •CH 2 LXVI LXVII LXVIII ence of hydrogen bromide and a peroxide. Chem.. . »• Mauthner. Chem. 26 of the article cited in reference 44. 044. physM. [2] 148.66 The allyl group in the allylphenols can be oxidized.. 27. 95 (1937). 30 (1940). Thus. to yield substituted phenylacetaldehydes 73> 76>76 and phenylacetic acids. 181.73 The 2-allylphenols in the presence of acid catalysts such as pyridine hydrochloride. / . 88 (1929).77 The ozonization procedure has been developed to give a good yield of 3..4. homogentisic acid LXIII is prepared readily by ozonizing the dibenzoate of allylhydroquinone LXIV. 2-allylphenyl acetate gives the isomeric dihydrobenzopyran or chroman (LXVII). Ann.29'78' t Ring * See p. 78 Smith.
This makes possible a separation of the two isomers. Another occasionally useful transformation of allylphenols is the isomerization to propenylphenols by strong alkali. the allyl compounds can add the elements of basic mercuric acetate.7-dimethylallyl aromatic derivatives are oxidized by mer* See p. 45. Ber. and this is a method of preparing iodo compounds like LXX. J. 810 Fletcher and Tarbell. Soc. 52 of the article cited in reference 44.. and less than the necessary amount of mercuric acetate is used. Roman. 68. and previous papers. 44. Chem. Soc. and Sperry.SYNTHETIC APPLICATION 19 closure of 2-(Y.. 81 Nesinejanow and Sarewitsch. Am. Chem. J. the 7. 394 (1915).* This isomerization also can be brought about by heating with soda lime without solvent/ but the phenolic hydroxyl must be etherified. If a mixture of propenyl and allyl compounds is present. 1476 (1935).' The halomercuri group can be replaced by iodine by treatment with potassium iodide.82 The propenyl compounds are oxidized to glycols..29 Treatment of 2-allylphenols with mercuric salts gives mercurimethyl-CHCH2HgX LXIX 79 80 81 LXX dihydrobenzofurans such as LXIX. 1431 (1943). Adams. Am. Soc. 66. 1842 (1923). Am. 79 ..Y-dimethylallyl)-phenol gives only the chroman LXVIII. 82 Balbiano. 2-methoxy-6allylphenol (LXXI) is changed to the propenyl compound LXXII by OH LXXI LXXII heating 1 part of the phenol with 2 parts of powdered potassium hydroxide and 1 of water for one hour at 170°. and mercurous acetate is precipitated. Chem.64 A solution of sodium or potassium hydroxide in diethylene glycol may be used for the isomerization. irrespective of the presence or absence of peroxides. 80 Mills and Adams. giving a solid addition product from which the allyl compound can be recovered by reduction with zinc and alkali. 48. Ber . . the allyl compound reacts preferentially and the unchanged propenyl compound can be separated by extraction or steam distillation. J. For example. However. 1781 (1922). as in the well-known isomerization of eugenol to isoeugenol.81a The propenylphenols can be distinguished from the allylphenols by their different behavior toward mercuric acetate.
however.84 and phytyl bromide 86 (a vitamin K synthesis) have been used in C-alkylation procedures. " 86 MacCorquodale et al.64 The propenylphenols can be ozonized to the hydroxyaldehydes.48-76 but these usually can be prepared more easily by standard methods.88 a.. 181. R = CH3) can be prepared by C-alkylation more OH OH K^ LXXIII LXXrV easily than the allyl compounds. Z.26 Compounds of type LXXIII cannot be made by the rearrangement of the 7-substituted allyl ethers. Chem.84 88 Maldno and Morii.4-. be prepared by direct C-alkylation of the sodium salt of the phenol in benzene solution. R = C6H5) can be made in 60% yield from sodium phenoxide and cinnamyl bromide in benzene. The silver salt of 2-hydroxy-l. J. and 15% of 2. The substituted allylphenols such as cinnamyl (LXXIII. 80 (1940). OTHER METHODS OF SYNTHESIS OF ALLYLPHENOLS Allylphenols and derivatives with substituents in the allyl group can . naphthoquinone is converted to a mixture of C-alkylation product and two isomeric ethers by treatment with allylic halides and benzyl halides. 40% of 2-allyl-4-methylphenol. 8% of allyl 2-allyl-4-methylphenyi ether.16 This method is not as good for the preparation of allylphenols themselves as the one involving preparation of the allyl ether followed by rearrangement. disregarded this fact. R = C6H5) and crotyl (LXXIII.16 The rearrangement of allyl 4-methylphenyl ether. yields 2-allyl-4-methylphenol in practically quantitative yield.. Soe. J. Thus 2-cinnamylphenol (LXXIII. 3201 (1926). because these compounds yield LXXIV by inversion.7-Dimethylallyl bromide. 48.16 It is interesting to note that chloro. so that the test must be used with caution..7-dimethylallyl bromide.and bromo-acetones do not yield Calkyl derivatives when treated with the sodium salt of a phenol in benzene. Thus the alkylation of p-cresol in benzene with sodium and allyl bromide yields 20% of allyl 4-methylphenyl ether. Fieser. 263.29 cinnamyl chloride.6-diallyl-4-methylphenol.20 THE CLAISEN REARRANGEMENT curie acetate. and the ether is easily obtained.16 7. because the more reactive substituted allyl halides give rise to more C-alkylation and less O-alkylation. physiol. Chem. 357 (1939). 84 . Am.. Biol. with formation of mercurous acetate. Chem. because a mixture of several products is obtained in C-alkylation.
1382. Soc. Soc. Soc. 469 (1940). however. J. Isoprene 91 condenses with phenol to yield 2. Chem. and phytadiene M condenses jvith trimethyl- CH3 0 LXXVI CH3 CH3 0 LXXVII hydroquinone under acid conditions to give the chroman LXXVII (vitamin E). 3467 (1939). Chem. Am.. Chem. Ungnade.. Am. 61. 1887 (1941). allylphenols can be obtained by the condensation of a phenol and a diene. 311 (1939). Fieser. Org. J. 4. 90 Smith and Ungnade. condensation of an allylic alcohol with a phenol leads to a chroman derivative. w 88 . / . 3216 (1939). Hoehn. Am.OTHER METHODS OF SYNTHESIS OF ALLYLPHENOLS 21 The condensation of allylic alcohols with phenolic compounds in the presence of an acid catalyst yields allylphenols. J. and Wendler. Tishler. This reaction was used 86 in a synthesis of vitamin K (LXXVo) by condensing phytol with 2-methyl-l. 91 Claisen. Fry. 4. 1982 (1940).88 Frequently. 54. and Work. however. 200 (1921).. 92 °' 93 butadiene and triFieser.. Am. Jacob..86 and to the condensation of phytyl bromide with the hydroquinone with zinc as a catalyst. J. Campbell. 88 Almquist and Klose. 298 (1939).2dimethylchroman LXXVI.. J. Soc.4-naphthohydroquinone in dioxane with oxalic or trichloroacetic acid as catalyst. Chem. but the product is usually a chroman. Chem. 920 Fieser. 62. 1938. 88 Bergel. Soc... and Gates.89-90 The reaction of an allylic halide with a free phenol in the presence or absence of an acid oatalyst (in contrast to the C-alkylation of the sodium salt of the phenol) frequently gives the chroman instead of the allylphenol. 2559. Todd. 92 Smith. the hydroquinone first formed was oxidized to CH8 H 2 CH=C(CH 3 )CH 2 Ci6H3i LXXVo LXXVi the quinone LXXVa. as in the synthesis of vitamin E (LXXVII) from phytot and trimethylhydroquinone. Chem. Dienes also condense with phenolic compounds. Chem. Org..87 This method of synthesis seems to be superior to the C-alkylation by the use of phytyl bromide and the sodium salt of the hydroquinone. 63. Biol. An interesting side reaction here was the formation of the isomeric diketone LXXVb. and Wawzonek. Ber. Chem. 61. / . 98 Smith and King. In some instances. 1SS. J.
96 Meisenheimer and Link. 29 of the article cited in reference 44. Richards. Soc. then with the allyl halide. 97 Winstein and Young. although * The topic discussed in this section is of great importance in the chemistry of vitamin E and vitamin K. Hoehn. Chem. and -they usually cannot be prepared by the Claisen rearrangement.*. these can be treated with sodium ethoxide in ethanol solution. 1863 (1940).97-98 and..38-40> 68 .. 68. .are prepared from the chlorides instead of the bromides6. and the same product is obtained from the hydroquinone and crotyl alcohol. "Smith. J. which condense with acetone in the presence of potassium carbonate. The condensation of free phenols with allylic halides.** EXPERIMENTAL CONDITIONS AND PROCEDURES Preparation of Allyl Ethers The most widely used method f of preparing allyl aryl ethers consists in refluxing the phenol with allyl bromide and anhydrous potassium carbonate in acetone for several hours.. Binkley. usually gives very good yields but is unsatisfactory for weakly acidic phenols. Ann. and Thayer. 3070 (1939). Rets. Am. and Whitney. and dienes may give allylphenols. Soc.76'9B and acetone may be replaced by the higher-boiling methyl ethyl ketone. Chem.22 THE CLAISEN REARRANGEMENT r methylhydroquinone yield LXXVIII. Substituted allyl chlorides and bromides usually can be employed successfully. Secondary ethers of the type ArOCH(R)CH=CH 2 . and Azorlosa. 477V(1941). The method . Chem. 28.. Binkley. 479.OH 'cH 2 CH=CHCH 3 CH 3 LXXVIII In summary. where R is ethyl or n-propyl. allyl bromide may be replaced advantageously by allyl chloride and sodium iodide.66 although the yields are poorer. / . 104 (1936).40-41-62 because the isomeric chlorides CICH(R)CH=CH 2 and RCH=CHCH 2 CI can be separated by distillation. and Thayer (reference 94). The procedure is also unsatisfactory for phenolic aldehydes. "Doisy. 254 (1930). it can be said that the 7-substituted allylphenols can be prepared by Oalkylation of the sodium salt of the phenol in benzene. probably owing to C-alkylation. Am. but frequently yields other products. 61.96 The corresponding primary and secondary bromides are in very mobile equilibrium. and more detailed information is available in the reviews of vitamin E by Smith (reference 78) and of vitamin K by Doisy. allylic alcohols. J.93 CH3 . Am. 98 Young. Chem. 62. Soc. t See p.
59. since the boiling point(of the product is higher than that of the ether. TTngnade. Am. in benzene. "" Hurd and McNamee. and Leekley.and O-alkylation products results from the treatment of phenol with 4-bromo-2-hexene and 4chloro-2-hexene.84 some C-alkylation as well as O-alkylation was observed.34 Allylation of 2-hydroxy-l.4-naphthoquinone has been carried out by treating the silver salt. The extent of C-alkylation as a side reaction in etherification varies.99" An appreciable amount of C-alkylation occurs when 2. Chem. the ampunt of C-alkyiation is greatly increased by carrying out the alkylation on the sodium salt of the phenol in benzene. Lauer. with allyl bromide. this method likewise is rapid and sometimes leads to better yields than the procedure using potassium carbonate and acetone.46" Conditions of Rearrangement The simpler allyl aryl ethers can be rearranged by refluxing at atmospheric pressure until the boiling point becomes constant. Soc. J. The Williamson synthesis.70 Since. Chem. 99 .. Smith.. 3079 (1939).CONDITIONS OF REARRANGEMENT 23 the allylic isomers can be separated by careful distillation. Am. the chlorides are much more useful for synthetic work.16 A complicated mixture of C. is more rapid than the procedure using acetone and potassium carbonate and gives good results. In preparing ethers of o-carbomethoxyphenols it has been found that the slow dropwise addition of aqueous sodium hydroxide or potassium carbonate to a refluxing mixture of the proper phenol and halide in methyl ethyl ketone gives a smoother reaction with yields much better than those obtained when all the alkali is added before refluxing is begun. * See p." 4-Hexenylresorcinol has been obtained in about 40% yield from the reaction of l-bromo-2-hexene.16'3B' **•66 Aqueous acetone also has been used as the reaction medium with allyl bromide and sodium hydroxide.6-dimethylphenol is treated with allyl bromide and sodium ethoxide in ethanol.16 this method is unsuitable for the preparation of allyl aryl ethers. 78 of the article cited in reference 11. * with cinnamyl bromide or 7. 61." The rearrangement is nearly always exothermic—so much so that it may become troublesome when large batches are run without solvent. J. and potassium carbonate in boiling acetone. in general. about 1% of allyl 2-allylphenyl ether is formed when phenol is used in the acetone and potassium carbonate method with allyl bromide. the boiling point rises until the reaction is complete. 104 (1937). resorcinol. using a sodium phenoxide and allyl bromide in methanol solution. Soc.7-dimethylallyl bromide the extent of C-alkylation is greater.
29 In the rearrangement of 1. 100 Kincaid and Morse.5-diallyloxyanthracene. if present. 1943. 215°).. solution of the residue in petroleum ether.47 and kerosene m have been employed as solvents with satisfactory results.f tetralin. but. such as hydrogen. Soe..36 Kinetic studies of the rearrangement "•68> 70 have shown that dimethylaniline has only a negligible effect on the rate. New York. or nitrogen. f See p. their acidity may be . carbon dioxide. .* The same result can be obtained more conveniently by mixing the ether with a solvent to act as diluent.so greatly diminished that they are practically insoluble in aqueous alkali. private communication. by extraction with dilute mineral acid. Better yields have been reported * with these basic solvents as compared to hydrocarbon solvents. Am. 2206 (1939).the rearrangement of saturated alkyl phenyl ethers by acidic catalysts. ether was heated in diethylaniline. private communication. in Gilman's " Organic Chemistry. 72 of the article cited in reference 11.11'29> 99> lf>1 Petroleum ether or benzene should be the solvent for the organic material when Claisen's alkali is used for an extraction. when the reaction was carried out in the presence of acetic anhydride and diethylaniline. the solvents most frequently employed being dimethylaniline (b. The very sensitive dihydroxy compound formed was protected from decomposition by acetylation. especially the 2. Chem. 61.102 The thermal rearrangement of allyl ethers is a process entirely different from . When the phenols are highly substituted. 06 of-the article cited in reference 11.p. and extraction with aqueous alkali to separate the" phenolic product from any neutral by-products and unchanged ether. A non-oxidizing atmosphere. 1M Wallis. t See p. J.103 The latter process seems to be intermolecular.6disubstituted ones. This device has been employed in work on naphthohydroquinone 101 and hydroquinone derivatives. 28) has proved of great service in isolating weakly acidic phenols. the rearrangement product was readily isolated in the form of its diacetate. John Wiley & Sons. 101 Fieser. and Fry." p. Paraffin oil. Campbell.24 THE CLAISEN REARRANGEMENT Ethers of higher boiling point frequently undergo undesirable side reactions when refluxed at atmospheric pressure.60 no pure product was obtained when the. 193°) and diethylaniline (b. The reaction mixture is usually worked up by removing the basic solvent. usually results in a better product. "Claisen's alkali" $ (p. gives consider* See p. and often better yields are obtained by refluxing under diminished pressure. 102 Sealock and Livermore. I l l of the article cited in reference 11. but it has been found 10° that dimethylaniline reduces polymerization during the rearrangement of cinnamyl phenyl ether and greatly improves the yield. 997 ff.p.
U. 722 (1941) \C. In the only instance 108a noted in the literature in which an acid catalyst was used to rearrange an allyl phenyl ether.. Experience with a variety of allyl ethers has indicated that in general it is not necessary to heat etchers above 200° to effect rearrangement.or 7-position of the allyl group increases the rate of rearrangement.6-dimethyl compounds react more rapidly.R. OC3H6 )CHS OH ' OH LXXIX LXXXI an excellent yield of LXXXI is obtained (Table I). Chem. The allyl ethers of 2-phenanthrol and 3-phenanthrol rearrange at 1000. The allyl ethers of the isomeric hydroxynaphthoquinones (LXXXII and LXXXIII) rearrange in a few minutes at 136-145° to give the same compound (LXXXIV). 18).430 (1942)1. 11.4. with guaiacol.4-dichlorophenol rearranges more rapidly than the allyl ether." a-Ethylio3« Bryusova and Joffe. and does not give a high yield of a pure product.. 36. Gen. A. .84 iOC 3 H B Substitution in the a. but the 4-nitro compound rearranges much more^lowly. 6-allyleugenol.61 Allyl 2-nitrophenyl ether gives a 73% yield after heating five hours at 180°. Allyl 4-methylphenyl ether rearranges completely in thirteen hours at 200° without solvent. The presence of acids in the Claisen rearrangement might be disadvantageous because the 2allylphenols might be isomerized to the heterocyclic compounds (see p.CONDITIONS OF REARRANGEMENT 25 able -para substitution and disubstitution. and that many preparations in the literature probably would give better yields if they were run at lower temperatures. When the rearrangement of LXXIX is carried out thermally.46 a-Ethylcrotyl phenyl ether rearranges to the extent of 10% in twenty-four hours at 120°. allyl 2-methoxyphenyl ether (LXXIX) rearranged at 78° in the presence of boron fluoride and acetic acid to give 38% of eugenol (LXXX). J.S.67 and the corresponding 2. the crotyl ether of 2.S. and the allyl ether of allylguaiacol as byproducts.and 2.
98-99°/2 mm. Preparation of Allyl 2. b. which is then extracted twice with 50-cc. nf>5 1. A heavy precipitate of potassium bromide begins to form soon after the refluxing is started.8 g. water is added.p.5% excess) of allyl bromide. (0.4 g. 78 of the article cited in reference 11 . 100 cc. f A mixture of 188 g.) that the distillation might be omitted unless a very pure product is desired. {85%) of colorless liquid.7 g. has been discussed (p. of methyl ethyl ketone is refluxed for four and one-half hours.080 mole. of allyl bromide. 242 g. 85°/19 mm. Tarbell. of powdered anhydrous potassium carbonate.46 A mixture of 10. dff 1. (0. t See p. d\\ 0.4 g. some of which rearrange at temperatures not far above 100°.73 OCH(C2H6)CH=CH2 XCO2CH3 CH3O1 COOCH3 LXXXV LXXXVI ' These variations in reactivity are usually not large enough to be of practical importance. of phenol. 90-100°) and the extracts are combined with the organic layer.26 THE CLAISEN REARRANGEMENT allyl 2-carbomethoxy-6-methylphenyl ether (LXXXV) undergoes the para rearrangement when the ester group is saponified with algoholic alkali. by Ann T. After cooling. The behavior of ethers of hydroxy acids. IDExperimental Procedures * Preparation of Allyl Phenyl Ether.. After drying over calcium chloride.5522. The aqueous layer is extracted twice with 50-cc. b. 9. The ether solution is dried over potassium carbonate. The residue is so small (6 g. About 1% of allyl 2-allylphenyl ether (a product of C-alkylation) is formed by this procedure.. and 300 g. giving 11. the residue is distilled under diminished pressure. 9. * Procedures checked. portions of 10% sodium hydroxide to remove any unreacted phenol and washed twice with water. in part. The yield is 230 g. portions of petroleum ether (b. after removal of the ether.6 A similar rearrangement 'accompanied by loss of carbon dioxide is observed during hydrolysis of LXXXVI.4-Dichlorophenyl Ether. of water is added and the organic layer is separated.9845.p. and.p.066 mole) of 2.258. (86%). and 50 cc. the product is taken up in ether and washed twice with 10% aqueous sodium hydroxide solution. the solvent is evaporated and the residual oil is distilled under diminished pressure. of acetone is refluxed on the steam bath for eight hours. 280 g.4-dichlorophenol. of finely ground calcined potassium carbonate. After cooling. 21.
nf> 1.5°/19 mm.. nf>° 1.36 Isomerization of 2-Allylphenol to 2-Propenylphenol.. to the usual situation.p. The compound solidifies in the receiver. dried. 230-231° at atmospheric * See p. a 61% yield of 2-allylphenol was obtained. the extract is dried over calcium chloride and distilled under diminished pressure. A 73% yield of material boiling at 103-105. with a refluxing time of one hour. 198-199°/740 mm. A considerable amount of tarry residue remains after distillation.5-87. To separate a small amount of 2-methyldihydrobenzofuran.5307. of guaiacol-like odor. and the mixture is extracted with ether..55 (five to six hours) the rearrangement is substantially complete with the minimum formation of undesirable by-products. gives a 73% yield of 2. from which the dihydrobenzofuran residue may be obtained by distillation. dried.1 1. the course of the rearrangement being conveniently followed by noting the refractive index at frequent intervals. and distilled under reduced pressure. 2-Allylphenol is dissolved in three times its volume of a saturated solution of" potassium hydroxide in methanol.28 is obtained.p. 2-Methyldihydrobenzofuran.5453. part of the solvent is distilled off until the temperature of the liquid rises to 110°.5-37° (corr. and the residue is refluxed six hours at this temperature. The ether solution is washed with sodium hydroxide solution. Ether should not be used for this extraction as it removes some of the phenol from the alkaline solution.. n^ 1.5823.5445. the product is dissolved in twice its volume of 20% sodium hydroxide solution and extracted twice with petroleum ether (30-60°). . during which an oily layer separates on top. and distilled. When no has risen to 1. is obtained.EXPERIMENTAL PROCEDURES 27 Preparation of 2-Allylphenol.27.5°/19 mm. 2-Allylphenol is a colorless liquid.* Contrary. giving a 75% yield of 2-propenylphenol boning over a range 110-115°/15-16 mm.). and on recrystallization from ligroin forms shining needles melting at 36.3-dimethyldihydrobenzofuran when applied to 2-(a-methylallyl)-phenol. this procedure was found more satisfactory than the rearrangement of allyl phenyl ether by refluxing in diethylaniline. 99°/12 mm. The allyl ether is boiled in a flask under a reflux tube. 2-Allylphenol is dissolved in four times its volume of acetic acid and treated with twice its volume of 45% aqueous hydrobromic acid. A 51% yield of material boiling at 86. b. The reaction product is washed free of the base. The same procedure. in fused state nf. then an excess of water is added. 80 of the article cited in reference 11. The alkaline solution is acidified and the phenol extracted with ether. 220°/ 760 mm. with the following properties: b. When the ether was refluxed for six hours in three times its volume of diethylaniline. The mixture is refluxed 20 minutes.
28 THE CLAISEN REARRANGEMENT pressure. with a small residue probably consisting of dicinnamylphenol. and crystallizes to a solid. 207-212°/12 mm. which. Auwers mb reports b.5-132°.p. of phenol in 100 cc.5811.. and-the residue is treated with four times its volume of Claisen's alkali. v. The benzene is distilled completely (by operating at reduced pressure near the end of the distillation). of cinnamyl bromide dissolved in a small amount of benzene..p. Twenty-five grams (60%). Preparation of 2-Cinnamylphenol. This procedure requires fewer extractions than the alternative method of dissolving the reaction product in petroleum ether and extracting the solution with Claisen's alkali to remove the phenolic material.p. and the residue is distilled. of 208-209°/ll mm. Auwers. 37-38°. C-Alhylation.). the ether solution is dried. 413. when recrystallized from hot petroleum ether or hot absolute formic acid. nf? 1. * Claisen's alkali is prepared by dissolving 350 g.4-119. water is added and the layers' are separated. 298 (1917). melts at 55. of potassium hydroxide in 250 cc.* The resulting solution is extracted twice with petroleum ether to remove the small amount of neutral material (2-3 g. of benzene is treated with 39. Ann. .8°/18 mm.p. the solvent is removed.5°.4 g. The phenylurethan melts at 131. The phenol is recovered from the alkaline solution by acidification and ether extraction. m. of water and diluting to 1000 cc. lost v .5-56. On redistillation the product has a constant b. After refluxing for five hours. b.8 g. 119. of 2-cinnamylphenol is obtained.16 The sodium salt from 18. with methanol..
Product Temperature. 8 Seep. Compound Time. 150-200 110 260 — At b. REARRANGEMENT OV OPEN-CHAIN COMPOUNDS A. 8 Seep. ° C. Ethers of Enols Conditions. hours " — 4 6 — — — 1 1 Temperature.Rearrangements Involving Migration to an Unsaturaied Side Chain Conditions Aryl Group in ArOCH2CH=CH2 Time. ° C.8 8 9 1 1 10 10 10 39 39 39 B.2.6-dimethylphenyl * References 104-129 appear on p 48.6-dichlorophenyl 2-Propenyl-4. hours 2-Propenyl-4-propyl-6-methoxyphenyl 2-Propenyl-4. 8 Yield 28% 28% 37% Reference * 26 26 26 .p. 255 255 <175 220 Solvent (or Catalyst) (NH4CI) (NH4CI) — — — — — — — \ Product ' Yield Reference * Ethyl O-allylacetoacetate Ethyl O-cinnamylacetoacetate O-Allylacetylacetone O-AHyloxymethylenecamphor Allyl vinyl ether Allyl a-methylvinyl ether Allyl ot-phenylvinyl ether 7-Ethylallyl vinyl ether containing 23% of a-isomer Ethyl allylacetoacetate Ethyl of-phenylallylacetoacetate Ethyl cinnamylacetoacetate Allylacetylacetone C-Allyloxymethylenecamphor Allylaeetaldehyde Allylacetone 7-Butenyl phenyl ketone 3-Ethyl-4-pentenal 3-Methyl-4-hexenal 4-Heptenal >85% — 20% >85% — — >85% 71% 76% 4% 18% 1.TABLE I. 168-178 5 7 160-173 177 Seep.
60 44 (p.5 3 — — "Long refluxing" 11 (p.5-Dimethyl 2-Allyl-3-(and -5-) methyl f 2-Allyl-4-methyl 2-Propyl-4-methyl 190-220 (Inert atmosphere) 2-Allyl (dimer) — 6-Allyl-2-methyl 207-231 — 2-Allyl-3-methyl. 27.4-dimethyl 2-Allyl-3.6-Diallyl-3-methyl 2. 58) 44 (p. 58) 44 (p. 34. 91) 26.Solvent (or Other ture.5-dimethyl . 28. 6-Allyl-3-methyl 210-240 (Inert atmosphere) 2-Allyl-4-methyl 200 — — Diethylaniline 237 200-210 (Inert atmosphere) — — — 230-270 — — (CH2O.3 1 13 0. 2. 29.6-DialIyl 6-Allyl-2. 106) 11 (p.67 M 44 (p. 79). Time. 104 105 44 (p. decomposition products) 2. °C. 56) 44 (p. 43). 45) i I 11 230-252 (Inert atmosphere) 6-Allyl-2-propyl-4-methyl (2-Propyl-4-methyl-phenol) 34 .TABLE II ortho REARRANGEMENTS OF ALLYL ABTL ETHEBS o A.4-DimethyI 3. Special Condition) None 2-Methyl 3-MethyI 4-Methyl 2-Hydroxymethyl 2-Allyl 2. Benzene Derivatives Conditions Product • Substituents in Phenolic Ring Yield Reference * Ring Substituents in OHo-sCHOHoOr" Hi. hours Several Tempera.6-Diallyl-4-methyl ">85% 78% 70% >85% — 80% >85% — 30% 10% 67% 10% ' 1.
I l l ) >85% 11 (P-107).2.3. 38) 1. 112) 70% 44 (p.5-Trimethyl 4-(0-Carbomethoxyvinyl) 2-Chloro 4-Chloro 2. 37) — 26.4-dichloro 6-Allyl-2-bromo 2-Allyl-4-bromo 55% 95.8 — — Few minutes at reflux Tetralin 213-220 2 2 0.3.3.3.4-Dichloro 2-Bromo 4-Bromo 2.3.4 1 '6-Allyl-2.5-trimethyl-4-acetamino >85% 95 2.5-trimethyl-4-formamino >85% 95 6-Allyl-2.5-1 185 180 225 225 — 230 — — Paraffin oil Refluxed in dimethylaniline (inert atmosphere) Paraffin oil (inert atmosphere) Dimethylaniline (inert atmosphere) Kerosene Kerosene Dimethylaniline (inert atmosphere) Paraffin oil 47 6-Allyl-2. t A mixture of the two lsomere was used.4-Dibromo * 3.5-Trimethyl-4-formamino 2.5-Dibromo 2-Nitro 4-Nitro 3-Acetamino 4-Amino 4-Acetamino 2.107 82% 47 >85% 44 (p.5-dibromo 6-Allyl-2-nitro 72% 44 (p. 40) 2-Allyl-4-nitro >85% 107a 6-AUyl-3-acetamino 2-Allyl-4-amino 2-Allyl-4-acetamino 70% 11 (p.6-Diallyl-4-acetamino — 11 (p. 100 6-Allyl-2.4-dibromo (phenolic by69% product) 11% 47 72% 2-AUyl-3.3. 2-Allyl-4-03-cftrbomethoxyvinyl) 6-Allyl-2-chloro 2-Allyl-4-chloro 6-AUyl-2. — 270 230-245 — 220-224 — — Reflux (to 256°) — "Long" 200-210 210-220 (Inert atmosphere) 1. 48. 59) 30-40% 44 (p. 42) 2-Allyl-4-phenylazo CO .6 5 1.45.106 ' 82% 80 >85% 46 >85% 44 (p.5-Trimethyl-4-acetamino 2-Allyl-4-acetamino 4-Phenylazo * References 104-129 appear on p.5 — 210-220 180 230 — 6 6 2 7 5 0.5-trimethyl .15 0.
2-Allyl-4-methoxy "Good" ylaniline — 3.5-trimethyl 2-Methoxy 2-Methoxy-4-methyl 3-Methoxy 3-Methoxy-6-carbomethoxy 4-Methoxy 2-Allyloxy 3-Allyloxy 4-AUyloxy 4-Acetoxy 4-Benuoyloxy 0.3.TABLE II—Continued ortho REARRANGEMENTS OF ALLYL ARTL ETHERS to Conditions Ring Substituents in Time.5-trimethyl — — 6-Allyl-2-methoxy J >85% — 6-Allyl-2-methoxy-4r-methyl >85% Refluxing dimeth.6-Diallyl-2rhydroxy § — — 4.3-Diallyl-4-hydroxy and 2.Solvent (or Other ture. 108 81.3.75 — — 2. 108 108 101 102 77 O .25 — 2 200-280 230 230 220-230 — — — 180 210 210-215 — 130-280 Tempera.75 6 0.6-Allyl-3-methoxy "Good" ylaniline Refluxing dimeth. Special Condition) 170-265 Product Substituents in Phenolic Ring Yield Reference * 6-Allyl-2-hydroxy >85% f 4-Allyl-2-hydroxy >85% t — 6-Allyl-3-hydroxy 45% — 6-Allyl-4-hydroxy-2. 108 109 1 109a 110 / 110a 110 31.5 1 — 0. ° C.2-AIIyl-3-methoxy-6-carbomethoxy 68% ylaniline (inert atmosphere) Refluxing dimeth.1 1. 32. hours 2-Hydroxy * 3-Hydroxy 4-Hydroxy-2.6-Diallyl-3-hydroxy — 2.5-diKerosene >85% allyl-4-hydroxy (in equal amounts) — 2-Allyl-4-acetoxy 80% — Mixture of benzoyl derivatives of >85% 2-allyl-4-hydroxy • 31.
6-diaUyl 2.6-Diallyl-2-methoxy 6-Allyl-2-methoxy-4-propyl 6-AUyl-2-methoxy-4-(7-hydroxypropyl) 3.3-MethyIenedioxy 2-Allyloxy-3-methoxy 2-AHyloxy-3-hydroxy ( 2-Fonnyl 4-Formyl 4-Acetyl 2-AUyl-4-formyl 2-Carbethoxy 2-Carbomethoxy 0. t The mixture contained the 6-allyl and 4-allyl derivatives in the ratio 5 : 4. 70) 70% >85% — — 79% — — —' 5 — 1 * 200 200 6-Allyl-2-formyl 220-230 2-Allyl-4-formyl 250-270 200-210 (Inert atmosphere) 2-Allyl-4-acetyl 2. § The product was not isolated from the reaction mixture. 108) 1 44 (p.6-Diallyl-4-formyl 250-310 6-Allyl-2-carbethoxy 230 6-Allyl-2-carbomethoxy >85% 66% 78% <60% * References 104-129 appear on p. 96) 44 (p. 25.6-Triallyl-3-allyloxy Mixture of 6-allyl-2.3-methylenedioxy (80%) and 4-allyl-2.5.8 — 4 185 Distillation in vacuum 200 190-200 (Inert atmosphere) Distillation in vacuum Distillation in vacuum 220-240 6-Allyl-3-hydroxy-4-nitro 3. t For products with boronfluoride-aceticacid (103a)t see p. 47) 26 48 108 108 33. 48.6-Triallyl-2-nydroxy 2.3-methylenedioxy (20%) 26%l| 57 108 44 (p. || The yield based on ether not recovered was 52%. which contained other substances also. 111 112 112 . 44 (p.6-Diallyl-2-hydroxy 4. 107) 112a 44 (p. CO CO .4.3-Hydroxy-4-nitro 2-Hydroxy-3-allyl 2-Methoxy-4-allyl 2-Methoxy-4-propyl 2-Methoxy-4-0y-hydroxypropyl) 2-Allyloxy-3-allyl 3-Allyloxy-4.
TABLE II—Continued ortho REARRANGEMENTS OF A^LYI* AHTL ETHERS Conditions Product Ring Substituents in 2 2 &116 * Time.5 0.75 6 0. 116) 113 113a 57 57 56 56 56 56 57 57 57 57 . 87).Solvent (or Other ture. ° C.75 0 33 Tempera.6-DialIyl-3-hydroxy-4-acetyl 2. hours 0.6-Diallyl-3-methoxy-4-acetyl 2-AUyl-3-hydroxy-4-propionyl 6-Allyl-3-methoxy-4-propionyl 2-Allyl-3-acetyl-4-hydroxy 2-Allyl-3-acetyl-4-methoxy >85% >85% 80% 54% 85% 50% 59% >85% 60% 20% 30% >85% 80% 74% 75% 44 (p. Special Condition) 220-250 220-230 210-300 230-250 230 190-200 200210-215 215 210 210 ' 205 200 180-230 220-230 — Substituents in Phenolic Ring Yield Reference * 4-Carbethoxy 2-Allyl-4-carbethoxy 2-Methoxy-4-formyl 2-Methoxy-4-formyl-5-brlomo_ 2-Methoxy-4-acetyl 3-Hydroxy-4-formyl 3-Methoxy-4-formyl 3-Hydroxy-4-acetyl 3-Methoxy-4-acetyl 2-AHyl-3-hydroxy-4-acetyl 3-Methoxy-4-acetyl-6-allyl 3-Hydroxy-4-propionyI 3-Methoxy-4-propionyl 3-Acetyl-4-hydroxy 3-Acetyl-4-methoxy 2-Allyl-4-carbethoxy 2.6-Diallyl-4-carbethoxy 6-AUyl-2-methoxy-4-formyl 6-Allyl-2-methoxy-4-forrnyl-5bromo 6-Allyl-2-methoxy-4-acetyl 2-Allyl-3-hydroxy-4-formyl 6-Allyl-3-methoxy-4-formyl 2-Allyl-3-hydroxy-4-acetyl 6-Allyl-3-methoxy-4-acetyl 2. 9*7 — — — — — — — — — -4 — — 44 (p. 89) 44 (p.5 0.5 — 0 5 — 1 1 1.75 2 2 0.
B. Time.7-Dimethyl-5-allyloxyindan l-Allyloxynaphthalene 2-Allyloxynaphthalene l-Allyl-2-allyloxynaphthalene 2-Allyloxy-l . Special Condition) . Polycyclic and Heterocyclic Derivatives •Conditions Compound 5-Allyloxy-6-methyIindan 4.6-diallyloxynaphthalene 2-Allyloxy-3-carbomethoxynaphthalene 4-Allyloxybiphenyl * References 104-129 appear on p.4-naphthoquinone 4-Allyloxy-l.4-naphthoquinone 240 Dimethylaniline 2-Allyl-3. 61) >85% 1 0 1 — 70% 49% 73% >85% >85% 85% 0 — 84 84 101 114 101 • 101 49 49 115 116 2-Hydroxy-3-allyl-l .15 0.4-Diallyloxynaphthalene 1.7-Dimethyl-5-hydroxy-6-methylindan 2-Allyl-l-naphthol l-AUyl-2-naphthol No reaction Yield >85% 75% Reference * 52 52 50-60% 44 (p.4-dihydroxy-5.3-Diallyl-l.7-dimethyl-l-naphthol 240 — 2-Allyl-5-methoxy-l-naphthol 200 Diethylaniline 2.Solvent (or Other ture.245 ' 280 230 — "Long heating" 135 Dimethylaniline Dimethylaniline — — — — Product 4-Allyl-5-hydroxy-6-methyUndan 4.2-naphthoquinone l-Allyloxy-3.4-Diallyloxy-5.4-diacetoxynaphtha(acetic anhydride.8-dihydronaphthalene 2.5-Diallylnaphthalene-2. lene inert atmosphere) 240-250 Kerosene 2.6-Diallyloxynaphthalene l.4-naphthoquinone 135-145 (Inert atmosphere) 2-Hydroxy-3-allyl-l .7-dimethylnaphthalene l-Allyloxy-5-methoxynaphthalene 1.5 2.3-Diallyl-l .75 1.8-di(inert atmosphere) hydronaphthalene 190 (Inert atmosphere) 1. ° C. hours 1 — 1 — — 0.5-Diallyl-2.6-dioI — — — Decomposition products l-Allyl-3-carbomethoxy-2-naphthol 3-AHyl-4-hydroxybiphenyl (mainly) I i oa — Distillation at 162 — — — . 48.5 5 2 Few minutes — — Tempera.
TABLE II—Continued ortho REARRANGEMENTS OF ALLTL ARTL ETHEBS Conditions Compound Time.6-Diallyloxyanthracene l. 3-Allyl-2-hydroxyfluorene 1.1 Tempera.6-diacetoxyanthracene —i — — 117 51 51 51 51 50 50 53 53 53 53 53 55 49 118 % 118 o 0 55% 0 60% 25% — 78% 62% 60% 0 64% 0 l-Allyl-2-hydroxyfluorene . Special Condition) 250-300 — 100 100 (Inert atmosphere) 150 — 160-180.Solvent (or Other ture.2-Dimethyl-3-allyloxyfluorene t.and 3-allyl-2hydroxyfluorenone — Decomposition products — 8-Myl-7-hydroxyquinoline — No reaction .31-DiaHyl-2-hydroxyrluorene a 4-Allyl-l .4<limet*iyl-3-hydroxyfluorene — Mixture of 1.2-dimethyl-3-hydroxyfluorene (Inert atmosphere) 2-Allyl-l. °C.15 — — 1.6-DiaHyloxydihydropleiadene 7-Allyloxyqumoline 7-Allyloxy-8-allylquinoline 0.5 — 2. — 235-238 — 230 215 200 — 230 250 Product i Yield Reference * — Diethylaniline (acetic anhydride) — Decomposition products — — — 3-Allyl-2-hydroxybiphenyl l-AIlyl-2-phenanthrol 4-Allyl-3-phenanthrol 10-AUyH-methyl-7-isopropyl-9phenanthrol Decomposition products l.1 —• — — 3 — — 0.4-Dutnethyl-3-aIlyloxyfluorene 2-Allyloxyfluorenone 1.6-diallyloxyanthracene ' 2-Allyloxyfluorene l-AHyl-2-allyloxyfkiorene and 3aIlyl-2-aIlyloxyfluorene 1.5-Diallyl-2. hours 2-AHyloxybiphenyl 2-Allyloxyphenanthrene 3-Allyloxyphenanthrene l-Methyl-7-isopropyl-9-allyloxyphenanthrene l-Allyl-2-allyloxyphenanthiiene 2.5-Dimethyl-2.5 — 0.
54 121 122 122 122 © ft 1 1 1 _ 75% 80% El w e 03 -4 * References 104-129 appear on p.3 0.2-Methyl-4-allyloxyquinoline 8-Allyloxyquinoline 4-AUyloxy-2.7-Diallyl-6-hydroxy-2-methylbenzothiazole Same compound as above l-Allyl-2-hydroxydibenzofuran 8-Allyl-7-hydroxycoumarin 8-A]lyl-4-methyl-7-hydroxycoumarin 8-Allyl-2-methyl-3-methoxy-7hydroxychromone 6. 48. . t Formed in ratio of 20 : 1 j structures were assigned to the isomers from relative melting points.7-Diallylfluorescein Allyl ester of 2-allylfluorescein >85% >85% — — — — 34% 20% —r 119 119a 119a 119a 55a 55a 55a 120 121 56 54 54 54 .and 5-allyl-6-hydroxy-2methylbenzothiazole t 5.3-dimethylquinoline (?) Allyl iodide and l.8-Diallyl-7-hydroxyflavone 8-Allyl-7-hydroxy-3-methoxyflavone 2-Allylfluorescein 2.2-dimethyl-4quinolone 7-Allyl.5 2.5 2.5 — 2.3-dimethylquinoline 4-Allyk>xy-2-methylquinoline methiodide 6-AHyloxy-2-methylbenzothiazole 6-Allyloxy-5^allyl-2-methylbenzothiazole 6-Allyloxy-7-allyl-2-methylbenzothiazole 2-AUyloxydibenzofuran 7-AUyloxycoumarin 4-Methyl-7-allyloxycoumarin 2-Methyl-3-methoxy-7-allyloxychromone 2-Methyl-3-methoxy-7-allyloxy-8allylchromone 7-Allyloxyflavone 7-AIlyIoxy-8-aIlylflavone 3-Methoxy-7-aDyloxyflavone 3-Allyloxy-6-hydroxyfluoran 3.5 1 1 1 175 240-245 235-250 235-250 220-230 L95-200 210-240 200 200-205 210-215 210-215 210-220 210-220 210-220 Sealed tube 3-Allyl-2-methyl-4-hydroxyquinoline 7-Allyl-8-hydroxyquinoline 5-Allyl-4-hydroxy-2.1 — — 0.6-Diallyloxyfluoran AUyl 6-allyloxy-9-phenylfluorone11-carboxylate "Short time" 200 190-290 180 0.5 1.25 1.8-Diallyl-2-methyl-3-methoxy-7hydroxychromone 8-Allyl-7-hydroxyflavone 6.
75) 44 (p.5 Temperature. 2-Carboxy-4. 79) 110a 11 (p. 112) 64% 45 23% 45 >85% 11 (P. 112) 27% 44 (p. 102) 60% 44 (p. 118) 35% 44 (p.4. 112) 20% 44 (p.6-Diallyl 4. 83) 44 (p. °C. ortho Rearrangemente with Displacement of Carbon Monoxide or Carbon Dioxide Conditions Ring Substituents in CH2=CHCH2OC«H5 Time.6-dichloro 2-Allyl-6-methyl 4-Allyl-2-carboxy-6-methyl 2.6-Triallyl 2-Allyl-4-methoxy 2-Allyl-6-methoxy 4-Allyl-2-carboxy-6-methoxy 60% 44 (p. 117) o .85).6-dichloro 2-Garboxy-6-methyl 2-Carboxy-6-allyl. 102) 20% 44 (p.6-Diallyl-2-fonnyl 2. >180 180-295 170-240 175-180 118 MOO '100-180 MOO Refluxing in dimethylaniline 110-250 Product Substituents in Phenolic Ring Yield Reference * 2.TABLE II—Continued ortho REARRANGEMENTS OF ALLYL ABTL ETHERS C. 117) 11 (p.6-diallyl 2-Carboxy-4-methoxy 2-Carboxy-6-methoxy — — 6 — — — 0. 83) 44 (p.6-Diallyl 4.4-Diallyl-6-methoxy 2-Allyl-6-methoxy 2-AByl-4-formyL-45-methoxy 4-Allyl-2-formyl-6-methoxy 6-Allyl-2-carboxy 2-Allyl 2-Allyl-4. hours 2-Formyl-6-allyl 2-FormyI-4-allyl-6-methoxy 2-Formyl-6-methoxy 2-Carboxy 2-Carboxy-4. 75) 44 (p. 80% 20% 53% 30% >85% — 76% 2% 44 (p.6-Diallyl-2-«arboxy 2.
°C. Special Condition) Diethylaniline (inert atmosphere) — — — — Diethylaniline Diethylaniline Diethylaniline Diethylaniline Diethylaniline Diethylaniline Diethylaniline — — > Product Substituents in i Yield Reference * 82% 60-70% 60-70% 60-70% 60-70% 50-60% 60-60% 50-60% 50-60% 50-60% 50-60% 50-60% 60-70% 60-70% 66.15 0. 200-215 200-240 200-240 200-240 200-240 210-235 210-235 210-235 210-235 210-235 210-235 210-235 205 205 Co CO .Solvent (or Other ture.5 0.123 66 66 66 66 66 66 ) 66 ' .5 0.5 0.15 0. /3-METHTLALLTL ETHERS Ring Substituents in /"*T3T ___f* Conditions Time.4-Dimethyl 2-Isopropyl-5/-methyl 2-03-MethylaUyl)-4-methyl 2-OS-Methylallyl)-5-methyl 2-Methoxy 3-(0-Methylallyloxy) * References 104-129 appear on p 48.5 0.15 0.15 0.5-Dimethyl 3.15 0.15 0.5 Tempera.5 0.5 0.5-Dimethyl 3.D. hours 2.4-Dimethyl 2.4-Dimethyl 2-Isopropyl-6-methyl 2-(J8-Methylallyl)-4-methyl 2-(|8-MethylaUyl)-5-methyl 2-Methoxy 4-08-Methylallyl)-3-hydroxy None 4-Chloro 2-Methyl 3-Methyl 4-Methyl 2-03-Methylallyl) 2.4-Dimethyl 2. 66 66 66 66 66 66 CH2r==C—CH2OCJH5 /~VTT /"\/"1 TT 1 4 5 <ftCH 2 C=CH 2 CHs None 4-Chloro 2-Methyl 3-Methyl 4-Methyl 2-(0-Methylallyl) 2. Rearrangements of Ethers Containing Monosubstituted AUyl Groups 1.15 0.
5 3. MISCELLANEOUS ETHERS. Special Condition) CH2=CHCH21!« s J J y pa \ ^ Substituents in Yield Reference * Allyl Group 216-223 — — — — Ring 43 43 42.5 1 — . BENZENE DERIVATIVES Conditions Product \ CH-CHCHO^N I'fi ±] Substituents in Time. 60. 7-Methyl 4-Carbethoxy (Butadiene) Diethylaniline 7-Ethyl None — 7-Ethyl 4-Carbethoxy . hours Allyl Group /3-Chloro /3-Bromo 7-Chloro 7-Chloro 7-Bromo a-Methyl a-Ethyl a-Ethyl None None None 4-Methyl None 4-Carbethoxy None 4-Carbethoxy ^ Ring 2 — — — — 1. (1.43 43 43 43 123a 40 62 62 222-240 201-225 200-236 220-246 — a-w-Propyl 4-Carbethoxy 7-Phenyl None /3-Chloro None (2-Methylbenzofuran) Tetralin (Phenolic products) — (Phenolic products) — (Polymeric products) — (1.Solvent (or Other ture.3-Pentadiene) — 4-Carbethoxy 7-n-Propyl Refluxing a-Phenyl None diethylaniline m 24% •20% 18-29% — — 8% 9-18% >85% Trace 84% 70% 9% — 58% 41 35.3-Dibromopropene) (Phenol) Refluxed at 50 mm. 68 . °C.TABLE II—Continued -ortho REARRANGEMENTS OF ALLTL ARTL ETHERS 2. 4 Tempera.
8 230-260 Distillation in vacuum Distillation in vacuum Distillation in vacuum 7-n-Propyl 2-(7-n-Propylallyloxy)3-hydroxy (?) -y-n-Butyl 2-(iMi-Butylallyloxy)3-hydroxy (?) 2-Hydroxy Geranyl 'a-Methyl a^r-Dimethyl a-Ethyl a-Ethyl (o-Cresol) a-Ethvl 4-Carbethoxy a.3-dihydroxy 6-Geranyl-2-hydroxy (?) I I s 1 -f 4.59 58 58 41 41 58 58 58 58 112 112 125 •y-n-Propyl None -y-ro-Propyl 2-Methyl T-n-Propyl 4-Carbethoxy •y-n-Butyl 7-ra-Butyl None 2-Methyl 0.8 — 1. 58 58 58 62 62 58.5 0.5-0.124 45 123a 39.68 36. 37.-y-Phenyl •/-Methyl •y-Methyl -^Methyl T-Ethyl •y-Ethyl " -y-Ethyl 4-Methyl None 2.59 58.£-Dihexenyl-2.4-Dichloro 4-Carbethoxy None None 2-Methyl 85% 85% 83% >85% >85% 44% 12% >85% 13% 40% 19% 27% Trace 35.2 1.8 230-260 0. Dunethylanihne — — — — — — — — — • a-Phenyl a-Methyl a-Methyl 4-Methyl None 2.7-Dimethyl 4-Carbethoxy (1.33 3 2 1.3-Pentadiene) a-re-Propyl None (Phenol) 2-Methyl a-7i-Propyl (o-Cresol) 4-Carbethoxy a-n-Propyl a-Methyl-r-ethyl 4-Carbethoxy a-n-Butvl None (Phenol) a-n-Butyl 2-Methyl (o-Cresol) z.4-Dichloro 4-Carbethoxy None 2-Methyl 4-Carbethoxy 0.5-0.3-dihydroxy i. 40.5-0.75 — — 200 200-210 Refluxing 210-227 220-235 — 195-233 — — 213-241 Dimethylaniline (ineVt atmosphere) Diethylaniline Diethyknikne Itefluxed at 50 mm. 28 Trace 15 Trace — — — sn — • References 104-129 appear on p 48 t The mixture contained the normal (inverted) and abnormal products in the ratio 1 : 2 .x-Diheptenyl-2.
4-diacetoxynaphthalene (?) .3-Dif arnesyl-1.4-Difarnesyloxy naphthalene Temperature. DERIVATIVES OF POLTCTOLIC HYDROCARBONS Conditions Compound Time.6-Di-(7-n-propylallyloxy)-fluoran 1. hours 2-Cinnamyloxy-3-carbomethoxynaphthalene 1.5 0. MISCELLANEOUS ETHERS.5 — 1 3 125 — 210-220 190-200 v _ — — — Ha-Phenylallyl)-2-hydroxy-3carbomethoxynaphthalene 2-(o-Methylallyl)-l-naphthol 3-(«-Methylallyl)-2-hydroxy-l.4naphthoquinone Same compound as above 2-Pentenylfluorescein 115 — >85% >85% — — — 36.2-naphtho-^ quinone 4Hr-Ethylallyloxy)-6-hydroxyfluoran •3. °C. acetic anhydride 2.TABLE II—Continued orfho REARRANGEMENTS OF AIAYL AKTL ETHERS 3 .(-y-MethylallyJoxy)-naphthalene "2-(T-Methylallyloxy)-ll4-naphthoquinone -4-(7-Methylallyloxy)-l.7-Dihexenylfluorescein 2.124 126 126 122 122 83 — Diethylaniline. Solvent Product Yield Reference * Distil] ation in vacuum Distillation in vacuum 140 0.
7-Dimethyl •y.99 58 58 58.(a.7. 48.5 200-230 — (o-Cresol) None — 2.7-Dimethyl Conditions Product Time.4-Dimethylpentadiene) * (Phenol) Yield 70-80% 28% 59% 38% "Much" "Little" 75% 10-20% 54% 10-20% — — 50-60% 15% 5% — — 70% 65% 23% 33% 20% ence * 15 40.4-C6H3(OH)[CH(CH3)CH=CHCH8](CO2C2H6) 1.T-Dimethyl «-Ethyl-y-methyl «-Ethyl-7-methyl «-n-Propyl-7-methyl <*-ra-Propyl-7-methyl «-n-Butyl-7-methyl a-n-Butyl-7-methyl •a.4-C6H3(OH)[CH(C2H6)CH=CH2](CO2C2H6) None — 2. 5 197-224 — (Isoprene.7-Dimethyl «. . — None 1 200 2-(a. 2.5 (o-Cresol) — None — — (Cyclohexadiene. ° C.36 64 64a 64a 64a 61 61 * References 104—129 appear on p.61 62 62 62 62 •a.61 127 58 58 58 63 63 63 35. Ethyl 4-hydroxybenzoate.a-Dimethylallyl)-phenol (With calcined soda) 4-Carbethoxy 3 .5 200-230 (o-Cresol) None — 0.(2-Cyclohexenyl)-phenol — None — — (Phenol and isoprene) o.2. Rearrangements of Ethers Containing Disubstituted Allyl Groups.5 200-205 (Phenol) 2-Methyl 0.7-Trimethylene (2-Cyclohexenyloxybenzene) 7.7-Dimethylallyl)-phenol Remixing Diethylaniline Same product as above —I (inert atmosphere) 4-Carbethoxy 1 — 1.5 228-230 (Phenol) 2-Methyl — 0.(a-Methyl-7-propylallyl)-phenol 0. TemperaRing Solvent hours ture.3-Pentadiene 208-213 Ethyl p-hydroxybenzoate 1.2.a. Benzene Derivatives Compound Allyl Group <«.(o-Methyl-7-ethylallyl)-phenol 0.7-Tetramethyl 61.E.5 200-230 (Phenol) 2-Methyl — 200-230 0.3-Trimethyl-5-carbethoxydihydrobenzofuran) — 1 160-170 — (2.2. Phenol) (Hexahydrobenzofuran) o.
5 230-250 — 4-Allyl-2-methyl-6-methoxypheno] 2 200 — 2.6-Dimethyl 2. 55) 108 128 72. ° C.4.3-Dimethoxy-6-hydroxy 2-Carbomethoxy-6-methyl 2-Carbomethoxy-6-allyl 2-Carbomethoxy-6-methoxy Conditions Time.6-diaDyl 2-Hydroxy-6-methoxy (?) 2.6-Diallyl-2-carbomethoxyphenol a. 96) 109a 44 (p. 77) 129.6-Dibromo 2-Bromo-6-methyl 2. 11 (p. hours 1 Tempera.6-dimethoxyphenol "Few 165-206 — 4-Allyl-2.6-Triallylphenol 2. Special Condition) Product Yield Eleference * 195-200 (Inert atmosphere) 4-AlIyl-2.6-dimethylphenol 0.TABLE III para REARRANGEMENTS OP ALUTL ABTL ETHERS t A.6-Tetraallyl-2-hydroxyphenol — — 4-Allyl-2-hydroxy-6-methoxyphenol 1 (Refluxed at 75 mm.4-Diallyl-6-methoxyphenol — 180-200 — 3.6-Dichloro 2.4. 118) i 55 I Q M S .) 4-Alryl-2.3-dimethoxy-6-hydroxyminutes" phenol (Distillation at 275-290) 4-Allyl-2-carbomethoxy-6-methylphenol — 250 — 4.6-Dimethoxy 2.5.5 225-248 Diethylaniline 2.73 74 44 (p.Solvent (or Other ture. AUyl Ethers of Phenols and Substituted Phenols Compound Ring Substituents in CH 2 =CHCH 2 OC 6 H 5 2. 75 201-212 — 4-Allyl-2-carbomethoxy-&-methoxyphenol — • 57% 10% 61% 46 46 pro i fV7 Q 23% Trace >85% 50% 56% 83% — — >85% 30% 76% 69% >85% So. 83) 44 (p.6-DiaUyl 2-Methyl-6-methoxy 2-Allyl-6-methoxy 2-Allyloxy-3.6-dibromophenol 1 2-AllyI-6-bromophenol f — (Refluxing tetralin) 4-Allyl-2-bromo-6-m§thylphenol 2-Bromo-6-methyrphenol 7 172 (Inert atmosphere) 4-Allyl-2. 107 43 43 70 11 (p.6-dichloropheiiol 2-Allyl-6-chlorophenol — (Refluxing tetralin) 4-Allyl-2.
.Solvent (or Other Allyl Group hours ture. BENZENE DERIVATIVES 7 2 8 « 2 0 or"S Substituents in O Ring Conditions H Product °O CH 2 CH=CH 2 Yield Reference * Substituents in AUyl Group a-Ethyl /9-Methyl 7-Phenyl 7-Methyl 7-Ethyl 7.7-Dimethyl < Time.7-Dimethyl 2.7 30 * Beferenoes 104-129 appeat on p. °C.5 Ring 2-Carbomethoxy6-methyl 2-(e-Methyla)lyl)6-methyl 2-Carbomethoxy6-methyl 2-Carbomethoxy6-methyl 6-Carbomethoxy2-methoxy 2-Methoxy 6. 48.7 70-80% — 85% 59% + 66 3 3 6.5 210-235 Diethylaniline /3-Methyl 6-methyl 4 — 7-Phenyl 2-CarbomethoxyDiethylaniline 6-methyI 7-Methyl (Refluxing diethylaniline) 2-Carbomethoxy3 6-methyl 2-Carbomethoxy3 (Refluxing diethylaniline) 7-Ethyl 6-methyl 2-Methoxy 220 7. t The pure product was not isolated. Special Condition) \ * 7-Ethjl 2-Carbomethoxy(Alkaline rydrolysis) 6-methyl 2-(/3-Methylallyl). Tempera. Ethers Containing Substituted AUyl Groups 1.B.0.
5 119a 1 . HETBROCYCLIC DERIVATIVES Conditions Compound Time.1 0. hours 7. 200-205 190-240 Alloimperatorin 4.7-DimethylaUyloxyfuranocoumarin (Imperatorin) 8-Allyloxy-7-allylquinoline 0. °C.TABLE III—Continued para REARRANGEMENTS OF ALLTL ARTL ETHERS 2.1 Temperature.7-Diallyl-8-hydroxyquinoline >85% Product Yield Reference * 4.
5 165-175 4-Crotyl-2.6-Dichloro~4-carboxy >170 >180 150-300 2. Product Yield Reference * Allyl Group Ring None None None None -y-Methyl 2. .6-Dichloro-4-carboxyphenoI) 44 (p.6-DiallyI-4-carboxy 2.6-Triallylphenol 50% 58% >85% >85% 75% 10% (Heating 10 hr.6-Diallyl-4-fonnyl 2-Methoxy-4-formyl-6-allyl 2.6-dichlorophenol (2. 118) 44 (p. hours _ .6-Triallylphenol 4. 108) 44 (p.6-dimethoxyphenol NaOH) • 1. Rearrangements Involving Displacement 7 -0HCH.4. — — Temperature.6-Dimethoxy-4-carbomethoxy 2.OQ Conditions Substituents in Time.C.4. 91) 73 46 46 * References 104-129 appear on p. 48. with 2 N 4-AUyl-2.6-Diallyl-2-methoxyphenol 2.
Nature. 64. Am. 126 Fieser. 56. 300 (1932) [C. 73. 1100 Arnold and Moran. Sci. 324 (1938). Chem. Lauer and Sanders. Soc. Proc Indian Acad. 57. Ber. Hoehn. Am. / . J.. 52. J. 857 (1927). 99 (1924). Soc.4923 (1942). 144.. Soc. Am. Soc. Soc. Research Tokyo. 458 (1941)]. Ber. 87. J. Chem. and Work.A. Auwere and Borsche. 48. Am. ""•Arnold. Phys.. 61. Soc. u »" Mander-Jones and Tnkojus. 49. / . Chem. 271 (1940) [C. 53 (1927) [Chem. Chem. 1700 (1930). Org. private communication. Soc. 1602. 1731 (1935). 1375. 121 Krishnaswamy and Seshadri.. 111 Baker and Savage. Soc. 65. J. Zentr. Chem. Ber. Soc. J. 246 (1938). prakt. v. and Pilgrim. 35. J. J. Bar. 305 (1939). 58. Chem.48 104 105 THE CLAISEN REARRANGEMENT Kincaid and Oberseider. Soc. J. 2636 (1936). 1090 Kawai and Sugiyama. 64.. and Stromberg. 116 (1937).A.. 1(17 Raiford and Howland. Am. 71. 1938. J. Schales. 1350 (1933)].. Kitazawa. Chem. 35. 73. 1016 (1939). Am. Wales. Chem. 1716 (1915). 1937. Am. 70. 2188 (1927)]. 41 (1921). J. 118 Ochiai and Kpkeguti. Chem. 180 Gilman and Van Ess. and Nomatsu. 6. 72. 1369 (1940). Soc. Soc. 3. Chem. 115 Bergmann and Berlin. Chem.S. [2] 108. prakt. 1051 (1931). Chem. Ber. Am. Chem. Am. 124 v. Chem. 2986 (1942). Greengard.. McCool.. 2570 (1932). Ber. 13A. 66. 109 Bergel. 54. 119 Mander-Jones and Trikojus. 112 Hurd and Parrish. 1130 Kawai. Nakamura. 1315 (1942). 129 Freudenberg and Klink. 19S (1943). Am.. 123 1280 122 . Short. J. / . [2] 102. Ber. 114 Hill. Yoshimura. J. and Ashino. 60.A. 117 v. Chem. Todd. Am. 59. 108 Hurd. 128 Trikojus and White. Org. Braun and Schirmacher. Am. J.. Sci. 4. and Wawzanek. Auwers and-Wittig. 1365 (1939). Chem. Soc. Chem. 64. Soc. 937. 53. 1011 Smith. Proc. 48.. 1328 (1940). 1938. Am. 110 Mauthner. II. 367 (1939). J. Soc Japan. Jacob. Soc. J. 112 (1937).. 113 Kawai. J. 127 Hurd and Williams. Chem. 43 (1941) [C. 538 (1923). J. and Schultz. Pharm. Soc N. 126 Kawai. Papers Inst... Chem. Roy. Ungnade. " ^ Arnold and McCool. 5499 Hurd and Schmerling. J.. J. 2190 (1926). 116 Gilman and Kirby.. Soc. Chem. Chem..
2.2-difluoroethane . Antimony Fluorides.CHAPTER 2 THE PREPARATION OF ALIPHATIC FLUORINE COMPOUNDS ALBERT L.2-Trichloro-3.2.3-Penta<Moro-3.l.l.2.3-Heptachloro-3-fluoropropane lIl.2-Difluoropropane l. Mercury Recovery Addition of Hydrogen Fluoride to Unsaturated Compounds Addition to a Triple Bond Addition to a Double Bond 49 51 51 54 56 58 59 59 60 60 61 61 61 62 62 62 62 63 63 63 63 64 64 64 65 65 66 66 66 66 67 .3. . .l. • 1. . .l-Difluoro-2. Preparation of Aliphatic Fluorides by the Use of Mercuric Oxide and Hydrogen Fluoride .2-dibromoethane and l-Fluoro-l.3-trifluoro-l-propene Benzotrifluoride Laboratory Procedure Industrial Procedure *• • • 2.2-tribromoethane .2.\ Construction of Apparatus and Preparation of Reagents Equipment Reagents .l. HENNE Ohio State University CONTENTS INTRODUCTION METHODS OP PREPARATION PAGE 50 51 Interaction of Organic Halides or Polyhalides with Inorganic Fluorides .2-tetrafluoroethane l.2. Preparation of Aliphatic Fluorides by the Use of Antimony Fluorides The Use of the Fluorides of Silver and Mercury Table II.2.3-Hexachloro-3-fluoropropane l.3-Hexaohloro-l. . and Hydrogen Fluoride -.3.2-Dichloro-l.3-trifluoropropane Dichlorodifluoromethane and Trichlorofluoromethane „ l.3-difluoropropane l.2.2.2.3. .l. .3-Pentachloro-2. .2. Preparation of Mercurous Fluoride Preparation of Antimony Trifluorodichloride Experimental Procedures Acetyl Fluoride v l. .2.l.2-Dibromofluoroethane and l-Bromo-2.l. The Use of Potassium Fluoride.3.2.3. Zinc Fluoride. .3-difluoropropane l. Table I.
2-Difluoropropane . . RfcH=CHR' + HF —> RCHis—CHFR' RCssCR' ^> RCF=CHR' ^ > RCF*—CH2R' 3. Replacement of the hydroxyl group of alcohols.50 ^~ ALIPHATIC FLUORINE COMPOUNDS PAGE Experimental Procedures Ethyl Fluoride Isopropyl Fluoride Cyclohexyl Fluoride 2. Direct fluorination of saturated compounds or addition of fluorine to unsaturated compounds. Interaction of organic halides or polyhalides with inorganic fluorides. Products Obtained by Direct Addition and Substitution of Fluorine Experimental Procedure Fluorination of Pentachloroethane Replacement of the Hydroxyl Group of Alcohols Synthesis of Fluorides Other than Hydrocarbon Derivatives Acids ») Aldehydes Alcohols Ethers Ketones Amines TABLE IV. ALIPHATIC FLUORINE COMPOTJNDS 68 68 69 69 69 69 71 73 73 73 74 74 74 74 75 75 75 76 INTRODUCTION Reactions of four types have been used for introducing fluorine atoms into aliphatic molecules. ~ Direct Fluorination and Addition of Fluorine Table III. Addition of hydrogen fluoride to olefins and acetylenes. 1. ROH + HF fc> RF + H2O . RX + MF -> RF + MX 2. RH + F2 -> RF + HF RCH=CHR' + F2 -> RCHF—CHFR' 4. These are listed below in the order of their v practical importance at the present time.
•Fremy.1 zinc. chim. 411 (1894). All replacement reactions of this type must be carried out under completely anhydrous conditions. ZINC FLUORIDE. such as that of an acyl or sulfonyl halide. chim. ANTIMONY FLUORIDES. The fluorides of thallium. Ann. ease of handling.e both with respect to ease of replacement and extent of side reactions. and its removal from the reaction mixture results in quantitative yields. 13 (1856). Iodine is most easily and chlorine least easily replaced. 193 (1836). 132.. Ber. however. The choice of the reagent is based on the reactivity of the halogen to be replaced. The last is used whenever possible because of its low tcost.. [2] 61. The most convenient method consists in heating gently a mixture of an acyl or sulfonyl chloride with zinc or antimony fluoride in an apparatus which permits the acyl fluoride to distil as it is formed. The difficulty of removing the last traces of water from oxygen compounds. Com' plete interchange also can be effected with hydrogen fluoride. 173 (1933). [7] 1. 6 Nesmejanov and Kahn. silver. is replaced by fluorine by the action of almost any inorganic fluoride. Ann. 370 (1934).2 and potassium3. Nature. but more elaborate equipment is required. antimony. particularly in commercial practice. and the possibility of producing water by decomposition. they have been used most often in replacement reactions carried out in open equipment. The most important are mercury.*•B have been used in isolated instances. Good results have been reported for the synthesis of formyl and acetyl fluorides from mixtures of formic or 1 8 Ray. and hydrogen fluoride. The acyl fluoride usually boils about 40° lower than the chloride. Ann. the use of chlorides has now become general. THE USE OF POTASSIUM FLUORIDE. chim. [3] 47.THE USE OF INORGANIC FLUORIDES METHODS OF PREPARATION 51 Interaction of Organic Halides or Polyhalides with Inorganic Fluorides The replacement of a halogen atom in an organic compound by fluorine may be effected by treatment with any of several inorganic fluorides. . AND HYDROGEN FLUORIDE A very reactive halogen atom. and high fluorine content. * Meslans. account for the fact that it is often difficult to utilize halogen compounds which contain oxygen in the molecule. which in consequence have not been used extensively.. Dumas and Peligot. With the increased availability of pressure equipment. Bromides occupy an intermediate plac. side reactions are most prevalent-with iodides.. 67.
Benzotrifluoride is obtained also from the chloride and hydrogen fluoride. 6 ta • .7 by allowing the intermediate mono.. treated with potassium fluoride in boiling acetic anhydride.10 . Soc. Compt. 10 Van Hove. acad. It reacts with antimony trifluoride so rapidly that control of the reaction is difficult.or di-fluoride to distil as formed. 389. CC12=CC1CF3. 11 Henne and Leicester. Belg. heated under reflux. Ann. (CH3)2CHFCH2C1. 492 (1938).. the reaction is easily directed. 7 Henne.6° An equimolecular mixture of hexachloropropene and antimony trifluoride. Belg. Am. the substituted allyl chloride. 864 (1938). / . thus.7 Since the replacement of each chlorine atom by fluorine lowers the boiling point by about 40°. 1074.. the remainder being lost through decomposition.6 Hydrogen fluoride cannot be used with allyl halides because the first reaction is addition to the double bond. 60.8 Benzotrifluoride is obtained in yields of about 60%. 1920. 35. CF2=CC1CF3. Chem. but benzal fluoride can be obtained in 40% yield by skillful manipulation.. Diphenyldichloromethane is transformed to diphenyldifluoromethane in 60% yield when it is rapidly heated with antimony trifluoride to 140° and held at this temperature only until the mixture is completely liquefied. roy. Meslans. Bull.. The intermediate chlorofluorides. 63. roy. Whaley.6 but an extension of this work to higher homologs disclosed that the reaction is first retarded and then stopped by the formation of a coating of potassium chloride on the reagent. CeHfiCC^F and C6H5CC1F2. Soc. when heated overnight in a closed steel container at 18O-2OO10 with an excess of antimony trifluoride. Chem. generates the trifluoride. Soc. is transformed quantitatively to the fluoride. [7] 1.7 Benzotrichloride resembles the allyl chlorides just described. chim. since hydrogen fluoride does not add to the double bonds of the benzene ring.52 ALIPHATIC FLUORINE COMPOUNDS acetic acid and benzoyl chloride. 3478 (1941). either of them can be produced quantitatively. 375 (1898). J. Am. are seldom found and then only in small amounts. 6a ' 9 Unpublished observations of the author.. 1913..9 The reaction of benzal chloride with antimony fluoride is even more difficult to control. 60. 882 (1890). Am. acad. 8 Swarts. Bull.11 In all the above preparations antimony trifluoride may be replaced by hydrogen fluoride. 374 (1894). I l l . 9 Simons and Lewis.6a Allyl fluoride has been obtained by gentle heating of a mixture of allyl chloride and silver fluoride. and Stevenson. methallyl chloride and hydrogen fluoride react to formthe chlorofluoride. Chem. quantitatively. CF2=CC1CF2C1. The operation consists in mixing the chloride with a large excess (300%) of hydrogen fluoride in a copper vessel equipped with a fractionating device which permits the escape of hydrogen chloride but returns hydrogen fluoride to the reaction mixture. Similarly. rend. J.
1939. Am. 29. Baltimore meeting of American Chemical Society. 22 Swarts. not more than 1% of chlorine should be added'to the antimony trifluoride. Am. in which all the halogen atoms are attached to one carbon atom. In more difficult preparations enough chlorine is added to transform the trifluoride to antimony trifluorodichloride. S.. that it would be of little practical importance if it could not be accelerated by the addition of small amounts (2Jto 5%) of a pentavalent antimony salt. however. With the types just mentioned. Swarts recommended the addition of about 5% of bromine or antimony pentachloride. When more halogen atoms are present in the molecule. ' The behavior of a number of chlorine derivatives of methane. 805. The reaction is so slow. A. 20 Henne. 13 14 12 . The yield given for each product is the maximum obtained when the reaction was adjusted for the preparation Swarts. Bdg. Chem. 2. J. discovered by Swarts about 1890..12"18 Next to allyl halides in ease of replacement are saturated polyhalides of the types RCX 2 R' and RCX3. The pentavalent antimony salt is usually. 31. 641. SbF3Cl2. roy.THE USE. A. pat. or when halogen and hydrogen are present on the same carbon atom. 889 (1936). 32. pat. ethane. roy. Renoll.22 has plroved the most important means of synthesizing organic fluorides.563 (1936) [Chem. 2434 (1937). [3] 24. " H e n n e and Renoll. 59. M4m. and propane toward antimony trifluoride activated by the trifluorodichloride is shown in Table I.878 (1937) [C. 474 (1892).. and Leicester. and from acetylene by addition of one molecule of hydrogen fluoride..901 (1937) [C. this procedure. pat. 58. Chem.421 (1937) [C. 61. pat. The current practice involves the addition of chlorine in amounts commensurate with the difficulty encountered in the halogen exchange. couronn&s acad. Chem. A. Soc. S. 16 V.. They are transformed to the corresponding polyfluorides RCF 2 R' 19>20 and RCF 3 Bo'21 by long refluxing with antimony trifluoride or hydrogen fluoride. the exchange becomes more difficult and side reactions (chlorinatien and loss of hydrogen halide) increase in significance. 5123 (1935)].118. 18 Grosse and Lind.710 (1935) [C.OF INORGANIC FLUORIDES 53 Vinyl halides are so inert that none has been converted to a fluoride "by halogen exchange. 61 (1901). 32. 5409 (1938)]. 938 (1939). pat.. Bdg. The reagent frequently must contain a high percentage of pentavalent antimony salt.. Zentr.. 587 (1938)]. Ger. 469. produced by adding free halogen to the antimony trifluoride.005. Soc. A. Am.. 5809 (1937)]. Fr.. BuU. 17 U. Vinyl fluorides have been synthesized from saturated polyhalides by dehalogenation with zinc and by dehydrohalo^genation with alcoholic alkali. and little or no chlorination occurs as a side reaction.. 21 Henne and Renoll. J... I. 2. acad. Soc. The interchange then gives nearly quantitative yields. " B r i t . 2258 (1937)]. J.
) CCl!!FCCl2CClF2 (quant.) CCI2F2 (quant.2 1.64 ALIPHATIC FLUORINE COMPOUNDS of the particular product.2 2 2 . TABLE I PREPARATION OF ALIPHATIC FLUORIDES BY THE USE OF ANTIMONY FLUORIDES Starting Material Products CCI3F (quant.2 1.24 23.) CH2CIF (80%) CHzFj (80%) No reaction CCI3CCI2F (quant.2 1.) CHC12F (quant.) CCI2FCCI2CCI2F (quant.) CCIF2CCI2F (quant.) CCI2FCCI2F (quant.) CCIF2CCIF2 (quant.2 1.2 1. were much lower. The yields from bromides. owing to concurrent decomposition reactions.26 25.2 1.24 25.26 26 26 CC1 4 CHClj CH 2 C1 2 1. 27 27 27 27 28 28 12 12 29 29 21 21 21 21 21 5a 5a CHCI2CCI3 CHCI2CHCI2 CH2CICCI3 CH2CICHCI2 CH 3 CC1 3 CH2CICH2CI CE3CH2CI CC13CC12CC13 to to to CCl2FCCl2CCl3 (quant.2 1.) 30 30 30 .~2 CHjCl CClgCClj to to ' 2 2 3 3 1. and particularly from iodides.) CHCI2CCI2F (85%) CHCI2CCIF2 (70%) CHCI2CHCIF (60%) CHCI2CHF2 (60%) CH2CICCI2F (80%) CH2C1CC1F2 (80%) CH2CICHCIF (60%) CH2CICHF2 (30%) CH3CCI2F (90%) CH3CC1F2 (90%) CH 3 CF 3 (90%) No reaction No reaction Note to to Reference 23.) CHCIF2 (quant.2 1.
474 (1892).) CC1F2CH2CFS (quant. 26 Henne. Belg. and Elmore. 60. 4... 402 (1936). Am. 59. The remainder of the material underwent loss of hydrogen chloride. • " Swarts. Chem.2 1. 58. Soc. Chem. / . Bull. J. couronnis acad. 404 (1936). •* Midgley and Henne. Am. 2491 (1938). 3476 (1941). Soc. Chem. Ind)Eng. Chem. For the preparation of this product.33 5a.) CCl2FCCl2CF8 (quant.) CHC12CC12CCIF2 (quant. 8S MoBee. For the preparation of this product.) 30 30 31 31 5a 5a 5a 19 19 19.2 IN IN ccuca^ 2 2.. 1726 (1934). 63. roy.2 2. 33 5a 5a 5a 5a CH8CC12CH8 CH3CF2COl3 CC18CH2CF8 1.. Bdg. [3] 24. 86 Swarts. Soc.2 1. J. J. 58. . Soc. Chem.. 2489 (1939). the antimony trifiuoride must be converted completely to SbF.4 2. antimony tnfluoride containing 10% of SbFjCIa was used. Chem. Am.2 1. Am. » Henne and Renoll. Soc.Cl2. Chem. Hass. Am. 3340 (1940). 542 (1930). 3.2 1. 1 87 Locke* Brode. J. Chem. M4m.. Am.) CH 8 CF 2 CH 3 (quant. 22.4 to to Reference CO CO CQ CO CHC1 2 CC1 2 CC1S CClsCHClCCls CC12FCHC1CCI2F (75%) CClFsjCHClCClaF (30%) CC1F2CHC1CC1F2 (30%) CH8CH2CCla CH 8 CHsCCl 2 F (40%) CH 8 CH 2 CC1F 2 (40%) GH 8 CH 2 CF 3 (40%) CH 8 CC1FCH 3 (quant.2 1. *• Henne and Hubbard.) CHC12CC1FCC1F2 (75%) CHC1FCC1FCC1F2 (20%) CC1JCHC1CC12F (75%) Note 2 2 1.THE USE OF INORGANIC FLUORIDES TABLE I—Continued 55 PREPARATION OP ALIPHATIC FLUOKIDBS BY THE U S E OF ANTIMONY FLUORIDES Starting Material Products CHC12CC12CC12F (quant. Henne..3 1. 62.. J.. Soc.4 2. 61. 82 Henne and Haeokl.. 56. 1400 (1937).2 1. Am. The remainder of the material underwent chlorination. 28 Henne and Ladd. Chem.) CH3CF2CC12F (60%) ' CH3CF2CCIF2 (10%) CC12FCH8CF8 (quant. J. 61 (1895). 2. »° Henne and Ladd. roy. J. Am. Soc. Soc. and Henne..) CC1F2CC12CF8 (quant. acad.
p. S. THE USE OF THE FLUORIDES OF SILVER AND MERCURY Silver and mercury fluorides are capable of effecting all the replacements which can be accomplished by the other inorganic fluorides and in addition some replacements which are not effected by the others. 76°). 5. TJ.847 (1931) [C. Side reactions and decompositions increase as the hydrogen content of the molecule increases. 2. pats. and difluoromethyl • bromide is transformed to fluoroform by mercuric Daudt and Youker. "Midgley. A. and McNary.705 (1935) [C.833.p. and carbon tetrachloride' (b.34 it can be used to transform a large amount of organic halide*to the fluoride with the aid of only small . 5123 (1935)]. pat.208 (1935). 29.p. trichlorofluoromethane (b. —CHC12 groups are changed slowly to —CHC1F groups and with greater difficulty to —CHF2 groups.34'36 3CC14 + 2SbF3 -» 2SbCl3 + 3CCljjF2 6HF + 2SbCl3 -» 2SbF3 + 6HC1 The process is carried out continuously by supplying carbon tetrachloride and hydrogen fluoride to a vessel originally charged with a quantity of antimony trifluoride containing a little pentavalent salt. A. 26. However.. The product (CC12F2. but rarely to —CF3 groups. 1047 (1932)]. 3. —CH2C1 and —CHC1— groups are not affected.. This is the method used in industry for the preparation of dichlorodifluoromethane. alkyl halides are transformed by silver fluoride into alkyl fluorides. 28. 34 . 2. Hydrogen fluoride alone undergoes exchange reactions only with very reactive organic halides. The presence of fluorine decreases the ease of replacement of halogen attached to an adjacent carbon atom.179 (1934).amounts of antimony salts. U. b. 2. 20°). 4. . S. 25°). —30°) and hydrogen chloride (b. 1.56 ALIPHATIC FLUORINE COMPOUNDS From these experiments it is clear that. they are converted to —CC12F and —CC1F2 groups. 29. Henne. or prevents such replacement. 1. The distillate is washed with water to remove hydrogen chloride. —CC13 groups are most reactive..p. Thus. and the dichlorodifluoromethane is finally purified by distillation. —85°) are removed continuously by means of a fractionating column which returns hydrogen fluoride (b.129 (1933). 5459 (1935).p.930.005.007..because it reacts with antimony chloride to form antimony fluoride and hydrogen chloride. in the reaction of a polychloroparaffin with antimony trifluoride activated by a pentavalent antimony salt: 1.
water decompose it rapidly. 884 (1936). 58. It reacts readily with alkyl^ chlorides and with polyhalides. roy. J. " 6-warts. and all its fluorine is available for interchange. Soc. the last reagent converts difluoroethyl iodide.l-difluoro-2-bromoethane. 1200 (1937). . Soc. Belg. but its action is easily Controlled. Bull. with alkyl bromides the yields range from 60 to 90%. forming mercuric salts and olefms. or to complete a reaction which can be brought to an intermediate stage •with the cheaper reagents. respectively. a^good method of preparing fluoroform consists in converting bromoform to difluorobromomethane by treatment with antimony trifluoride and transforming this intermediate to fluoroform by reaction with mercuric fluoride. Am.39 It reaets rapidly. CHBr2CHF2. J. Soc. Chem.. [3] 31. the various halogen-containing groups fall into the order discussed in connection with antimony"trifluoride. " H e n n e and Midgley. 59.. Consequently. 1060 (1938). 1. often violently. Soc. Chem. 887 (1936). Mercurous fluoride 36> "• 38 converts alkyl iodides readily to alkyl fluorides. CHF2CHBr2.1. CHF2CH2I. Mercuric fluoride is by far the most effective reagent. The reagent can be used in the presence of such solvents as hydrocarbons or their fluorine derivatives. Chem. "Henne and Renoll. Vinyl halides are not affected. Am. With respect to the relative ease of replacement.1. 58. Silver fluoride is difficult to prepare in anhydrous form. _ Substances capable of. Mercuric fluoride is an expensive reagent. it is used only after the cheaper fluorides have proved ineffective. 675 (1896). For example. more convenient reagents despite the lower fluorine content of mercurous fluoride. alkyl chlorides have not been extensively studied. because the only go'od method of preparation known consists in the treatment of mercuric chloride with fluorine.38 All the above reactions are carried out by refluxing the halogen compound with mercurous fluoride.THE USE OF FLUORIDES OF SILVER AND MERCURY 57 fluoride. acetylene tetrabromide is converted to a mixture of dibromethylene. therefore. Chem. and it has the further disadvantage that only half of its fluorine is available because the exchange reaction stops with the formation of the compound AgFAgCl. Mercuric fluoride and mercurous fluoride are. 4 » Henne.and tetrafluoroethane. Am.2-tribromoethane with antimony trifluoride to give l.2-trifluoroethane is best synthesized by treatment of 1. to trifluoro. J.. Mercurous fluoride is not a satisfactory reagent for polyhalides because it tends to remove halogens from adjacent carbon atoms. and difluoroethylidene bromide. generating. and dibromoethylidene fluoride. but its action is impeded by ethers and stopped completely by ketones. Am.40 Similarly. usually at temperatures below 130°. it does not produce olefins. acad. Thus. 60. CHBr=CHBr. which is converted to the desired 88 Henne and Renoll.. / .
21 and 1. The mercury halide produced can be recovered and used for the preparation of mercuric oxide for another run. and adequate mechanical means of dissipating the heat must be provided in orfler to keep the reaction under control. Am.36 Several procedures have been devised to circumvent the necessity of synthesizing mercuric fluoride.41 The oxide is instantly converted to the fluoride.2. CHBr2CHF2. J. Soc. may be employed. 60. The reaction is strongly exothermic.58 ALIPHATIC FLUORINE COMPOUNDS product by reaction with mercuric fluoride. prepared by passing hydrogen fluoride into a mixture of mercuric oxide and the organic reagent. Examples of preparations effected by this method are given in Table II.38 Methyl fluoride was prepared in yields of better than 80% by dissolving one equivalent of iodine in a large quantity of methyl iodide and progressively feeding one equivalent of mercurous fluoride into the solu" Henne..1. through the same sequence of treatments. TABLE II PREPARATION OF ALIPHATIC FLUORIDES BY THE USE OF MERCURIC OXIDE AND HYDROGEN FLUORIDE " Starting Material CHBr 2 CHBr 2 CH 2 BrCHBr 2 CH 3 COCH 2 CH 2 Br CH2C12 CHCU CH3CHC12 CH3(CH2)6CHC12 (C6H6)2CC12 (CfrEWsCCl CHC12CC1F2 CHF2CC13 Products CHBr 2 CHBrF CHBr 2 CHF 2 CH 2 BrCHBrF CH2BrCHF2 CH3COCH2CH2F CH2F2 * CHC1F2 CH 3 CHF 2 CH 3 (CH 2 ) 6 CHF 2 (C6H6)2CF2 (C 6 H 6 ) 3 CF CHF2CC1F2 CHF2CC1F2 Yield 80% 80% 80% 80% 60-70% 70-80% 70-80% 70% 80% 75% 40-60% . such a salt acts substantially as a mixture of mercuric fluoride and mercuric halide. The nascent salt. which reacts at once with the organic halide.2-tetrafluoroethane is prepared from acetylene tetrabromide by way of the difluorodibromide. 1569 (1935)- . Another procedure consists in adding a halogen to mercurous fluoride in order to generate a mercuric fluorohalide. Chem.
Since the lines are practically straight. The great majority of reactions reported in the literature were performed in platinum equipment. It is. A side reaction appeared.6" CONSTRUCTION OF APPARATUS AND PREPARATION OF REAGENTS Equipment. soc. 1). the boiling point usually is lowered by about 70° for each halogen replacement. but this is not recommended. stainless steel. nickel. therefore. Bull. When an organic bromide is transformed into a fluoride. 46. prepared from mercurous fluoride and chlorine. 56). When very low-boiling compounds are involved. the dephlegmator is equipped with a pressure gauge. The very easy interchanges can be done in glass. as have also magnesium.38 proved capable of converting methylene chloride and methylene bromide quantitatively to CH2F2. and acetylene tetrabromide to CHF2CHBr2. and a releasing needle valve. This mode of operation often permits a quantitative conversion. 10 (1937). 'especially in the case of ethylene bromide which was transformed to a mixture of ethylene fluoride and ethylene chlorobromide. chim. it is possible to draw the vapor curve of any fluoride whose boiling point at one pressure can be estimated with a degree of accuracy sufficient to be of great help in the synthesis. . All interchange reactions must be carried out under rigorously dry conditions. and at temperatures high enough to permit the reaction the practical difficulties of operation are such that the process is without value. Steel equipment with silver lining is convenient when mercury salts are handled. Clean steel equipment is most convenient in the laboratory and can be built inexpensively from standard pipe fittings. "Swarts. The combined readings of the thermometer and the gauge indicate the progress of the reaction when referred to a pressure-temperature chart such as that illustrated (Fig.EQUIPMENT 42 59 tion. The boiling points of chlorides are lowered by about 40° for each replacement by fluorine. tribromoethane to CHF2CH2Br. Mercuric fluorochlori. advantageous to run the interchange in a reaction chamber surmounted by a column and to allow the desired fluorides to distil as formed. and Monel metal. and some of the results which were difficult to duplicate in other equipment were due to the very beneficial effect of platinum itself. At room temperature there is practically no reaction between hydrogen fluoride and mercuric chloride. a thermometer well. It has not yet been possible to employ hydrogen fluoride in conjunction with mercuric fluoride in a process comparable to that with hydrogen fluoride and antimony fluorides (p. Copper has been used successfully..de. Bdg.
of red mer- curic oxide in a mixture of 28 cc. water is shaken vigorously in a bottle with 40 g.60 ALIPHATIC FLUORINE COMPOUNDS Reagents.F * CCtjFCC^F CCU I J '5 2O in / r / - > 27 / 28 -H00-BO-6O-«0-2O 1 2 S O 2O 4O 6O SO 100 I2O WO I6O I8O2OO22O24O 26O280 3OO33O34O 39O 38O 40O TEMPERATURE *F ' Fia.F. 1. and the excess mercury is decanted. Excellent grades of the crystalline anhydrous fluorides of zinc and antimony are available commercially. All operations should be carried out in diffused light. at which point mercurous nitrate starts to crystallize. The moist mercurous carbonate is added immediately in small portions and with constant stirring to a mixture of .38 A solution of 40 g. A solution of 4 cc. Hydrogen fluoride can be obtained in convenient steel containers equipped with dependable needle valves. The reaction mixture is next poured into a freshly prepared solution of 48 g. of mercury until the mercury ceases to dissolve readily. Preparation of Mercurous Fluoride. of concentrated nitric acid and 60 cc. 2 CH. of water. of water saturated with carbon dioxide. of potassium bicarbonate in 200 cc.CI 3 CHFiCCIFj 5 6 7 8 CcrFaCCIK CCI. of water is then added to redissolve the crystals. of concentrated nitric acid in 45 cc. the resulting mercurous carbonate is filtered by suction in the presence of a few pieces of solid carbon dioxide and finally washed thoroughly with 1400 cc. of if 4OO A f / / y VAPOR PRESSURES OF ORGANIC FLUORIDI / / / z / y f t / / / / ©2*° l » / / / / f / A / / / / / JlSO • / / A / y 1 I 1 40 8 30 i 2O £ 15 IO O y ft / / / / f / / / // / / // / / / / J / / / / / / z 1 CCI.
chim. The use of organic solvents for washing and drying does not simplify the process. The mixture is stirred and heated until a dry. and then heated for an hour on the water bath. bottle stoppered with rubber is placed 150 g. Preparation of Antimony Trifluorodichloride (SbF3Cl2). 61 100 cc. 59. and a few grams of sodium fluoride is added. The operation is ended after the absorption of the desired quantity of chlorine. The salt must be removed from the dish and stored immediately in tightly stoppered copper or resin containers. The reaction vessel is alternately heated gently. the^bottle is stoppered and allowed to warm to room temperature with shaking. Soon the reaction slows down as indicated by the rate of pressure fall when the needle valve is closed. of acetyl chloride^ It is cooled to —15°.. Analysis indicates the product to be essentially pure mercurous fluoride. This powder is immediately scraped off the walls. and the whole is weighed. The container is closed and allowed to stand overnight at room temperature. The mixture is cooled to 0°. to flow and expose fresh surfaces of crystalline antimony trifluoride. then allowed to cool in order to permit SbF3Cl2. After /vigorous shaking to 43 Colson. of 48% hydrofluoric acid and 260 cc. A known quantity of antimony fluoride is placed in the vessel. described on p. the yield is quantitative. the needle valve is closed. EXPERIMENTAL PROCEDURES Acetyl Fluoride. portion of the salt is added. It is then cooled. Ann. the vessel is evacuated. which is a viscous liquid. the valve is closed. "which is then heated on the water bath. and the connection with the chlorine tank is removed. . with evolution of heat. a second 10-g.EXPERIMENTAL PROCEDURES . and the use of chemical reagents inferior to the chemically pure grade causes complications. [7] 255 (1897). Acetyl fluoride boils at 20°. of water in a platinum dish. Part of it is absorbed rapidly by the salt. This is made in the' steel reaction vessel. and the product is distilled. (b) * One mole of hydrogen fluoride is condensed into 10 moles of » acetic anhydride cooled to 0°. The reaction mixture is cooled. of zinc fluoride has been added in this way the temperature is allowed to rise gradually to 50°. crushed in the bottom of a platinum crucible. Weighing indicates the amount of chlorine present in the vessel. and 10 g. and the bottle is stoppered and shaken as before. (a) 2 In a pressure. of anhydrous zinc fluoride is introduced. Connection is established to a chlorine cylinder. The-yield is about 80 g. sandy powder is obtained. When 100 g. When the absorption practically ceases. and the needle valve is opened to permit qhlorine to fill the vessel.
For purification. only hydrogen chloride escapes. The fluorine utilization is about 90%.5 to 1. Laboratory Procedure. is quantitative. Benzotrifluoride (C6H5CF3). vertical pipe to act as a mild dephlegmator. the mixture is subjected to distillation. together with a small amount of CC1^=CC1CC1F2. 20°. The pipe is connected to a downward metal condenser whose flared end comes in contact with the surface of a large quantity of water in a wide-mouthed bottle. Heating is regulated in such a fashion that distillation proceeds rapidly.62 ALIPHATIC FLUORINE COMPOUNDS remove any residual trace of hydrogen fluoride.. and distilled (b. The yields computed on the basis of the benzotrichloride are from 60 to 65%.2-Trichloro-3. are placed in a metal container fitted with a 30-cm. the contents of the receiver and the reaction flask are united and gently warmed to drive off most of the hydrogen fluoride. the water is drained from the condenser. 103°). If the difluoride is wanted instead of the trifluoride the distillation is adjusted at 130°. distilling at 87. 575. At first. in the molecular proportion of 1. Industrial Procedure. If the monofluoride is desired.9°. washed with dilute carbonate. . an outlet tube. and the purity of the product.593 [Chem. The crude distillate is mostly the desired product. The reaction mixture is brought rapidly to 130-140°. 609 (1933)]. The temperature of the bath is adjusted to maintain a steady distillation at about 90° at the top of the dephlegmator. Otherwise an appreciable amount of organic material remains and is difficult to remove from the antimony trichloride.** Into 500 parts of benzotrichloride cooled to 0° in a copper flask equipped with a stirrer. After completion of the reaction. dried. b. Zentr.3. Benzotrifluoride distils at 103° and collects in the bottom of the water bottle. At the end of the operation. the distillation is made as rapid as possible.3-trifluoro-l-propene (CC12==€C1CF3).l. the speed of the reaction. and there are no side reactions. The yield of acetyl fluoride. II. benzotrifluoride is subjected to s"team distillation. and an inlet tube reaching to the bottom.which temperature the reaction starts in a lively fashion. at . later. Considerable decomposition of the benzotrichloride occurs. is introduced 200 parts of hydrogen fluoride over a period of seventy-two hours. so that some unchanged antimony trichloride will distil over.*'-* Benzotrichloride and antimony trifluoride.7 In a dry flask equipped with an efficient dephlegmator an equimolecular mixture of hexachloropropene and antimony trifluoride is heated in an oil bath.p.p. prolonged heating is distinctly detrimental. but this is compensated by its low #cost. a mixture of hydrogen fluoride and benzotrifluoride distils and is condensed in a metal receiver cooled with ice and salt. The remainder is eliminated by agitation with powdered M Ger. l. The fluorine utilization is complete.. pat.
2.3-Pentachloro-3. PROCEDURES 63 sodium fluoride. The subsequent operations are identical with those of the preceding procedure. This operation. flask a mixture of 1970 g. The liquid reaction . of 1. During this treatment.3-Hexachlor6-3-fluoropropane (CHCI2CCI2CCI2F). The reaction starts promptly and is regulated by means of an ice bath intermittently applied. and the heating is continued at 140° <for another six hours.p.l.2. is added. 168°).2. washed with hydrochloric acid—to remove antimony salts—then with water.l.2. l. 30 g.1.3.2tetrachloro-3.2.2.3-difluoropropane (b.3. the lower layer containing most of the antimony trifluoride gradually liquefies and dissolves in the upper layer of organic material.2.propane molecule. of SBF3CI2 is heated to 140-150° and held at this temperature for eight hours. It is then cooled. and. the product is distilled. of 1. 35. 300 parts of benzotrifluoride. l.30 In a 3-1. it is slowly heated to 130-140° and maintained at this temperature for five hours. yield.p. of antimony trifluorodichloride is vigorously stirred so that the temperature does not exceed 50°. cooled to 0°.3.p.p. of octachloropropane. The crude product (weight 1740 g.C2Cl6. 210°). and 1.25 moles of antimony trifluoride containing 5% of bromine by weight. of antimony trifluoride.2°). l.5 moles of 2. After the mixture has cooled to 30°.3-difluoropropane (CHC12CC12CC1F2). of reaction product containing approximately 60 g. 130°). The yield is 907 g.80 In a round-bottomed flask equipped with an air-cooled reflux condenser a mixture of 960 g. The vapors passing through the condenser are caught in a water gasometer or in a receiver cooled with solid carbon dioxide.3. At the end of the operation the vessel is heated to about 70°.2. flask.3-trifluoropropane (b. The following day. of antimony pentachloride is heated for eight hours at 140°.2-Difluoropropane (CH3CF2CH3).2.p.3-heptachloropropane and 1245 g. of 1.2-dichloropropane.30 In a 1-1. The more abundant by-products are CCl2=CCl2.3. 103°. of 1.2.) contains approximately 400 g.19 In a reaction vessel equipped with an ice-cooled reflux condenser is placed 1.3.1.l.3-heptachloropropane and 740 g.1. -0. and 40 g. The vessel is cooled in ice. of 1. quickly performed. of difluoride. resulting from the cleavage of the .2. of SbF3Cl2 is added. CCI3CCI2F. and>dried. After filtration. yields about 85% of 2. 180 g.3-Heptachloro-3-fiuoropropane (CCI3CCI2CCI2F).3.5°) and 10 to 15% of 2-fluoro-2-chloropropane (b.EXPERIMENTAL.1. b. a mixture of 1160 g. poured into water. the remainder of the material consists of ethylenic derivatives and of fluorine derivatives of ethane.2.3-pentachloro-3. CC12FCC12F.l.2-difluoropropane (b.3.1. of trifluoride and 1000 g.2. 315 g.p. 2.3-hexachloro-3-fluoropropane (b. and 435 g.2. The distillation tailings contain chlorofluorides which can be reworked in a subsequent operation.2.
After the temperature of 140° is reached.3°. solidifies at room temperature. 152..2. The boiling . which gradually becomes homogeneous.1 mole of antimony pentachloride. The reaction is regulated by intermittent cooling and heating in order not to overtax the reflux condenser. of antimony pentachloride is added. A further portion of 80 g. The mixture is then cooled. 560 g. the washing. and distillation are performed as in the preceding cases. of antimony pentachloride is heated on a steam bath for twelve hours.p.3-HexacMoro-l. and heating on the steam bath is continued for two hours. decanted from the crystalline antimony salts into a flask equipped with a water-cooled reflux condenser.8°. of antimony. 500 g.5 ° ) . a mixture of 2 moles of carbon tetrachloride and 1 mole of antimony trifluoride is cooled to 0°.2. It is advisable to have ice water ready to chill the mixture if it threatens to escape control.l.2. and contains about 300 g. m. 25°) and CCl2F2(b. of antimony pentachloride is heated for five hours on a steam bath. of octachloropropane.p. 97°) and unchanged octachloropropane. of SbF3Cl2..l. after cooling. it is separated into about equal parts of the monofluoride (b. . The reaction mixture. the mixture is allowed to warm until the reaction starts.Bo In a flask connected to an ice-cooled reflux condenser. The crude product amounts to 700 g. Then. amounting to 910 g. and to the liquid layer. then is washed and dried. l. A further quantity of 100 g. of antimony trifluoride. is allowed to cool before it is poured into aqueous acid. of octachloropropane. drying.3-trifluoropropane (CCI2FCCI2CCIF2). of difluoride is obtained by fractional distillation at 90 mm.2.p.3.p. Dichlorodifluoromethane and Trichlorofiuoromethane. By fractional distillation at 90 mm. The reaction mixture is then heated slowly to 140°. and the heating is continued for twenty hours. the heating is continued for two hours.3. is 194°. At the . The crude product amounts to 1092 g.3-difluoropropane (CCUFCC^CCUF).64 - ALIPHATIC FLUORINE COMPOUNDS mixture is poured into commercial hydrochloric acid while still hot 'and is washed free of antimony salt. » l. The distillate is a mixture of CCl3F(b. from which about 750 g. 237°.80 In a round-bottomed flask equipped with an air-cooled reflux condenser a mixture of 1220 g. of the trifluoride (b.80 In a round-bottomed flask equipped with an air-cooled reflux condenser a mixture of 1500 g. point at 760 mm. and the freezing point is 29. of antimony pentachloride is then added in small portions. and 75 g.. because the reaction is quite active at the start. The Uncondensed vapors are led to a receiver cooled with Bolid carbon dioxide. The crude product. is added 400 g. trifluoride.p.p. —30°) whose composition depends on the efficiency of the dephlegmation but is usually 50-50 in a laboratory operation. After addition of 0. f.3-PentacMoro-2. and 75 g.
The residual SbF2Cl3 is utilized to convert hexachloroethane to trichlorotrifluoroethane which 'is then available for the next operation.2.2-dibromoethane and l-Fluoro-l. this causes the mercuric bromide to crystallize out . and rectified. it yields 0. 3.p.6°) are condensed in Dry Ice. which is an excess of 15% over the theoretical quantity required. The material left in the distilling flask is cooled overnight.l-Difluoro-2. The utilization of the antimony fluoride is complete. 174°). Fig. and the pressure falls. a small amount of trichlorofluoromethane can be distilled from the excess carbon tetrachloride.4 gram molecule of CHFBrCHBr2 (b. The transformation of the trifluoride into the tetrafluoride is quantitative. and the mixture is heated gradually to 140°. based on the mercuric oxide. The valve is closed until more tetrafluoride is formed. — l.p. Steam distillation of the product takes place promptly and carries along some acetylene tetrabromide. then to 1^0°. dried.2-tribromoethane. When this is complete the reaction vessel is evacuated.2-tetrafruoroethane (CC1F2CC1F2). the mixture is poured onto cracked ice and washed roughly by decantation to remove the excess a'cid.p. 61. The needle valve is opened in such way as to permit the passage of CC1F2CC1F2 vapors. yellow. When the tetra r fluoride vapors are withdrawn. 1.6° A known quantity of SbF3Cl2 is prepared as described on p. which is an 80% yield.EXPERIMENTAL PROCEDURES 65 end of the operation.l. The needle valve is closed. and an equimolecular quantity of CC1F2CC12F is drawn in. 1 gram molecule of red mercuric oxide is added and the mixture immediately stirred to prevent the formation of a heavy paste or cake. 47°) starts to distil. These vapors (b.p. grayish white. and finally gleaming white at the end of the reaction.2-Dichloro-l. The pressure rises. The flow of gas is regulated so that the temperature of the reaction mixture does not exceed 40° to 50°.2. the temperature rises. 107°) and 0. l. The distillate is decanted from the water. At this point it is found that about 2. An aqueous layer of concen'trated hydroflaoric acid floats on the surface. Dry hydrogen fluoride from a commercial cylinder is led into the liquid through a metal tube (flexible copper tubing is convenient). At the end of the reaction. preferably in ice. The temperature and pressure readings at the top of the equipment are referred to the vapor-tension diagram. the trifluoride (b. The white salt is pure mercuric bromide.3 gram molecules of hydrogen fluoride has been used.5"1 a To 3 gram molecules of acetylene tetrabromide in a tall metal container (preferably nickel) cooled externally with water. It is then placed in a distilling flask with twice its volume of water and heated with a free flame kept in constant motion to prevent foaming. The red color of the mercuric oxide fades progressively to pink.6 gram molecule of CHF2CHBr2 (b.
Zentr. and most of the following observations are based upon the author's experience. and addition of the alkyne to liquefied hydrogen fluoride. At higher temperatures.and di-fluoro derivatives. . and C4H9CF2CH3. The claim46 that mercuric ion is needed as a catalyst is apparently unfounded. The filtrate separates into a layer of acetylene tetrabromide and a layer of water. By distillation of the chloroform it is possible to recover the acetylene tetrabromide. At 0°. although details of the preparations were not given. The methods would be costly if the mercury could not be recovered and reworked. and the remainder is filtered with suction and air-dried on the filter.18 The literature offers practically no details to cover the mode of operation. Pure mercuric bromide is left on the filter. then suddenly to react with explosive violence.977 [Chem. 1. at —20°. as illustrated by the synthesis of CH3CF2CH3. By a procedure analogous to that just described. 1310 (1936)].2. covered with chloroform. C3H7CF2CH3. The solid material is removed from the filter.. pat. there is a tendency for the reagents to accumulate. They have been correctly reported 18 to yield pure 2. vigorously shaken for twenty minutes.1-difluoroethane.41 Addition of Hydrogen Fluoride to Unsaturated Compounds ADDITION TO A TEIPLE BOND Hydrogen fluoride reacts readily with alkynes. C2H5CF2CH3.2-difluoroethane. I. Acetylene and hydrogen fluoride react at room temperature to give vinyl fluoride and 1. At higher temperatures the yield was only 30%. The reaction temperature had to be lower for good results. of acetylene tetrabromide. The aqueous layer is separated as completely as practicable. The reactions are very violent and uneven. At low temperatures. continuous gentle agitation. Mercury Recovery.2-tribromoethane was converted to the mono. 621. It is claimed * * that aqueous as well as anhydrous hydrogen fluoride can bring about the reaction. The filtrate is a chloroform solution containing from 75 to 100 cc.2-difluorides exclusively. the yield of mixed products was 50%. The author's investigations lead to the recommendation of a reaction temperature 'of about — 20°.2-Dibromofiuoroethane and l-Bromo-2. Homologs of acetylene are more convenient to handle. and then filtered by suction. placed in a bottle. 45 Ger.. Details of a simple procedure for recovering the mercury by converting the mercuric bromide to the oxide and heating the oxide have been published. The boiling points are 121° and 57°.66 ALIPHATIC FLUORINE COMPOUNDS completely and facilitates filtration. much resinification takes place. 1.. 60-65%. respectively.
Phva. Ethylene yields ethyl fluoride.46-48 The operation consists in passing hydrogen fluoride through a solution of the fatty acid in methylene chloride. J. When hydrogen fluoride adds to an olefin. 275 (1940). Waeker.10-difluorostearic acid is cited in the patent literature. and it has not been established whether a single product or a mixture is formed.9.. The operation consists in feeding the olefin into liquefied hydrogen fluoride. Chem.. cyclohexene gives cyclohexyl fluoride. CH3CHF(CH2)8CO2H. The difficulties increase if the product is a secondary and especially a tertiary fluoride. The higher temperature favors the formation of primary fluorides but has an opposite effect on tertiary fluorides. with stirring or shaking. chloroform. Cyclopropane yields n-propyl fluoride when the reaction is conducted very slowly at 0°.' ADDITION TO A DOUBLE BOND 67 Reversing the order of addition. then to allow gradual heating over a period of one to two hours to 75° or 90°. yields 10-fluoroundecan-1-oic acid. under pressure if needed. Hydrogen fluoride adds " Groese and Lind. The reaction is reversible and is often accompanied by polymerization of the olefin. but if the temperature is not well regulated an isomerization takes place to yield isopropyl fluoride. Undecylenic acid. The reactions are all non-catalytic and take place in paraffin or metal containers equally well.60 The addition of hydrogen fluoride to stearolic acid in methylene chloride solution to give 9.46-47 but very few experimental details have been published. 799. which is favored by excess hydrogen fluoride.432 (1936) [C. 26 (1338). ADDITION TO A DOUBLE BOND Hydrogen fluoride reacts with olefins to yield monofluoroalkanes. Chem. Org. The yields are from 60 to 80%. 3. or using an ether as a solvent.. as either 9. Dleic acid yields a fluorostearic acid of unknown structure. Yields of about 80% are obtained and probably can be improved by devices to minimize the mechanical losses. . uncontrollable speed-up. at room temperature.10-difluorostearic acid or a mixture is much more likely to be the reaction product.or 10. causes a marked retardation of the reaction. or carbon tetrachloride. and Lind. 7585 (1936)]. pat. A successful method is to prepare the mixture at—40° to —60° in a metal container. Concentrated aqueous hydrofluoric acid does not react with olefins.. the fluorine becomes attached to the carbon with the least hydrogen. 48 Fr. with subsequent sudden. 30. J. propylene yields isopropyl fluoride. A.46 This claim should be verified.46 Hydrogen fluoride adds easily to unsaturated fatty acids. 44. C10H19CO2H. Increased time of reaction always favors side reactions. "Grosse.
The hydrofluorination of CH3CH=CHC1 (or of CH 3 CH=CHBr) fails to give the expected addition product but yields •an appreciable amount of C3H6C12 (or C3H6Br2. apparently the 1. the reaction proceeds to completion.60 The operation consists merely in mixing the reagents at low temperature in a steel container. Isocrotylchloride. and the temperature is kept at 90° throughout the addition. After 85 g. washing. 73.1trihalopropane results exclusively. A similar reaction is observed when 2-chloro-2butene is treated with hydrogen fluoride. CHC1=CC12. 177 (1940). Henne and Haeckl. sealing. The autoclave is equipped with a stirrer which is operated during the addition. Soe. It adds to ketene to form acetyl fluoride. FCONH2. and to cyanic acid in ether solution cooled to — 78° to form carbamyl fluoride. It must therefore be (CH3)2CFCH2C1. In all cases. Preliminary studies have indicated that CH3CC1=CH2 gives mostly CH3CF2CH3. A conversion of about 50% is observed. Addition also takes place with allyl chloride. together with some CH3CC12CH3. CH2=C(CH3)CH2C1. . 4. (CH3)2C=CHC1. but the position of the fluorine atom has not yet been ascertained. Chem. Ber.46 Ethylene from a storage tank is forced intermittently into an Allegheny metal autoclave which contains 200 g. cooling.6° No addition has been observed in the case of CHC1=CHC1.2-dihalopropane in both cases) and a large amount of polymeric material.68 ALIPHATIC FLUORINE COMPOUNDS to oleyl alcohol to give a fluorostearyl alcohol of unknown structure.1. of hydrogen fluoride. letting stand overnight at room temperature..6" A mixture of CH2=CC1CH2C1 and hydrogen fluoride forms CH3CC1FCH2C1. The primary reaction product is the expected CH3CH2CC1FCH3. and the secondary product is CH3CH2CF2CH3. and methallyl chloride. 2692 (1941).he latter is formed by loss of hydrogen chloride from the primary product and subsequent addition of hydrogen fluoride. 63. and if excess hydrogen fluoride is present CH3CF2CH2CI appears as a by-product (about 25%). Am. a 1. J. and the balance of the chloroolefin is recovered. more readily to CH3CH=«CC12. yield the same addition product. pouring onto cracked ice. If the operation is altered by keeping the container overnight at 40°.49 Unpublished observations indicate that hydrogen fluoride adds with difficulty to CH 3 CH=CBr 2 . or CCl2=CCl2.. and rapidly and quantitatively to CH3CH=CC1F and CH 3 CH=CF 2 . stirring 49 M Linhard and Betz.6" EXPERIMENTAL PROCEDTTRES Ethyl Fluoride. "of ethylene has been introduced. and distilling.
400 g.DIRECT FLUORINATION AND ADDITION OF FLUORINE 69 is continued for another hour. "Le fluor et ses composes. (64%) of 2. The method has possibilities which still await technical improvements. b.p. Cyclohexyl Fluoride. and only recently has it been improved to the point where it is not dangerous when the proper precautions are taken. stirred. has the reaction been sufficiently well controlled to offer a practical method of preparation of organic fluorides. Isopropyl Fluoride. The procedure has always been performed on a very small scale. and the vapors are passed through water and then condensed in a receiver cooled with solid carbon dioxide. Lower reaction temperatures retard the addition. Paris. b. dried.p. 2. however. is passed through a soda-lime tube. to replace another halogen.2-difluoroethane. . When the reaction is carried out in a solvent which is immune to fluorine or reacts only slowly with it. at 10° it is only 54%. the reaction mixture is allowed to warm. of precooled cyclohexene is added dropwise over a period of seventy-five minutes. The crude ethyl fluoride. and distilled under 300 mm. CH3CF2CH3. Most organic compounds burn or explode when brought in contact with fluorine.3°) is introduced into 4 moles of liquefied hydrogen fluoride in a metal container held at —23° by means of a carbon tetrachloride bath to which enough solid carbon dioxide has been added to keep it mushy.46 The procedure is the same as for ethyl fluoride except that the temperature is kept at 0°.46 In a copper container fitted with inlet. The reaction occurs at once. pressure (b. or to add to a double bond.' obtained in 81% yield.p. outlet. In very few cases. 0°. decanted. After cooling to —35°. After completion of the addition.4°). whereas higher temperatures favor polymerization.1°. several reaction products have been obtained. 1900. isopropyl fluoride boils at -10. and stirrer is placed 200 g. The yield is 61%.p.08. Direct Fluorination and Addition of Fluorine The direct action of fluorine.61 has been used to replace hydrogen. The distillation of the condensate yields 54 g. In all cases." G. The reaction mixture is poured into a copper beaker filled with cracked ice. --37. —23. 71-71. of anhydrous hydrogen fluoride. care must be taken not 61 Moissan. The yield is 60%. first reported by Moissan.2-Difluoropropane (CH3CF2CH3). then the mass is cooled with solid carbon dioxide and allowed to distil through water.60 The vapor of 1 mole of propyne (b. Steinheil. and the ratio of hydrogen fluoride to propylene is held to 1.7°. then rectified. Care is exercised to prevent the escape of any vapors.
Many accidents have occurred when mixtures of fluorine and an inert gas (usually nitrogen) were passed through a solution of an organic compound. 788 (1941). Am. 20 (1933). 56. Am. 2773 (1934). 62.. Am. and Miller. lead tetrafluoride or iodobenzenedifluoride. 3302 (1940). / .62 The interaction of fluorine with an organic compound liberates a quantity of energy which is frequently of the order of magnitude of. Am. In a few isolated instances it has been possible to. it is preferable to allow the reaction to take place at the surface of the liquid and in the vapor phase. " D i m r o t h and Bockemuller. Soc. Soc. 60. Chem. 63. M Calfee. Even in the most favorable cases. 55. 2792 (1941).. «• Hadley and Bigelow. " F u k u h a r a and Bigelow. where a smooth reaction takes place. Ber.. 427 (1933).66'66> 67 The products obtained by the action of fluorine on a number of organic compounds are listed in Table III. and Bigelow. Chem. Chem. / .. 1171 (1940). 57 Calfee and Bigelow. 516 (1931).013. "Bigelow and Pearson. namely. 928 (1934). 4614 (1933). Soe. It is estimated M that the addition of fluorine to a double bond liberates 1(2! calories per mole. Soc. •• Fukuhara and Bigelow. 198 (1937). / . Chem.63"66 The most satisfactory procedure for carrying out the reaction between fluorine and a gaseous compound consists in diluting both reagents with an inert gas. Chem. J. Chem. Careful control qf the temperature throughout the reacting masses is therefore essential. / . 89. and in bringing them together at the surface of a copper gauze. while the diluent passed through the solution unabsorbed. respectively.63' B6~M When fluorine is to react with a liquid compound. 63. S.. and Bigelow. 341 (1940). from lead tetraacetate or iodosobenzene and hydrogen •* Calcott and Benning. Soc. Am. preferably nitrogen. 62. Calfee. / . whereas chlorine liberates only 30 calories. Fukuhara. Chem. Am. 2.. Chem. 62. Pearson. M Bigelow. Am. 62. treat an unsaturated compound with a derivative capable of giving off free fluorine. or greater than. x . J.. Soc. Sac. / . Cook. 2072 (1937). lukuhara. V. 3552 (1939). A. For this mode of operation. Am. Am. Soc. and Bigelow. J... Am. Ann. 59.Am. J. 61. •» Miller. 6900 (1935)]. Chem. Soe.. Chem.030 (1935) [C.. Soc. Chem. "Young. in carbon tetrachloride or difluorodichloromethane. Young. 64. ra Fukuhara and Bigelow. J. 67. Soc. 267 (1940).. 59. 506. Ber. M Miller. Chem.. J. much decomposition occurs and carbon tetrafluoride is frequently the main reaction product. pat. the best solvents are the fluorinated refrigerants available commerciauy (CCI2F2 and C2F4CI2) or liquefied hydrogen fluoride. the energy which binds the carbon atoms in chains. Fukuhara. 60 Calfee. " Fredenhagen and Cadenbach. •« BookemuUer..70 t ALIPHATIC FLUORINE COMPOUNDS to allow the fluorine to accumulate in the solvent. and Bigelow... These accidents were caused by the fact that fluorine dissolved. which are formed. Am. Soc.
CHF 2 CH 2 C1 CF 3 COCFs. CF4 is t h e major product. Z. 69 70 . Compt. 69. CHC12CFC12. CH 2 FCOCH 3 .C1« n-CieH34 CHsCH=CHCO 2 H 55. 69. C2F«. Higher members of t h e series are also produced. CH 2 FCH 2 F. C4H2C16.. allgem. C H a 2 C F C l 2 . anorg. Soc. 71 Simons and Block. 276 (1890). CF2C12. 1407 (1937). Ruff a n d K e i m . CzF4. ' CHF 2 CF S CF 4) CF 8 C1. 61. CHC12CC18 CFC12CFC12. 69. CFC12CFC12.DIRECT FLUORINATION AND ADDITION OF FLUORINE TABLE III PRODUCTS OBTAINED BY DIRECT ADDITION AND SUBSTITUTION OF FLUORINE 71 Starting Material C CH4 C8H6 Products Note Reference CF 4 . Ccrmpt. 56. Am.2 1 68. 70. C4H2C18 C6C16F6 CH 2 FCHF(CH 2 )i 3 CH 3 CH 3 CHFCHFCO 2 H 1. Lebeau and Damiens. C 2 F 6 .2 60 63 CHCI3 C2HCI5 CHC12CHC12 CCl2=CCl 2 CHCl=CC! a 67 67 67 67 67 C. / . 59.. FOCCOF. 58 66 3 66 1. CHFC1CC13. CH 3 COF. CsF 8 CF 4 . CF 3 CF 2 C1. C 4 F 2 C1 8 CHFC1CFC12. 168. 71 57. 110. C4C11O CHC1==CC12. 2 4 9 (1930). C 3 F 8 CF 4 . 1340 (1926). 68 Moissan. C 2 F 6 . C2C16. rend. CH 2 FCHF 2 .. Chew. CHF 2 CHF 2 . rend. C2C1« CFC12CFC12> C2C14.. 3. CFC1=CC1 S .. C 2 HFC1 4 . 61 dH&Cl CH8COCH8 1. 192. COF 2) CF 4 CC13F. T h e product is a mixture of two diastereoisomeric pairs.2 1. C 2 F 4 . 2. Chem. 70. CFC12CC13. 2964 (1939). 71 68.
1585 (1936). A variety of fluorine generators ha*ve been proposed. 60.. Am. 58. Am. 52. aluminum. Soc. 5 3 . 96 (1938) . / Am.. 5cm FlO. Am.78 They have been made of magnesium. Chem. 2175 (1924). 134 (1940). Soc. J. J. Monel metal. 2. 79 Henne. Chem. 4302 (1930).. Syntheses. 8 7 9 (1934). 76 Dennis.10-difluoroanthracene. For laboratory purposes copper is both convenient and inexpensive. Soc. Soc. I.1-Diphenylethylene yields a difluoride. 78 Simons.. Am. 522 (1931). 74 Schumb and Gamble. They all have about the same efficiency and differ only in details of construction. Inorg. fluoride.79 71 71 BockemUUer. Chem. Direct fluorination requires equipment seldom available in the laboratory but easily constructed.72 ALIPHATIC FLUORINE COMPOUNDS fluoride. 71 D e n n i s a n d Rochow.73"77 all involving the electrolysis of an acid salt of potassium . 64.63. and stainless steel. Am. Veeder. Chem. Soc . Ber. J. J. Chem. 3263 (1931). 66. 46. Soc. A laboratory generator which has been found satisfactory over a long period of operation has been described. 77 Miller a n d Bigelow. anthracene gives rise to a mixture of 9-fluoroanthracene and 9. Chem. Simons.n 1. J.. a n d Rochow. It is claimed 72 that small amounts of hydrogen fluoride or silicon tetrafluoride are needed to cause the reaction of aryl iodofluorides and olefins.
the equilibrium mixture usually contains less than 40% of alkyl fluoride.67 The apparatus shown in Fig. 88-100°. in case of a too sudden reaction. In use. of CHC12CC12F.8 g. 130-140° (solid). of CC13CC13. 297 g. The stirrer then acts as a pump to force a rapid countercurrent flow of liquid along the horizontal section which divides the lower part of the vessel. chim. (4) 11. and. 148-156°. rend. is subjected for ten hours to the action of fluorine..5 g. Compt. and temperature control is obtained by surrounding the reaction vessel with a suitable bath.6 g. (5) 12. (6) 91. 100-130°. It is also impracticable to remove the water. 2 is constructed from brass tubing with silver soldered joints. 15. Replacement of the Hydroxyl Group of Alcohols The interaction of an alcohol and hydrogen fluoride gives an alkyl fluoride. From 350 g.. 156-159°.67 Pentachloroethane. [7] 1. but higher than hydrogen fluoride. heated to 90° in the apparatus described in the preceding paragraph.6 g..9 g.5 g. of CHC12CC13. 346 (1894). Preliminary distillation yields the following fractions: (1) 7. It is impracticable to remove the organic fluoride from the equilibrium mixture (except for the first few homologs). When the acid and the alcohol are -merely heated together. The fact that water is formed necessitates platinum equipment. 93.. Fluorine is passed in through a roll of copper gauze. functions as a safety valve.66-66 of which the following one is simple and efficient.. of CC12=CC12. . By repeated fractionation the following products are isolated: 5 g.. EXPERIMENTAL PROCEDURE Fluorination of Pentachloroethane. oily semi-solid residue. Ann. One arm of the U-shaped vessel is closed by a rubber stopper which supports the fluorine inlet tube. because the agents capable of fixing the water promote the decomposition of the fluoride into a mixture of olefin and hydrogen fluoride.. (2) 28.2 g. 83.EEPLACEMENT OF THE HYDROXYL GROUP OF ALCOHOLS 73 Various mechanical means of providing a constantly renewed surface have been proposed.. 1080 (1892). as indicated in the drawing.1 g. the vessel is filled up to the horizontal division. 28. of material. of CC12FCC12F. of reaction product (partly crystallized at 0°) is obtained. 140-148°.4 g.80 but the reaction is reversible. (7) 45.. (3) 57.6 g. 115.4 g. The rubber stopper is protected on the inside by a covering of thin copper foil. the organic fluorides boil at lower temperatures than the alcohols. 2 g. Other metals ate always sufficiently corroded to produce salts which catalyze the decomposition of the alkyl fluorides. of C4C11O. Glass equip80 Meslans.
319. Zentr. 102 (1933). . Chem. acad. Since it is now possible to add hydrogen fluoride efficiently to olefins.87 an example of an unusually efficient Kolbe reaction..63 When replacement of halogen or addition of hydrogen fluoride is attempted.6" Anhydrides. Belg. 13 (1903). roy. enough water is usually formed to stop the reaction or alter its course. 4 3 .. soc. the conversion of alcohols to alkyl fluorides is of interest only in a few special cases. II... Bull. it is difficult to introduce fluorine into a molecule containing oxygen. Bvtt. 721. Only recently has acetone been transformed into monofluoro. 87 Swarts..88 This reaction. 4 2 . BuU. roy. The methods claimed in the patent literature for the synthesis of alkyl fluorides from alcohols have many disadvantages. 88 Swarts. Zentr. acad. M Swarts. Trifluoroethanol has been obtained by catalytic reduction of trifluoroacetic anhydride on platinum black. 4 7 1 (1934). 88 Swarts. chim.and hexafluoroacetone in experiments explicitly described. H.84 The synthesis of trifluoroacetic acid * has been performed by oxidation of benzotrifluoride or its metaamino derivative in chromic anhydride-sulfuric acid mixture. It has been observed that the reduction of a fluoro acid yields the alcohol directly. BuU. I. Belg. roy. 339. 1898.88 Alcohols. It has been obtained also in a 90% yield by oxidation of CF3CC1=CC12 with alkaline permanganate.23 CC1F2CO2H. Swarts. chim. Partly fluorinated acetic acids have been synthesized by interchange of halogens between halogenated acetic acids and mercurous fluoride. Acids. roy. acad. 84 Swarts. Aldehydes. Trifluoroacetoacetic acid 86 and its esters have been obtained from trifluoroacetic esters by ester condensations. acad. 1926. Belg. but usually has yielded indefinite fluorine-containing derivatives in which the location of the fluorine was not ascertained. 8. 581 (1907). Belg. Belg. 689. Belg. esters. I.74 ALIPHATIC FLUORINE COMPOUNDS ment cannot be employed. and also that the oxidation of a fluoro alcohol does not stop short of the acid. which 81 8i M Swarts. Chem. Examples are CClaFCOzH. soc.M CBr 2 Fd0 2 H ) 83 and CBrF2CO2H. The electrolysis of sodium trifluoroacetate yields hexafluoroethane. Swarts. Synthesis of Fluorides Other than Hydrocarbon Derivatives In general. Fluorinated aldehydes are unknown.81 CHFICO2H. Chem.1237 (1906).. BuU. Direct "fluorination of oxygen compounds has been tried repeatedly.. and amides have been obtained from the acids by the usual procedures... 710 (1903). 1907. BuU. Zentr. 343 (1922). with a yield of about 50%.
. roy. (CHF 2 CH 2 ) 2 NH. 1904.92 Ethers.1. unfortunately. Chem. 1929. 563. acad. 1927. such as the formation of CF3OCH3 from the trichloro derivative. Bull. Belg. has never been successfully duplicated despite the attempts with a variety of catalysts and conditions. a mixture of the primary amine.96 Amines.. acad.. 179.AMINES 75 was performed by Swarts. Bull. chim. 1927. 132. Fluoro ethers have been obtained either by replacement. 1927.1-trifluoroacetone. 96 Ray. They have also been obtained by halogen interchange. 1902 (731). . Examples are CHBrFCF 2 OCH 3 from CHBrFCF 2 Br. roy. 2070 (1936). 108. is obtained. secondary amine.86 Fluoroethanol12 has been made by saponification of its acetate. 96 Swarte. The synthesis of fluorinated ethyl amines has been accomplished 96 by heating CHF 2 CH 2 I to 130° in a sealed tube with concentrated aqueous ammonia.90 which had been obtained from trifluoroacetoacetic ester.. roy. Belg. sei. Bull. Am. 94 Swarts. upon a polyhalide. Bull. acad. Nature. Swarts. 762. with consequent formation of an olefin. soc. The reaction of two molecules of methylmagnesium bromide with an ester of trifluoroacetic acid has been used for the synthesis of tertiary trifluorobutyl alcohol. was not described. 57. Belg. 749 (1933).94 v It is to be noted that the use of alcohols with longer chains minimizes the importance of the ether formation and favors the elimination of one molecule of halogen acid. 1911. 175. Belg. Fluoro ketones have been obtained from fluoro acetoacetates and sulfuric acid. Bull.86 Examples are CF3COCH3 and CHF2COCH3. chim. such as CH 2 FCOCH 3 from CH 2 ICOCH 3 and thallium fluoride.. CF3(CH3)2COH. acad. soc.. Belg. (CHF 2 CH 2 ) 3 N. Belg. J. Swarts. Difluoroethanol M has been obtained from CHF 2 CH 2 I and mercuric oxide in water at -140° in sealed tubes. roy. 90 91 » Swarts. Bull. and tertiary amine. Ketones.93 or by the action of alcoholic potassium hydroxide. which was obtained from the acetate of bromoethanol and silver or mercury fluoride. CHF 2 CH 2 NH 2 . It must be concluded that Swarts used a particularly suitable catalyst which. 98 Booth and Burohfield. 92 Swarts. 195. Soc. M and CH 2 FCF 2 OCH 3 from CH 2 FCF 2 Br and methanolic potassium hydroxide. Trifluoroisopropyl alcohol89 has been obtained by the reduction of 1.
280° and 25 mm.5°. 65°.8 3 ° 1 M.p.24 ICN + AgF at 220° (25%) 99 CBr4 + AgF at 140-150° 98 CCU + SbF 2 + SbCI6 24.099 B. -40. CH4 + F 2 CHClBr2 + SbF 3 + Br2 at 60° 23 CHBr 3 + SbF s + Br 2 at 110-120° 106 CHOs + SbF 3 + Br2 23. d181.195.406 24. 71.6°.p.7 2 ° M.p.4216 M.. CdaFs in arc. b.8° Graphite + Fa. below . 70. 50-60° CCI4 + SbF 8 + SbClg " 23. -114°. + 51.p.p.100 F 2 + COC12 over CaF 2 at 2000°. CHsCHgOH + 103 •t2 CC14 + F 2 + As(54%). b. -160°.8°.p.4256 B. 103 C + F 2 (55%). <?°1. C2H6C1 + F 2 .3866 Sublimes at . 89°.8° M.102. tf*\. CHC1.\m.9058 B. 107° B.p. -29. 105 F 2 .p.p. CF 4 + CO 101.p.p. <Fl. b.p. »181.4944. 110-120°. .p.5°.26 CHI 3 + HgF + CaFa 107 HCO 2 H + CeHsCOQ + " K F (16%) 5 CHBr 3 + SbF» + Bra at 110-120° CHC13 + SbF 3 + SbCl6 40. -128° B. CC14 + F 2 (74%). b. d°1.p.p.TABLE IV ALIPHATIC FLUCHUKE COMPOUNDS • Formula Structure Physical Properties Preparation (yield. b. 23. -14. d161. 81.1° M. CBr4 98 + AgF. -181°. b.p.p.8 0 ° . -81. CH3COCH3 + F 2 . (*°1.p. 100° B. CClaFa + F 2 (best yield) 102.26 . 25.p. 60. -183. 245° M.p. 101. 38°. -146°.55 M. 24. in arc. . 97 CBr 4 + SbF 3 + Br2) 4 hr. b.2 6 ° .p. 104. d202. -34. remarks) Reference t (CF)* CFBr 3 CFCI3 CFN CF2Br2 CF2C12 CF2O * CF3CI CF 4 CHFBrCl CHFBr 2 CHFC12 CHFI 2 CHFO ' CHF 2 Br CHF2C1 HCOF Explosive crystals B.
-78.p. 21. 147. .p.p.p. 107 106 26. 63. CHI 3 + HgF + CaF 2 CHBr 2 F + Zn + C2H5OH -> C H ^ B r + CH3F CH3F + Cl2. CH3SO4K + KF at 160-200° CH»SO2C1 + ZnF2 CH3OH + HFSOg CBr 2 aCOCl + SbF 3 + Br2 at 100° CCl!i=CaF + Br2 CHFBrCBrg + KOH CBr2==gBrF + Br2 CCl3CCl2F + Zn (CC18CO)»O + SbF.ffi59. n^l. 42. 72.9° M.p. 70. n201.4360 B. 137.p.5541.6° M.366. 75° M.4°.p.54821 M.107 40.p. -122°. n ^ l ^ l M.p. b. + Br2 at 90-100°. 124.9°. . n201.^m B.9 . 51° B. 114° M.2° CH3SO2F FSO3CH3 CClBr2COF CCl2BrCClFBr CFBr=CBr 2 CC1F=CC12 CFa 2 COCl CFClBrCOF CF2=CBr 2 CFBr=CFBr CClFBrCClFBr OCl2BrCF2Br B. 110 111 112 113 27 114 114 27 23 27 113 94 115 116 116 + IF6 CHF2Br + HgF 2 . . -141.p.p.p. -51.p. 46. 92°. 139. CHgCl2 + SbF s + SbClB CH 2 I 2 + HgF at 120° Cyanic acid + HF in ether (very violent) CH2C22 + SbF 3 + SbClj.9 CHI S + HgF + CaF 2 at 80-150°. CHI3 101.p. dPl. b.3°.p.194V. CFCISCO2H + PCI5 (violent) C2C16 + SBFS + Cl2 CClBrjCOCl + SbF 3 + Br2 at 100° CHBrjCFaOC^s + CH3CO2K + K2CO3 CHBrFCBr 2 F + NaOCaHs C C l F = C a F + Br2 CF2=CC12 + Brj! H-jNCOF CH3F CH3FO2S CHJFOJS C2FBr 2 ClO C2FBr 2 Cl 3 CiFBr3 C 2 FBr 5 C 2 FClg CaFCljjO C2FC16 C2F 2 BraO C2F2Br2 C2F2Br2Cl2 * Preparations reported after January 1. b. 176° M.1°. 4.7° B.p. 45. 138.2°.p.427 B. -82. -163°.8 2 ° . b.p.p.5° M. d161.2° B. 122.p.p.p. b. are not included t References 97-IS3 appear on pp 92-93. <P1.5°.CHF 2 I CHF a CH2FBr CH2FCI CHaFI CHjFNO CHJFJ M. 1.5° • B. d?°2.9° B. 32.p. 101. CH2C12 + AgF at 180° CH 3 I + HgF.p. 18-20° B. 0 ° B. 101. b.p. b.8°.p.p. 108 109 49 20.3°.26 3.p.6° M.
p. 92. -130. «201. .9°. b.4666 M. n25l.5666.p.2°.p. 22.9°.5°. . 14. b.6447.7°. 34° M. -144°.1°.p. b. b.p. n°1. 485° M. d2B1.p. b. b. 24.3777 M.p.p.p. b. -36./ \ ^ X 5 ^ " I" " #^T1 CC13CF2C1 + Zn (CC13CO)2O + SbF 3 + Br2 at 95° CHF2CH2OH + Cl2 in sunhght C2C16 + SbF 3 + SbCl6 CHCI2CHF2 + Cl2 CFBr2CF2Br + Zn 23 23 27 116 118 27 118 27 27 116 85 27 CC1F=CF2 + Br2 CFBr=CF2 + Br2 CF2CICFCI2 + Zn C2C1« + SbF3Cl2 CH 3 CF 3 + Cl2 CF3CONH2 + P ^ CF4CICF2CI + Zn C2F3N C2F4 CF3CN CF 2 =CF 2 .p. ^1.p. b. -115°. -110.35572 M.4936.p.p.81W>. 99°. 21. 18. B.p. dP\.9° B. 45.3°. -78. 186. 62.p. remarks) Reference * 117 117 94 27 • 27 116 C2F2Br2O C2F2Br4 C2F2CI1! CFBr2COF CBr2FCBr2F CBr3CBrF2 CC1F=CC1F.p. 117°.p. «261.89 B.4272 B.65°. b.6 1 ° M. 91° B.9°. d181. 47.p. 40.p. 75. n71.p. d*>2.6°.p.p. d°1.p.5°.4° CBr8COCl + SbF3 + Br2 at 130° CFBr=CFBr + Br2 CBr2=CF2 + Br2 CCI2FCCI2F + Zn V^V^IQJ? V . eis CF2=CC12 CFC12COF CF2CICOCI CFC12CFC12 CF2CICCI5' CF2==CFBr CClFBrCF2Br CFBr2CBrF2 CC1F=CF 2 CC12FCC1F2 CF3CCI3 C2F2CI2O QjFjiCLi C2FsBr C2F3Br2Cl CjFsBrj C2F3CI C2F3CI3 B.p. 31° B p.4950.p. -157.TABLE IV—Continued ALIPHATIC FLUORINE COMPOUNDS oo Formula Structure Physical Properties Preparation (yield.5° M. trans CC1F=CC1F. <f2.p. d°1. b.5635.2Zl8.4°.8°.5° M. b. n°1. -2.p. 92.5°.4130 M.3798 M.p.0°.2 7 ° M.
p.59707 CBr 2 =CHF + Br2 M. 90.p.62 57. -106°.p. nnl. . . -20°. b. 163.p. 204°.879 M. d161. 70. n171.4°. 3. d°1.5°. -94°. 88.5°.p.p.CiF4Br8 djF 4 Cl2 CF-jBrCF^r CF2C1CF2C1 CF 3 CFa 2 (COF)2 CF3COF C2F2O2 CjF4O C 2 C1F S QiFe C2F«N2 C2HFBra0 CjHFBraOz C!!HFBr2 C2HFBr2 C!!HFBr2Cl2 QjHFBrisO CF 3 N=NCF 3 CHFBrCOCl CFClBrCO^ CBrF=CHBr CHF=CBr 2 CHClBrCClFBr CCl2BrCHFBr CHBr2COF CHFBrCOBr CFBr2CO2H CBr^CHB^ CBr3CHBrF CC12=CPF CHC1=CC1F CHC12COF CFC12CO2H CHCIFCCI3 C 2 HFBr 2 0 2 C2HFBr4 C^FGU C»HFCa»O CjHFCl^ CWFCI4 By-product of preceding CH3COCHs + F 2 CFsCOjiNa at 340° C2CI6 + SbF2Cl2.7°>d201. -108. b. <2172.p.8°.3073 B.p. dM2.p.3°.2 ° B.4°. -133° B.4954 C2F4 + Br2 QjCle + SbF3Cl2 27 27 27 63 85 27.3961 . du1. 35.p.p.lSOl CCIi!=CHF + Br2 CBrF=CHBr + (O) B.5° CFC12COC1 + H2O M.p.51&) CHC1=CC1F + Br2 B.p. b.2833.5°.1°. 98°.p. 26° B. d"2.p. CHFBrCHBr2 + KOH B. -95.p. b. b. d^. about .7 9 ° M. ^1.p. 182° B. d171. -112°. C2H4 + F 2 AgCN + F 2 CHFBrCOiiH + P Q 6 CFClBrCO2C2H6 + KOH .40364 B.2898 B~.5 9 ° M. 198° CBrF=CBrF + (0) B.5°.2908.5 ° . n161. 211°.87 119 82 113 94 114 28 82 114 82 83 94_ 94 28 28 12 23 28 * References 97-153 appear on pp 92-93. CHClFCCls + Zn n201. 26.p.5312. d161.6253.p.372 CHC^CCl^ + Zn B.4525 M.9094 CBr2CHBr2 + SbF 3 + Br2 B. b.4032.p.149 M. -106°.8°.p.CHC12COC1 + SbF3Cl2 M.4802.p.8°. . CHF=CC1 2 + Cl2 n201.p.p. QsHsCl + F 2 Electrolysis of CF3CO2Na. 37.9386. b. b.p.p.p.3 8 ° M.p. n161.p.3°. dlo2. 162. CBr2FCH2Br + KOH CHF2CHBr2 + NaOCiiHs. 46.3314 CBr 2 =CHF + (0) M.p. b.p. . <Z172. 163.p. n171. n°1.3833. dss2.5°. . 112. 116.
4° B.54472.6223. n171.p. b.5°.p.5°. 22.p. b.82 B. d202. 145-160° B.p. 19.5492.5025 B.p.5° M.0°. 28°. d°1.9°. <F2. . #*2.2°.p. nM1. -130° CHCljjCCls + SbF3Cl2 CBrFjCE^Br + CH3CO2K + K2CO3 CHBrFCBr2F + Zn CHF2CX)2H + Br2 at 160° CHC1=CF 2 + Br2 CBrsCHFBr + SbF 3 + Br2 CF2=CHBr + Br2 CHa2CClF2 + Zn CHF 2 CO 2 H + PCI5 CHF 2 CO 2 H + Cl2 C2HC16 + SbFsCl2 CHClFCa 3 + SbF 3 + Cl2 CHC12CHF2 + Cl2 CHF 2 CONH 2 + P2O6 CF2BrCHFBr + Zn CBr 3 CHFBr-+ SbF3 + Br2 CHCI2GC!IF2 + SbF3Cl2 ^ Oxidation of triftuorotoluidine By-product of preparation of CHC^CCliF F 2 + C2H« By-product of ICN + PF 6 120 118 117.?&\% n ^ l ^ l l B.4° B.3846 M.6°.p.1 2 " M. n171.5078 B. b.5°. d201.6130.3889 B.3979 B.26 B. 76.3916 B. 73. d°1. 72.p.5m\. dP\.p.4487 B.4171 B. d261.p. -82.p.p. 146°. 118.6°. -103°. 118 28 85 28 61 119 .8-23.p.327 M. nlo1.6028.p. n°1.p.2713. n201.p.6°.p.4° B.7°. dlo2. -15.p. 121.p. d1()1.p. . 22. 40°. 116.p. 6.TABLE IV—Continued ALIPHATIC FLUORINE COMPOUNDS Formula ^ Structure Physical Properties Preparation (yield.p. 72. b. remarks) Reference * 28 94 83 84 28 117 94 28 84 81 28 28 28 CHC12CC12F C2HF2Br C2HF2B1O2 • C2HF2Br!!Cl C 4 HFaBr 3 C2HF2CI C2HF2CIO C2HF2CIO2 C2HF2C1S C2HF2N C2HF3 C2HF3Br2 G2HF3CI C2HF3O2 C2HF4CI C2HFB QjHFeN CF2=CHBr ' CHF=CBrF CF2BrCO2H CHClBrCF2Br CFBr2CHFBr CHBr 2 CBrF 4 CHC1=CF 2 CHF2COCI CF2C1CO2H CHClsCClFf CHClFCa2F CHF2CC33 CHF2CN CHF=CF 2 CBrF2CHBrF CHC1FCC1F2 CF3CO2H CHF 2 CF 2 C1 CF 3 NHCF S M. «P81. n201. 2. 71. 143. 25° M.p.496. n201.p. <Z251.p.p. b.8337.5 1 ° .9°.5". -48.5° B. n*1.
88.p. .4776 B. 215° Ester -f NH4OH M. B.54S7. b.8°. dn2.p.p.4248 CHCIsCHCl2 + S s F 3 + SbCl6 B.p. CH2BrCHF2Br B. b.8° or 30-35° B. 74° CHBrFCOjC^HB + K I and saponify CHJFCONHJ + PA B.p.44815 M.p.p.5°. b. 174°.p. .p. -104.932.p.p. 92-93.p. 93°. b. nls1. 102°.1°.6709. n201.54321 CBr3CH2Br + SbF3 + Br2 CHjBrCClaP + Zn B.p.d 2(l 1. d"1. -25.6°. tf6lM72.p.879. 110. n201.p. n171. a^l.p.6054.p. nM1. 131. n^l^SSO M.8 3 ° B.1-21 81 82 SB C2H2FBrClNO CFClBrCONH2 CHClBrCHCIF C2HisFBrCl2 CjHsFBrOs C2H2FBr2NO C2H2FBr3 CjH2FCl C2H2FCI2NO CjHjFCa^ CaHsFIOj C2H2FN C2H2F2 CHjjBrCGlzf CHFBrCOaH CFBr2CONH2 CHBr2CHFBr CH2BrCBrtF CHs=CClF CHF=*CHC1 CFCljCONH-s CH 2 ClCa2F CHOjCHFCl CHIFCOsH CHjFCN "CH2==CF2 CHClBrCHF2 CHF2CHBr2 CF2BrCH2Br CF2C1CONH2 COT2CHCl2 . S6° or 39. 10-11° M.5638 B. 60°. at 60°.5° or 6.7-125. dS01.7566.p.3690 CHClBrCHClBr + SbF 3 + Br2 CHBr2CHBr2 + HgF 2 CBraCHaBf + SbFa + Brj Ester + NH 3 CHCI2CHCI2 + SbF 3 + SbCls CzH^BrCl C2H2F2Br2 C2H 2 F 2 C1NO C 2 H 2 F 2 C) 2 * References 97-153 appear on pp. <J161.4063 or 1.p. 107.473.24223. 124.4204 M. d172.4173 B.p.b. 136° CHBrFCHjBr + CHsCOaK + K2CXJ.r.5°/ B.p. CFBr2CO2C2H5 + concentrated aqueous NH« CHBr2CHBr2 + HgF 2 B.5° CHF2CHCSa + Zn. CFBrsCH2Br + Zn CHFaCHBrs + Zn From the acid CHGlBrCHOBT + SbFs + Brg CH2BrCCl8Br + HgFa C H F B T C O B T + ice 12.94 114.5492 M.5°. 117 82 36 Sa 82 117 38 121 5a 82 33 28 82 82 85 122. 82.p.8°. 49°. 78.5°.4°. -58°. n"l.0730 CHF2CH2Br + NaOC2H6. 183° M. <J171.4626 M.p. n251.4921. CHjClCGla + BbFs + SbCfe nM1. ft171. CHC1FCHC12 + Zn B.p.7097 or 1. 0*1.p.p. (P2. (i172.QjHsFBr CHjpOFBr CHF=CHBr B.p.5a 36 39 94. ra161.3120. 126. 1«3°. 12. 82°. 93718 mm.
0369 CH2CICCI3 + SbF3 + SbCls CHF2CH2OH + CrO3 CBrF2CH2Br + AgF CF3CH2OH + PBr 5 CHBrjCHBra + HgF 2 CHCI2CHCI2 + SbF 3 + SbCls CHC12CHC12 + SbFsCl2 Ester + NH4OH (48%) CHBr 2 CHF 2 + HgF 2 C2H2 + ' H F CHClBrCH2Br + SbF 3 + Br2 Ester + 20% NH4OH By-product from CH2BrCHBr2 + SbF 3 + CHBr2CH2Br + SbF 3 + Br2 or HgF2 CH3CCI3 + SbF 3 + SbF3Cl2 CH2C1CHC12 + HgF 2 39.p.1°.50084 M. -160. M. d17-61.26333.4163.TABLE IV—Continued AllPHATIC FlAJORINE COMPOUNDS 00 to Formula Structure Physical Properties Preparation (yield.p.p.p.p. -54°.p.8383 B.p.p.2°. b.p.p.4546 M. 20.2673.43 . 17°. b.p.8°. d°1. 35°. b. 46.p.389.p.5° B. n201. 96.2° B.5°.36175 B. 31.8°. cFl.125 21 21 82 C2H8FCI2 C2H3FINO C2H3FO CH3CCI2F CHCIFCH2CI CHIFCONH 2 CH3COF Ester + NH3 CHsCOCl + ZnF2 or (CH3CO)2O + HF 2. dlo1.5°. nM1. 92.p. 122°.p.p. -72. 250° 3-p. d°1.7°.2 3 ° M.p. remarks) Reference * 29 122 94 123 36 82 36 85 36 124 36 82 125 CH2CICCIF2 C2H2F2O2 C2H 2 F 3 Br C2H2FSC1 C2H2F3NO C2H2F4 C2H3F C 2 H 3 FBrCl C 2 H3FBrNO C2H3FBr2 CHF2CO2H CH2FCF2Br CF3CH2Br CHF 2 CHFBr CHF2CHFCI CF3CH2CI CF3CONH2 CHF2CHF2 CH2=CHF CHClFCH2Br CHFBrCONHs CH2FCHBr2 CHFBrCH2Br . dlo2. »101. 117.5°. n201.3090 M.3814. -101.2°. d61.41132 M. b.365 B.5° B.p. <P°1. 134. 26.9°.51759 B.874. 6. n201.p.8291. b. dlo1.p. . -67. (Pl. M. n201.7°.p. b. 44° B.6°. n°1.p. 73.38679 B. 162. 74.5°. n61.36193 M.p. 41°.
15.p. b.5°.8°.p. b.p.p. 89.312.p.p.310 > B. b.4681 M. 138°.p. b.3° B. d"1. ^1. 113°.82445.7° M. 51. n161.17576.4070 B.1° M. 237° Ester + soda C1CO2CH3 + T1F in the cold CHBr2CH2Br + HgF 2 CH3CCI3 + SbF3 + 8bF3Cl2 CHC14CH2C1 + HgF 2 CCI3OCH3 f + SbF 3 CHF2CH2Br + KI Ester + NH 3 CHF2CH2I + HgF 2 CH3CCI3 + SbF3 + SbF 3 a 2 CCI3OCH3 f + SbF3 (CF3CO)2O + H 2 + Pt CH2BrCH2Br + HgF 2 •CH3CC13 + SbF 3 + SbF3Cl2 From the sulfonyl chlorides CH2ICH2I + HgF 2 From ester and ammonia CH3CHC12 + SbF2 + SbF 3 + SbF3Cl2 CH2BrCH2Br + HgF 2 » Difluoroethylurethan + H N 0 3 CHF2CH2Br + HgO CyisBr + HgF 2 Fluoroethyl acetate + cone. -46.p.' b. 5° M.p. ' B.3528 M.34701 M. 92-fl3. 67. 10-11° M. 108° B. n201.p. 55.p. 165° B. 98-102° M. -9. <i261.6° B. 96°. dl. .p. -143.p. n121.p.5°. 134°. -24.5°. <2181. 40°.06 M.p.3°. HC1 QiHuSC^Cl + 70% KF HFSO3 + (C^Fs)!!© CHF2CH2Br + NHj C2Cl8 + SbFs + SbF3Cl2 ' 113 1 39 21 21 68 93 84 21 21 93 88 21 21 llf 21 113 21 21 96 91* 39 121 111 112 96 30 Q^Br CjH^FCl CjjH4FCISO2 C 2 H 4 FI C2H4FNO 0^2x14^ 2 ^ CH3CHC1F CHaCHClSOijF CH 2 FCH 2 I CH2FCONH2 CH 3 CHF 2 CHjFCH^ CHF2CH2NHNO2 CHF2CH2OH CHi!FCH2OH CHF2CH2NH2 CCI3CCIOT QsHsFO CjHsSO^ QSHJSOJF CWsFfcN C3FCl7 * References 97-153 appear on pp. b. n201.p. 111° M.CjHsFOij C2H3F2Br CJHSFJCI CEkFCO^ FCO2CHs CHF 2 CH 2 Br CH3CC1F2 CHF 2 CH 2 CI CF2C10CHs t CHF 2 CH2l CHF 2 CONH 2 CHF 2 CH 2 F CH3CF3 CF3OCH3 t CF 3 CH 2 OH CH2BrCH2F CiiHsFjsClO CiiHsFisI cyawwo C2H3F3 C 2 H3F 8 O M. 97°.p..2433.p.p.3739.p. -26. b. dl. trichloromethyl ether was not proved.6°. the structure of the.p. 108°/35 mm.p.3084 M. 71.7° B.p.5°. dM1.p. b.3757 B. -43.p. dls2.p. -105°.p.4° B. -37.5°. 30° M. -107°.p. 35. M.5°. dM1.10. »1. -96°.p.p. 33°. b. 19. -84°. n 10 l .2°.p.p. t The product may have been another isomer.p.2°.42261 B.p. b. -74. b. 74.5° B. b. 28.p. 103.p.39400 B. b. 57.45°.7044) n261.p.p.p.p.
M.9°.4°. n201. C + F 2 CCUCHClCCls + SbF 3 + SbCIle C3F6O CsFg QHFCU ccisCHacazF . d 20 !. d201.p.p. «201.p. 112. 112.2° M. 71.2 8 ° ' M. 194. n201. 112.p.p.p.5° M. d ^ U l S S .30 31 * 30. 298°.3960 M.p. -129°. -183°. b.TABLE IV—Continued ALIPHATIC FLUORINE COMPOUNDS Formula Structure Physical Properties Preparation. -4. b.1 5 ° . d^LSlO^ nml . b.4002 M. .p.7702. 12°. b. d201. 101 30 CW3U CCI3CCI2CCIF2 CCI2FCCI2CCI2F CC13CF2CC13 CCI3CF2CCI2F CCI3CCIFCCIF2 CCI2FCCI2CCIF2 C 3 F 3 CU M. d201.7702. d201. b. b.p. b. b.p.p. 43. 41°. b.?! 0 ^.p. n201.5°. 194.3 6 ° B.5°. 112.9°. .3°.p.p.p.p. 207°.p. b.p.3958 M.4392 M.5 8 ° . ( F l ^ g O .5-37°.5°.9°.p. 193.3°. d201.4S94 M. dlo1.p.5°. 35.p. nw1. remarks) Reference * 30 30 20.p. 51°.p.50105 CHC12CC12CC1F2 + Cl2 C3CI8 + SbF 3 + SbF3Cl2 CH 3 CF 2 CH 3 + Cl 2 CCl 3 CF 2 Ca 3 + SbF3Cl2 CHC12CC1FCC1F2 + Cl2 C3CI8 + SbF3Cl2 Br2 + CC1F=CFCC1F2 CC12FCC1FCC1F2 + Zn CI2 + CH2C1CF2CF2C1 l-'Ul^Ov-'lr OOlr 2 ~r ODX 3UI2 C 3 F4Br 2 Cl 2 CgF4Cl2 C3F4C14 CClFBrCFBrCClF 2 CC1F==CFCC1F2 CClsCFiiCF^l CCl^CClFCClFi! CC1F2CC12CC1F2 CC13CC1FCF» CC12FCC12CF3 CF3COCF3 C3C18 + SbF3Cl2 CCl2=CFCF 3 + Cl2 CC13CC12CF3 + SbFsCl2 CH3COCH3 + F 2 C2H8 + F 2 .p.555 B.33 19. b. 152.4° M.p. .p. b. 154° B.6992. 112.76188. -42.47996 B. 154. JI 2 0 1. (yield.31 5a 5a 33 5a 31 5a 5a 63 62.p.7254. 153.0°. -12. n ^ l ^ e i M.p.4°. .
41967 B.ZZZm B. n201. 67.9°.77384.4143. 0^1. 60°.p. (^1. ra201.71720.972 CHCI2CCI2CCI3 + SbF 3 + SbCl6 CHCI2CCI2CCI3 + SbF 3 + SbCIs CCI3CHCICCI3 + SbF 3 + SbCl6 Cl2 + CH2CICF2CCI3 or CH3CF2CH3 CCI3CHCICCI3 + SbF 3 + SbF3Cl2 CHCl2CCl2CCl3 + SbF 3 + SbF 3 Cl 2 Cl2 + CH2C1CF2CF2C1 CClsCHClCCla + SbF 3 + SbF3Cl2 CHC12CC1FCC1F2 + SbF 3 Cl 2 CH3CF 2 CH 3 + Cl2 CH2ClCF2CCl3 + SbF 3 Cl 2 CH 2 aCF2CCl 3 + S b F 3 a 2 CH3CF 2 CH 3 + a 2 CH3CF2Ca a + SbF 3 Cl 2 CF3COCH2CO2C2H5 + 10% H2SO4 CH2C1CC12CH2C1 + HgF 2 CH 2 ClCa2CH 2 Cl + HgF 2 CH 3 CF 2 CH 3 + Q 2 CHC12CF2C1 + KOH + CH3OH CHF2COCH2CO2C2H6 + 10% H2SC>4 CF 3 CHOHCH 3 + PBr 3 + Br 2 From CF 3 COCH 3 CH2=CHCH 2 I. n^l.4376.6475.33 89 5a 5a 19. n201.43 * References 97-153 appear on pp 92-fl3. 129.3464 M.p. dlo1.73162. nM1. d161. n201. 128. (^1.414.41569 B.p. b.31 33 31 31 33 33 33 19. n201. 88° B. d201.4°.33 31 30. n201.282 B.33 126 127 92 90 6 19 128 128 2.p.p.p.6404. d ls 2. d201. (CH3CH2CO)2O + HF 30 30 30 19.69124. 110-112°.3914 B.6°.p. n201.8°. 167.p. d181. d201.7°.4409 B.6-90°. dM1.50311 B. ra201.38327 B. n201.4641 B. n201.5813.1644. 158-159°. 210°. cPl.p. 168. (Pl. n201. rPl.p.p. fll. d201. 91.3O42 Liquid at .33 19.p. (Pl. ^ " l ^ e e e . dao1.5225.p.37613 B.45972 B.p. n171. 49°.p. d°1.C3HF2C16 C3HF3C14 C3HF4Ca3 C3H2F2C14 C3H2F3C13 C3H2F4C12 C3H3F2C13 C3H3F3O C 3 fl4FCl3 C 3 H 4 F 2 Cl2 C3H4F2CI2O 63H4F2O C3H4F3Br C3H4FaNO C3H5F C3H6FBrCI C3HBFBr2 C3HBFC12 CsHsCOF CCI2FCCI2CHCI2 CHCI2CCI2CCIF2 CCI2FCHCICCI2F CHCI2CF2CCI3 CCI2FCHCICCIF2 CEfC^CaFCC^ CHC12CF2CF2C1 COF2CHC1CC1F2 CHCIFCCIFCCIF2 CH2CICF2CCI3 CH2CICF2CCI2F CH2CICF2CCIF2 CH3CF2CCI. 104°.9°. 130°.+ AgF CHsCClBrCHjBr + SbF 3 + Br 2 CH 2 =CHCH 2 F + Br 2 CH 2 =GHCH 2 F + Cl2 CH3CH2COC1 + Z11F2. 150. 21.p. 96°. 89.09 B.3387 B. n201.p. CH 3 CF 2 Ca2F CF3COCH3 CH2CICCIFCH2CI CH2CICF2CH2CI CH 3 CF 2 CHC1 2 CHCI2CF2OCH3 CHF 2 COCH g CF 3 CHBrCH 3 CF 3 (CH 3 )C=NOH CH 2 FCH=CH 2 CH 3 CFClCH 2 Br CH 2 BrCHBrCH2F CH2CICHCICH2F CH3CH2COF B. 49°. dM1. cPl. 103°. 174°.p. 79°. n201.6747.p.6368.5877.Zmi B.p. 44°. cF>1.p.p.46241 B.8°.p.633 B.327 B.3°.p. 102° B. 46.8°.3 ° B. d160. 108.p.3750 B. 118-119°. n201.4°.3534 B.4175. tPl. 00 Cn .4470 B.7557.45503 B.p.p.
nM1. dlol. d 1.33 94 90 19 20 19 94 129 46 67 20 88 71 67 88 .p. 72° or 78° 95. 77. .p.p. 35.p.2 ° .p. 47° M.p.31720 CF3COCH3 + H 2 CH3CCI2CH3 + SbF 3 B.p.p.p.p.1°. 40° M.p.35856 CH3CH2CHCI2 + HgF 2 B. 152720 mm. n 1. remarks) Reference * 95. b.5°.3 2 ° CsHjI + AgF M.p.TABLE IV—Continued ALIPHATIC FMJOBINE COMPOUNDS \ Formula Structure Physical Properties Preparation (yield. b. nlol. ePl.3118 CH3CC12CH3 + SbF 3 CHF2CH2Br + KOH + CHgOH B. 4°. -0. -150°. 7-8° B. d201.5°. d151.2°. .OO72. 4° C + F2 M. b. n" 42 61. -133°.4°. d201.5139 CF 3 CO 2 H + P2O5 M.9272.8994. d181.1613 C1CO2C2H6 + T1F B.p. 45° 16 16 B. 76. 57° B.p. nw1.p.p. (CF3CO)2O + H2 + Pt n 18 l 2812 B.5°. CH3CF2C2H6 + Cl2 d201.2799. 55-56° CHa=CCl 2 + F 2 M.3506 Cl2 + CHaCFjCHj CH2FCF2Br + NaOCH3 B. b. -65. -84.p.p. b. 55. 113 95 19 19.38860 SbF 3 + CH3CClBrCH2Br B. 10872 mm.p. 55°.p. 104°.p. b.6102 or 1. .9 4 ° CH2=CHC53 + HF C2C14 + F 2 M..2023..p. b.4725. CH3COCH3 + F 2 CH2ICO2CHs + AgF or T1F B.6 5 ° . 111 y CaHsFO CsH6FO 2 C3H5F 2 Br C3HBF2CI C3H6F3O CH2FCOCH3 CH2FCO2CH3 FCO 2 C2H B CH3CF2CH2Br CH3CF2CH2C1 CH2FCF2OCH3 CF3CHOHCH3 CH3CFCICH3 CH3CH2CHF2 CH 3 CF2CH 3 CHF2CH2OCH3 CsHeFCl C3H 6 F 2 CsHeF/) C3H7F C 4 F 2 C1 8 CH3CH2CH2F CHsCHFCH3 CCI2FCCI2CCI2CCI2F CC13CF2C2C15 C4F6O3 C4F 10 C4H2F2C16 C4H2F6O2 (CF 3 CO) 2 O CF3CO2CH2CF3 CH2ICOCH3 + T1F.p. .p. n ^ l ^ e M.2°.p. CH2BrCOCH3 + T1F.9205. oPO.p.
p. d^LO^e.p. d ^ l ^ O .81°.550 B. 151°.61289. 138°.p. 77.2°. 72. b.p. d211. n201. 58-60° B. 67°/25 mm.p. d1B1. 121°.4°. 6.8°. 180°. nlo1. n171. b.9825.p.O45 M.77097 B.p.7851.3794 B.p. 119. 81°. 173°.p. 137° B. Semi-solid B. d141. rf161. <ii71. dl61.p. <2171.p. 100-112713 mm. JI 1 6 1. b. 61. 150-160° B. d171. 79.p. 99.3949 B. 97°.5 4 ° .p. d161.p.p. rPlM&l B.p.3313. 106°.p.p..85". .4410 Hydrolysis of ester with HC1 CHjFCOijH + P2O5 CCaBr2CO2C2H6 + AgF CBrsCOsC^Hs + AgF CCI2FCOF + C2HBOH CF2C1COC1 + C2H5OH CH3CF2C2H6 + CI2 CF 3 C(CH 3 )OHCH 3 + PBr 5 CF8C(CH3)OHCHS + PBrB 86 130 113 117 23 81 20 92 92 86 TVI.2l± B.p.p. 154°.p.1953 B.4490 B.p. 120°. nlo1.p.p.p.5727 mm. du1. 179°.9158 B.7°.p.37792 CF 3 CH 2 OH + CH3COCI From acid Acid halide + QsHsOH CHBrFCO2Et + Cal 2 CF2BrCHBr2 + KOH + C2H6OH CHCI2CF2CI + KOH + C2H5OH Acid + C2H6OH CH3COCI + CHF2CH2OH Crotonic acid + F 2 CF 3 C(CH 3 )=CH 2 + HBr CBrF2CHBrF + NaOC2H5 (CHF2CH2)2NH + HNO2 By-products of oxidation of CBr2=CHF CHCIFCHCI2 + NaOCitHB Bromoacetate + AgF or HgF C4H6FBr02 C^eFIOj C4HgF2Br2O C4HsF2Clz0 C4H6F2O2 C4H«FsBr C^eFJBrO C4H«F1N 2 O C 4 H 7 FBr 2 0 C 4 H 7 Fa2O C^TFOJ CHFBrCO2C2HB CHFICO2C2H5 CHBr2CF2OC2H6 ' CHC1SCF2OC2H5 CHF2CO2C2H5 CH3CO2CH2CHF!! CH3CHFCHFCO2H CF3CH(CH3)CH2Br CBrF2CHFOC2HB (CHF2CH2)2NNO CHBraCHFOQiHs CHCI2CHFOC2HB CH2FCH2OCOCH8 88 85 82 82 94 126 84 84 66 92 131 96 12 12 132 * References 97-153 appear on pp. d171.C^gFjOj C 4 H4F S O 3 C 4 Ij8FBrC102 C4H6FBr2O2 C4H6FCI2O2 C4H5F2CIO2 CF3COCH2CO2H (CHjFCOhO CFClBrCO2C2H6 CFBr2CO2C2Hs CFCI2CO2C2H5 CF2CICO2C2H5 CFi(CH3)C=CH 2 CF3C(CH3)BrCH2Br CFsC(=NH)CH r CONH2 CH3CO2CH2CF3 CF3CO2C2H5 ClH^Clj C4H5F3 C4H5F3Br2 C4H5F3M2O C4H5F3O2 M.p. d121. d?*\. 106°.3° or 45. 130°. d6l.4072 B.. 23 . 7978 mm.1800 B.5587 B.6716 B. dM1.252 M.32058 B. B.1781 M. d231. dlo1.6121. d301. 92-93.
133 94 86 92 96 134 20 135 136 47 137 47 20 71 20 92 92 CF3CO2R + 2CHsMgI CHF2CH2Br + NH S CH3CBrICH2CH3 + H F CH3CCI2C2HS + SbF. d161.5°.p. d120. b. 30.8°. 32°. .p.p. n lo 1.30412 B.. . CHF 2 CH 2 Br + KOC2H5 C4H9I + HgF HF + butene (CH3)2CHCH2I + AgF HF + isobutytene CHSCF2C3H7 + Cl 2 \ C5F2CI10 CsFia C 6 H 7 F 2 a» CUHJFJOJ C + F2 CH3CF 2 C»H7 + Cl 2 CF3CHOHCH3 + CHjCOCl \ CH3(CF3)CHOCOCH3 Allophanate of CF3CHOHCH3 CBHrFsNijOs .2°.1°.C(ONHt)=CHCONH 2 CF3C(CH8)2OH (CHF 2 CH 2 )2NH CH3CF2C2H5 C2H6OCH2CHF2 C5H7CH2F CH3CHFC2H6 (CH3)2CHCH2F (CH8)3CF CCI3CF2C3CI7 B.37665 B. 30° M.TABLE IV—Continued ALIPHATIC FLUOBUJE COMPOUNDS Formula Structure Physical Properties Preparation (yield. b.3241 M.p.p.p. b.p. 124. 20. 97° M.O39 B. n121. 114^115° M.lQOS B. 85.3314 M.1 0 ° .p. 25.p. d2Ol.75°. 160° Isobutyric acid + F2 CH2CICOC2H5 + KF. 120° or 126°.p.p. <2100.7824.p.1823. d^l.49 B. dl.p.74. 66.p. BrCH2CO2C2H6 + T1F CBrF2CH2Br + NaOC2H5 NH 3 + CFSCOC^COJCJHB 66 82. n 2 0 ! . remarks) Reference * C4HrFOj CH3(CH2F)CHCO2H CH2FCO2C2HS CH2BrCF2OC2H5 C4H 7 FjBr0 C^FsNjOi! C 4 H T F.p. d160.7 7 ° .3366 Liquid at +16° M.6°/75 mm.p. d°0.O926. n 15 1.p. 50°. 80-82°/13 mm. d1Bl. n 16 1.7527. 81 6°.31862 B. 12.0 C4H7F4N C4H8FI CiHgF-s C4HgF2O C4H9F CF. B.7884.3419 B.p.p.4°. 52° B.9164. <*161. 10-15° M.p. n121. n»»1.
62. b. b. CF3C(ONH4)=CHCO2C2HB at 100° 86 B.5° tso-CsHuBr + HgF 139 B.6°. n*°1. 55.7° in H 2 O CF3COC1 + NaOC4H9 CHF2CH2O1H + P + Br2 Na in CHsOH + aceto-l-fluoro-d-glucose-6chlorhydrin CHa2CF 2 Cl + KOH + sec-butyl alcohol Saponification of acetofluoroglucose by 1% CH3ONa in abs.3375 M.p. 77.lSih.p.8958.p.p. 86.p. ^0.3553 * References 97-153 appear on pp.p. n^issss B.p. 53.p. 86 B.5° C2H5OCH2CHBrCH2Br + AgF or HgF 138 M.8°. <?°1. b. (CH 3 ) 2 C=CHCH 3 + HF 47 n441.3790 C2H6OCH2CHFCH2Br + NaOCH 3 138 B..p.sgig.353 B. 145 18 18 B.p. b. n151.p.215. 100.3 9 ° .9024.p. d^. .6°.p.p. 157° C2H6OCH2CHBrCH2Br + HgF or AgF 138 B.3357 CH 3 CC1 2 C 3 H 7 '+ SbF 3 20 B. 44. 188° C 2 H 6 OCHjCF=CH 2 + Br2 138 B. 138°.41° CH3CHBrCO2C2H5 + AgF + CaF 2 66 M. 37. .p. (^0. d221. 131. b. 160°.p.896.9166.5°. CH 3 0H CH=CC 4 H 9 + HF CH 3 C^CC 3 H 7 + HF 5a 142 143 C 6 H»F 6 O 4 P C6HioFC104 CtHi 0 F 2 Cl 2 O CaHnFOs C 6 H 12 F2 C6H12F2 126 144. n221. 154°. nwlA059 M. b.p. 118-125°. -121°. n181.2°.2418.p. . 1577145 mm.p.4 ° .5° CF3CO2C2H6 + C H 3 C O 2 C 2 H B + NaOCjHs .p.p. . or glass. 185° Difluoroethylamine + ethylchlorocarbamate 96 B. [a]|.p.p. 138. 114.p.0268.4051 M. 253-255° ' Dec. 92—93. nwl.72Sti CsHnBr + HgF 139 B. CHF 2 CO 2 H + CH3CO2C2H6 + NaOC2H6 127 d201.p. . [a]D°88. ^o. CaHsCFaCsH? B.p.8°.8°.p.2°. 70°/28 mm. 25.50° CH 3 CHIC 3 H 7 + AgF 140 B.C 6 H 9 FBr 2 0 QjHgFO CeHgFOa C6H9F2NO2 C5HioFBrO C5H10F2 C5H10F2O CgHnF C2H6OCH2CBrFCH2Br CH2=CFCH2OC2H6 CH3CHFCO2C2H5 CHF2CH2NHCO2C2H6 C 2 H 6 OCH 2 CHFCH 2 Br CH3CF2C3H7 C 2 H 6 OCH 2 CHFCH 2 F CH3(CH2)4F (CH3)2CH(CH2)2F CH^HFCSHT CH2FC(CH3)C2H6 C2H6C(CH3)2F CBFM C6H7F3O3 C6H8F2O3 C6H8F3NO2 C6H9F3O2 CF3COGH2CO2C2HB CHF2COCH2CO2C2H6 CF3C==NHCH2CO2C2H6 CF3CO2C4H9 (CHF 2 CH 2 ) 3 PO 4 d-Glucosyl fluoride-6chlorhydrin CHa2CF2OC4H9-sec d-Glucosyl fluoride CHsCFaCJI.8 in water B. 51° or 60° C+F 2 71 M. b.8°. dF0. 59. 86.p.8 0 ° .p. d150.9° Bromide + AgF in acetonitrile 141 M.
93.0106.3748 B.SSSg.0834. [«]g)138.4°.5°. Normal Bromide + HgF »211. 134-135°. d100.8° HF and f ructosepentaacetate tose [«]D S 83.p. -104°. d^O.5°.2° in water Heptaacetylfluorolactose + Na in CH3OH cc-Lactosyl fluoride NH 3 in CH3OH on 6-(tetraacetyl-|8-glucoGentiobiosyl fluoride [a]g"33.M.p. 151-152°. (^0.37098 C»Hi3CHCl2 + HgF 2 CHF2C6Hi3 B.p.5°. CeHisBr + HgF Iodide + HgF By-product of preparation of CeHnF 8ec-Hexyl iodide + Ag2SiFe Bromoacetal + T1F By-product of nitration of CeHsCFg CjHisF CgHuF C 10 H 2 iF C11H15FO7 CuHieFClO? CuHwFOg C12H21FO10 B. 183.798 Iodide + AgF B. d°0.47° in water [sinters 180°] sido)-2.3° Iodide + AgF (violent) Normal B. 86. n^l^oSS CH3CF2C5H11 CH^CCsHn + HF M. 142.6°.TABLE IV—Continued ALIPHATIC FLUORINE COMPOUNDS Formula Structure Physical Properties Preparation (yield." M.p.95° in -6-chlorhydrin ^ CHCls 2-Fluorotriacetylfruc. d161.p.819. 112.8959.p. b. 69-72° B. d°0.2°. -73°.SOSQ. nw1.3°.p.8002.p.p. n261. [a]|.p. Normal 2-Fluorohexane 2-(or 3)-Fluorohexane 2-(or 3)-Fluorohexane CH2FCH(ocya:6)2 CFjC4H7(CO!iH)2 Trifluoromethyl adipic acid CF3COOC5H11-WO C6H13FO2 C 7 H8F 3 O 4 CyHnFaOa C7H14F2 B. 117-118°.3. 119.5-tribenzoyl glucosyl fluoride . «201. n201. cPHi. remarks) Reference * 136 140 136 146 147 85 90 20 18 139 139 139 139 148 143 149 150 144 CeHiaF .3855 CH3(CH2)6CHFCH3 B. 82.7°.p. 139.p.3693 M.p.p.792 Bromide + AgF FluorotriacetyW-araM. ( F O ^ i e .p. 119. n161.02° in Corresponding acetyl derivative + HF binose CHQs Aceto-1-fluoro-d-glucose.p.5°. d?°0. b. 60725 mm.3683 B. [«]g-128.p.3530 CF8CO2H + isoamyl alcohol B. 119.
3° M.27° B. [a]g^2.2 mm.p.9° in CHCI3 M.OS0 in CHCI3 M. . M. [alg'gO.p.p. 7°. 81° M. b.7* M. [a]$15° * References 97-153 appear on pp 92-93. Mg>119. 287°. <J170. b.p.CBHWFOS Ci 6 H 2 iFOii C16H32FJ (2-Fluoro-3-methyltriacetylfructose) l-Methyl-2-fluorotriacetylfructose a-Acetofluoroglucose Fluorotetraacetylglucose Fluorotetraacetylfruetose Fluoroacetyltetraacetylglucose Cetyl fluoride M.p. [a]i458. 113. 10370. 98°.809 M.4°.p. [a]g>-88. 140°.2 mm. [«&O-116.p.p. 68° M. [a]|.2110o in CsHsN By benzoylation in CjHsN M.OS0 M. 110-112°..3..p. 119-120°. 70-74° M.4° in CsHuN M. [a]§2l. 94°.p.p. 104-11270.p. Mg'SO.p.p. 108°.43° in CHCI3 M.5a 144 151 144 144 144 Ci 6 H M F CHHMF C18H34F2O2 C18H34F2O2 C18H36FO2 C 2 6 H 2 6 FO 6 C26H36FOn CsiHsoFOg C M H27FO 9 C41H41FO17 Monofluorostearic acid 6-Triphenylmethylglucosyl fluoride Fluoroheptaacetylcellulose Triacetyl derivative of 6-triphenylmethylglucosyl fluoride Tetrabenzoyl-d-glucosyl fluoride 6-Tetraacetyl-0-gluccsido-2.p. 181724 mm.p. 187°. [a]|?-90. Solid room temp.p.6° HF + 3-methylfructose Methylation of 2-fluorotriacetyl fructose AgF in CH3CN on cr-acetobromoglucose Acyl derivative with HF Pentaacetylfructose and HF Tetraacetylglucose + ZnCl2 + fluoroacetic anhydride Hexadecene + F 2 By-product of CgHi7I + AgF Hexadecane + F 2 + CO2 Stearohc acid and HF in CH2C12 Oleic acid + F 2 Oleic acid + HF PI13CCI in CsHbN + d-glucosyl fluoride Acetyl derivative + H F By acetylation in CBHJN • 149 149 150 151 151 130 66 139 66 152 66 153.p. b. 195-196°. 147-148°.p. 112°.5-tribenzoylglucosyl fluoride M.
Chem. *8 Rathsburg... 13. anorg. [3] 33. Bretschneider.. Soc. 104 Ruff and Keim. 817. Ann. Chem. 147 Ray.. 31. rend. pat. acad. 4. Bull. J. Goswami. J... J. 201. Chem.. 119 Ruff and Willenberg. Belg. 17. Belg. and Schlessinger. chim. 197. Am.. 724 (1940). 69. Bull.. Belg. chim. Z. Bull. 1921.937). chim. 65. 110 Moles and Batuecas. Chem. roy. anorg. allgem. Chem. 24 (1932). 939 (1930). Am. 523. rend. Ann. acad. 75 (1931). roy. and McArthur. Ber.. 27 (1926). Rec trav. 39. 728. 245 (1931). [3] 15. acad. 5809 (1937)]. 6265 (1941)]... Atti acad. Am. 108 Thornton. 106 Lebeau and Damiens. phys. / . Z. Burg. 393. Bull. Compt. 116 Swarts. Soc. Luchsinger. J. 103 (1919).' 99 Cossuth. 102 Ruff and Keim. 121 Swarts. 148 Brauns. Soc. and Ray. Belg. 128 Meslans. 182. roy. roy. 206. 1285 (1925). Chem. 56. pat.. Compt. Polanyi.. 302. rend. 41 (1939). 641.. 255 (1931). / . 108 Collie. 60. Chem. Bull. Belg. Zentr. 131 Swarts. Bull. 32.. roy. / . roy. trav. Chem.. 31*77 (1933).. Chem. Chem. aUgem. 186 Swarts. Indian Chem.. 201._160 (1907). 352 (1889). 400. 2051 (1940).. 140 Bergmann. 51. soc chim. 20. 7. 804 (1901). 357. 44. 30 (1923). 1261 (1933). 113. chim. anorg. 188 Desreux.. 11(l Henne and Wiest. 93 (1935). acad. 101 Simons. Belg. Wiegand.. Belg... Kalte-Ind. J. chim.. Bull. 46. Zentr. Chem. 353 (1920). J. 1099 (1897). allgem. 55. Chem.449 (1940) [C. 299 (1936). Soc. 113 Swarts. Belg. 18. Ber. 1901. Am. Bull. 12. 100 Plank and Seger. Rec.. 108. 126 Swarts. 47. 427 (1936). acad. Ber. 112 Meyer and Schramm. 35...S. acad. soc. 1995 (1927). J. allgem. Bull. and Miltschitzky.92 .. Bond.R. J. acad. soc. 201. II. Soc. chim. 31. 494. 537 (1919). 129 Meslans. 114 Swarts. 66. Bull. 101 (1932). Am. Ann. 118 Swarts. 489 (1881). 702 (1898). Belg. ges. 1909. 62. Chem. 1 (1935). 143 Helferich and Bredereck. and Ebert. Compt. 25.. 137 Young. Bretechneider. Butt. Indian Chem. roy. 1484 (1924).. Soc. 166 (1909). Chem.A. Z. Soc. Ber. 73. Z. 447. phys. 141 Brauns. Chem. 123 Swarts. 1914. Soc. 62.. 1340 (1926). 148 Paterno and Spallino. 111 (1889). anorg.. 3477 (1940). Bull. J. Chem. acad. chim. chim.. Soc. m Brit. 1421 (1934).878 (1937) [C. Soc. 107 Ruff. allgem. 142 Swarts. acad. [7] 1< 382 (1894). [5] 15. Chem. Trans.. 364 (1924). Am. 966 (1929). 109 Van Arkel and Zanetsky. Belg. 146 Helferich and Peters. Belg. 111 Davies and Dick. 669 (1918). 127 Desirant. 188 Swarts. 46. 317. 843 (1936). 1897.S. 281 (1899). 122 Swarts. J.. 442. II. 144 Helferich. 191. Gen. Z. 130 Brauns. anorg. roy. 117 Swarts. II. 1458 (1934). U.' ALIPHATIC FLUORINE COMPOUNDS REFERENCES TO TABLE Ruff. Lincei] [2] 16. roy. 134 Petrob.. Bauerlein. 106 Swarts. 189 Swarts. 28. Faraday Soc. 483 (1932). Z. 120 Swarts. Soc. J. 167 (1. 132 Swarts.. Chem. I. 124 Ger.A. II. 1910. 1899. 133 Ray. 97 .. soc. 1 (1934). 1134 (1896). Zentr..471 (1897). and Szabo. Bull.
Standards J. 1M Ger. 45.. 833 (1923). Ber. Research.A. Am. Soc.. 2314 (1936)]... Bur. A.977 (1935) [C. 449-456 (1931). 6. 799.432 (1936) [C. pat. Helferich and Gootz.. 30. 160 161 . pat. 62. 621. 30.. 163 Fr.REFERENCES TO TABLE 149 93 Brauns. J. Brauns. . 7585 (1936)]. Chem. 2505 (1929).
(S-Unsaturated Aldehydes Aromatic Aldehydes Monosubstituted Benzaldehydes Disubstituted Benzaldehydes Tri. Aldehydes with Two a-Hydrogen Atoms. A. CONDITIONS ^ 98 98 99 100 100 102 103 103 105 107 108 109 110 Concentration of Alkali Solvents Temperature EXPERIMENTAL PROCEDURES 110 110 110 Ill 2-Methyl-2-ethylpropane-l. Isobutylene Glycol and a-Hydroxybutyric Acid Pentaerythritol m-Hydroxybenzyl Alcohol and m-Hydroxybenzoic Acid m-Bromobenzyl Alcohol and w-Bromobenzoic Acid o-Methoxybenzyl Alcohol o-Nitrobenzyl Alcohol and o-Nitrobenzoic Acid The Crossed Cannizzaro Reaction INTRODUCTION Ill Ill Ill Ill 112 112 112 113 The reaction in which two aldehyde groups are transformed into the corresponding hydroxyl and carboxyl functions. has been termed the Cannizzaro reaction. AI94 .3-diol m.and Tetra-Substituted Benzaldehydes Heterocyclic Aldehydes The Crossed Cannizzaro Reaction EXPERIMENTAL. existing separately or in combination as an ester. in the Presence of Formaldehyde a. in the Presence of Formaldehyde ." .CHAPTER 3 THE CANNIZZARO REACTION T. Los Angeles CONTENTS PAGE INTRODUCTION MECHANISM OF THE REACTION SCOPE OF THE REACTION . 94 96 97 Aliphatic Aldehydes Aldehydes without a-Hydrogen Atoms Aldehydes with One a-Hydrogen Atom Aldehydes with One a-Hydrogen Atom. GBISSMAN University of California.
1'2-3. 180 (1925). Lebensm. 8 Schweiger and Geilinger. 160. ch%m. ges. Numerous examples«. and certain of them 6 suggest possible application in preparative methods. 7 Josephson and von Euler. Am. 10 of these have been studied in vitro by the aid of tissue preparations. 8 Tishohenko. CHO + NaOH Dismutations of the same type. Z. 28. 6 Parnas. and alkoxides of metals such as aluminum or magnesium in alcohol solution or in suspension in inert solvents. 246 (1887). soc. Soc.. Mitt. Z. 47. (Pflilgers). s. Ann. J.A. 45. Chem. The conversion of benzaldehyde into a mixture of benzyl alcohol and sodium benzoate is an example.*•6 Oxidation-reduction reactions similar to the Cannizzaro process are brought about in the living cell by certain enzyme systems.of aldehydes in basic or neutral solution also has been effected by catalytic metals. 10 Abderhalden and Wertheimer.. in aqueous or alcoholic solution.. 415 (1923) [C. it will be restricted. 116 (1926). but involving two unlike aldehyde molecules. 1605 (1937) . physiol. [5] 4. 49 (1924). 322 (1912). 298 (1910). The dismutation .^ . 20. 41 (1924). such as nickel and platinum. 575 (1937). Other reagents which can be employed to bring about the dismutation include alkali amides in liquid ammonia. 2294 (1923)].».. 17. *. Chem. 4 Child and Adkins. in the present discussion. 204. Biochem. Z. 198. 31. Soc..INTRODUCTION 95 though this name has been applied at various times to the reactions brought about by a variety of agents... physiol. 11 Delepine and Horeau.. Physiol. 646 (1887). ' " Levene and Christman. 120. Biol. rend. Chem. / .> II r—-+ HCO2Na The most commonly employed procedure for carrying out the reaction consists in shaking or stirring the aldehyde with strong (50%) alkali. (a) Compt. 1525 (1937). 135. alkali alkoxides in alcohol solution.. Ber. will be classed as "crossed" Cannizzaro reactions. Arch. Ber. The reduction of benzaldehyde to benzyl alcohol by means of formaldehyde and alkali is an example. Chem. J.11-12 It seems likely that there is a closer analogy between Meisenheimer. Hyg. (6) Bull. prakt. 127. 15... H2CO . 9 Kuhn and Hecksher. 442. 2184 (1925).. 5 Claisen. without heating. * Marshall. 3013 (1923). 1 .. 86. 20. J. to the dismutation of two similar aldehyde groups into the corresponding alcohol and carboxylic salt functions by means of aqueous or alcoholic alkali. Chem. Chem. 798 (1925).
"Physical Organic Chemistry. Ann. Enke. 392 (1939). 18 Haller and Bauer.17 is the following. McGraw-Hill. 1940. Eistert.13-14>1B One mechanism.. [10] 9. Ann. Stuttgart. 16 Grignard and Fluchaire. 116. A181. 379 (1938). Monatsh. amide-ester interchange brought about by the amide ion being the last step. and takes into account the ester interchanges which have been observed to occur. 72. based upon a proposal by Lock. 1938. 5 (1928). 145 (1909). with OR"" in place of 0H~. 350. chim. 16. "Tautomerie und Mesomerie.. 14 16 . physik." p. oRCHO + OH" ^ RCH OH oRCH + RCHO . The transformation of benzaldehyde into benzamide and benzyl alcohol by the action of sodamide 18 proceeds analogously. 17 Fredenhagen and Bonhoeffer.16 who patterned his suggestion after those put forward by Grignard and Fluchaire 16 and by Fredenhagen and Bonhoeffer. Chem. Eitel and Lock. 13 Hammett..96 THE CANNIZZARO REACTION these enzyme and catalytic reactions than between either of them and the true Cannizzaro reaction. The formation of esters when an aldehyde is treated with an alkoxide follows the same scheme. MECHANISM OF THE REACTION A number of mechanisms have been suggested for the Cannizzaro reaction.=± RCHOCHR \ OH I I OH OOH RCHOCHR -> RCHJSOCR + 0H~ ? i RCH20CR OH OOH RCH20CR -* RCH20H + RCOs" 0 0- oThis mechanism adequately coordinates the well-known variations of base-induced dismutations of aldehydes into a general picture and makes it unnecessary to suppose that different bases act in different ways. phys. Z." p. chim. New York.
Am. .. Lachman 19 has shown that benzyl benzoate can be isolated in the reaction between benzaldehyde and aqueous sodium hydroxide if precautions are taken to avoid'high temperature and an excess of alkali. J. Highly purified benzaldehyde undergoes dismutation to the extent of only 2-4% under conditions which result in 25-80% reaction with "ordinary" benzaldehyde. Soc. J. It has been shown by Kharasch and Foy n and confirmed by Urushibara and Takebayashi M that the presence of peroxides markedly accelerates the heterogeneous Cannizzaro reaction. Electron-attracting groups (e. 26 Lock. It has been shown17 that the alcohol which is formed when the reaction is carried out in heavy water contains no deuterium in the —CH2— group.26° but the problem is still obscure. and Miller. 24 Chute..Such is found to be the case. and formalde19 Laohman. Chem. Chem.A..g. J. Soc.explanations have been advanced to account for the effect of peroxides. Trans.. Am. 81.g.21 and Bailar. Chem. halogen. 45. Thus.20 Weissberger and Haase. and Wright.. 58. and Miller 21° on the effect of substituents upon the rate of the reaction.. 1510 (1935). —CH3. chim.. Japan. 37. Monatsh. J. «* Molt. trav. 21 Weissberger and Haase. / . Soc. 782 (1941).. but the reaction is accelerated markedly by the addition of a trace of hydrogen peroxide. 72.g. 6. 57. 260 Weiss. Orchard.24 Various . 22 Kharasch and J o y . Barney. Org. 2S Urushibara and Takebayashi. Bee. The view tiiat the first step in the reaction proceeds by an initial coordination of the base (e..and particularly those groups such as —O~ and NR2 which can furnish electrons directly to the carbonyl carbon atom) decrease the rate. OF THE REACTION 97 It would be a consequence of this mechanism that under certain conditions an ester might be isolated as one of the products of the reaction. 157 (1941). OH~) with the aldehyde carbonyl group is supported by the investigations of Lock. 232 (1937). 7394 (1937)]. 2356 (1923). 2110 (1936).16 Molt.SCOPE. —NOa) increase the rate. Am. Chem. 410 (1939). Bull.26. SCOPE OF THE REACTION The Cannizzaro reaction is characteristic of aldehydes which have no hydrogen on the a-carbon atom.. Soc. S-Bromofurfural dismutates only slowly with 30% sodium hydroxide in ether. properly substituted aliphatic aldehydes. 12. 56. —OCH8. Chem. Faraday Soc.. This is evidence for the view that the transfer of the hydrogen atom takes place intramolecularly without interchange with the solvent. 535.. 1934. 210 Bailar. Chem. and electron-repelling substituents (e. Barney. such as aromatic and many heterocyclic aldehydes. Soc. 328 (1937) [C..
methylethylacetaldehyde in isovaleraldehyde). upon treatment with-50% aqueous potassium hydroxide at room temperature is converted quantitatively into 26 Lederer. 293 (1920).27-28 but the results are inconclusive.. 13. 421. 302 (1901). Ber. For example. BvR^soc. In another case28 the extent of the supposed Cannizzaro reaction was deduced only from a decrease in the alkali concentration as the reaction between acetaldehyde and alkali was followed by titration. 88 Bottinger.30'31 Glyoxylic acid disproportionates in a normal manner to yield glycolic and oxalic acids. Monatsh. 645 (1901). Rosinger. undergoes the Cannizzaro reaction to yield methyl alcohol and formic acid. HOCH2C(CH3)2CHO. 30 Lieben. although generally under conditions quite dissimilar to those employed with aldehydes of the first class. 879 (1906). 22. 86. 82 Debus. 420. 29 Neustadter. hydroxypivalaldehyde. 262 (1920).. chim. isobutyraldehyde is reported to undergo quantitative conversion into isobutyric acid and^isobutyl alcohol when heated with barium hydroxide solution at 150° in a sealed tube.g. / . The first products usually are those formed by aldol condensation. [3] 17. In some cases workers unable to repeat earlier experiments26> 29 attributed the previous results to impurities in the reactants (e. 338. Monatsh.98 THE CANNIZZARO REACTION hyde. Ann. 536 (1901).. 22. 336. 346 (1904)'.. The •Gannizzaro reaction often occurs indirectly when aldehydes containing a-hydrogen atoms are treated with alkali.. Monatsh. 28 Hammarsten. 27. Aliphatic Aldehydes Aldehydes without a-Hydrogen Atoms.26 There are reports that aldehydes containing two hydrogen atoms on the a-carbon atom undergo the Cannizzaro reaction. For example. Ann. the simplest member of this class. 1932 (1880). 27 . 81 Delepine. and these may undergo Cannizzaro reactions of either the normal or crossed variety.. Soc. 22. 1391 (1904). a reaction analogous to both the Cannizzaro reaction and the benzilic acid rearrangement of a-diketones: RCOCHO + NaOH -> RCHCOONa OH The readiness with which higher aldehydes undergo the Cannizzaro reaction and the extent of the reaction vary with the nature of the groups present on the a-carbon atom.. 938 (1897)..32 •33 a-Ketoaldehydes and glyoxal undergo intramolecular dismutation under the influence of alkali. Monatsh. It has been observed with aldehydes which have a-hydrogei atoms.. Formaldehyde. Chem.
. 4. 67. Webb. their behavior is discussed on p. 25. Phys. Buss. Soc. Since. The most useful examples of the Cannizzaro reaction as applied to aliphatic aldehydes are those involving /S-hydroxyaldehydes formed by aldol condensation of aldehydes which have a-hydrogen atoms or of these aldehydes with formaldehyde. 81 Acid .ALDEHYDES WITH ONE a-HYDROGEN ATOM 99 /3. 188 (1904). The products of this reaction are the glycol formed by reduction of the aldol and the acid formed by oxidation of the original aldehyde. 86 Conant. / . 614 (1881). 22. the fihydroxyaldehyde is not isolated. and Mendum. 66 (1901). Chem. 354 (1898). 24 (1934). Monatsh. hydrolysis to the hydroxyaldehyde preceding the dismutation. 19.1488 (1924)]. Aldehydes of the type RR'CHCHO under suitable conditions39 (Table I) can be made to condense smoothly to the aldols. Vienna. ' Aldehydes with One a-Hydrogen Atom. Monatsh. Monatsh..29-39'40. 88 « Danilov. 1923. J. 49. 86 Hinterberger. but when treated with 50% alcoholic potassium hydroxide it yields 50-60% of neopentyl alcohol and pivalic acid. Soc. Certain aliphatic aldehydes which have no hydrogen atoms on the a-carbon atom undergo cleavage under the influence of alkali. Am. dissertation. The conversion of a trihaloacetaldehyde to the haloform and the alkali formate is the best-known example. 18.. yielding triphenylmethane and the alkali formate. a-Hydroxyisobutyraldehyde undergoes smooth dismutation with dilute sodium or potassium hydroxide (3-10%) to yield isobutylene glycol and a-hydroxyisobutyric acid.• RCHCH—CCHO < > RCHCH—CCH2OH + RCHCOjH R' R' OH R' R' OH R' R' Aldol Glycol Wessery.. Monatsh. " Herrmann.. 282 (1917) [C..38" Aldehydes in which the a-carbon atom is part of an ethylenic or acetylenic system do not give the normal Cannizzaro reaction.37-38 The same products can be obtained from a-bromoisobutyraldehyde. 88 Danilov and Danilova. 102. 663 (1883).36> 36 This apparently greater reactivity of the hydroxyaldehyde is to be attributed at least in part to its greater solubility in 50% aqueous alkali.34 Pivalaldehyde is only slightly affected by 50% aqueous alkali. followed by a crossed Cannizzaro reaction between the aldol and the original aldehyde. A. examples will be classified under the headings of the reactants which serve as the actual starting materials. Monatsh. Under other conditions the aldol condensation may be the first step./3-dimethyltrimethyleneglycol and hydroxypiyalic acid. 51. Ber. 1122 (1900). 40 Fossek. " Franke and Kohn.. 1246 (1929). Triphenylacetaldehyde undergoes a similar cleavage..a i v R R I R(R')CHCHO I 2RCHCHO .. 87 Franke. 21. Chem. 2. in these reactions.
iOo
THE CANNIZZARO REACTION TABLE I Reference 41 41 41 39 39 29
R
R'
Base
Conditions
Products (yields)
CH3
CH« CH 3
CH3
CH 3 GH8
CH, CH 3 CH 3 CH 3 CH,
Aq. K2CO8 Aq. KOH NaOAc Ca(OH) 2 Ca(OH) a
Room temp. Room temp. 100° —
C2HS 1 A KOH T
Aldol only Aldol, glycol, acid Glycol-i-butyrate Aldol (40%), Glycol (10%), glycol isobutyrate (20%), acid (16%) 150" , Isobutyl alcohol (8%), glycol (18%), acid Glycol (40%), acid (21%) 0-100°
This reaction appears to be of limited usefulness as a preparative method. The fact that the ester is sometimes isolated39> 41 is of interest in connection with the mechanism of the Cannizzaro reaction (p. 97). Aldehydes with One a-Hydrogen Atom, in the Presence of Formaldehyde. Aldehydes of the type RR' CHCHO may condense with formaldehyde according to the following equation. RR'CHCHO + H,C0
OH-
R' \
R
CHO
C
\
CH20H
The /J-hydroxyaldehyde so formed may then undergo a crossed Canniazaro reaction with formaldehyde to yield a /3,/3-disubstituted trimethylene glycol. R' CHO R' CH2OH
\ R
+ H2C0 \
OH"
\
C \
HC02H
R CH CH80H C 20H This reaction has been found to be a useful method of preparing jS,0disubstituted trimethylene glycols. Examples are given in Table II. Aldehydes with Two a-Hydrogen Atoms, in the Presence of Formaldehyde. Aldehydes of the general type RC(CH2OH)2CHO are formed by the condensation of formaldehyde with aldehydes having two a-hydrogen atoms. RCH2CHO + 2H2CO > RC(CH2OH)2CHO •
ATT
_
ALDEHYDES WITH TWO a-HYDROGEN ATOMS TABLE II RR'CHCHO + HCHO — RR'C(CH2OH)2 + HCOOH
Amount of Alde- HCHO hyde 2* 1* 48 g. 45 g.
101
R
R'
Base
Product
Yield
Reference
CH 3 CH 3 CH 3 CH 8 CH 3 C2H6 CH 3 C3H7
CH 3 C6H6 100 g.
* Parts by weight, t Weight of formalin.
_ 1* 2.08* 12% ale. KOH 32.8 g.f KOH 23 g. 17.9g. f KOH 16.8 g. '
(CH3)2C(CH2OH)2 (CH3)2C(CH2OH)2 (CH3)(C2H6)C(CH2OH)il (CH3)(C3H7)C(CH2OH)2 (CH3)(C6H6)C(CH2OH)2
20*40% 70% 77% 84% 81%
42 43 44 44 44
In the presence of excess formaldehyde a crossed Cannizzaro reaction ensues, leading to a trimethylol alkane. RC(CH2OH)2CHO
H2CO -^-> RC(CH2OH)S
HCO2-
In the special case of acetaldehyde the reaction is that used in the wellknown method of preparing pentaerythritol.46 CH3CHO + 4H2CO + £Ca(OH)2 -* C(CH2OH)4 + (HCO2)Ca/2 Because of the technical importance of pentaerythritol, this reaction has been the subject of considerable investigation. The condensation is best effected by calcium hydroxide46 in aqueous solution at moderate temperatures (15-90°), using an excess of formaldehyde over the ratio (4CH2O : ICH3CHO) required by theory. A ratio of 5 : 1 has been found tov give satisfactory yields (73.5%), a smaller proportion of formaldehyde causing the production of considerable amounts of the ether, [C(CH2OH)3CH2]2O.47 In technical practice an excess of 40-60%
Meyersburg, Monatsh., 26, 41 (1905). "Fischer and Winter, Monatsh., 21, 301 (1900). " F r a n k e , Monatsh., 34, 1904 (1913). 46 Org. Syntheses, Coll. Vol. I, 2nd ed., 425 (1941). 46 Corbellini and Langini, (Horn. chim. ind. applicata, 15, 53 (1933) [C. A., 27, 4526 (1933)]. 47 Friederich and Brtinn, Ber., 63B, 2681 (1930).
42
102
THE CANNIZZARO REACTION
of the lime required in the above equation generally is used,48' 49>60 although less than the stoichiometric amount of the base has been recommended in at least one instance.61 The use of promoters such as copper oxalate,62 formamide,62 and sugars M has been described, as has also the use of quaternary ammonium bases.44 The preparation of pentaerythritol in 56% yield on a laboratory scale has been described in Organic Syntheses.*6'iS The modified procedure of Friederich and Brunn 47 gives better yields and is described in the experimental part (p. 111). Propionaldehyde 65 and isovaleraldehyde 66 have been converted to the corresponding trimethylol derivatives, CH3C(OH2OH)3 and (CH3)2CHC(CH2OH)3, by treatment with formalin and calcium hydroxide; although the yields are not specified they appear to be good. Phenylacetaldehyde 66 did not give the expected product. The only useful Cannizzaro reactions involving the use of aldehydes having one or two a-hydrogen atoms are those already described, in which the aldehyde first undergoes an aldol condensation. ^ The direct dismutation of aldehydes of these types has been carried out successfully only by means of enzyme systems or catalytic metals (p. 95). Such reactions do not represent the true Cannizzaro reaction and as yet have found little practical use. The smooth and practically quantitative dismutation of straight-chain aliphatic aldehydes of four to seven carbon atoms under the influence of the enzymes of hog-liver mash 6 suggests that practical applications of this method may be found. a,/3-Unsaturated Aldehydes. a,|3-Unsaturated aldehydes do not undergo the normal Cannizzaro reaction, but dismutation of ethylenic aldehydes of this type may be brought about by other reagents, such as aluminum alkoxides, under conditions similar to those of the Tishchenko reaction.67 The action of aqueous or alcoholic alkalies induces changes of another sort, leading to cleavage or condensation. In the presence of dilute alkali and formaldehyde, acrolein, crotonaldehyde,47 and cinnamaldehyde m give pentaerythritol in good yields. The reaction involves the cleavage of the a,j8-unsaturated aldehyde by a reversal of
Backer and Schurink, Bee. trav. chim., 50, 921 (1931). T. R. Paterson, U. S. pat., 2,011,589 [C. A., 29, 6610 (1935)]. t0 T. Sakai, Jap. pat., 94,210 [C. A., 27, 2697 (1933)]. 61 Deutsche Gold und Silber-Scheideanstalt, Fr. pat., 744,397 [C. A., 27, 3953 (1933)]. *» J. A. Wyler, U. S. pat., 2,206,379 [C. A., 34, 7301 (1940)]; U. S. pat., 2,240,734 [C. A , 35, 5135 (1941)]. " Kusin, J. Gen. Chem., Ser. A, 5,1527 (1935) [Chem. Zentr., I, 330 (1937)]. " J. A. Wyler, IT. S. pat., 2,152,371 [C. A., 33, 5188 (1939)]. M Hasaens, Ann., 276, 76 (1893). M van Marie and Tollens, Ber., 36, 1342 (1903). 87 Endoh, Bee. trav. chim., 44, 866 (1925).
49 48
MONOSUBSTITUTED BENZALDEHYDES
103
the aldol condensation, followed by the condensation of formaldehyde with the acetaldehyde so formed (p. 101).
OH" HCHO
CH3CH=CHCHO + H2O ^—^ 2CH3CHO > C(CH2OH)4 Aldehydes containing the grouping —C=C • CHO do not undergo dismutation when treated with alkali but are cleaved readily to yield the corresponding acetylene and formic acid. Propiolaldehyde and phenyland methyl-propiolaldehydes are cleaved smoothly in the following way.68 NaOH -> RO^CH + HCO2Na Aromatic Aldehydes The formation of benzoic acid when benzaldehyde is treated with aqueous alkali was first observed by Liebig and Wohler.69 Some years later Cannizzaro 60 recognized that benzyl alcohol is formed also. Later studies have shown that aromatic aldehydes which are not diorthosubstituted generally react smoothly to give the corresponding snyl carbinols and aromatic acids in good yields. The usefulness of the reaction, which in the past has been employed largely as a route to the alcohol rather than the acid, is somewhat limited in practice by the modern developments in reduction procedures, by means of which an aldehyde may be converted into the desired alcohol with a possible yield of one mole per mole of aldehyde rather than the one-half mole attainable by the use of the Cannizzaro reaction. The crossed Cannizzaro reaction, in which the aldehyde is reduced not by another molecule of its kind but by one of formaldehyde, is, however, also capable of yielding the alcohol in amounts approaching one mole per mole of aldehyde, and is applicable to a wide variety of compounds. The Cannizzaro and crossed Cannizzaro reactions can be carried out with a minimum expenditure of time and do not require elaborate equipment or special reagents. For the convenient reduction of an aldehyde which is inexpensive and readily obtainable, these procedures, especially the latter, are particularly suitable. Indeed, the reservation regarding cost and availability scarcely applies to the crossed reaction since it is convenient and affords excellent yields. Monosubstituted Benzaldehydes (Table III). The smooth dismutation of monosubstituted benzaldehydes carrying non-functioning groups to give the corresponding benzyl alcohols and benzoic acids is a general
58 68
(R=H, CH3, C6HS)
Claisen, Ber., 31, 1023 (1898); 36, 3664 (1903); 44, U66 (1911). Liebig and Wohler, Ann., 3, 252 (1832). 60 Cannizzaro, Ann., 88, 129 (1853).
104
THE CANNIZZARO REACTION
reaction having no serious limitations. When the substituent is a functional group the Cannizzaro reaction proceeds normally except in a few special cases, namely, o- and p-hydroxybenzaldehyde and p-dimethylaminobenzaldehyde. It is probable that o- and p-amino- and alkylamino-benzaldehydes would also fail to undergo normal dismutation, but examples have not been described. It has been reported 61 that jw-dimethylaminobenzaldehyde is unaffected by strong aqueous alkali.
TABLE III 2XCjH4-CHO + O H " -> X C 6 H 4 C H 3 O H + X C 6 H 4 C O O Yield of
x=
4-CHs 4-*-C8H7 2-OCH» * 2-OCHs 3-OCHa 4-OCH3 3-OCH3 3-OH 3-C1 3--Br 2-1 4-1 2-NO2 3-NO2 3-NO2 4-NO2 4-NO2
Alkali * X C«H4CH2OH Ale. KOH Cone. ale. KOH 25% ale. KOH , Cone. KOH 25% ale. KOH 25% ale. KOH Cone. ale. KOH 50% KOH 50% KOH 50% KOH 50% ale. KOH 50% ale. KOH 35% NaOH 35% NaOH 14% KOH 15% NaOH 35% NaOH X-C6H4COOH
Reference
— — — — — — 90% 92-97% 89% 90% 81% 91% 90% — — 96%
-
— — 76% — — 94% 90% 88% 90% 87.5% 84% 91% 90% — — 90%
62 63 64 65 64 64 66 67 68 68 68 68 68 68 69,70 71 68
* Aqueous unless otherwise stated
el 62 M
Cocker, H a m s , and Loach, J. Chem. Soc., 1938, 751. Cannizzaro, Ann., 124, 255 (1862). Kraut, Ann., 92, 66 (1854). M Spath, Monatsh., 34, 1996 (1913). •'Stoermer, Ber., 44, 1850 (1911). 66 Pschorr, Ann., 391, 43 (1912). « Lock, Ber., 62, 1177 (1929). • ! Lock, Ber., 63, 855 (1930). M Becker, Ber., 15, 2090 (1882). 70 Lock, Ber., 6 6 , 1527 (1933). 71 Busier, Ber., 1 6 , 2 7 5 (1883).
DISUBSTITUTED BENZALDEHYDES
105
Since it is highly probable that the Cannizzaro reaction proceeds by way of a step common to many addition reactions of the carbonyl group, namely, an initial attack upon the carbonyl carbon atom by a nucleophilic reagent (for example, a strong base), the failure of o- and phydroxybenzaldehydes to undergo dismutation is readily explicable. In the presence of alkali the anionic oxygen formed by ionization of the phenolic hydroxyl group could, by virtue of its strongly basic nature, contribute to the resonance structure: 0 /-
- o=/ y=c > c\ <\—/ \H H
o-
The effect may be considered a competition between one base (anionic oxygen) acting intramolecularly and another (hydroxyl ion) acting intermolecularly. The failure of, p-dimethylaminobenzaldehyde to react can be ascribed to a similar contribution of an electron pair from the basic dimethylamino grouping. If the hydrogen atom of the hydroxyl group in o- or p-hydroxybenzaldehyde is replaced by a methyl group, then the Cannizzaro reaction can be effected. m-Hydroxybenzaldehyde reacts normally to give good yields of the dismutation products. There is no obvious explanation for the failure of m-dimethylaminobenzaldehyde to undergo the reaction. All the nitrobenzaldehydes undergo normal dismutation under proper conditions. In general they require less concentrated alkali (15-35%) than most other aldehydes (50%) and more careful control of the temperature Stronger alkali and higher temperatures lead to decreased yields of products difficult to purify and to the formation of side products such as azobenzenecarboxylic acids.68 An aldehyde which carries substituents sensitive to alkali may undergo other changes involving these groups. An example is found in o-acetylaminobenzaldehyde, which undergoes an intramolecular condensation leading to 2-hydroxyquinoline.72 H N
S
CO I
NaOH
CH 3 CHO Disubstituted Benzaldehydes (Table IV). Benzaldehyde derivatives carrying two other substituents in the ring dismutate normally when at
N
" C a m p s , Arch. Pharm., 237, 682 (1899).
106
THE CANNIZZARO REACTION
least one ortho position is open, except 2,4-dinitrobenzaldehyde and those compounds in which one of the substituents is a hydroxyl group ortho or para to the formyl group (see p. 104). When both ortho positions are filled with halogen or nitro groups the reaction of the aldehyde with alkali takes a different course; the, formyl group is removed as formic acid and is replaced by a hydrogen atom. CHO OH-HCO2(X=Br, Cl, I, NO2)
2,4-Dinitrobenzaldehyde undergoes the same kind of change, but 2nitro-4-halo- and 2-halo-4-nitrobenzaldehydes undergo normal dismutation. A free hydroxyl group ortho or para to the formyl group interferes with both the cleavage and the dismutation reactions. The effect of two ortho alkyl groups is not recorded. Examples of the cleavage
TABLE IV _ X Y C e H s - C H O + O H - -» XYC6H3CH2OH + X Y C 6 H 3 e O O Yield of X Y Alcohol Acid Reference
2-C1 3-C1 3-OMe 2-1 2-C1 2-Br 3-OH 2-NO2 3-OH 2-C1 3-OH 3,4-BenzoG8naphthaldehyde)
•
5-C1 5-C1 5-OMe 3-OH 3-OMe 5-OH 4-OMe 5-OH 4-OH 3-OH 4-NOa ' —
90% 90% 88% 80% 80% 70% 86% 70% 0* 87% 39% ^80%
84% 90% 88% 80% 80% 80% 80% — 0* 96% 97% 82%
70 73 73 74 75 67 67 67 67 76 67 77
* After treatment with 50% potassium hydroxide for twenty-four hours, 95% of the aldehyde was recovered. 78 Lock and Nottes, Monatsh., 68, 51 (1936). 74 Lock and Nottes, Monatsh., 67, 320 (1936). 76 Lock and Hoseaus, Monatsh., 62, 178 (1933). 78 Lock and Hoseaus, Monatsh., 55, 307 (1930), 77 Sah, Rec. trav. Qhim., 69, 461 (1940),
TRI- AND TETEA-SUBSTITUTED BENZALDEHYDES
107
reaction for 2,6-dihalo-, 2,6-dinitro-, and 2,4-dinitro-benzaldehydes are not tabulated but may be found in the articles referred to in Table IV. Tri- and Tetra-Substituted Benzaldehydes. No important deviation from the limitations discussed above are to be noted when further substituents are present, provided that at least one position ortho to the formyl group is open. When an ortho or para hydroxyl group is present neither dismutation nor cleavage occurs under the usual conditions of the reaction. An ortho-axaino group acts similarly; 2,5-dichloro-6aminobenzaldehyde was recovered after treatment with 50% KOH at 100° for four hours.78 Groups other than halogen or nitro in the two ortho positions also can influence the mode of reaction. For example, while opianic acid can be transformed in good yield into hemipinic acid and meconine,79 pseudoopianic acid loses the formyl group under the influence of strong alkali.8?
CHO COOH
OCH 3 CH3 OCH3 The reaction ofFseudoopmnic acid with alkali is of special interest, since it leads hydrastinine to oxyhydrastinine and hydrohydrastinine.81 '
a
+ HCO2-
OH-
NHCH8 CHO
Hydrastinine
•N—CH 3 CO
Oxyhydrastinine
78
CH2
Hydrohydrastinine
Lock, Ber., 68, 1605 (1935). " Beckett and Wright, J. Chem. Soc, 29, 281 (1876). 80 Perkin, Jr., J. Chem. Son., 57, 1054 (1890). 81 McGeoch and Stevens, J. Chem. Soc, 1934, 1465,
108
THE CANNIZZARO REACTION
Hydrohydrastinine does not arise by ring closure of the corresponding alcohol during the reaction, since the alcohol is stable to alkali under the conditions of the reaction. Further examples of the Cannizzaro reaction for polysubstituted benzaldehydes are given in Table V.
TABLE V
POLYSUBSTITUTED BENZALDEHYDES
Yield of Substituents Acid 90% 2,4-diBr-5-OCH3 80% 2-Cl-3-OH-5-Br 90% 2-Cl-3-OCHs-5-Br 86% 2-Br-3-OH-4-OCH3 92% 2-Br-3,4-diOCH3 ' 85% 2-Br-3,5-diOCH3 87% 2-Cl-3,5-diOCH3 Alcohol 95% 85% 90% 80% 73% 90% 90% 50% 50% 50% 50% 50% 50% 50% KOH; 60-70°; 4-5 hr. KOH; 60-70°; 4-5 hr. KOH; 100°; 5 hr. KOH; 100°; 30 hr. KOH; 100°; 15 hr. KOH; 100°; 8 hr. KOH; 100°; 3 hr. 75 75 75 82 82 82 73 Conditions Reference
Aldehydes which are cleaved under the conditions of the reaction have been omitted, but pertinent references may be found in the literature cited.
Heterocyclic Aldehydes
The Cannizzaro reaction of heterocyclic aldehydes has been examined in a few cases only. Furfural,83 a-thiophenealdehyde,84 and a-pyridylaldehyde 86 undergo the reaction normally to give the expected products. 3-Formyl-l,2,5,6-tetrahydro-l-ethylpyridine resinifies upon treatment with potassium hydroxide,86 a behavior consistent with the observation that it is structurally similar to an a,/3-unsaturated alicyclic aldehyde. 3,4-Dibromothiophene-2,5-dialdehyde undergoes a complex series of reactions, involving both cleavage (loss of —CHO) and dismutation, when treated with alkali.87 Of particular interest in this connection is the fact that under certain conditions the ester composed of the usual
Lock, Monatsh., 64, 341 (1934). Org. Syntheses, Coll. Vol. I, 2nd ed., 276 (1941). 84 Biedermann, Ber., 19, 636 (1886). 86 Harries and Lenart, Ann., 410, 107 (1915). 86 Wohl and Losamtsch, Ber., 38, 4170 (1906). 87 Steinkopf and Eger, Ann., 533, 270 (1938).
88 82
S. J. and several have been discussed above (pp... 1825. Nenitzescu and Gavat 89 observed that equimolal mixtures 'of benzaldehyde or anisaldehyde with formaldehyde led to the formation of both possible acids and alcohols. J. 7. Chim. There is reason to believe. 905 (1935). 30. Gen. Soc. A. was formed. Chem. and little of the corresponding acid. 947 (1937) [C. Bui.. a-Pyrrolaldehyde appears to be stable to alkali. and that if formaldehyde was present in large excess the aromatic alcohol. 16A.S. Davidson and Bogert90 have worked out experimental conditions for carrying out the reduction of aldehydes by this means to give 85-90% yields of the alcohols. Gillespie. 99-102). Am. 42 (1934) [C. J. and Stern. TABLE VI RCHO + HjCO Aldehyde Veratraldehyde Piperonaldehyde Anisaldehyde Opianic acid Phthaldehydic acid Anisaldehyde Furfuraldehyde m-Nitrobenzaldehyde p-Isopropylbenzaldehyde p-Phenylbenz aldehyde 88 OH- RCH2OH Yield of Alcohol 85-90% 85-90% 85-90% 70-90% 70-90% 70-90% 70-90% — 42% — Reference 90 90 89.90 91 91 91 91 89 92 93 Fischer. 80 Davidson and Bogert. 31. 5572 (1936)]. M . 98 Koelsch and Geissman. 91 Rodinor and Fedorova. Ber. Studies of the crossed Cannizzaro reaction have not embraced so wide a variety of structural modifications as the examples discussed above in connection with the normal dismutation.88 ' The Crossed Cannizzaro Reaction Examples of this reaction have long been known. 1074 (1928). 5338 (1937)] 92 Cooke. Rom&nia.THE CROSSED CAtfNIZZARO REACTION 109 dismutation products could be isolated. Soc.. 67. The procedure may therefore be looked upon as a method for reducing aromatic aldehydes. U. Applications of the method to aldehydes of the aromatic series have been reported more recently. and Macbeth. unpublished observation. 61. Chem. Nenitzescu and Gavat. 1938.R. A. Chem. Beller. Soc..
. aqueous 'alkali alone is usually a sufficient solvent (or diluent). Temperature Often a spontaneous rise in temperature is observed when the aldehyde and alkali are shaken together. Alcoholic alkali may be preferred. The use of less than about 50% alkali usually prolongs the time of the reaction atad. since the products are not sensitive to the action of caustic. offers no advantages. 50% alkali (sodium or potassium hydroxide) is most generally used. vigorous shaking to form an emulsion of the aldehyde in the caustic solution is recommended. The crossed Cannizzaro reaction is carried out in methyl alcoholic solution. yields of the normal dismutation products are excellent. The use of alcohol or other solvent inert to the alkali may aid either in .110 THE CANNIZZARO REACTION however. where 15-35% alkali is sufficient to bring about the reaction and. At 45°. careful temperature control is seldom necessary.solution or dispersion of the aldehyde and is sometimes advantageous. Nitrobenzaldehydes react vigorously with 35% alkali. With aldehydes which react slowly the reaction mixture may be heated on the water bath until the reaction is complete (as noted by the disappearance of the characteristic aldehyde odor). none of the nitrobenzyl alcohol being obtained. Alcoholic potassium hydroxide (about 25%) has been employed with success for the dismutation of methoxybenzaldehydes but appears to offer no particular advantages since o-methoxybenzaldehyde is converted into the alcohol in excellent yield by the action of concentrated aqueous potassium hydroxide. " EXPERIMENTAL CONDITIONS Concentration of Alkali For aromatic aldehydes. except for nitrobenzaldehydes. and if the temperature is not controlled the reaction may proceed past the initial stage and lead to the formation of the corresponding nitrobenzoic acid and azobenzene carboxylic acid. for difficultly soluble aldehydes. that certain of the influences of structure upon the course of the reaction will operate in the crossed reaction as well. This may be moderated by cooling under the tap. Solvents Except as noted above. to control it so as to reduce the extent to which side products are formed.
.. The calcium is precipitated with oxalic acid. 101) and the conversion of furfural into furfuryl alcohol and furoic acid are described in Organic Syntheses. 70%).p. of calcium hydroxide and 75 g. Pure pentaerythritol melts at 260°. leaving the acid as • a crystalline residue (6. The pentaerythritol which separates weighs 50 g. of water is added 12. and after removal of the ether the producl is distilled. cooled. The residue is taken up in 200 cc.3-diol. of hot ethanol. b.5% of the theoretical amount) and melts at 258°. The same products are obtained if a-bromoisobutyraldehyde (31 g. of 10% NaOH as described above.5 g. The ether is removed. The resulting solution is warmed on the water bath to complete the reaction. The temperature of the mixture is maintained at 15° during the addition of the acetaldehyde and then gradually raised to 45°. The preparation of pentaerythritol (p.47 To a mixture of 18.2 g. of 10% NaOH in the cold being followed by further treatment with 40 cc. of formaldehyde in 500 cc.3 cc. of sodium hydroxide in 25 cc. The yield of the glycol. of water is slowly added 22 g. the calcium oxalate removed by filtration. After purification of the acid by distillation it melts at 80° (corr. Isobutylene Glycol and a-Hydroxybutyric Add.EXPERIMENTAL PROCEDURES EXPERIMENTAL PROCEDURES 111 The Cannizzaro reaction with benzaldehyde is described in a number of manuals of organic laboratory practice. After twelve hours the excess alkali is neutralized by passing in carbon dioxide. is nearly the theoretical amount. It melts at 42°. and the resulting solution allowed to cool.).3 g. 218-220°.42 To a mixture of 46 g. of . of methylethylacetaldehyde and 82 g. of potassium hydroxide. (73.** Below are a few typical examples of the reaction covering a number of the modifications discussed in the foregoing pages. 177-179°). of a-hydroxyisobutyraldehyde is added dropwise 40 cc. of 10% aqueous sodium hydroxide. Removal of the ether leaves the glycol as a honey-colored oil which is purified by distillation (b. and the filtrate evaporated to dryness under reduced pressure. The aqueous residue is extracted thoroughly with ether. of acetaldehyde. a preliminary treatment with 87. Pentaerythritol. 2-Methyl-2-ethylpropane-l.p.45 ^ m-Hydroxybenzyl Alcohol and m-Hydroxybenzoic Acid. and most of the alcohol is removed by distillation.) is used. and extracted with ether. The alkaline solution remaining after extraction of the glycol is acidified and extracted with ether.67 To a solution of 25 g.7 g. of formalin (40%) is added with cooling a 12% alcoholic solution of pqtassium hydroxide containing 23 g.37 To 16.
and the mixture becomes warm. of potassium hydroxide in 60 g. the mixture warming slightly. The yield of o-methoxybenzyl alcohol boiling at 245-255° (or 119°/8 mm.9 g.2 g. The alkaline solution is acidified and the ra-bromobenzoic acid collected. of o-methoxybenzaldehyde with a solution of 126 g. After standing at 30° for two days the mixture is diluted with much water and the product is extracted with ether.). The . is 73° (corr. saturated with sodium bicarbonate. after drying.6%) of m-hydroxybenzyl alcohol. After all the aldehyde has been added the mixture is warmed on the water bath until the aldehyde odor has disappeared (one hour).). of water is shaken until a stable emulsion has formed. is 13. m. of 35% aqueous sodium hydroxide solution. After one hour at 50-60° the solution is acidified with dilute hydrochloric acid. Spath. N o-Nitrobenzyl Alcohol and o-Nitrobenzoic Acid. The aldehyde dissolves slowly. the mixture is»w§rmed to 50-60°.112 THE CANNIZZARO REACTION m-hydroxybenzaldehyde. 128°/10 mm. m-Bromobenzyl Alcohol and m-Bromobenzoic-Acid. (91%). reference 64). The yield of pure material. the ether is removed. after one recrystallization from benzene the m.2%) of m-hydroxybenzoic acid. At this point the mixture is diluted with much water and yields o-nitrobenzyl alcohol upon extraction with ether.8 g. of o-nitrobenzaldehyde is added in one portion 60 g. m. 68°. 74° after orie recrystallization from 50% alcohol.) is 54 g. 155°) is 96%. Removal of the ether and distillation of the product yields 89% of the alcohol.68 To 30. m. The yield of acid (m.5 g.66 A mixture of 140 g. The temperature rise which occurs on shaking the mixture is moderated by cooling in running water. The residual solution is acidified and extracted with ether. 202° (corr. (94.p. After the mixture has been shaken for a short time it becomes more fluid but then solidifies completely at a time when the temperature has reached 45°. From the ether solution is obtained 5.68 The following procedure is applicable to monohalogen-substituted benzaldehydes in general: m-Bromobenzaldehyde is added slowly to an excess (5-7 moles) of 50% aqueous potassium hydroxide. (93. b.p. and the product is distilled. After dilution of the reaction mixture with water the mbromobenzyl alcohol is extracted with ether. and rapid solution of the aldehyde takes place. and.p. o-Methoxybenzyl Alcohol. Any unchanged aldehyde is removed by washing the ether solution with sodium bisulfite solution.p. removal of the ether and recrystallization of the residue from water affords 6. and extracted with ether. Acidification of the alkaline solution after removal of the o-nitrobenzyl alcohol yields o-nitrobenzoic acid. With certain halobenzaldehydes the addition of a small amount of ethanol hastens the reaction.p. (cf.p.
of water. * The preparation of p-tolyl carbinol by the crossed Cannizzaro reaction is described in Organic Syntheses. Vol. of water is added rapidly.90. and 100 cc. the oily layer separated. 146° after recrystallization from water. and reflux condenser are introduced one mole of the aromatic aldehyde. of sodium hydroxide or 168 g. three-necked flask fitted with a dropping funnel. A similar procedure is followed with the m.EXPERIMENTAL PROCEDURES 113 yield of pure acid. (96%). of methanol.2 g.3 moles) of formalin. The solution is heated to 65°.of the alkaline solution yields 2-5% of the aromatic acid. m. . Acidification. the benzene removed. and the aqueous layer extracted with four 150-co. the temperature being maintained at 65-75°. diluted with 300 cc. comparable yields being obtained. The mixture is then heated at 75° for forty minutes and finally refluxed for twenty minutes.* Into a 2-1. (1.p. is 15. and the flask is surrounded by cold water while a solution of 120 g. 590 (1943). The combined oil and benzene extracts are dried. 700 cc. The solution is cooled. 2. mercury-sealed stirrer. CoU. portions of benzene. The Crossed Cannizzaro Reaction.and p-nitrobenzaldehydes. and the product distilled under reduced pressure. The yields are 85-95%. (3 moles) of potassium hydroxide in 120 cc.
Comparison of Yields with Aluminum and Stannic Chloride in the Friedel-Crafts Method Table VI. l-Keto-l.3'. Cyclizations by the Friedel-Crafts Stannic Chloride Method . > 124 125 126 127 130 The Friedel-Crafts Method Table II. .4-tetrahydrophenanthrene With Thionyl Chloride Procedure II.2. Products of Cyclization in the Phenanthrene Series METHODS OP CYCLIZATION . . . Cyclization of 7-Phenylbutyric Acid to Tetralone-1 Table IV.CHAPTER 4 THE FORMATION OF CYCLIC KETONES BY INTRAMOLECULAR ACYLATION WILLIAM S. .2. . Table III. l-Keto-l. 2-Phenyltetralone-l With Thionyl Chloride * Cyclization of Anhydrides •. Some Cyclizations by the Friedel-Crafts Aluminum Chloride Method 114 130 133 134 135 136 136 136 137 138 140 141 144 145 145 146 147 148 . JOHNSON The University of Wisconsin CONTENTS INTRODUCTION .3.4-benzpyrene Stannic Chloride . . . .2'. T H E SIZE OP THE RING INFLUENCE OP THE'REACTIVITY OP THE AROMATIC NUCLEUS PAGE 115 116 118 Ortho and Para Directing Groups Mela Directing Groups Polycyclic Nuclei STERIC FACTORS OTHER THAN RING SIZE DIRECTION OP RING CLOSURE 118 120 122 122 124 The Benzene Nucleus • The Naphthalene Nucleus The Phenanthrene Nucleus Table I. .3. Table VII. Cyclization of /3-Phenylpropionic Acid to Hydrindone-1 . Aluminum Chloride With Phosphorus Pentachloride Procedure III.4-tetrahydrophenanthrene Table V. With Phosphorus Pentachloride Procedure I.4'tetrahydro-3. Cyclization of 7-3-Pyrenylbutyric Acid to 4'-Keto-l'.
.5. 36. .. . Soc. Chem. 33. Springall. Some Cyclizations with Sulfuric Acid Other Methods 'Stannic Chloride on t h e Free Acid Phosphorus Pentoxide Miscellaneous Methods and Reagents Table X I . T H E INFLTTENCE OF T H E M E T H O D ON T H E D I B E C T I O N OF CYCLIZATION .177 INTRODUCTION The cyclizations of 7-phenylbutyric acid (I) to tetralone-1 (II) and of . Ann. /3-phenylpropionic acid (III) to hydrindone-1 (IV) exemplify a type of intramolecular acylation which has served as an important tool in the synthesis of polycyclic hydroaromatic and aromatic compounds. 2 1 . Repta.. . Ann.1-2> 3 Such ring closures have been effected by a variety of methods generally involving either the direct cyclodehydration of the acids or the cyclodehydrohalogenation of the acid chlorides by an intramolecular FriedelLinetead. . Some Cyclizations with Stannic Chloride on t h e Free Acids . Soc.8-hexahydro-l. 336 (1936). 8 Fieser.4. Chem.. 1937. Ring Closure with Sulfuric Acid Table I X . Cyclizations with Hydrogen Fluoride T h e Sulf uric Acid Method Procedure V. .7. Repts. . . . 8-Keto-3. Table X I I .INTRODUCTION The Hydrogen Fluoride Method General Procedure Procedure IV. "Chemistry of Natural Products Related to Phenanthrene. . 301 (1939). Comparison of Yields Obtained by t h e Sulfuric Acid and FriedelCrafts Methods Table X . . Table X I I I . Eeinhold Publishing Corp. 115 PAGE 157 158 158 160 162 164 165 166 169 169 170 170 172 173 174 174 Table X I V . Some Cyclizations with Phosphorus Pentoxide . Table V I I I . .2-benzanthracene . Some Cyclizations b y Heating t h e Free Acid Chlorides . Cydization of 7-2-Phenanthrylbutyric Acid .6." 2nd ed.
. 144 (1928).. Braun and his collaborators found that the susceptibility of an acid to cyclization depends upon the size of the ring to be formed. the reagent and reaction conditions are sometimes critical and may have an extrinsic and secondary effect on the course of ring closure. also are not considered in this chapter. of naphthols from 7-phenylcrotonic acids. 394-428. or sulfur in the side chain. (6) the reactivity of the aromatic nucleus." pp. (c) steric considerations other than ring size. Acids containing nitrogen. Reinhold Publishing Corp. This order may not be preserved unless comparisons are made on ring closures into nuclei which are similarly activated. • Leuchs. this reaction has been covered by reviews through 1939 (references 1 and 2). Ring closure into a non-aromatic nucleus containing an ethylenic bond has been applied successfully but is not within the scope of this chapter. a treatment of this subject may be found elsewhere (reference 4). oxygen. THE SIZE OF THE RING In a study of the fundamental structural problems'involved in ring closure by intramolecular acylation. 1941.116 THE FORMATION OF CYCLIC KETONES Crafts reaction. * v.6 VI Thomas.4" The structural aspects which determine the inherent capability of these acids to undergo ring closure. or of indones from atto-cinnamic acids represents analogous reactions which are not discussed in this chapter. "Anhydrous Aluminum Chloride in Organic Chemistry. Ber. 61. In addition. 61. 441 (1928). Ber. leading to heterocyclic ketones on cyclization.6.4 This chapter presents a discussion of these methods and the various problems involved in the formation of cyclic ketones by the ring closure of aryl-substituted aliphatic acids. . The tendency toward formation of rings of various sizes is as follows: six > five > seven > others. of fluorenones from o-carboxybiphenyls. v. are: (a) the size of the ring formed. of anthrones and anthranols from o-benzylbenzoic acids. and which consequently control the course of the cyclization. including the effect of substituent groups. Braun. 4 . The fact that sixynembered rings are formed in preference to five-membered ones was demonstrated by the cyclization of a-benzyl-Y-phenylbutyric acid (V) to 2-benzyltetralone-l (VI). « 40 Formation of anthraquinones from o-benzoylbenzoic acids..
/3'-diphenyladipic acid to a chrysene derivative. 64.7 In all cases the cyclizations were accomplished by the Friedel-Crafts method (p. Braun and Rath. Soc.7-Diphenylbutyric acid (IX). which has the structural possibility of cyclizing to 3-benzylhydrindone-l. Ann.8. 1936. and the structures of the resulting ketones were proved. 8 and by the formation of 3-carboxy-4-phenyltetralone-1 upon ring closure of diphenylmethylsuccinicracid. 258 (1929). 10 v.. under the same conditions with which hydrindone-1 and also tetralone-1 were prepared in 70-80% yields. This preference regarding ring size is illustrated also by the cyclization of . J. C02H £12 0 CHj—CH2 XI v.9 Cyclization to form a five. gave only the product (X) of six-memberea ring closure. •-Hewett. Braun and Manz. 468.6 /3. 8 7 XII . Ber. 2461 (1931). This predilection for five-ring formation was inferred from the observation 10 that benzosuberone (XII) was obtained repeatedly in yields of approximately 20% from S-phenylvaleric acid (XI). Further substantiation was found in the conversion of benzylsuccinic acid (VII) into 3-carboxytetralone-1 (VIII) as the only product of cyclization which could be isolated. 130). 1182 (1927).. 60. Braun and Irmisch..THE SIZE OF THE RING 0 117 COaH C6H6 None of the isomeric hydrindone was obtained. v.rather than a seven-membered ring is always realized provided that both modes of ring closure are subject to the same intrinsic cyclizing influence. 596. Chem. Ber.
and Caasel. Wedekind. 323.12 INFLUENCE OF THE REACTIVITY OF THE AROMATIC NUCLEUS Ortho and Para Directing Groups. The formation of 4-phenylhydrindone-l from j3-2-biphenylpropionic acid afforded further substantiation. since the acid has the structural possibility of cyclizing to a seven-membered ring ketone. . Braun. 60. ' The formation of a six. Ber. Experimental foundation. was afforded by examination of the ring closure of /3-benzyladipic acid (XVII). The failure of phenylacetyl chloride and benzoyl chloride to cyclize under the conditions of the Friedel-Craf ts reaction has been reported. which was found to yield only the tetfalone derivative XVIII. respectively. Bayer. In general the common rules of orientation regarding intermoleoular acylation can be extended to the 11 1J v. moreover..or three-membered ring has been fbrmed by intramolecular acylation.118 THE FORMATION OP CYCLIC KETONES COjH (CH2)3C.H6 Hj—CH—(CH2)r-V^ XIII CO2H CH2CH2CO2H (CH2)2CO2H XVIII Proof of the premise was found in the cyclization 7 of a-benzyl-5-phenylvaleric acid (XIII) and of a-benzylglutaric acid (XV) which gave the hydrindone derivatives XIV and XVI.. Ann. and none of the isomeric benzosuberones.11 No examples have been found in which either an eight-membered ring or a four.in preference to a seven-membered ring follows as a corollary from the above considerations. 2602 (1927). 246 (1902).
" Krollpfeiffer and Sch&fer. seemed to offset in part the preference for the formation of a six-membered ring. Manz. J. Ann. consisted solely of 5-methyl-3-phenylhydrindone-l (XX). 64. 277 (1929). but the formation of the seven-membered ring ketone XCIII was definitely favored over the production of the phenanthrene derivative XCV.... Cyclizations meta to an ortho.H6 XXI XXII The powerful activating influence of the methoxyl group is indicated by the fact that 7-m-methoxyphenylbutyric acid (LIII. p. 620 (1923). therefore. The product of reaction. Soc.ORTHO AND PARA DIRECTING GROUPS 119 intramolecular reaction. 175). Braun. 56. 125) can be cyclized under the mildest conditions in 96% yield. arising from acylation para to the methyl group. p. 14 . and Reinsch. 13 v. For example.14 In the cyclization of 7-5-methoxy-l-naphthylbutyric acid (formula XCIV. Am. the 7-substituted tetralones XXIV were prepared 16 from the corresponding arylbutyric acids XXIII. was the only ketone encountered. Chem. Ber. This has been substantiated13 in the ring closure of /3-m-tolylhydrocinnamic acid (XIX). No material was found which corresponded to cyclization into the unsubstituted nucleus. obtained in 60% yield. A similar result was observed in the ring closure of a-benzyl-/S-»»-tolylpropionic acid (XXI). para directing substituent are known. the course of the ring closure seemed to depend somewhat upon the reagent and conditions of the reaction. formed in 75% yield by substitution at the para position to the methyl group. 468. The activating influence of the methoxyl group. Bachmann and Thomas. CO2H 0 C. so ring closures are preferably directed to one of these positions rather than into an unsubstituted nucleus. 94 (1942). Thus as ortho and para directing groups enhance intermolecular acylation. The hydrindone XXII.
. Soc. 139.. 16 " a more powerful directing substituent.120 THE FORMATION OF CYCLIC KETONES CO2H C CH2 R = CH3)C8HB. J.5% yield. I t is well known that groups which direct entering substituents to the meta position exert an inhibitory influence on intermolecular acylation. Chem. Soc. 928 (1942). prakt. The common use of nitrobenzene as a solvent in the Friedel-Crafts reaction is made possible by the deactivating effect of the nitro group. 16 the p-methoxy derivative X X I I I (R = OCH 3 ) was converted by the same treatment to 7-methoxytetralone-l (XXIV. J. and in at least one case opposite conclusions regarding the direction of cyclization were reached by sound methods. Braun and coworkers (reference 13) seemed to show that cyclization took place into an unsubstituted benzene nucleus rather than into the position meta to a methyl subetituent. 18 Johnson and Shelberg. 1923.. 64. 61.OCH8 xxiv Although there seems to be some question in regard to the influence exerted by an alkyl group thus situated. Chem. 169. " Fieser and Hershberg. Chem. Am.. 157) to the extent of 92%. ring closure of the pmethoxy derivative LXXXI (p. Chem. 1272 (1939). J prakt. Am.17 Similarly /3-phenylpropionic acid (III) was cyclized by hydrogen fluoride in 73% yield..16 while under the same conditions. unpublished observation. Braun'a assumptions are in error.' " Campbell and Todd. R = 0CH 3 ) in only 61. m Ingold and Piggott. 157) took place only to the extent of 3%. Chem. J. Meta Directing Groups. Soc.19 the p-nitro isomer failed to cyclize. such as the methoxyl group. The intramolecular reaction is similarly restrained by the presence of substituents which give meta orientation. Although /3-o-nitrophenylpropionyl chloride (XXV) has been cyclized successfully with aluminum chloride to the hydrindone XXVI in 7 3 % yield. however. 1 8 In addition. 1469. Thus while 7-phenylbutyric acid (I) was cyclized by hydrogen fluoride (p. / . appears to have a definite deactivating effect. More recent work [Pfeiffer and Roos.20 15a The work of v..OCH3 xxm R = CH3lCsH5. the comparison of yields is consistent with the premise that a six-membered ring is formed more readily than a fivemembered one. »• Hoyer. 13 (1941)] has shown. that some of v. 94 (1934).
* . III. 28 Manske. 37 (1939) [C.» The latter evidently arises from the eyclization of XXVIII. 178S (1931). which involves acylation meta to the carbonyl group. Thus eyclization of the acid chloride of 7-phenylpimelic acid (XXVII) by the Friedel-Crafts method (p. / . Braun and Weisabach. Soc. a small amount of /3-p-nitrophenylpropionaldehyde (yield 15%). although a small amount of the diketone XXXII was produced. 2837 (1940)]. Trans. Am. 130) gave two products: the tetralonepropionic acid XXVIII and the diketone XXIX. 34. O C0 2 H CH2 CH 2 XXVII C0 2 H CH2 XXIX CH2 XXVIII In the eyclization of /3-phenyladipic acid (XXX). 63.. COSH CH2C00H CHj—C02H XXX XXXI XXXII • l G»gnon and Hudon. S3. which consisted mainly of starting material. contained.22. surprisingly. Roy. 64. the main product was the keto acid XXXI. 41 v.MET A DIRECTING GROUPS 121 N0 2 XXV The product. Chem. A. The resistance of some other acids to ring closure because of the presence of the nitro group has been recorded.21 The carbonyl group seems to have less influence than the nitro group in hindering intramolecular acylation. Ber. Canada. 1104 (1931). Soc..
. were the benzhydrindones XXXIV and XXXVI. J. T>. for example. The necessity of the acylation occurring meta to the methoxyl group does not seem to account fully for the behavior because 7-0-methoxyphenylbutyric/acid has been cyclized to 5-methoxytetralone-l in fair yield24 and other ring closures meta to the methoxyl group are known.. 1934.15-26 Although XXXVII has been cyclized by means of hydrogen fluoride. In general. arylpropionic and arylbutyric acids in which the aryl group is a polycyclic aromatic nucleus cyclize readily.. respectively. Chem. Soc. R. Soc. STERIC FACTORS OTHER THAN RING SIZE The extraordinary difficulty experienced in preparing 5-methoxy-8phenyltetralone-1 (XXXVIII) from 7-(4-methoxy-3-biphenyl)-butyric acid (XXXVII) possibly may be explained by the hindering effect of the phenyl substituent ortho to the point of ring closure. Cyclization into the a-position of the naphthalene nucleus.16 24 86 Lockett and Short. Haworth and Sheldrick. 1950. 1939. The ring closure of the substituted naphthylpropionic acids XXXIII and XXXV proceeded smoothly. takes place more easily than into the benzene ring. It is noteworthy that this type of ring closure requires more drastic cyclizing conditions than are necessary for the usual type of intramolecular acylation. formed in yields above 70%.13 None of the isomeric ketones was found. YTYTTT XXXIV CH 2 C 6 H 8 XXXV The products. the yield was very low. J. 787. Chem. Polycyclic Nuclei.122 THE FORMATION OF CYCLIC KETONES Examples of intramolecular acylation ortho to a carbonyl group are well known in the cyclization of o-benzoylbennoic acids to anthraquinones.
STERIC FACTORS OTHER THAN RING SIZE 123 Some of the other conventional methods of ring closure. 1940. 49 (1940). J.. Chem.. Fieser and Hershberg. 1738 (1936).CHj) CH. J. An illustration is afforded by the cyclization of Y-8-methyl-2naphthylbutyric acid (XXXIX) to the linear anthracene derivative XLI instead of the expected ketotetrahydrophenanthrene. Soc. Chem. Hewett. Am. . . / 28 27 28 Fieser and Bradsher. J. failed to give any of the ketone XXXVIII.27 A similar abnormal course of cyclization28 has been observed in the benzylbenzoic acid derivative. In like manner the tetramethyl derivative XL gave the product of linear ring closure XLII in good yield. 62. 68. Am. Soc. Chem. Soc.26 X X X I X (H.ED XL (R . The only cases of cyclization of 7-2-naphthylbutyric acids in which the ring does not close into the reactive 1-position to form a phenanthrene derivative are those in which either this position is blocked or the 8-position is substituted. 293. moreover. The latter clearly seems to be an example of hindrance.25 The orientation influence of the methyl substituent would not be expected to affect the course of the reaction in such a manner. o-(8-methyl-2-naphthyl-* methyl)-benzoic acid (XLIII) to give the linear benzanthrone XLIV.
all attempts to induce the acids XLVI 3 0 and XLVII 3 1 to undergo cyclization resulted only in the formation of intermolecular condensation products. 56 (1917). The hydrindenylacetic acid XLV could not be cyclized.. 81 v. with which cyclization usually takes plaee at the position para to the substituent.. This structure. 82 v. Braun and Rath. Ber.TT DIRECTION OF RING CLOSURE The Benzene Nucleus. On the other hand. 145 (1929).vn All these product's of cyclization would contain two fused five-membered rings mutually fused to a benzene nucleus. Braun and Anton. represents a highly strained system. Thus 6-methoxytetralone-l (LIV) was obtained u " v . 956 (1928).29 even though the five-membered ring might be expected to close. 60. 61. Ber. Brauft. 62. CO2H H2CO2H xivm xx.M XLV 3XYI XT. Braun and Reutter.. 30 v. Ber. Danziger. Moreover. Ber. 1922 (1926). The main problem in direction of cyclization is presented when both positions ortho to the acid side chain are available and ring closure into both would result in the formation of two isomerie ketones. \ . In the benzene series the only acids having these structural properties are the meta substituted phenylbutyric and phenylpropionic acids. and Koehler. formula XLVIII. the basic polycyclic structures represented by formulas XLIX through LII can be formed by the intramolecular acylation reaction.124 THE FORMATION OF CYCLIC KETONES A different type of steric interference is revealed by the resistance to formation of certain types of polycyclic ring systems.. 69.10-so.
.. 58. For example. The cyclization of jS-2-naphthylpropionic and 7-2-naphthylbutyric apids generally leads to angular ring closure into the reactive 1-position of the nucleus. Am. Examples may be found in Tables VI through X I I I .83 Occasionally a case may be found in which some of the isomeric ketone arising from ortho cyclization is formed. R = CH 3 ). respectively. The free hydroxy acid LV (R = H) was shown to respond similarly to cyclization giving the ketones LVI (R = H) and LVII (R = H) in«80 and 14% yields. The resulting ketones therefore have the basic structures LVIII and LIX. J. 572 (1936).THE NAPHTHALENE NUCLEUS 125 in 96% yield from 7-m-methoxyphenylbutyric acid ( I I I I ) . R >. Soe. although in small proportion. respectively. 123). 2 ' CH8O Lin CH3O a small amount of 7-methoxyhydrindone-l (LVII.CHs) accompanied the main product LVI (R = CHs) in the cyclization of mmethoxyhydrocinnamic acid (LV. Chem. Johnson and Anderson. Linear ring closure may be realized only under extraordinary circumstances (p. Similar results were obtained with 7-m-tolylbutyric acid. The ring Evnt LIX closure of 7-l-naphthylbutyric acids nearly always results in the formation of 1-ketotetrahydrophenanthrene (LX) derivatives which arise 83 84 Fieser and Dunn. unpublished observation.84 O (CH2)aCO2H LVI Lvn The Naphthalene Nucleus.
2-eyclization seems to be preferred. Soc. with /3-1-naphthylpropionic acids. 2335 (1940).over five-membered ring formation. Chem. however. / . « Fieser and Gates. Soc. Soc. When the butyric acid residue is attached to the nucleus at the 3-position.126 THE FORMATION OF CYCLIC KETONES from acylation at the adjacent 2-position of the nucleus. 902 (1935). 1934.. Compt. The results of experiments on ring closure of the unsubstituted -y-phenanthrylbutyric and /3-phenanthrylpropionic acids are summarized in Table I. 4. Ring closure in the opposite directions would necessitate the formation of rings of more than six members. In at least one instance37 some of the five-membered ring product of 1. in part. forming a 1.. to position 2 giving a chrysene derivative LXIV. formulas XCIII through XCV). 1855 (1940) 91 Mayer and Sieglitz.4-benzphenanthrene ketone1 LXXII. Chem. 18 Fieser and Novello. and to position 10 yielding the triphenylene derivative LXXIII. to position 3 to form a 3. involving the formation of a seven-membered ring.86-36> "•38> 39 The course of the reaction is probably decided by the preference of six. 3. Chem. or impositions. Of the higher polycyclic systems. 62. 801. respectively. 365. 1835 (1922). The alternative direction of cyclization is into the peri position. 175. Darzens and Levy. Am. In the butyric acid series (column 2) no problem in direction of ring closure arises when the acid side chain is attached at the 1-.5-Benzhydrindone-l (LXIII) was isolated in 6% yield from the cyclization of /3-1-naphthylpropionic acid (LXI) in addition to an 81% yield of 7-perinaphthanone (LXII).2-benzanthracene derivative LXX. 4-. 0 usi jssn Lxm The Phenanthrene Nucleus. by the presence of activating groups appropriately situated (see p. This seems to be quite generally true not only for the unsubstituted acid but also 85 86 Cook and Hewett. Cyclization goes. The peri ring closure is generally predominant.. The inherent resistance to this reaction may be overcome. Am.. . Ber. rend. 55. J. the phenanthrene nucleus is the only one which has received much general * attention with regard to cyclization of the aliphatic acid derivatives.. although doubtless the activities of the 8.2-cyclization was formed. J.and the 2-positions are not identical. 62.
VJJ1 (ratio depends on method) .41 42 LXIV EXV (predominant) 0 (See Table XIV) 43 42. cf.TABLE I PBODTTCTS OP CYCLIZATION IN THE PHENANTHBENE SEBIES Position (x) of attachment of -(CH 2 )nCO 2 H From 7-z-Phenanthrylbutyric Acid Reference From /3-x-Phenanthrylpropionic Acid Reference 40. 44 I.It IX LXVH LX.
Chem. Am. Org. 1302 (1933). 1933. Hoch. 207. Soc.. 47. / . 175 (1937). Ber. 1933. Bachmann.. Org. Ber. Chem. 921 (1938). E.. Org. 69. 61. 69. Soc. ^ 60 Bachmann and Edgerton. 297& (1940). 2207 (1937). 61. 66. Chem.. J. Haworth and Mavin. 42 Bachmann and Kloetzel. Bergmann. J. Soc. Am. 2610 (1936).52 and 42 9 g 1. 41 40 Cook. J. 3. Am. Soc. 62. Am. Chem.TABLE I—Continued 45. rend. Chem. / . 48 . "Bergmann and Hillemann. Am.53 s TTgYTTT LXXIV 47 1XXV Bachm'ann and Struve. 1331 (1938). and Berlin. 51 E. Soc. Chem.. Am. J.. 1012. 62 Fieser and Joshel. 46 Bachmann and Bradbury.. 416 (1940). Chem. 2.. 1592.48 LXXI 50 Unknown LXXII 51.. Chem. 434 (1938).. Chem. Chem. / . Soc. J. / . 1647 (1939). Chem. 43 Fieser and Johnson. 59. 60. Compt. Soc. 2958 (1939). 63 Weizmann. J. / . Soc. Bergmann and Blum-Bergmann. 4 » Hillemann.46. 5.. 1441 (1937). 46 R D.
62. Chem. 59. a small amount of the isomeric linear cyclization product was isolated also. J. Investigations on other polycyclic nuclei are not sufficiently extensive to warrant a discussion at this point. perinaphthane.4-cyclopentenophenanthrene ketone (LXXI) in -good yield. Some of these are considered in detail in the following pages. Soe. J.10-dihydrophenanthrene.. however. pyrene. 1302 (1937). Soe.4-benzpyrene.68 While the latter oyclized exclusively to the 3-position. which cyclizes almost exclusively to the 2-position. 3. " Bachmann and Cheraerda. J. 2660 (1940). This tendency toward 3.4-cyclization also was realized with the 0-methyl homolog. chrysene. Robinson. «• Cook and (Mrs. 1984. 68 Burger and Mosettig. 1.1-cyclization. Org. M. 36 (1941). 176). 1938. Chem. Cyclization of jS-3-phenanthrylpropionic acid gave the 3.) A. 605. " Bachmann and Edgerton.or 9-position. Soc.2-benzanthracene. almost one-fifth of the total ketone obtained from the propionic acid consisted of material formed by 2. J. 428. in the unsubstituted acid the ring may be induced to close either into the 3. A number of the following cyclizations fall into this category..66 Although cyclization of 7-2-phenanthrylbutyric acids generally seems to favor the formation of the chrysene structure.and LXXIV and LXXV from the 9-derivative.or 1-position.THE PHENANTHRENE NUCLEUS 129 for acids containing substituents both on the side chain M-66-56 and in the nucleus. The cyclization of /3-phenanthrylpropionic acids proceeded in two directions a when the acid side chain is located at the 1. giving mixtures of ketones LXV and LXVT from the 1. J. From this observation^ it appears that no valid generalization can be made regarding the proportion of isomers formed in any ring closure which ^has the inherent tendency to take place in two directions..*9 Here.67 In one instance the isolation of a small but significant amount of the isomeric 3. This should serve as a warning regarding the inadvisability of drawing conclusions from such analogies.. 6. anthracene. In both examples the principal direction of ring closure is opposite to that which would be predicted on the basis of the behavior of 7-3-phenanthrylbutyric acid. Am. Chem. and others may be found in Tables IV through XIII. fluorene. A similar type of discrepancy was found in the 2-substituted propionic and butyric acid derivatives of 9. Chem.43 depending upon the experimental method used for cyclization (see p. « Cook and Haalewood. A number of individual cyclizations involving nuclei such as acenaphthene..4-benzphenanthrene derivative arising from 3. Am. . Chem. Soc.4-cyclization was reported.
69 When heated at about 120° under diminished pressure. The disadvantage of heating Friedel-Crafts acylation reaction mix'tures as long as hydrogen chloride is evolved has been demonstrated in the acetylation of benzene to acetophenone. and (6) reagents of inadequate -purity. 327 (1935).5. the use of a FriedelCrafts type of catalyst greatly facilitates ring closure. Soc. 202 (1943). In addition to these methods. •° Schroeter. 81 Smith and Spillane. 2003 (1924).7-tetramethylhydrindone-l. In general.130 THE FORMATION OF CYCLIC KETONES METHODS OF CYCLIZATION Probably the two most generally useful methods for effecting intramolecular acylation are by the Friedel-Crafts type of reaction on the acid chloride and the action of anhydrous hydrogen fluoride on the free acid. Revs. From a general survey of the literature it appears that the most common causes of poor yields in the Friedel-Crafts cyclization of acid chlorides are (a) reaction conditions which are too drastic. in the preparation of the chlorides of 7-arylbutyric acids by warming with phosphorus pentachloride for a short period. 3.63 An increase in the reaction 68 Schroeter. Bet.62> w but the advantage of mild conditions has not been generally appreciated.69-60 7-6-Tetralylbutyric acid upon such treatment gave 40% of ketone. 59. Am. was obtained. Soc. 2025 (1924). in at least two instances cyclic ketones were obtained in addition to the acid chlorides. to insufficient purity of reagents. in part.3. 17.. Ber.. 809 (1937). An extreme case is represented by the attempted conversion of j8-(3. cyclizations have been effected by the use of sulfuric acid and other reagents. Heating an acid chloride in the absence of a catalyst is a recognized method of cyclization (Table XIII). 67. J. An apparent necessity for heating the reaction mixture in order to induce cyclization may be due. The optimum conditions are those which are mild but still sufficient to complete cyclization. J. "CaUoway. the acid chloride lost hydrogen chloride to an extent approximating completeness.5-dimethylphenyl)-isovaleric acid into the acid chloride.61 Only the product of cyclization. Thus. 65. The Friedel-Crafts Method Many acid chlorides can be induced easily to eliminate the elements of hydrogen chloride intramolecularly. Chem. Chem. The vital effect of the presence of impurities on the Friedel-Crafts reaction is fairly well known. however. Chem. Am. •• Calloway and Green. along with the expected acid chloride. 57. .. so that the total yield of ketonicmaterial was 83%..
unpublished observation. Soc. and Dermer. low yields of hydrindone-1 (LXXVII) were obtained from /3-phenylpropionyl chloride (LXXVI) and aluminum chloride when the reaction mixture was heated too long. 8. J. Chem. the cyclization was completed in a few seconds and the yield • still further improved to 90%. 9. Six examples (4. 11) of the Friedel-Crafts Dermer. M Johnson and Helms. Chem.68 A high-boiling oily substance was the main product. 143. in general. C6H6C(CH3)=CHCOC6H5. and IV. Kipping. 65 M . in the preparation of hydrindone-1 from pure instead of crude /3-phenylpropionyl" chloride.ble II experiments on the formation of hydrindone-1 from 0phenylpropionic acid by various methods have been listed according to increasing yields. formed by condensation of two molecules of acetophenone was the chief by-product and became essentially the main product when the ketone was present in greater molar quantities than the aluminum chloride.THE FRIEDEL-CRAFTS METHOD 131 time resulted in a decrease in yield and increase in formation of high-boning oxygen-containing substances and tars. it is significant that a higher incidence of good yields is found under milder reaction conditions. also... in the cyclization of arylbutyric and arylpropionic acids by the Friedel-Crafts method. Dypnone. Soc. 1894. This may be seen by arranging the results of a cyclization in the order of increasing yields as iri Tables II. 1919. which has been shown 6e to contain some hydrindenylidenehydrindone-1 (LXXVIII). 63. Although other factors may enter.20 The conditions just discussed apply. Chem. Am. Johnson. Soc. it was shown M in several instances that a rapid decrease in yield resulted as the reaction time was increased. 480. The chlorine-containing compound C 18 Hi 5 0Cl isolated by Kipping 66 may therefore be the product formed by addition of hydrogen chloride to LXXVIII. 7. III. ixxvn Lxxvm On the other hand.67 With pure aluminum chloride. 10. J. 17 Ingold and Thorpe. Wilson. Similarly. the reactivity was so increased that only a few minutes' heating was required to bring about ring closure in markedly improved yields. J. 2881 (1941). In Ta. In the reaction of acetyl chloride and toluene under the influence of a variety of catalysts.
. The condensing agent thus was always present in excess.132 THE FORMATION OF CYCLIC KETONES ring closure may be found. it was found unnecessary to heat the reaction mixture in order to obtain 96% yields (example 8).hydrindone-1). A comparison of yields of some other cyclizations found in Table V affords further evidence in favor of the superiority of mild reaction conditions. The reaction was conducted in an inverse manner in that the acid chloride was added to the mixture of aluminum chloride in petroleum ether. consistent yields of 80% were obtained. chim.For the preparation of the acid chloride from the free acid.12 but the generality of this procedure has not been demonstrated. It is apparent that excellent yields (examples 9 and 10) were obtained when the reaction mixture was heated for only a short period or not at all. Mention of the use of the intermediately active ferric chloride may be found. The technique of heating until the evolution of hydrogen chloride ceased resulted in very poor yields (examples 1 and 2). in light of the observation M that the formation of undesired bimolecular ketone condensation products is inhibited by the presence of aluminum chloride in excess of one mole. . but by operating in the cold (example 8). The better yields (Table III. The inverse Friedel-Crafts technique has been used in a few other instances (Table y i l . In the cyclization of 7-3-pyrenylbutyric acid (Table IV) the higher yields obtained by the Friedel-Crafts reaction (examples 7 and 8) again involved the use of mild conditions. Even with the mild condensing agent. 16. examples 6 and 7) of tetralone-1 obtained by the action of aluminum chloride on 7-phenylbutyryl chloride also involve the use of milder reaction conditions. Ann. The superior yield reported in 11 was obtained by a procedure which seems to warrant further investigation. 340 (1921). M Haller and Bauer. stannic chloride. Nitrobenzene has served as a unique solvent in conjunction with aluminum chloride. The most common solvents are benzene and carbon disulfide. and the yields are generally good.. Repetition of example 4 by other investigators 68 gave similar results (50-55% yields of. a condition which might serve as an explanation of the success of the cych'zation. The catalysts or condensing agents which have been employed most frequently for intramolecular acylation by the Friedel-Crafts method are aluminum chloride and the less active stannic chloride. phosphorus pentachloride "and thionyl chloride have been used most frequently. Others such as petroleum ether and sj/m-tetrachloroethane also have been employed successfully. examples marked with "a"). since a complex is formed reducing the activity of the catalyst.
THE FRIEDEDOBAFT8 METHOD TABLE II CYCMZATION OF JS-PHENTLPROPIONIC Acm TO HYDRINDONB-1 133 Exam.. Miller and Rohde. Chem. 269 (1910). A noticeable increase in the rate of reaction was thus brought about.. soe. Soe. 1897. 940 (1927). 267 (1933). Soe. Am.. Ber. Soe. 2553 (1939). (a) Friedel-Crafts reaction on the acid chloride. Bull.. (d) The reaction was run inversely in that the acid chloride was added to the mixture of aluminum chloride in petroleum ether. 376. 70 69 . J. 33.Condensing Agent ple 1 . chim. 1924. Chan. 1887 (1890). 61. / . 2185. 78 Unger. Stevenson.. (c) Reaction was vigorous in the cold. (6) Procedure same as in example 7. Ann. "Thiele and Wanscheidt. Chem. 504. 238. [4] 41.. and Thorpe. Ann. "Amagat. 71 Price and Lewis. 71 Revis and Kipping.. J. Concentrated sulfuric acid 2 3 4 Concentrated sulfuric acid 5% Fuming sulfuric acid Aluminum Solvent Warm Conditions Yield 0% 10% 27% 55-60%* Reference 69 70 71 65 72 16 73 67 130° for 15 minutes 140° for S'minutes -60-70° petroleum ether Heat 20-30 minutes (a) chloride 5 6 i Hydrogen fluoride Chloroacetic anhydride (a) Aluminum chloride (a) Aluminum chloride (a) Aluminum chloride (a) Aluminum chloride Aluminum 26 hours at 20° Anisole Petroleum ether Petroleum ether Petroleum ether Benzene 170° for 48 hours Heat only a few minutes 73% 74% 75%* 7 8 Cold '80% 68 9 (6) Reaction over in a few seconds \ Cold (c) (d) 90%* 20 10 90%* 74 11 (a) chloride 60-70° petroleum ether (d) Warmed until complex dissolved 95%* 76 * Yield based on acid chloride. Speight. except that purer acid chloride was used.
74 Mayer and Stamm. J. Coll. Am. (6) Kipping suggests that the by-product is of the hydrindylidenehydrindone type. 55. Chem. J. 144. 2. Soc.5 hours) Water bath (3 hours) 10% • 2 (6) 10%* 27% 49% 50% 70%* 77 3 4 5 6 35 78 15 74 Benzene Cold Carbon disulfide (c) 7 Warm for 10 minutes 74-91% 79 chloride g Hydrogen fluoride 16 hours at room temperature 92% 16 * Yield based on acid chloride. 669 (1943). Vol. Ber. 1424 (1923). 4652 (1933).. n Martin and Fieser. (c) Allowed to stand until the evolution of hydrogen chloride became vigorous. " Kipping and Hill. Soc. then hydrolyied.. 56. Org. 1899.134 THE FORMATION OP CYCLIC KETONES TABLE III CTCLIZATION OF T-PHENYLBTJTYRIC ACID TO TETRALONE-1 Exam.Condensing ple Agent 1 Solvent Conditions Yield Reference 76 (a) Aluminum chloride (a) Aluminum chloride 96% Sulf uric acid Concentrated sulf uric acid Concentrated sulfurie acid (a) Aluminum chloride (a) Aluminum 70-80° petroleum ether 100-110° petroleum ether Heat until all hydrogen chloride is evolved Heat until all hydrogen chloride is evolved 100° for 1 hour Water bath (3. Chem. 78 Home and Shriner.. . (a) Friedel-Crafts reaction on the acid chloride. Syntheses.
2'. 1079 (1935).. and Streeck. and Soh6n. Am. Am. " Fieser and Fieser.. J. Ber.Condensing ple Agent 1 Solvent Conditions Yield Reference 80 P2O5. and Newman. 531. Soe. 3 hours refluxing 80-86% { 83 84 38 7 4 hours at room temperature. Chem.3'. POClj. H Cook and Hewett. Chem.. AlClg (o) All failed 2 34 Zinc chloride Stannic chloride Stannic chloride . Corell. Vetter. J. J. 1682 (1941). " Vollmann. Soe. Becker. 398.4-BENZPYRENE 135 Exam. Long. 193S. 59. 80% H 2 SO 4 . Soe. 80 . Carmack. Ann. and Safir. (b) Aluminum chloride (a) Stannic chloride (6) Stannic chloride (b) Stannic chloride Benzene Fuse at 180° for 1 hour Fuse at 115-120° for 1 hour Fuse at 110-112° for 1 hour 8 hours at room temperature 16% 19%37% 66% 80 80 81 5 82 6 Carbon disulfide Benzene 3 hours at 0°.. Chem. Am. 57. (b) Same as (a) except that reaction was carried out in the presence of the phosphorus compounds remaining after the formation of the acid ohlonde with phosphorus pentachlonde. CKem.. 85-05% 4 hours refluxing 8 hours at room temperature 96% 8 Benzene 86 (a) Friedel-Crafts reaction on the acid chloride. 782 (1935). 475 (1937).4'-' TETRAHYDRO-3.. Soe. 84 Fieser. 68. . Winterstein. / .THE FRIEDEL-CRAFTS METHOD TABLE IV CTCLIZATION or 7-3-PYKBNTLBUTTKIC ACID TO 4'-KETO-1'. 63. 86 Bachmann. Hershberg. 1 (1937).
355 mole) of powdered phosphorus pentachloride in portions with swirling and cooling in ice water. Thus no ketone could be obtained from j8-p-methoxyphenylpropionyl chloride and stannic chloride by procedures similar to those described below. The following procedure for the cyclization of 7-l-naphthylbutyric acid serves as a representative example of this method.86 Purification of the acid chloride by distillation or crystallization is generally unsatisfactory. consistently good yields (86%) of LXXXII (p. Of thirty-eight acid chlorides which have been cyclized (Table VI).324 mole) of 7-l-naphthylbutyric acid in 300 cc. Soc. private communication. With Phosphorus Pentachloride. L. Procedures involving the use of phosphorus pentachloride and thionyl chloride are described in the following discussions of stannic and aluminum chloride in cyclizations. Table V) the yields were definitely better with stannic chloride...4-tetrahydrophenanthrene. 157) resulted. (0. The Borsche a n d Eberlein.2. It has been found generally expedient to* treat the acid in such a manner that the by-products on formation of the chloride are readily removed. and few of the polycyclic acid chlorides can be distilled even under reduced pressure without considerable decomposition. examples with asterisks). Chem. twenty-one were converted to the ketones in yields of 90% or over. The milder condensing agent. for polynuclear and other acids having a strong cychzation susceptibility. 88 A. STANNIC CHLOBIDE Stannic chloride has been shown to be generally effective in the Friedel-Crafts reaction in bringing about ring closures into polycyclic nuclei.88 To a mixture of 69. but this reagent has serious disadvantages. One of the simplest and most satisfactory procedures88 consists in treating the acid to be cyclized first with one equivalent of phosphorus pentachloride in benzene.3. roundbottomed flask is added 74 g. appears to be less satisfactory for more difficult ring closures. 4 7 . 1460 (1914). Ber. thus excluding all material which might interfere with the cyclization.5 g. (0. Procedure I. however. see Wilds. Recommended. 1421 (1942) 87 81 . J. 64. Wilds.136 THE FORMATION OP CYCLIC KETONES Phosphorus trichloride also has been employed.18 With the aluminum chloride method. however. In six instances (Tables IV and V) the acid chlorides had previously been cyclized with aluminum chloride.87 l-Keto-l. and in all but one (example 5. Am. then with stannic chloride (Table VI. of thiophene-free benzene (dried over sodium) contained in a 1-1. Both techniques are likely to be wasteful.
A small amount of ether (about 25 cc.) is added to hasten the hydrolysis of the stannic chloride addition complex (which is soluble in ether). ' With Thionyl Chloride. it is perhaps less generally advantageous than phosphorus pentachloride. of concentrated hydrochloric acid. The procedure was essentially the same as Procedure I. thionyl chloride presents some advantage in that these by-products of the reaction are gaseous and therefore may be eliminated readily. A second crop from the filtrate amounts" to 4. 94-95°. giving 56.. (about 0. 63. Although thionyl chloride has been more widely used in the preparation of acid chlorides for cyclization with both stannic and aluminum chloride.38. the reagent has a •• Fieser and Heymann. run). 5% aqueous sodium hydroxide.WITH THIONYL CHLORIDE 137 i flask is protected from moisture by a calcium chloride tube which is removed only during the addition of reagents. of dry thiophene-free benzene is added rapidly with swirling or mechanical stirring. the best yields (example 8) were obtained when the suspension of solid complex was stirred for eight to nine hours at room temperature.2 g. After separation. the organic layer is washed with several portions of 5% hydrochloric acid. of material of the same melting point. even when the hydrolysis of the complex was effected immediately after the addition of the stannic chloride. The time and temperature of the action of the stannic chloride have been varied. If it is desired to obtain the acid chloride essentially free of by-products. moreover. m. After standing for fifteen minutes in ice water the mixture is hydrolyzed by the addition of ice followed by 250 cc.7 mole) of anhydrous stannic chloride in 80 cc. may be converted completely to the ketone only after several hours at the stannic chloride stage. ~ The total yield is 95%. and after standing at room temperature for an hour nearly all the acid and phosphorus pentachloride are in solution. The mixture is warmed on the steam bath for about five minutes. and finally again with water. At this point a solution of 80 cc.p. Chm. 2333 (1941). In the cyclization u of /S-methyl-7-3-phenanthrylbutyric acid (5-g. Soe.5 g. the yield of ketone was 97%. and the mixture is shaken until all the complex is dissolved. whereupon an orange-yellow complex separates. of colorless ketone. . except that a three-necked flask fitted with a mercury-sealed stirrer was employed. Am.Mi M Thus in the cyclization of 7-3-pyrenylbutyric acid (Table IV). Other acids. water. Since. J. and then is chilled until the benzene shows signs of beginning to solidify. Heat and hydrogen chloride are evolved during the vigorous reaction. in order to ensure complete reaction. however. After evaporation of the solvent the residue is crystallized (distillation for purification is unnecessary) from methanol.
/ ..94 In spite of the many disadvantages. excellent yields of ketones (Table VI. M Koelsch. Am. Soc. Compt. M Carre and Libermann. 62.93 or. Thus in the cyclization of j8-methyl-7-3-phenanthrylbutyric acid it was found that.. On the other hand.2. / . even after taking the usual precautions in removing the last traces of ether and thionyl chloride. 60.3. Chem.M Even a trace of the reagent which is often almost impossible to remove without spoiling the acid chloride may cause a noticeable decrease in the yield of ketone. In addition to the above precautions the mixture could not be heated much above 40° during removal of the ether without decomposition. An expanded description of the procedure of Bachmann and Wilds (reference 95). rend.87. J.. Procedure I/. thionyl chloride has been used with considerable success in numerous cyclizations.. in conjunction with stannic chloride and benzene for the cyclization. it can be removed readily when used in excess. 1422 (1934). Am. 60.. the yield was 86% as compared to 97% obtained by the phosphorus pentachloride method.64 In the same work a similar result was noted with 7-3-phenanthrylvaleric acid. A generally effective procedure for preparing the acid chloride involves the treatment of a dry ethereal solution of the acid with an excess of thionyl chloride and a drop or two of pyridine as a catalyst. Chem.4-tetrahydrophenanthrene.84 When thionyl chloride is used in conjunction with stannic chloride it is usually necessary to remove the thionyl chloride completely before cyclization.138 THE FORMATION OF CYCLIC KETONES boiling point of 79°. 176 (1938). Chem.M. 199.79 The treatment of Y-3-pyrenylbutyric acid with thionyl chloride was found to require exceptional care.90 By this method. Am. J. *' Bachmann and Wilds. Am. Soc.w describing a deleterious action of thionyl chloride. Among these are six examples in which the use of the reagent directly upon the acid resulted in the formation of tarry decomposition products. without the introduction of pyridine in more than catalytic amounts. 11 M . Soc. suction flask with a calcium chloride tube attached to the side Fieser and Peters. Chem.95° In a 125-cc.96 l-Keto-l. • 8a Private communication. a number of instances are on record 48> Mi Mi 90> M. Am. Soc. 2255 (1938).. 3885 (1933). Chem. 54. and in three others M-90> 91 it was found necessary also to use thionyl chloride of a high degree of purity. Commercial thionyl chloride may also promote undesirable side reactions to give sulfur-containing material. The ring closure of -y-1-naphthylbutyric acid affords a typical illustration of the procedure. •» Fieser and Desreux. Fieser and Snow. / . 2084 (1940). 55. Soc. examples without asterisks) were obtained. 4373 (1932). it may fail to give good yields of acid chlorides. In one case 48 the difficulty was eliminated by employing ether as a solvent.
The drying tube is then removed and suction (water pump) gradually applied to remove all the ether and excess thionyl chloride. It is advisable to distil (a two-bulb type flask 96 is satisfactory) the crude ketone under reduced pressure (1-2 mm. The acid chloride.1 mole) of commercial thionyl chloride and then^l3 g. (about 0. of dry benzene is added and the process repeated. The yield of material m. D. .0-11. of dry. of dry ether containing 2 drops of pyridine. "Experiments in Organic Chemistry. After a few minutes at the full pressure of the water pump about 5 cc. Heath and Co.13 mole) of stannic chloride in 15 cc. As in Procedure I the mixture is chilled. 250 and 318. is transferred into a 200-cc. (0.) before recrystallizing from methanol.. A list of ketones which have been prepared by the Friedel-Crafts stannic chloride method may be found in Table VI." 2nd ed.. The. 1941. pp. (0. C. with the vacuum pump for about five minutes. and after being swirled for five to ten minutes at 5° the mixture is hydrolyzed (using 50 cc. The flask is stoppered and allowed to stand in the hood at room temperature for one-half hour with occasional swirling.06 mole) of 7-l-naphthylbutyric acid. The last traces of volatile substances may be removed by reducing the pressure to about 1 mm. •* Fieser. Yields marked by an asterisk were obtained from acid chlorides prepared by the phosphorus pentachloride procedure. 94-96° is 11. (92-94%). temperature should not be permitted to exceed 40°. thiophene-free benzene. A piece of porous plate is introduced. and the mixture is warmed for ten minutes on the steam bath in order to complete the reaction.WITH THIONYL CHLORIDE 139 arm is placed 25 cc.p.2 g. of benzene is added. of concentrated hydrochloric acid) and worked up as in Procedure I. which remains as an oil. 15 cc. roundbottomed flask with the aid of 60 cc. all others were obtained from acid chlorides prepared from thionyl chloride. To the cooled mixture are added 8 cc.
Am. Kon and F. 99 Bachmann and Holmes.5 hours ture. 1 minute cold (b) Stannic chloride in benzene (a) 6 hours at room Aluminum chloride temperature in benzene lS. J. Soc. Ruzicka. Chem. Chem. 98 . 62. phosphorus compounds not removed before addition of condensing agent.. (d) About 17% of unreacted acid was recovered. J. Chem. 187. The yield based upon acid which reacted was 65%. J.5 hours reflux in benzene (6) 92% 99 72% 66 81% 89 (c) 81% 92-94% 100 COaH 5 minutes cold 95 Stannic chloride in benzene (6) 24 hours at 0° 74% HD 2 C—CHj -CH* Aluminum chloride in nitrobenzene (6) 42 1. Chem. in benzene reflux (6) 1 hour cold 90% 64 Stannic chloride in benzene (6) 16 hours at 0° 86% Aluminum chloride in sym-tetrachloroethaae OCH. Am. 100 Drake and McVey.5 hours reflux Stannic chloride in carbon disulfide (d) 54% (o) Acid chloride formed with phosphorus pentachloride. " Fieser and Johnson.hours at room (o) Stannic chloride in temperature benzene 12 hours at room (o) Aluminum chloride t e m p e r a t u r e . 61. 4. 2750 (1940). (c) Crude distilled ketone. 1936. 464 (1939). Soc. 2. C. J. J. Soc. (ft) Acid chloride formed with thionyl chloride. Org.140 THE FORMATION OF CYCLIC KETONES TABLE V COMPARISON OP YIELDS WITH ALTJMINTTM AND STANNIC CHLORIDE IN THE FRIEDEL-CRAFTS METHOD Acid Condensing Agent and Medium Conditions Yields Referof Ketones ence 77% 97 Several hours at (a) temperaAluminum chloride room 1. 168 (1939).
0 . Table V.95 9-ethyl 7-methoxy 9-methoxy 2-methyl 4-methyl 77% 90-95% 92% 95% 91% 101 102 99 103 104 88% 6-ethyl 4.FRIEDEL-CRAFTS STANNIC CHLORIDE METHOD TABLE VI CYCIJZATIONS BT THE FBIEDEL-CRAFTS STANNIC CHLOBIDE METHOD 141 Ring System of Ketones Prepared Naphthalene Yields Reference CH.5-Methylenephenanthrene Hs' 92%* 6-ethyl Cychpentenophenanthrene 54% Examples. Phenanihrene 96%' 14 92-94% • 88. 54% 60% 104 104 105 106 42 42 .
Table V Example 3. Table V Yields Reference 90% 74-80% 54 89 91% 48 7-methyl 8-methyl 1'-methyl 3.8.10-tetrahydro 64% 86% 72% 68% 107 40 107 40 40 ••65^'' 7 6 92% 91% 40 57 11-methyl .9.2-Bemanthracene Example 1.4-Benzphenanthrene 97%* 88%* 89% 64 54 57 o-O^Q Chrysene I 7 0 96% 60 74% * 3-methyl 2-methyl.142 THE FORMATION OF CYCLIC KETONES TABLE YI—Continued CTCLIZATIONS BY THE FRIEDEL-CRAFTS STANNIC CHLORIDE METHOD Ring System of Ketones Prepared 1. 1-methyl 7.
FRIEDEL-CRAFTS STANNIC CHLORIDE METHOD TABLE VI—Continued CTCLIZATIONS BT THE FBIBDBL-CRAPTS STANNIC CHLORIDE METHOD 143 Ring System of Ketones Prepared Reference 50 Triphenylene 101 Cholcmthrene 4-methyl 6-methyl " 7-methyl 3.4-Benzpyrene 108 108 109a 85 3'-methyl 2'-methyl l'-methyl 110 110 110 .
ALUMINUM CHLORIDE The examples of intramolecular acylation by the use of aluminum chloride in the Friedel-Crafts reaction occur in the literature so frequently that no attempt has been made here to enumerate all of them. 108 Bachmann and Chemerda. Chem. 63. 1685 (1941). Yields. Soc. Soc. 2494 (1941). 63. 50 (1941). 62. Chem. Am. J. and Wilds.. Soc. 106 Bachmann and Sheehan. those without asterisk were made with thionyl ohloride. 824 (1940). 4. The greater activity of the latter reagent was apparently not necessary in these instances. 6. / . Chem. J.. Am. 63. Org. / . Org. are more often hard to duplicate. Chem. Am. J. 2601. 63. 4. 110 Bachmann and Carmack.. .Sheehan. 1940. 62. 104 Baohmann and Edgerton. In five out of six ring closures. 107 Bachmann and Struve. Chem. Org. Elliott. Am. Am. J. Soc.5-Dimethylene-3. The reaction conditions generally seem to be more critical with aluminum chloride than with stannic chloride. / . 106 Baehmann and. 1OT (a) Bachmann and Safir. J. Baohmann. J. 855 (1941). Table VII includes several different types of arylpropionic and arylbutyric acids which have been cyclized by this method.. 204 (1941). Soc. 111 Bachmann and Carmack. 727. Chem. perhaps as a result. 63. 2598 (1941). There 101 102 Bachmann and Struve. These facts are doubtless due in part to the greater reactivity of aluminum chloride and to the difficulty commonly experienced in obtaining samples of this reagent which do not vary in catalytic effect. Soc.144 THE FORMATION OF CYCLIC KETONES TABLE VI—Continued CYCMZATIONS BY THE FBIEDEI/-CBAIT8 STANNIC CHLORIDE METHOD Ring System of Ketones Prepared Yields Reference 4'. 456 (1939). Chem. Am. Soc. Chem. Chem. and Linstead.4-benzpyrene 98%* 111 o* Prepared by the phosphorus pentachlonde method. 2219 (1940). J. Cole. Chem. better yields were obtained with stannic chloride than with aluminum chloride. Chem. 103 Burnop.. (6) ibid. 472 (1939). J. Am. A pronounced influence of the grade of the aluminum chloride already has been mentioned. Soc.
. p. 113 112 .. Chem. Ind. C.7-diphenylbutyric acid was effected in 94% yield only after the volatile phosphorus compounds had been removed from the reaction mixture. An excellent method of introducing the reagent slowly without exposure to the atmosphere has been described." 2nd ed. J. 116 Newman.-otherwise the yield was only 77%. Am. Newman (references 114 and 115). An expanded description of the procedure of M. Nitrobenzene also has been used as the solvent (examples marked by ('fc" and " / " ) .. Anal. Ed. 313 (1936). n«o Private communication. The method already described for the use of stannic chloride in conjunction with phosphorus pentachloride in benzene is a modification of the older aluminum chloride method (Table VII. There is some indication that the phosphorus oxychloride formed in the preparation of the acid chloride interferes with the cyclization when aluminum chloride is used. ^Phenyltetralone-l.1"-1Ui 116 seven acids have been cyclized in yields of 85% or better. The technique is essentially the same as that described in Procedure I except that efficient stirring (the Hershberg wire stirrer112 is highly satisfactory) generally is necessary while the aluminum chloride is added in portions with cooling. 311. The intermittent addition is accomplished by raising the containing flask. Soc. Fieser. of benzene (which has been dried over sodium). Am. Heath and Co. 870 (1940). D. examples marked by "k"). Soc. 60. the optimum time and temperature may vary for each acid. 63. With Phosphorus Pentachloride. The following description of the cyclization of aj-y-diphenylbutyrio acid is a typical example of the form of procedure. however. Chem.11*1 In a 500-cc. round-bottomed flask fitted with a calcium chloride tube are placed 88 g. . The application of the method is discussed below without reference to such distinctions. 8. "Experiments in Organic Chemistry.4 mole) of phosphorus pentachloride and 100 cc. Procedure III.WITH PHOSPHORUS PENTACHLORIDE 145 seems to bo. J. ««Newman. 63. 8. Eng.1M By removing the phosphorus oxychloride under reduced pressure before introduction of the aluminum chloride.. J. To this is added in portions with swirling Hershberg. Am. Soc. 2295 (1940).. Thus. Chem.1" The aluminum chloride is placed in an Erlenmeyer flask fitted to one of the apertures of a three-necked flask by means of a section of rubber tubing of large diameter. Chem. 111 Newman. The critical phase of the reaction is during the aluminum chloride treatment.. the cyclization of a. No single set of directions can be given which is entirely general. (0. 2947 (1938). which can be cut off frem the system at any time by kinking the rubber tube. a definite uee for aluminum chloride where oyolization is difficult. 1941.
38 mole) of a. After filtering by gravity through a dry filter paper containing some anhydrous sodium sulfate. (0. of dry thiophenefree benzene into a 1-1. After cooling to room temperature during an additional half-hour period. 118 Newman and Joshel. 76-77°.p. of ether is added to aid in the separation of the layers. 60. Chetn. thus avoiding anhydride formation according to the reaction RCOOH -K RCOC1 -> (RCO)2O + HC1. A good procedure for the cyclization of -y-phenylbutyric acid to tetralone-1 is described in Organic Syntheses. (The reaction temperature is more readily controlled with lumpy aluminum chloride than with finely powdered grades. Soc. of dry benzene. The residual oily acid chloride is transferred with 380 cc. the mixture is heated for a few minutes on a steam bath. 111 Perkin and Robinson.. Chem. Another method of separating the phosphorus compounds is by the use of petroleum ether. The mixture is then heated for one-half hour each at 40° and 60°. and finally with saturated salt solution. Soc.1166 After the vigorous reaction subsides and the reactants are nearly completely dissolved. The yield of colorless ketone is 74-75.) The aluminum chloride is added to the stirred solution at room temperature over a period of one-half hour (external cooling is sometimes necessary). urt injg ac j ( j j s added to the phosphorus pentaohloride so that the latter will always be present in excess.146 THE FORMATION OF CYCLIC KETONES a suspension of 91 g. 117 Fieser and Bowen. 145) containing 53 g.4 mole) of aluminum chloride. (0. J. The organic solution is washed successively with dilute hydrochloric acid. water. water. and all the volatile material is removed at the water pump at 100° or less to avoid discoloration of the acid chloride. / . 485 (1938). and the mixture is heated for a short period. although the reaction time and temperature may have to be altered and mechanical stirring may be required. Am. is soluble. the mixture is poured onto ice»and hydrochloric acid. 62.5 g.7-diphenylbutyric acid in 200 cc. J. the solution is concentrated and the product purified by distillation at reduced pressure as in Procedure II. Soc. then aluminum chloride.™ The acid is treated with thionyl chloride. a mercury-sealed wire stirrer. the excess of which is removed under reduced pressure.119 With Thionyl Chloride.112 and a rubbertubed addition flask (p. This description may be considered a general procedure. m. and about 100 cc. dilute sodium hydroxide solution. (92-94%). 2103 (1940). Am. . Other solvents such as carbon disulfide48> 109> U7 and sym-tetrachloroethane118 have been found successful in the cyclization stage. 1907.. carbon disulfide is added. A condenser and receiver are then set for reduced-pressure distillation. in which the acid chloride. but not the phosphorus oxychloride. Chem. three-necked flask equipped with a condenser (calcium chloride tube). 1073.
CYCLIZATION OF ANHYDRIDES 147 A more generally useful procedure may be developed by preparing the acid chloride according to Procedure II and conducting the cyclization as in Procedure III.121 COjH LXXX 120 121 Haworth and Sheldnek. Soc. Am. Cyclization of Anhydrides. sym-tetrachloroethane also may be used. Chem. The product of ring closure is a keto acid LXXX.. 1935. Instead of the acid chloride. examples marked by "h").90 The manipulation may be facilitated by the fact that aluminum chloride is soluble in nitrobenzene and can therefore be added in solution. Chem Soc. 62. 972 (1940) . / . 636.. J. The average yield of ketone on ring closure of 7-3acenaphthylbutyric acid by this method was 74%. ' ' Directions for using nitrobenzene as the cyclizing solvent have been described in detail. This resembles the intermolecular acylation with succinic anhydride. an intramolecular anhydride of the type LXXIX may be used for cyclization by the Friedel-Crafts reaction (Table VII. Newman and Joshel. Nitrobenzene *•66> 120 is a generally effective solvent for the reaction. and a similar procedure is generally followed.
CO2H 55-60% 75% 80% 90% 65 67 68 20 aU^J CH2 (S ' (a) 90% (o) 95% 80% 75% 75% (6)* 70%* 74%* 95%* 64-82% 94%* 90% # 74 75 22 122 13 123 124 91 125 126 127 128 129 128 128 128 117 128 128 128 » 128 (See Table II.6-dimethyla.J 2-bromo-5-methyl.J 2-cbloro• 2-chloro-5-methoxy2-chloro-^-methyl2-chloro-3-methyl2-chloro-4-methyl2-chloro-5-methyl2. . .3-dichloro-|8-metnyl2.) 2-bromo-5-isopropyl. 133) /9-acetic acid j9-(9-anthrone-10-yl)a-benzyl-3-methyl2-bromo2-bromo-5-t-butyl-1 . )• mixture 5-bromo-2-methyl. p.4-dimethyl2.3-dichloro2. ..5-dimethyl-1 .148 THE FORMATION OF CYCLIC KETONES TABLE VII SOME CYCLIZATIONS BY THE FMEDEL-CRAFTS ALTJMINUM CHLORIDE METHOD Acids Submitted to Cyclization Yields of Ketones Reference BENZENE DERIVATIVES P-Phenylpropionic acid .a-diphenyl/3. ^mixture 5-bromo-a.. „ . .] 2-bromo-a.. .2-dimethyl- 93%* 65% 76% 90-95% (c)(d)95%* — — 85% 66% 70% — (e) 6-28% 80% — — — 80% 96%* 82%* 128 130 119 68 131 131 131 68 132 133 . . „ .(3-diphenyl5-isopropyl-a.. „ . _. _.ot-diethyl3. .4-dimethoxya.1 ..5-dichloro2.5-dichloro-/3-methyla.a-dimethyl2.2-dimethyl.1 5-bromo-2-isopropyl. .5-dimethyl2. ^mixture 5-bromo-2-t-butyl.
THE FRIEDEL-CRAFTS ALUMINUM CHLORIDE METHOD TABLE VII—Continued 149 SOME CYCLIZATIONS BY THE FMEDEL-CBAFTS ALUMINUM CHLORIDE METHOD Acids Submitted to Cyclization 3-metboxy4-methoxy3-methoxy-4-methyl4-methoxy-a-methyla-methyl3-methylTS-pheny]/3-methyl-o-phenyl8.23 142 5.3.(3. cf.4-metb.5-trichloro2. 2-phenyl/3-o-tolyl0-p-tolyl2.6 143 144 5 120 9 (See Table III. p.3. 134) 7-acetic acid iS-aniByl-^methoxy-Y-acetic acid a-benzyla-bromo4-bromo|3-carboxy^-carboxy-3.4-dimethoxy-7. 70% 75% 66% 70% (/)(«30% 60% 10% 10% 70% 74-91% * .ylene dihydroxy2-nitroa-phenyl/3-phenyl.4-dimethoxyphenyl)iS-carboxy-Y-phenyl- . s^^Jl 8 CH2 f *y i:H2/3 Some (i) (j) 80% 60% 80% 77-84% * 60-65% (/)(A)91%* C/)W 72% 22.5-trichloro-|8-inethyla-p-xylyl a-CHjCHjCOaH a-CH2CHsCH2C6H6 y-Phenylbutyric acid CO2H t i^^X. 141 128 128 13 7 7 76 77 74 79 (0) 35% (/) 20% 86% (d) 42% * — 70-80% 82% 60% — (e) 15% (ff) 73% — — — 80% . \CH 2 a Yields of Ketones Reference 20 134 135 18 136 137 138 139 13 140 119 19 137 137 7 13. 15a 13.
4. .0-dimethyla.2-dimethyl-5-isopropyl/3.150 THE FORMATION OF CYCLIC KETONES TABLE VII—Continued SOME CTCLIZATIONS BY THE FRIEDEL-CRAFTS ALTJMINTJM CHLORIDE METHOD Acids Submitted to Cyclization <x./3-diphenyl4-ethyl«-ethyl-2-methyl0-ethyl-2-methyl4-isopropyl5-isopropyl-2-methyl4-methoxy2-methoxy-a.4-dimethyl2.5-trimethyl^methoxy-jS^jS^trimethyl4-methoxyiS.2-dimethyl7.3-dimethyl2.7-dimethyl0.3-trimethyla-methyl/3-methyl7-methyl2-methyl3-methyl4-methyl/3-methyl-a-o-tolyl- Yields of Ketones Reference 145 146 147 146 76 146 146 76 148 149 81% — 90% 92.4-dimetbyl-3-mefhoxya. 161 76 116 — — — 75% 70% 73%* 48% 70% (a) 82% 81%* 90% 72% 92%*.5% 85-90% (/)(a) 94% — — 58%* 87%* (a) 94% (a) >100% (a) 59% * 80% (i) 83% * 76 146 150 151 146 152 153 154 154 155 104 156 156 157 158 25 154 154 154 145 76 159 160 76 156 33 150.4-dimethyl-2-methoxya.4-dimethyl7.2-dimethyla.4-dimethyl/5.4-dimethyla.2.2-dimethyl-5-isopropyla.5% 75% — 90% 72% 89%* (a) 94% 76% — — (a) 92.
4-trimethyla.2. 15a 165 146 146 164 164 146 146 151 146 11 22^ 23 166 0 H i /9 H 1 trans 68%* 166 1 7 H 1 .3-trimethyla.(*)78%* Reference 162 163 75% (0 33-46% (c)(j) 52% • — — ' ' 70% 80% — — (a) 95% 90% 92% — (a) 82% — 55% 17%.2-trimethyl-" /3.2.4-trimethyl/3. (i) 45% 53%. 7-p-tolyla. cf.7.4-trimethyl7.4-methylene dihydroxyHYDRINDENE DERIVATIVES 7 1 4 .7.ds or trans <m) 20% (m)(d) 3(M0% (m) 45% (m) 50% (m)10 167 168 169 163 S-Phenylvalerie acid 3.4-trimethyl7.7.115 140 7 8 118 164 164 13.0.2.4-methylenedihydroxya-phenyl/3-phenyl/3-phenyl-7-acetic acid 7-phenyl-/3-acetic acid /3.2.5-tetramethyl-.7.THE FRIEDEL-CRAFTS ALUMINUM CHLORIDE METHOD TABLE VII—Continued 151 SOME CYCIMATIONS BY THE FBIEDEL-CRAFTS ALTTMINTTM CHLORIDE METHOD Acids Submitted to Cyclization 4-methyl-|3-p-tolyl-7-acetic acid 3.2-trimethyl«.7.2.4-trimethyIa.4-tetramethyli8.5-trime^hyl/3-CH2CH2CO2H 7-CH2CH2CO2H Yields of Ketones (i) 43% • — (c) 94% * .2.|3. (») 6% 58%* 114.
3.4-tetrahyaro1.2.4-tetrahydroP-2-Napkthylpropionic acid o-benzyl1-bromo• a-ethyli8-phenyl(/) 70% (P) (5) (P) (ft) 88% * (a) 72% • 35-45% (r) (/) 70% (r) — 39 13 39 39 39 173 174 32 39 • 13 39 39 13 .4-tetrahydro2-Naphthylacetic acid l-phenyl-l .4-tetrahydroo-phenyl2-phenyl-l .2.3.3.4-tetrahydroa-methyl-2-phenyl-l .2.2.3.3.2.152 THE-FORMATION OF CYCLIC KETONES TABLE VII—Continued Sous CTCUZATIONB BT THE FRIEDEL-CBAFTS ALUMINTJM CHLORIDE METHOD Acids Submitted to Cyclization P-l-Hydrindylpropionic acid •Y-1-Hydrindylbutyric acid y-5-Hydrindylbuiyric acid NAPHTHALENE DERIVATIVES 8 1 Yields of Ketones Reference 32 10 170 20-36% (m) 15% 83%* 1-Napkthylacetic acid 4-bromo2-ethyla-ethyl-2-phenyl-l .4-tetrahydroP-1-Naphthylpropionic acid CH2CH2COjH (/) — 85%* (c) {n) (c) (TI) (ft) 69% (c) 8 1 % • 40% 70%* 39 106 114 114 172 115 32 9 V (o) 34% a-benzyl4-bromoa-ethyl4-methoxy2-methoxy-j3-phenyl2-methyl1.2.3.
7-dimethyl-6-methoxy8-methyl7-methyl--y-isopropylACENAPHTHENE DERIVATIVES 7 8 100 98 98 175 176 10 177 25 175 » (i) 86% * • (o)(m) 4 1 % * 82% («) 12% (j) 30% * (i) 16% * (k) 74% * i 1 P-7-Acenaphthylpropionic acid 8a. 1.2.4-tetrahydroy-2-Naphthylbutyric acid jS.THE FRIEDEL-CBAFTS ALUMINUM CHLORIDE METHOD TABLE VII—Continued 153 SOME CYCLIZATIONS BY THE FRIEDEL-CRAPTS ALUMINUM CHLORIDE METHOD Acids Submitted to Cyclization y-1-Naphihylbutyric add CH2CH2CH2COjH Yields of Ketones Reference < 81%* W 4-methoxy5-methoxy6-methyla-n-propyl1.' 31 92 4 8 .2.3-tetrahydroy-l-AcenapMhylbutyric acid y-3-Acmaphthylbutyric acid FLUORENE DERIVATIVES 5 4 65% (/) 73% (/) 87% 30 90 178 p-9-Eluorylpropionic acid y-2-Fluorylbtftyrk acid PERINAPHTHANE DERIVATIVES 8 '33% ' ' .3.
1.8-tetrahydroANTHRACENE DERIVATIVES (/)(•) 3 1 % • (fc)(0«7%* (/) 69% (/) 74% * * ) 32% * (/)(«) 95% • (/)«)81%* (/)(fc)(u) 57% • (*)(«) 6 3 % * (fc) 77% * tf)(«65% (t) 35% (/) 62% • (fc) 72% * (c) 74% * • 42 58 44. l-dimethyl-7-isopropyl0-methyl(3-9-Phenanthrylpropionic acid y-2-Phenanthrylbutyric acid 9.3-tetrahydroftf-PerinapMhanepropioniC acid 9a.3-tetrahydroPHENANTHKENE DERIVATIVES 6 Yields of Ketones Reference 60% 75% 30 30 1 JO 0-1-Pkenanthrylpropimdc acid f)-2-Phenan(hrylpropKmic add 9. cf.10-dimethylene-S.6. cf.2. 179 42 180.10-dihydro/3-methylP-&-Phenanihrylpropionic and P. 181 90 56 48 y-2-Anlhryibutyric acid BENZANTHRACENE DERIVATIVES l.7. 1.10-dihydro•Y^-Phenanthrylbutyric acid a-carboxy-7-methyll-methyJ-7-isopropyly-4^Phenanthrylbufyric acid l. 181 49 42 43 43 97 56 182. cf.2-Benianthracene-5-acelic acid .2.154 THE FORMATION OF CYCLIC KETONES TABLE VII—Continued SOME CTCXIZATIONB BY THE FMEDEL-CRAPTS ALTJMINTFVI CHLORIDE METHOD Acids Submitted to Cyclization Perinaphthane-7-acetic acid 9a.
.. 115.4r-tetrahydrochrysene-l-acetic acid PYRBNB DERIVATIVES (c) 82% * 1096 y-S-Pyrenylbutyric acid (k) 56% * 82 * Yields marked by an asterisk were calculated from the acid. 2. Chem. 127 Fieser and Seligman. Gagnon and Gravel. cyolized to 2-position. 54 132 Koelsch and Le Claire. / . J. 177). Yield "almost quantitative. J. / . Am. Chem. 150. Yield calculated from acid consumed. . Soc. Research. Chem. (1935). Ind. Double cyclization. Crude neutral fraction. rend. 8. and Iball. Phosphorus oxychloride not removed. Mixture of isomers (see p. Soc. mixture of ketones from cyclization in both directions. 129 Fieser and Hershberg. 11.. 6. 131 Bachmann. Soc. Crude oily product in good yield. J. Chem. Chem. Am. 186 Chakravarti and Swaminathan. Org. 20% unchanged acid recovered. 1472 (1910). Phosphorus oxychloride separated with petroleum ether. Soc. l80 Haller and Bauer. «l/»n-Tetraohloroethane solvent. / . 479 (1937). 942 (1935). Soc.. Yield poor. Soc.. Cyclic anhydride used instead of acid chloride. Hoyer. J." Phosphorus oxychloride removed at reduced pressure.3. Nitrobenzene solvent."351 (1927). Chem. Hewett. Yield for meso form. Soc. J. Peri ring closure. Am. Soc. 5321 (1933)]. 157 (1939).THE FRIEDEL-CRAFTS ALUMINUM. After six hours' boiling in carbon di«ulnde. 1936. Cook. Ber. Compt. 2050 (1936). Chem. group lost. Soc. Most of the others were based upon the acid chloride. Ruppert. J. 101 (1934). Chem. 57. m v. 139. Can. Chem. 59. . 29% yield. 134 Brand and Horn. 2174. diketone also prepared from racemic but no yield given. J. A. cyclized to 10-position. prakt.2% yield. 138 Whittleston. Yield above 85% * (private communication). Plulipps. 61. J.. 68. Mixture of isomers. Am. 825 (1937). 128 Mayer. 57. 126 Bruce and Fieser. Am.. 59. Chem. prakt.2.CHLORIDE METHOD ^ TABLE VII—Continued _ 155 SOME CTCLIZATIONS BY THE FRIEDEL-CRAFTS ALUMINUM CHLORIDE METHOD Acids Submitted to Cyclization Yields of Ketones Reference CHBTSBNE DERIVATIVES ll-Methyl-l. J. 242 (1934). 27. 394 (1937). 69. J. Abnormal reaction. 92 (1919). 516 (1941).. 600 (1933) [C. (a) (6) (c) (d) (e) C O ig) (*) (0 (f) (k) (0 (m) (n) (o) (p) (8) (r) (s) (() (u) 122 125 Inverse type Friedel-Crafts reaction. Seven-membered ring formed. Chem. 52. and Schmitt. 1966 (1928). Am. 61. 126 Brace and Todd. Ber. 186 Fieser and Lothrop. Am.. Chem. 1M Fieser and Seligman. Auwers and Auffenberg.
and Irineu. Am. Helv. 173 Koelsch. Chem. 399 (1937). Chem. Chim. Chem. 63. Chim. 1687 (1918) "'Ruzicka and Ehmann. 1844 (1941). 15. and Morgeli. 1326 (1936). / . 176 Orcutt and Bogert. 1333. J. / .. 1938. Chem. Ada.. Soc. 164 Ruzieka. 710 (1922). 63. Ada. 176 Kon. 423. and Roe. 319 (1941). / . Thomas. Ada. Mayneord. 1901.. Soc. Ada._ ieo Weygand and Schroder. Ber. Chem. 154 Ruzicka. 13 (1941). 68. Hewett. 1285 (1930). Ada. Chem. Soc.. J. 74B.. Soc. 397. Chem. J. Soc. see reference 181 regarding structure.. 1776 (1937). Chim. J. Chim.. 44. and Lawrence. Soc. 169 Bachmann and Struve. 1938. Heilbron. • "° Plentl and Bogert. 166 Wilkinson. Am. Chim. 15. Soc. Ada. Ber. J. 166 Crawford. J. Am. 168 Borsche. 61. 181 Ruzicka and Waldmann. Helv. Chem. Narracott and Reid. 1618 (1940). Am. Chem. 54. Chem. Chem. Haworth and Sheldrick. 170 (1938). 149 Rupe and Schiitz. Chem. 62. 923 (1922). 182 Adelson and Bogert. / . Chem. 1938. Chem. J.156 188 189 THE FORMATION OF CYCLIC KETONES Kipping and Clarke. Soc. / . 151 Heilbron and Wilkinson. Soc. MiUidge. [&] 5. 4347 (1932). Bull. 608 (1939). 60. 359 (1911)]. 1934. 9. 5. soc. 63. Chem. Ada. J. Soc.. 1146. Helv. Ber. 160 Ruzicka and Morgeli. 148 Linstead. 1937. 128. Am. 102 (1935). 607. 63. / . Chem. 181 Fieser and Clapp. Soc. Chim. 1931. Soc. 1930. Heh. Soc. 59. 163 Rapson and Short. Soc. 180 Adelson and Bogert. 141 Pfeiffer and Roos. Soc. J. 5. 19. Soc. 1933. 1163 (1941). Helv. J. 179 Hillemann. 168 Ruzicka and Mingazzini. 177 R. 230. Am. and Wilkinson. J. 19. Hewett. Chem.. 159. 1402 (1930). 370 (1936).. 178 Fieser and Peters. 168 Ramart and Hoch. 69. 1933.237 (1910 [Chem. Helv. 913. r. chim. 2942 (1911). 1934. Helv. Soc. 142 Ramage and Robinson. Soc. J. Chem. 162 Plattner and Magyar. Helv. J. Zentr. J. 54. 778. 162 Ramage. 1991. J. Chim. 147 Ruzicka and Hosking. Lichtenstadt. Chim. 24. Ada. 171 Ger. 59. 58.. 314 (1933). J. J. 2165 (1937). 71. Ber. 166 Cook. 883 (1937). Chem. D.. 864. and Walpole. 144 Fieser and Seligman. Am. J. 146 Schroeter. Chem. Chem. Soc. "'Bergs. 174 Klyne and Robinson. Helv. Ehmann. Chem. Chem. 172 Koelsch and Richter. 166 Harvey. Chem. 848 (1938). 907 (1932). and Hofmann. 169 Borsche and Roth. 1936. 140 (1932). J. Cook. 174 (1921). . Soc. 1930. 992 (1926). Soc. pat. 16. Am. Am. Chem. 127 (1941). Soc. Soc. 1727. 377 (1936). 2537. J. 1903. 13. 51. Ada. 167 Kipping and Hunter. Ada. Hosli. Soc. Chem. Am. 170 Fieser and Seligman. Soc. Helv. Ser. 989 (1941).. Am. prakt. 602. 69. Soc. Chim. J. Am. 167 Ruzicka and Stoll. Chem. Chim. Ber.
the method lies in the simplicity of manipulation and in the consistently good yields. whereas other methods. perinaphthenone.39 always gave considerable amounts of the dehydrogenation product. It has been shown M that in the cyclization of ro-hydroxyhydrocinnamic acid (LV. including the Friedel-Crafts. /3-1-Naphthylpropionic acid (LXI) cyclized37 with hydrogen fluoride to give perinaphthanone-7 (LXII) in excellent yield. (It is significant that in spite of the low cyclizat^on susceptibility of LXXXI no intermolecular acylation occurred. were unsuccessful. the Friedel-Crafts method gave consistently good yields (86%) of LXXXII. although benzene was used as the solvent. which seems to have a strong tendency to undergo selfcondensation. nineteen were accomplished in yields of 87% or better. Hydrindone-1. R = H) the unprotected phenolic residue offers no complication with hydrogen fluoride.18 Although the yield could be raised to 36% by operating under pressure.) CO2H CH3O^ LXXXI LXXXII || The success of hydrogen fluoride as a cyclizing agent may be attributed in part to the fact that it manifests only a comparatively slight tendency to promote ketonic condensations and other undesirable side reactions. the total yield of phenolic ketones (LVI and LVII. The unique cyclizing power of hydrogen fluoride is shown with 7-(4-methoxy-3biphenyl)-butyric acid (formula XXXVII). 94% of unchanged acid was recovered. if only to the extent of 16%. The general procedure consists in allowing a solution of the acid in hydrogen fluoride to stand for a few hours in an open vessel at room temperature. The examples in Table VIII include the cyclizations of a 'number of different types of arylbutyric and arylpropionic acids. The excellence of. Other methods 36 ' 36 . Of the twenty-nine ring closures.THE HYDROGEN FLUORIDE METHOD » The Hydrogen Fluoride Method 157 In 1939 it was observed 16 that anhydrous liquid hydrogen fluoride is an excellent agent for effecting intramolecular acylation of aryl substituted aliphatic acids. R = H) was 94%. Since that time a number of cyclizations have been performed with this reagent (Table VIII). 0-p-methoxyphenylpropionic acid (LXXXI) was cyclized in only 3 % yield by hydrogen fluoride.26 In contrast. was prepared in satisfactory yield (Table II) using hydro- . Ring closure was realized.
"Experiments in Organic Chemistry. Chem. The cyclization of Y-(9. This process may be hastened in a current of air. The acid dissolves readily on swirling. water..10-dihydro-2-phenanthryl)-butyric acid is poured approximately 100 g.6. With heed to these precautions hydrogen fluoride can be handled safely and easily. Heath and Co.158 THE FORMATION OF CYCLIC KETONES gen fluoride. 62.7.5." 2nd ed. 188 Fieser. J. p. If the tank is previously chilled to about 5°.2-benzanthracene.8-hexahydro-l. fuming will be reduced. 10.p. and the colored solution i8!o When spilled on the skin hydrogen fluoride produces severe burns which become apparent only through pain several hours later.4.. Soc. If the acid is extraordinarily insoluble it may be necessary to employ mechanical stirring. 388. 11). the mixture should be stirred occasionally with a metal spatula. although copper flasks also may be used. and the reaction is often complete in ten to twenty minutes.) The ketone may then be purified in the customary manner. If 1. Platinum vessels appear to be most satisfactory. 184 Fieser and Johnson. examples 8. (This latter manipulation is not recommended for large-scale runs. and glycerol. Liquid hydrogen fluoride (b. goggles and rubber gloves must be worn. Consequently. C. The reactions may be carried out in the hood in an open container without provision for reflux. Am. or by heating gently on a steam bath.. General Procedure.1 g.he acid does not dissolve at once.4°) containing only 0. 14> ^ n expanded description of the procedure of Fieser and Johnson (reference 184). D. It is highly corrosive to tissue. 576" (1940). 1941. it should be handled with care.1-0. 19.183 The vessel containing the acid to be cyclized is tared on a rough balance in the hood and filled with 7 to 30 parts (based on the weight of acid) of hydrogen fluoride from the inverted tank through a copper tube. 8-Keto-3. of Y-(9. A colored soluble complex almost always is formed. although better yields have been obtained by the FriedelCrafts method (Table II. of liquid hydrogen fluoride. 9. The cyclization of yphenylbutyric acid to tetralone-1 (Table III) is perhaps best effected by this new method. 8< . Procedure IV. or the solution may be poured into a beaker containing ice and the product quickly collected by suction filtration or by ether or benzene extraction followed immediately by a washing with soda solution. Parts that have been in contact with the reagent should be washed immediately with water and then treated with a paste of magnesia.1820 and the vapors are very toxic.2% of water is available commercially in steel cylinders.10-dihydro-2-phenanthryl)-butyric acid 184 serves as a typical illustration of the procedure.18*° Into a platinum vessel containing 7. It is usually expedient to allow the mixture to stand at room temperature for several hours so that most of the excess reagent will evaporate.
60-80°) yields 5.5%) of pure ketone.5°. and concentrated to remove the benzene.129 1846 186 The double melting point corresponds to two polymorphic forms (reference 97). This is washed with water. As much as 67 g.5-97. of 7-2-naphthylbutyric acid. A single crystallization from ligroin (b. using 500 g.5-90. (89. has been cyclized at one time. The method also is applicable to the cyclization of o-benzylbenzoic acids to anthrones. Adkins and Lohr. m.p. giving 6. 89. The reagent is then largely removed with a stream of air and the residue neutralized with sodium carbonate solution and extracted with benzene.5°.186 The yield of pure~ketone was 94%.p.2 g. shaken with a little anhydrous sodium sulfate. (94%) of nearly colorless ketone. of hydrogen fluoride.92 g. remelting1846 at 96.GENERAL PROCEDURE 159 is allowed to stand at room temperature for about two hours. The residual oil is distilled under reduced pressure as in Procedure II. unpublished observation .
5% (d) 16% 121 17 16 («) 8 1 % 4 3 37 9-methyl Phenanthrene 3 96% 38 94% 185 2.3-dimethyl 8-CH2CH2-9 (/) 89% 88% 186 16 .160 THE FORMATION OP CYCLIC KETONES TABLE VIII CYCMZATIONS WITH HTDKOGEN FLUORIDE Ring System of Ketones Prepared Hydrindene O Yields Reference O—i 4 73% 80% 1 9 4 ^ 16 5-hydroxy 7-hydroxy jS-methoxy Naphthalene 0 14% J ° 34 18 («) 3 % (6) 36% 92% 6 4 16 3-acetic acid-4-phenyl 7-methoxy 5-methoxy-8-phenyl Perinaphthane 0 8 89% (c) 61.
CYCLIZATIONS WITH HYDROGEN FLUORIDE TABLE VIII—Continued CYCLIZATIONS WITH HYDEOGEN FLUORIDE 161 Ring System of Ketones Prepared Yields Reference 94% 185 187 186 1-methyl 2.2-Benzanthracene (g) 74-81% 186 89 78% 5-methyl 3.3-dimethyl Benzflwrene 93% 91% 188 Pyrene CH.4-dihydro 3. 31% 1.4-dihydro-3'-isopropyl-10-methyl Triphenylene 82% 90% 93% 43 184 181 87% 52 .
57% acid recovered.. 152 (1888). Soc. (d) Friedel-Crafts and sulfuric acid methods failed to give any ketone (reference 26). Lothrop and Coffman..5-benzhydrindone-l was isolated. 63. 62. unpublished observation. (e) Small amount (6%) of 4.4-Benzpyrene 70% 89 (a) Acid recovered unchanged. / .162 THE FORMATION OF CYCLIC KETONES TABLE VIII—Continued CYCLIZATIONS WITH HTDBOGEN FLTJOMDB Ring System of Ketones Prepared 4-methyl 2-methyl 2. (g) Lower yield on larger runs. Ann.Daudt. 782 (1941). 63. Johnson and Goldman.. Soc. 1293 (1940). 14. (c) Unchanged acid amounted to 34%. Ber. J. Chem. and Roser. Chem.5-Meihylenechrysene Yields 88% 93% (/) 7 1 % Reference 52 52 186 95% • 90% 189 0 189 3. Am. The Sulfuric Acid Method It has been known for some time 190 that sulfuric acid can be used as an agent for dehydrating 7-arylbutyric and j8-arylpropionic acids to Fieser and. *90An early instance has been reported by Reimer. 1802 (1881).. • 187 188 188 . Soc.3-dimethyl 4. total yield of ketone 87%. 2564 (1941).. 247. J. Chem. Am. (6) Reaction conducted in closed container under pressure for five days. 94%. (/) Mixture of diastereoisomers. 189 Fieser and Cason. Am.
A collection of typical cyclizations with sulfuric acid is given in Table X. the a-methyl and a-ethyl homologs have been converted to the tetralones in 98% and 86% yields respectively.4-dimethylphenylbutyric acid was isolated 16 from the water-soluble fraction produced on cyclization. although the reaction conditions may sometimes be quite critical.and tri-molecular condensation of hydrindone. Although it has since been possible to obtain hydrindone in 27% yield by the sulfuric acid method. Successful cyclization. 193 Haworth. The method usually gives at least some of the cyclized material.191 Similarly a-methyl-7-l-naphthylbutyric acid was cyclized in 91% yield. 182 Bachmann and Wilds. Thus. . Thus an attempt 16 to cyclize y-p-methoxyphenylbutyric acid with concentrated sulfuric acid failed. A further difficulty rests in the tendency of the reagent to sulfonate. unpublished observation. Thus a monosulfonic acid of 7-2. whereas 7-phenylbutyric acid has not been cyclized in yields exceeding 50% with sulfuric acid (Table III). Extensive sulfonation may occur when highly activated nuclei are involved.192 although in the case of the unsubstituted acid yields over 75% 193 could not be obtained. Early attempts to cyclize 0-phenylpropionic acid. J.71 the conditions appear to be extremely critical. 76 (1934). no ketone was produced. 64. The yields by the sulfuric acid method generally are lower than by the Friedel-Crafts or hydrogen fluoride methods.THE SULFURIC ACID METHOD 163 cyclic ketones.. Chem. A simple procedure which has been followed frequently consists in dissolving the acid to be cyclized in 4 to 10 parts of 80-98% sulfuric acid and warming the mixture on the steam bath for one-half to three hours. The examples in support of this are so numerous that no attempt is made to cite them all (see Table IX). particularly the uncyclized acid. was realized with the Friedel-Crafts method. One of the disadvantages of sulfuric acid as an acylating agent is its strong tendency to promote ketone condensation reactions. and only a sulfonic acid was obtained. The yields of ketone were only 10-15%. resulted only in the formation of hydrindenylidenehydrindone (LXXVIII) and truxene. Occasionally the introduction of some fuming sulfuric acid 71 or temperatures over 100° 70 may prove efficacious. 1125. This peculiarity may be explained by the fact that ring closure of acids containing a substituent in the a-position gives rise to ketones lacking the usual reactive methyl1 1S1 Brunner and Grof. for example. There seems to be some indication that a-substituted 7-arylbutyric acids can be cyclized by sulfuric acid in better yields than the unsubstituted acids.65 These substances were shown to be the result of the di. however. 1932. Monatah. Soc.
J. For the sulfuric acid method of cyclization there is no single procedure which is entirely general. it may be necessary to alter the conditions and concentrations. An interesting application of sulfuric acid cyclization was reported m in which 0-benzylglutaric acid (LXXXIII) was cyclized to the keto acid LXXXIV by the action of concentrated sulfuric acid at room temperature. It may be presumed. D.193 For the conversion of 7-arylbutyric acids into cyclic ketones. After one hour's heating on the water bath the colored solution is cooled. The method of R. and the distillate crystallized from a suitable solvent. and extracted with ether. This seems to be a CO2H CH2 LXXXIII P2 X CHCH< CH2CH2CO2H LXXXV 1M Stevenson and Thorpe. Soc. therefore. The extract is washed with water. the solvent is removed. The yield of crude material was 88%. . that the conditions for cyclizing ^-substituted acids by any method are in general less critical than for acids retaining both ahydrogen atoms. The possibility of interfering ketone condensations of the type discussed above is therefore eliminated. and the reaction time and temperature. which removes traces of colored sulfonation product. and dried over anhydrous potassium carbonate. may be critical. but the description serves only to indicate the form of procedure. the residue distilled under reduced pressure.164 THE FORMATION OF CYCLIC KETONES ene group. Being a structural feature this is true regardless of the method of cyclization. Procedure V. diluted with water by pouring onto ice. then with dilute aqueous ammonia. the finely powdered acid (1 part) is added gradually with stirring to a mixture of concentrated sulfuric acid (3 volumes) and water (1 volume). Ring Closure with Sulfuric Acid. because the concentration of the acid. 1717. Chem. In order to obtain optimum yields. Haworth1W has been used in the ring closure of a large number of acids. 1922.
The ring was closed by the action of concentrated sulfuric acid at 0° for forty minutes. (e) See Table IV.78 197 15 155 193 193 43 58 80 48 142 Attwood./3. Stevenson.196 A similar type of cyclization was reported196 in the case of the tricarboxylic acid LXXXV. 1935. J. Chem. 1923.7-Triphenylbutyric acid 7-1-Naphthylbutyric acid (c) 7-2-Naphthylbutyric acid 7-2-Phenanthrylbutyric acid (d) 7-(9. / .85 48 142 27% 50% 79% 50-55% 25% 70-75% 70-75% 44% 30% 0% 0% 0% 71 15. (6) See Table III. 2009. Rapson and Robinson.7-Dianisyladipic acid (a) See Table II. (c) See Table V. Soc.10-Dihydro-2-phenanthryl)-butyric acid (c) 7-3-Pyrenylbutyric acid (e) l.97 38. 1755. (d) See Table XIV. Chem. and Thorpe.THE SULFURIC ACID METHOD 165 general reaction for dicarboxylic acids which are capable of forming cyclic anhydrides.100 104 43 64. 196 196 197 Reference FriedelReference Crafts 95% 74-91% 96% 87% 58% 81-94% 90% 80-91% 77-90% 85-96% 74% 80% 75 79 14 104 155 95. but the yield was not recorded. TABLE IX COMPARISON OF YIELDS OBTAINED BY THE SULFTJRIC ACID AND FRIEDEL-CRAFTS METHODS Best Yields of Ketones Acids Submitted to Cyclization Sulfuric Acid /3-Phenylpropionic acid (a) 7-Phenylbutyric acid (6) 7-m-Methoxyphenylbutyric acid 7-p-Ethylphenylbutyric acid a. Chem.2-Benzanthracene-5-acetic acid /3. Robinson and Thompson. Soc. 1938. Soc. 1285. 3-Carboxytetralone-l (LXXX) was thus obtained from benzylsuccinic acid. . J.
/9-diphenyl3-ethoxya-ethyl4-ethyl5-ethyl-4-methoxy-2-methyl3-methoxya-methyl4-methyla-phenyl- (e) W(d) 82% (e) 72% 70% 10-15% 25% 70% 86% 50-55% 94% 79% 98% 80% (/) 57% 195 195 202 203 202 204 15 15 155 205 191 15 206 197 191 15 155 .4-dimethoxy-a.4-dimethyl3./3-dicarboxy3./3-dimethyl3.4-dimethoxy-/3-methyl2.4-dimethoxy3.4-dimethoxy-a-phenyl3.4-dimethyla.166 THE FORMATION OF CYCLIC KETONES TABLE X SOME CTCLIZATIONS WITH SUUFUBIC ACID Acids Submitted to Cyclization (3-Phenylpropionic acid CO2H Yields of Ketones Reference 10% 27% 2-bromo3-bromo4-bromo/S-carboxyi8-carboxy-o-phenyl3-chloro4-chloro3-chloro-a-methyl2-chloro-5-methyl5-chloro-2-methyl4-iodoa-methyl0-methyl2-methyl3-methyl4-methyla-phenyl/3-CH2COOH y-Phenylbutyrie add CO2H 10% 40-60% 22% (fl) — 55-60% 63% (6) 56% 60% 25% 30% 49% 70 71 198 69 69 70 190 69 198 69 199 198 69 70 200 69 69 201 70 35 78 15 j3-carboxy /3.
4-dimethyla.'Ob ' 5 4 1 0H i2 CH 2 a 70-75% 1 193 a.«-dimethyla.a.(c)(ft) 60% 166 166 a TT — 207 0-CH2CO2H y-l-Naphthylbutyric acid (c) 88% 194 cme y CH 2 .5-dimethyla-ethyl6-methoxya-methyl4-methyl5-methyla.SOME CYCLIZATIONS WITH SULFUBIC ACID TABLE X—Continued SOME CYCLIZATIONS WITH SULFUBIC ACID 167 Acids Submitted to Cyclization Yields of Ketones Reference 142 196 f\QO/ 1 \ " / \ff) a-CHCH2CO2H CH2CH2CO2H (Pi- a H \ 0 I transle) 68% cis.4-trimethyly-2-Naphthylbutyric acid • " 82% 85% — — 0") 60% (k) 84% 70% 91% 65% 70% 89% (0 208 209 210 211 210 210 212 193 192 211 210 209 CO2H CH2/3 8 CH27 4 / CH 2 a \ 70-75% 193 5 ./3-cyclopentanoa.5-dimethyl7.
2'.2-Dihydrophenanthryl-4^acetic add y-2-Phmanthrylbutyric add 9.5.8. Pure ketoue.2-Benzanthracene-5-acetic add l'.6-dimethyl0.10-hexahydroV-Naphthylmethyl-2-benzoic add Yields of KetoneS 80% 60% 50% 80% 50% 60% 75% 70% 00 25% 75% 69% 70% — 40% 60% 30% # $ • 75% 69% 29% - Reference 209 210 210 213 210 210 214 214 210 193 210 213 213 15 27 27 215 215 215 35 46 58 46 216 217 216 80 — 8 'Q^o2cX) Double cyclization.8.] . (J) 97% 218 2'.8-octahydrol.7.8-dodecahydroy-1-Pyrenylhutyric add 3.7.6-dimethyl7.6.2.7.9.4. (h) Mixture of da and trans isomers.7-trixjttethyll.2.10-octahydr<H y-9-PhenanthrylbiUyric add 1.7.8a.7-dimethyl7-ethyl-6-methyl7-ethyl-6-isopropyl6-isopropyla-methyl/3-methyl6-methyl7-methyl-6-isopropyl5.7.6-trimethyla.5.l. Heating unnecessary. U) Yield baaed on keto acid. Sulfurio-acetic acid mixture used for cyclization.3.3. j3.a-dimethyla.8-tetrahydro5.6.5.6.7.6.7.8-tetramethyla. Y-trimethylj3.7'-dimethoxy(a) (6) (c) (d) (e) (f) © 97% 218 (a) Dimethyl ester used for cyclization.5. (*) 9% acid recovered. Crude ketone.6-dimethyl6.4. (0 Seven-membered ring produced. (i) Variable results.6-trimethyl7.168 THE FORMATION OF CYCLIC KETONES TABLE X—Continued SOME CYCLIZATIONS WITH STILFTJRIC ACID Acids Submitted to Cyclization a.3'.4. Mixture.10-dihydroy-3-Phenanthrylbutyric add 4b.9.6. [References to table on next page.7-dimethyl<*.6.4'.
STANNIC CHLORIDE ON THE FREE ACID Other Methods
169
The extent of consideration given to the methods of cyclization discussed below is not intended to be an indication of the relative merits of the methods but is-necessarily limited by the available experimental data. Stannic Chloride pn the Free Acid. Ring closure by heating the free acid with stannic chloride at 100-120° has been shown to be successful on several types of acids.38- "• "• 66 ' 80 - 18B - a19 These and some other acids which have been cyclized by this method may be found in Table XI. In four instances (items 3, 7, 14, 17) stannic chloride treatment gave better results than sulfuric acid. Eleven of the acids in Table XI (items 3, 5, 8, 9, 10, 12, 13, 14, 16, 17, 18) have been cyclized also by the Friedel-Crafts method on the acid chloride. With seven acids (3, 6, 8, 9, 12, 14, 17) the yields were better, while with four (5, 10, 16, 18) they were lower, than with stannic chloride. Except for one (18) of these latter acids, however, there seems to be some question as to whether the optimum conditions for the Friedel-Crafts reaction were employed. Of the acids (4, 6,12) which have since been cyclized with hydrogen fluoride, considerable improvement in yields was realized. It may be suggested tentatively that ring closure by the action of stannic chloride on the free acid is generally inferior to both the FriedelCrafts and hydrogen fluoride methods. Some advantages seem to be afforded, however, by the simplicity of manipulation.
»•» Miersch, Ber., 25, 2109 (1892). 199 Fieser and Seligman, J. Am. Chem. Soc., 58, 2482 (1936). 800 Young, Ber., 25, 2102 (1892). 201 Miller and Rohde, Ber., 25, 2095 (1892). 101 Haworth and Mavin, J. Chem. Soc., 1932, 1485. 208 Robinson and Young, J. Chem. Soc., 1935, 1414. 204 Haworth and Atkinson, / . Chem. Soc., 1938, 797. 205 Peak, Robinson, and Walker, J. Chem. Soc, 1936, 752. 201 Harland and Robertson, / . Chem. Soc., 1939, 937. 207 Bluminfeld, Ber., 74B, 524 (1941). 208 E. Bergmann and Blum-Bergmann, J. Am. Chem. Soc., 69, 1572 (1937). 209 Sengupta, J. prakt. Chem., 152, 9 (1939). 2 " Haworth, Mavin, and Sheldrick, J. Chem. Soc, 1934, 454. 111 Haworth and Mavin, J. Chem. Soc, 1932, 2720. 212 Haberland, Ber., 69, 1380 (1936). 218 Haworth, Letsky, and Mavin, / . Chem. Soc, 1932, 1784. 214 Haworth, J. Chem. Soc, 1932, 2717. 816 Haworth and Bolam, J. Chem. Soc, 1932, 2248. 216 Cook and Haslewood, J. Chem. Soc, 1935, 767. 217 van de Kamp, Burger, and Mosettig, / . Am. Chem. Soc, 60, 1321 (1938). 218 Fieser, J. Am. Chem. Soc, 55, 4977 (1933). 219 Cook and Hewett, / . Chem. Soc, 1933, 1098,
170
THE FORMATION OF CYCLIC KETONES
Phosphorus Pentoxide. The direct dehydration of arylbutyric and arylpropionic acids has been accomplished in some instances with phosphorus pentoxide in organic solvents such as benzene or toluene (Table XII). The procedure involves treating the solution of the acid with 1 to 10 parts of powdered phosphorus pentoxide and boiling the suspension for one to three hours with mechanical stirring. The addition of a portion of Filter-Cel equal in weight to the amount of acid being cyclized may improve the reaction by holding in suspension the phosphoric anhydride, which otherwise tends to form a sticky coagulum.192 After the reaction is terminated, the excess phosphorus pentoxide usually is decomposed with dilute alkali and the product purified in the customary manner. The method appears fairly general and has the advantage over sulfuric acid in that no substitution reactions comparable to sulfonation can take place. On the other hand, the strong dehydrating action of phosphoric anhydride readily promotes further ketone condensations. Thus, phosphorus pentoxide reacted exothermically with /3-phenylpropionic acid220 to form truxene in about 40% yield. No hydrindone-1 was obtained. A modificatioa of the phosphorus pentoxide method involves the use of syrupy phosphoric acid.221 This affords the advantage of a homogeneous reaction mixture, but there is no indication that the method is an improvement, since so little experimental work is available. Miscellaneous Methods and Reagents. Some other methods of cyclization may be mentioned, although the generality of the procedures hardly has been demonstrated. The technique of heating the free acid chloride under reduced pressure already has been mentioned. The yields are generally inferior, and often the method may fail because the acid chloride either decomposes or distils unchanged. Some of the acids which have been cyclized by this method may be found in Table XIII. Ring closure by heating the free acid has been accomplished but appears to be of no practical value. Thus, 7-hydroxy-hydrindone-l was prepared in 3% yield by slow distillation of m-hydroxyhydrocinnamic acid at atmospheric pressure.222 By boiling a solution of a-p-anisyl-7-3-methoxyphenylbutyric acid (LXXXVI) in phosphorus oxychloride for five minutes, the cyclic ketone (LXXXVII) was formed in 73% yield ;J22° unchanged acid amounting to 16% was recovered. This same method applied to the trimethoxy acid
Kipping, J. Chem. Soc, 1894, 269. Koebner and Robinson, / . Chem. Soc., 1938, 1994. 222 Knake and Salkowski, Ber., 49, 2103 (1916). 2220 Dodds, Goldberg, Lawson, and Robinson, Proc. Roy. Soc. (London), B127,140 (1939); Goldberg and Robinson, J. Chem. Soc., 1941, 575.
Ml 220
MISCELLANEOUS METHODS AND REAGENTS
171
LXXXVIII gave the tetralone derivative LXXXIX in 99% yield. A modification of the phosphorus oxychloride method was used to cyclize CO2H CH CH2
LXXXVI (R = H) LXXXVIII (R = CH3O) LXXXVII (R LXXXIX (R =- <
7-2-methoxyphenylbutyric acid in 55% yield. syra-Tetrachloroethane was used as the solvent, and the mixture was boiled for two and onehalf hours.24 This was an improvement over the phosphorus pentoxide method which gave a yield of 16%. The excellent method for cyclizing o-benzylbenzoic acids to anthranol acetates, by heating the acid in- a mixture of acetic acid and anhydride with zinc chloride as a catalyst,223 has been used also in the preparation of cyclic ketones of the tetralone type. In this way 7-3-acenaphthylbutyric acid has been cyclized in 78% yield;224 7-2-phenanthrylbutyric acid *• and the 9,10-dihydro derivative 97 in 5 1 % and 59% yields respectively; and a,/3-dimethyl-7-2-naphthylbutyric acid in 90% yield.186 Another reagent, fused zinc chloride, which has been more commonly used for the ring closure of o-benzylbenzoic acids, was applied to the cyclization of 7-3-pyrenylbutyric acid (Table IV, example 2). The reaction was carried out at 180°, and the yield was 16%. An interesting ring closure has been described in an attempt to effect an acylation of anisole with j3-phenylpropionic acid in the presence of chloroacetic anhydride.73 Only intramolecular acylation occurred, giving hydrindone-1; the yield after heating for forty-eight hours at 170° was 74%. 3,3-Diphenylhydrindone-l was similarly prepared in 67% yield. This further stresses the preference for intra- over inter-molecular acylation.
M !M
»Fieser and Hershberg, J. Am. Chem. Soc., 59, 1028 (1937). Fieser and Hershberg, J. Am. Chem. Soc, 60, 1893 (1938).
172
THE FORMATION OF CYCLIC KETONES . TABLE XI
SOME CTCLIZATIONS WITH STANNIC CHLOBIDE ON THE FREE ACIDS
Acids Submitted to Cyclization p-Phenylpropionic add a,5jdimethyl-2-isopropyl5-methyl-2-isopropyly-Phenylbutyric acid 3-methoxyP-1-Naphthylpropionic acid • fl-'ir-Naphihylpropionic acid y-1-Naphthylbutyric acid a,i8-cyclopentano5-methoxy6-methoxy•Y-2-Naphthylbutyric acid /Vy-dimethyl-6-methoxy6-methoxy-5-methyly-2-Anthrylbutyi~ic acid y-1-Phenanthrylbutyric acid •y-3-Phenan(hrytt>utyrii; acid a-methyll-methyl-7-isopropyly-3-PyrenylbiUyric acid a-methyl-
' Yield? of Ketones
Reference
1. 2. 3. 4. 5. 6.
(a) 69% (6) 90% 85-90% (c) 45% 32% 70% (d) 13% W 40% 68% 70% 72% 34-77% 65% — 75% 29% 49% 37% 80%
139 139 225 35 219 226 208 98 227 226 177 228 56 41 45,47 55 182; cf. 181 81 81
7.
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
(o) Cydisation process repeated twice on recovered acid. (&) Calculated from acid consumed (about one-half). (c) Ring closure in two directions to give mainly perinaphthenone resulting from dehydrogenation of the normal cyclization product perinaphthanone, and a small amount of 4,6-benihydrindone-l. (d) Toluene used as a solvent. (e) Abnormal cyclization; gives variable results (see p. 175). "» Peak and Robinson, J. Chem. Soc., 1937, 1581. »M Hoch, BuU. soc. chim. [5] 5, 264 (1938). " ' B u t e n a n d t and Schramm, Ber., 68, 2083 (1985). •*• Hill, Short, and Higginbottom, J. Chem. Soc., 19»6, 317.
MISCELLANEOUS METHODS AND REAGENTS TABLE XII
SOME CTCLIZATIONS WITH PHOSPHORUS PENTOXIDE
173
Acids Submitted to Cyclization P-Phenylpropionic acid 3,4-dimethoxy2,5-dimethoxy3,4-methylenedihydroxyy-Phenylbutyric acid 4-methoxy2-methoxy8-Phenylvaleric acid 3,4-methylenedibydroxyy-1-Naphthylbutyric acid a,/3-cyclopentano5-methoxy7-methoxya>-methyl-6-methoxyy-2-Naph(hylbutyric acid 6-s-butyl-7-methyl3,7-dimethoxy6-ethyl-7-methyl3-methoxy6-methoxy-7-methyl0
Yields of Ketones
82%
Reference
119
(a) 82% 87% 61% 16% (6) 10% (6) 19% 11% 47% 83%
86%
229 119 230 24 86 86
208
24 230 103 192 ' 231a 2316 231a 232 233
(c)(d) 86% — 30% — — 80%
(e) 63%
221
6-methoxy•• p-9-Phenanthrylpropionic acid y-9-Phenanthrylbuiyric acid l,2-Benzan(hracene-5-acetic acid 2-methyl-l,2,3,4-tetrahydro-»
(o) (b) (c) (d) (f)
!M
(e) 19%
32%
68% 51%
221 53 51 208
Crude yield As the semicarbazone. Yield based on acid consumed (about nine-tenths). Filter-Cel used in cyclization. Syrupy phosphoric acid used in cyclization.
Arnold and Zaugg, J. Am. Chem, Soc., 63, 1317 (1941). "° Plimmer, Short, and Hill, J. Chem. Soc., 1938, 694. 231 (o) Ruzioka and Kaufmann, Hdv. Chim. Ada, 24, 939 (1941); (6) Haberland and Siegert, Ber., 71, 2619 (1938). 831 Haberland and Kleinert, Ber., 71, 470 (1938). m Short, Stromberg, and Wiles, / . Chem. Soc., 1936, 319.
174
THE FORMATION OF CYCLIC KETONES
TABLE XIII
SOME CYCLIZATIONS BY HEATING THE FREE ACID CHLORIDES
Acids Submitted to Cyclization
Yields of Ketones
Reference
P-Phenylpropionic
acid
3,4-methylenedihydroxyy-PhenylbiUyric acid
(«) —
(b) 60% (6) 40% (o)-
86 6 15 86 86 86 234 161 234 60 234 235 59
a-benzyl2,4-dimethyl3,4-methylenedihydroxyS-Phenylvaleric acid
3,4-methylenedihydroxyy-1-Naphthylbutyric acid
Failed (o) 55% (c)(6)65% (d) 50% 88% (6) 67%
(d)(b)(e) 83%
4-methoxy-6-methyl4-methoxy-5,6,7,8-tetrahydro5,6,7,8-tetrahydro•y-2-NaphthyIbutyric acid
5,6,7,8-tetrahydro(o) (6) (c) (d) («)
Phosphorus trichloride used to form the acid chloride. Phosphorus pentachloride used to form the acid chloride. Twelve per cent acid recovered. Thionyl chloride used to form the acid chloride. Mixture of ketones (see p. 175).
THE INFLUENCE OF THE METHOD ON THE DIRECTION OF CYCLIZATION
In an acylation reaction which gives a mixture of isomeric ketones, the proportion of these isomers can sometimes be altered more or less by changing (a) the solvent, (6) the temperature, and (c) the entire method of acylation. To what extent the proportion of products may be altered, if at all, by such experimental changes cannot be predicted. The influence of the above factors on the course of the reaction has been demonstrated for intermolecular acylation. Changing the solvent from benzene to nitrobenzene in the Friedel-Crafts acetylation of naphthalene makes it possible to obtain principally the /3-isomer instead
JM 236
Schroeter, Miiller, and Huang, Ber., 62, 645 (1929). Radcliffe, Sherwood, and Short, J. Chem. Soc., 1931, 2293.
INFLUENCE OF METHOD ON DIRECTION OF CYCLIZATION 175 of a mixture of the a- and /3-substitution products.286 That a change in reaction temperature may influence the proportion of isomers was shown in the succinoylation of acenaphthene.90 Changing the method of acetylating acenaphthene from the Friedel-Crafts to the hydrogen fluoride technique was found to make possible the preparation of a new acetoacenaphthene in yields which can be accounted for only by a definite change in the proportion of isomers.16-237 In the present problem of intramolecular acylation the conditions which have been most effective in altering the direction of ring closure have been those which involve different methods of cyclization. The case of 7-5,6,7,8-tetrahydro-2-naphthylbutyric" acid (XC) affords an example of the possibility of controlling, at least partially, the direction of ring closure by using different methods. When the free acid chloride
(CH,),CX)IH
xo
xci
xcn
was heated under reduced pressure, an 83% yield of a mixture of about equal quantities of l-keto-l,2,3,4,5,6,7,8-octahydroanthracene (XCI) and 4-keto-l,2,3,4,5,6,7,'8-octahydrophenanthrene (XCII) was obtained.69 On the other hand, when the acid (XC) was cyclized with warm concentrated sulfuric acid, a homogeneous product, which proved to be the ketooctahydroanthracene XCI, resulted in 75% yield.16 Another instance of selective ring closure was reported 98 in the cyclization of Y-5-methoxy-l-naphthylbutyric acid (XCIV). The (CHs)8CO2H
SnCl
" 0 + SomeXCIII OCHs xcv
Friedel-Crafts reaction with aluminum chloride in sywt-tetrachloroethane gave 7-keto-4-methoxyhomoperinaphthane (XCIII) in 41% yield. Heating the free acid with stannic chloride, however, produced l-keto-8-methoxy-l,2,3,4-tetrahydrophenanthrene (XCV) in 40% yield
S8 JS7
«Eivkin, J. Qen. Chem. U.S.S.R., 6, 277 (1935). Fieser and Kilmer, J. Am. Chem. Soc, 62, 1354 (1940).
176
THE FORMATION OF CYCLIC KETONES
as the only product isolated. The stannic chloride method upon repetition m proved to be unreliable as it gave the phenanthrene derivative less frequently than the product of pen ring closure. The phosphorus pentoxide cyclization was shown also to give the aeven-membered ring closure.24- »» A striking example of selective orientation is illustrated by the cyclization of 7-2-phenanthrylbutyric acid (XCVI). By the hydrogen 0 (CH2)3COaH
xovi
xovn
fluoride method, a high yield pf ketone resulted consisting almost entirely of 8-keto-5,6,7,8-tetrahydro-l,2,-benzanthracene (XCVII), which was obtained pure in 78% yield.43 In contrast, the pure isomeric 4-keto-l,2,3,4-tetrahydrochrysene (XCVTII), was obtained in 74% yield by the Friedel-Crafts stannic chloride method,107 and in 5 1 % yield by the zinc chloride acetic acid-anhydride technique.43 When the ring was closed with sulfuric acid a mixture resulted from which only the chrysene derivative (XCVIII) could be isolated, and this in poor yield. An apparent influence of the solvent was noted in the action of aluminum chloride on the chloride of XCVT, which gave mixtures of the two ketones in which the benzanthracene derivative (XCVII) predominated. This isomer constituted about Wo-thirds of the total using benzene as a solvent, and a still higher proportion (about nine-tenths) in nitrobenzene solution. A difference in reaction temperatures also may have influenced these ratios. That the temperature may affect the proportion of isomers is indicated by the fact that, when cyclization with stannic chloride was conducted at room temperature instead of in the cold, a mixture of ketones resulted instead of a single ketone.107 A summary of the results of the experiments on the cyclization of 7-2phenanthrylbutyric acid may be found in Table XIV. The sharp contrast between the direction of ring closure with hydrogen fluoride (item 6) and with stannic chloride in the Friedel-Crafts* reaction (item 1) is quite striking and of obvious practical significance. Some further indications that hydrogen fluoride has an unusual influence on the ori488 M
Kon and Soper, J. Chem. Soc., 1939, 790. » Hill, Short, and Stromberg, / . Chem. Soc, 1937, 1619.
INFLUENCE OF METHOD ON DIRECTION OF CYCLIZATION 177 entation in intramolecular acylation are given by the cyclization of a,/3-dimethyl-7-2-naphthylbutyric acid186 and of 7-2-anthrylbutyric acid.89 In both reactions there .was a definite indication that some of the linear isomers were formed along with the normal products of ring closure. In the first this partial defiance of the normally strong tendency toward cyclization into the 1-position of the naphthalene nucleus seems to be significant. TABLE XIV
C Y C L I Z A T I O N O F -y-2-PHENANTHBYLBtrTYRic A C I D
Method of Cyclization
Yield of Total .L 1CXV4 \J1 J . \J LCvX Crude Ketone
Yield of Benzan- Yield of Chrysene thracene Ketone Ketone XCVII XCVIII 74% (m.p. 122-124°) 14% . (m.p. 112-117°) '58% (m.p. 124-125°)
1. Friedel-Crafts—stannic chloride (thionyl chloride) method m 2. Friedel-Crafts—stannic chloride (phosphorus pentachloride) method 24° 3. Friedel-Crafts—alumi' num chloride (phost phorus pentachloride) method 4S in benzene in nitrobenzene 4. 85% Sulfuric acid 4S 5. Acetic acid-anhydride with zinc chloride 4* 3. Hydrogen fluoride43
74% (m.p. 122-124°) 80%
35% 17% (m.p. 115-116.5°) (m.p. 122-125°) 51% 5% (m.p. 110-114°) (m.p. 118-124°) (6) 23% (m.p. 123-125°) 53% (m.p. 124-125°) 85% 78% (m.p. 114-118°) (m.p. 117-118°) 91% (a) 70% (m.p. 90-110°) 44% (m.p. 90-112°) 62%
(a) Crude distilled neutral oil. (!>) All attempts to isolate any of XCVII failed.
2i
" Fieser and Johnson, unpublished observation.
Use of the Hahn Condenser 201 Procedure III. PAGE 179 The Nature of the Reaction Advantages of Aluminum Isopropoxide over Other Alkoxides T H E SCOPE OF THE REACTION 180 181 18? Selective Reduction of Carbonyl Groups Stereochemical Configuration of the Reduction Products Limitations of the Method Side Reactions Condensation Dehydration of the Alcohol Migration of Double Bonds Ether Formation Further Reduction to a Hydrocarbon '. . . Preparation and Amount of Aluminum Isopropoxide Apparatus Recovery of the Isopropyl Alcohol EXPERIMENTAL PROCEDURES . .5 Equivalent of Aluminum Isopropoxide.4-Dinitrophenylhydrazine) 200 Reduction of Aldehydes 200 Procedure I (For Volatile Aliphatic Aldehydes and Ketones) 200 Reduction of Crotonaldehyde 200 Procedure II (For Aromatic Aldehydes) 201 » Reduction of Benzaldehyde with 0. The Use of Aluminum Ethoxide 202 178 . Reduction of Keto Esters Reduction of Esters of Hydroxy Ketones Reduction of a-Bromoketones SELECTION OF EXPERIMENTAL CONDITIONS 183 185 186 187 187 188 189 190 191 191 192 193 194 Solvent and Temperature . . . .CHAPTER 5 REDUCTION WITH ALUMINUM ALKOXIDES (The Meerwein-Ponndorf-Verley Reduction) A. ^. WILDS University of Wisconsin CONTENTS INTRODUCTION . . . 194 195 196 197 198 Aluminum Isopropoxide 198 Acetone Test Reagent (2. L.
He showed.CHSCHO The reaction is reversible. 788' (1927). This has the additional advantage of preventing side reactions such as an aldol condensation between the original aldehyde and acetaldehyde. This mild and specific method of reducing carbonyl compounds became' known as the Meerwein-Ponndorf-Verley reduction 4 and in the next decade was used successfully in a number of instances. 228 (1937). By the use of aluminum isopropoxide. Chem. that the reaction can be made more general by employing the aluminum derivatives of the more readily oxidizable secondary alcohols. 444. 138 (1926). RCHO + CH8CH2OH ( > RCH20H -f. [4] 37. Butt. Ann. 537. soc.-2. chim. Meerwein and Schmidt. AKOCJHJ). 41. 34. (London). 39. Reduction of Ketones with Aluminum Isopropoxide . Chem. Reduction of Aldehydes with Aluminum Alkoxides Table II. Repts. further. Angew.4-tetrahydrochrysene in Toluene Reduction of Acetals or Enol Ethers StFBVEY or ALUMINUM ALKOXIHE REDUCTIONS REPORTED IN THE LITERATURE . In 1926 Ponndorf3 reported that in independent work he also had evolved this new method of reducing aldehydes. and (6) Bersin. The reduction of the aldehyde occurs at the expense of an equivalent amount of ethanol which is oxidized to acetaldehyde. Procedure V (For Ketones Resistant to Reduction) Reduction of 4-Keto-l. but the equilibrium can be shifted to the point of complete reduction by removal of the acetaldehyde with a stream of dry hydrogen or nitrogen.. ketones as well as aldehydes could be reduced satisfactorily. angew.. 53. 871 (1925).. 179 PAGE 202 203 203 204 204 204 205 Table I. 266 (1940). the acetone formed being removed from the equilibrium mixture by slow distillation. 4 Reviews of the Meerwein-Ponndorf-Verley reduction have been published by (a) Linstead. Soc. 8 Ponndorf. 221 (1925). Ann.INTRODUCTION Reduction of Ketones ' Procedure IV (For Ketones Boiling aSbve 175-200°) Reduction of Benzophenone '. Z. The method of reduction with aluminum ethoxide was found applicable to several aldehydes but to only a few ketones of special types.3. 2 1 . particularly Verley. Chem.. INTRODUCTION 206 209 In 1925 it was discovered independently by Verleyx and by Meerwein and Schmidt2 that an aldehyde can be reduced to the primary alcohol by treatment with aluminum ethoxide in the presence of ethanol.
The carbonyl compound and aluminum isopropoxide. 33. However. Ber . it is "usually preferable to employ enough of the reagent to accomplish the reduction directly. Ber. (I). Maanedsblad. It has been shown that under the influence of light 6 or at temperatures of 200 to 300°3 the equilibrium between the alcohol and the carbonyl compound is brought about slowly without a catalyst. since an exchange reaction of the solvent with the aluminum derivative of the reduction product regenerates the aluminum isopropoxide. was not fully apparent until 1937. R' \ H \ CH3 / R' \ H / / CH3 c=o + / R Al/\ ^-0 c CH3 <± = / R c \ A l 0-^ + o=c \ CH3 The reaction involves the transfer of one valence bond of the aluminum atom and one hydrogen atom from the alkoxide to the carbonyl compound. The Nature of the Reaction The reduction of aldehydes and ketones is carried out very easily. however. .180 REDUCTION WITH ALUMINUM ALKOXIDES with unsaturated aldehydes and ketones. 17. when Lund B applied the method to a variety of aldehydes and ketones and studied the scope and limitations of the reaction.2> s When isopropyl alcohol is the solvent the aluminum isoR' \ R i O—A1(OC3H7)2 / C 0 H \ C CH3 / CH 3 propoxide may be considered a catalyst. He also developed a simple method for determining completeness of reduction.4-dinitrophenylhydrazine. prepared from aluminum and isopropyl alcohol. 2911 (1900). 34. The general equation may be represented as follows. which consisted in testing the distillate for acetone with 2. Zentr. 6 Ciamician and Suber.1. The exact mechanism of this transfer is unknown. 70.. 1520" (1937). 1530 (1901). Its general value. although an intermediate aluminum derivative of a hemiacetal (I) has been postulated. 3480 (1937)]. 169 (1936) [Chem. are heated in boiling isopropyl alcohol solution with provision for slow distillation until no more acetone is formed. also Kern. At these high tem6 Lund.
In the presence of the aluminum alkoxide the reaction occurs readily at temperatures of 20 to 80°. 10 Baker and Adkins. Am. Chem... J. Chem.. 58. ibid. 3364 (1939). Soc. J. and the yield of product is improved.. Kirschnick. / . 12 Meerwein. including magnesium ethoxide. 4973 (1930). 56... 4967 (1930). It was only gradually appreciated that aluminum isopropoxide is equally suitable for the reduction of aldehydes and superior to the ethoxide for this purpose. von Bock. Chem. Lenz. 211 (1936). prakt. Chem. or zirconium alkoxides. "Young. Chem. 44. The reaction between an aluminum alkoxide and a ketone can be reversed.. Soc. In general. 52. J. Am. 11 Gomberg and Bachmann. Bachmann and Kloetzel. 3305 (1940). 1151 (1938). 61. in the reduction of butyraldehyde.2 chloromagnesium ethoxide. and as a result many undesirable side reactions are avoided.13 However. and Migge. Rec. This is the basis of the Oppenauer oxidation of a secondary alcohol to the ketone. chim. J.and bromo-magnesium alkoxides. Soc. Shankland an* Gomberg. Am. Chem.ADVANTAGES OF ALUMINUM ISOPROPOXIDE 7 181 peratures eerie oxide or sodium acetate * will accelerate the reaction.46'8 The aluminum derivative of the alcohol is prepared by means of aluminum t-butoxide and is oxidized with a large excess of acetone or cyclohexanone. 100 (1936). Hartung. J.. • Adkins and Cox. Soc.. They have the advantages of being much weaker condensing agents than sodium or magnesium alkoxides and of being soluble in both alcohols and hydrocarbons. and benzaldehyde. yields of products are 20 to 25% higher with aluminum isopropoxide. from the concentrations of ketones and alcohols at equilibriuin the determination of the relative oxidation-reduction potentials of a number of ketone-alcohol systems was made possible. crotonaldehyde.11 and sodium. 60. Am. and Cfossley. . side reactions are reduced. the isopropoxide induces a more rapid reaction. 52. 62. ibid. 2210 (1937). 137 (1937). [2] 14t. 202 (1922). Soc. Thus. trav.2 iodo. 59. 8 Oppenauer.10 Advantages of Aluminum Isopropoxide over Other Alkoxides Although a number of metals have been used as their alkoxides for the reduction reaction. Am. A polarographic study by Adkins and co-workers '• 10 of the position of the equilibrium between various ketones and a single alcohol demonstrated the true equilibrium nature of the reaction. in specific cases yields of 85 to 100% have i Mffligan and Reid.12 up to the present the aluminum derivatives have been found to be the best reagents.1 stannic. The general superiority of aluminum isopropoxide over aluminum ethoxide for the reduction of ketones was recognized *•8 even before the work of Lund.
Syntheses. Di-n-propyl ketone.to the carbonyl group.. nitro groups. For example. With a few low-boiling ketones difficulty may be experienced in separating the resulting alcohol from isopropyl alcohol. Am. such as unsaturated aldehydes and the carotenoids. 193. Soc. on the other hand. Since the reducing agent is such a specific one. Vol. The rate of reduction also depends upon the amount of reducing agent used. no pinacol formation has been observed. especially in the reduction of aromatic aldehydes. "Chalmers. 14 . thus the yields of reduction products from diethyl ketone ^ and methoxyacetone n are reported to be 60% and 40%. and pinacols are not reduced further by the reagent. private communication. are reduced. J. including those a. respectively. " Gardner and McDonnell. * For certain exceptions see p. Reduction of aldehydes and ketones has been carried out successfully with quantities ranging from a few milligrams to more than 500 g. carboxylic esters. side reactions are more significant and the yields are consequently lower when extremely sensitive compounds. the aldehydes are usually more reactive. 598 (1943).8 The possibility that the nitroso group may be reduced by aluminum alkoxides has been suggested. Org.fi. 220 (1934). Coll. Styta and Lauersen. The length of time required for a reaction. 63. 2279 (1941). Quinone and cyclohexanone are reduced completely in a few minutes. camphor requires twelve to twenty-four hours. Chem. and reactive halogens * are not reduced by this reagent. the yields in aluminum isopropoxide reductions range from 80 to 100%. in contrast to other reductions involving metals in acid or alkaline media. Furthermore.. other groups susceptible of reduction are not affected. J. 17 Adkins and Rossow. usually has little effect on the final yield.6 but no details of such a reduc-' tion have been published.182 REDUCTION WITH ALUMINUM ALKOXIDES been achieved with aluminum ethoxide. the reduction of the carbonyl group does not stop at an intermediate stage. however. or even to catalytic hydrogenation in certain of these cases. THE SCOPE OF THE REACTION The aluminum isopropoxide reduction has been carried out with aliphatic and aromatic aldehydes and ketones. since removal of the acetone which is formed ensures complete reduction in any event. The time required for a reduction varies greatly with the particular aldehyde or ketone. carbon-carbon double bonds. [2] 139. prakt. Chem.2-12< 14>16-16 In general. gives a 92% yield of the carbinol. 2.8 As would be expected.
the aldehyde (VI) was obtained in 68% over-all yield. 6. / . Hdv. Stodola and Kendall. thus protecting it from the action of the reducing agent.SELECTIVE REDUCTION OF CARBONYL GROUPS Selective Reduction of Carbonyl Groups • 183 Some efforts have been made to employ the aluminum isopropoxide reduction in such a way that only one of two or more carbonyl groups in the molecule would be reduced. 360 (1941). Most of this work has been based upon the conversion of one of the carbonyl groups to an enol ether or acetal. This type of protection also has been employed successfully in the sterol field. CHm. The a- CHO CHOAc keto acetal (IV) was reduced to the corresponding hydroxy acetal (V). Chem. Org. Frey. The thioacetal [RCOCH(SC2H5)2] corresponding to IV was resistant to reduction and could not be employed for this purpose.. 839 (1941). 24. After reduction the 3-keto group was regenerated by treatment of the enol ether with acid.18 After cleavage of the acetal linkage and conversion to the diacetate. and Reichstein. The 3-enol ether (VIII) of 16-benzalandrostenedione (VII) was reduced selectively 19 to the carbinol (IX). Another C.H6 vn 18 19 VJXl Schindler. Ada. In this manner it was possible to reduce the dimethyl acetal of phenylglyoxal (II) " to the corresponding hydroxy acetal (III) in 55% yield. .
184 REDUCTION WITH ALUMINUM ALKOXIDB8 method for protecting one ketonic group while another is reduced has been applied to androstenedione (X). 23. Technical aluminum containing traces of copper and zinc brought about some reduction of the ketone group as well as the aldehyde group.reported to depend upon the use of pure aluminum in preparing the isopropoxide.22 When the reduction was carried out for a short time. It must be pointed out that the last two reductions were carried out with very special types of molecules. In view of these encouraging steps toward selective reduction of one carbonyl group in the presence of others. Chim. "Fischer. and the ketone group in the molecule was unaffected. Treatment of the latter 1.940 (June 21. only the aldehyde group in the methyl ester of mesopyropheophorbide b (XIV) was reduced. II J xn Two interesting examples of partial reduction without any protection of either carbonyl group have been described. V. Miescher and Fischer. 81 . Organon.21 The remainder of the material consisted of unreacted diketone as well as some of the corresponding diol.and irans-testosterone (XIII) was obtained by reduction of androstenedione (X) with aluminum 2-butoxide in s-butyl alcohol. 168 (1939). and Hev6r. 645. 429 (1940)]. more work along these lines is desirable. 842. Mittenzwei. Ada. (I). Helv. A 70% yield of a mixture of w's.20 This compound was converted into the 3-pinacol (XI) with sodium amalgam and then reduced by aluminum isopropoxide UT?81% yield to the pinacol (XII) of testosterqne. Zentr. p a t . Several selective reductions have been successful with porphyrin derivatives. Fr.. 154 (1940). 1939) [Chem.2-glycol with lead tetraacetate regenerated the ketone group with cleavage of the molecule to give testosterone (XIII). and that other examples 20 N. Ann. This selective reduction is.
5 . the reduction of benzil (XVII) or benzoin (XVIII) is reported to give 90% of weso-hydrobenzoin (XIX). In many cases it has been found that both isomers are formed. dependCH2CH3 CHO CH 2 CH 8 CH. the reaction results in the creation of an additional asymmetric center. Stereochemical Configuration of the Reduction Products In the reduction of an optically active ketone. often in comparable amounts. CH8 XIV ing not only upon the speed of reduction but also upon the reduction potential. differences in the ease of reduction of various types of carbonyl groups undoubtedly exist. However. W CH-COH O xvin -CH—CHOH OH XIX .6 Numerous other examples may be noted in the tables at the end of this chapter. and two diastereoisomers are possible. The oxidation-reduction series ••10 for various ketone-alcohol systems may give a clue to the direction in which progress may be made. reduction of camphor (XV) gives a mixture of borneol and isoborneol (XVI). However.STEREQCHEMICAL CONFIGURATION 185 of selectivity which have been found in these compounds cannot always be extended to simpler molecules. For example.
reduction will occur. Org. 24 . Chem. If a phenolic ketone or a keto acid forms a salt which is R R—C—CH—COOC2H6 0 xx R R—C—C—COOC2H6 0 R A1( R)8 R A1(OR)8 O Al(OR)2 H ° ) R—C R C—COOR OH R xxr insoluble in the reaction* medium. 1939. 0 CH3 xxn xxru Sabina ketone (XXIV)26 and the esters of chelidonic acid (XXV) 5 are reported not to be reduced by aluminum isopropoxide in boiling isopropyl alcohol solution. Although no reduction of J-menthen-4-one-3 (XXIII) occurs in isopropyl alcohol solution. 1415. 1939. 4-Ketotetrahydrochrysene (XXII) does not undergo reduction23 with aluminum isopropoxide in boiling isopropyl alcohol but can be reduced to the carbinol in 76% yield by substituting toluene as the solvent. i. Soc. J. /3-keto esters (XX) and /3-diketones which are capable of enolization form the aluminum salt of the enolic form and are not reduced. or if the phenolic or acid group is converted to the ether or ester. Malcolm and Read.186 REDUCTION WITH ALUMINUM ALKOXIDES Limitations of the Method With certain types of compounds this method of reduction fails.24 substitution of the higher-boiling isobutyl alcohol results in an 84% yield of stereoisomeric carbinols.. In general. « Short and Read. / . Apparently no attempts have been made to "Bachmann and Struve. 1037.* However. Chem. reduction may proceed slowly or not at all. J. If the salt is moderately soluble. Soc. reduction proceeds smoothly. Chem. if there are no enolizable hydrogens (XXI). 461 (1939).
that of boiling 28 Wayne and Adkins. Condensation. Although aluminum alkoxides are effective in bringing about the mesityl oxide type condensation of ketones. CH3 \_COCHa XXVI / ~ \ However. Aldol condensations often are possible not only between two molecules of the aldehyde but also between the aldehyde and acetone. as. J. 0 0 ROOC CH CH3 CH3 XXIV XXV Side Reactions Several different types of side reactions have been observed during aluminum isopropoxide reductions. such as catalytic hydrogenation. Chem. .CONDENSATION 187 carry out these reductions with higher-boiling solvents. The yields are often lower in the reduction of aldehydes if the acetone is not removed as it is formed.6 As no appreciable condensation of this type occurs if dilute solution (approximately 0. These. side reactions become more important. There are some indications that certain sterically hindered ketones may be resistant to aluminum isopropoxide reduction. for example. are encountered only occasionally and usually are not a source of difficulty. but this is far from general. often can be applied successfully. it should be noted that other procedures. 3401 (1940). Soc . 62. With aldehydes.13 Higher temperatures. for example.10 it seems possible that dilution may improve the yields with particularly sensitive ketones such as cyclopentanone.26 aluminum isopropoxide rarely induces this reaction to any significant degree in the reduction of ketones. however.05 molar) is used. Am. In the event of apparent failure of the method. in the formation of dypnone (XXVII) from acetophenone (XXVI). the remainder of the material probably having undergone the above-mentioned condensation. with cyplopentanone only a 33% yield of cyclopentanol was obtained.
however. chim.. Usually. the Tishchenko reaction can occur to produce the ester. [5] 2.. but not always. 3013 (1923).^ 5 * BCOOCH. 29 Grubb and Read. 1309 1552 (1906)]. Soc. is disadvantageous with aromatic aldehydes (see p. OH XXXI Tishchenko.. 242. J. RCOOCH2R:27 2RQH0 . J. 298 (1935). Soc. Chem. 1934. »»» Child and Adkins.482 (1906) [Chem. (II). 1939. For example. 195). 80 Short and Read. 45. 27 . d-pulegone (XXVIII) upon reduction at 120 to 170° for twenty hours gave over 40% of a mixture of menthadienes (XXX) and only 5 to 10% of the carbinols (XXIX). BvU.188 REDUCTION WITH ALUMINUM ALKOXIDES xylene as a solvent. Am. Chem. In addition.Phya. Chem. increase the amount of polymerization and condensation of unsaturated aldehydes such as crotonaldehyde.. Soc.355. an abnormally high temperature was used to carry out the reduction.13 The excess.R This reaction occurs to a greater extent in benzene than in isopropyl alcohol. 1306.13. In the reduction of 4ketotetrahydrochrysene (XXII) 23 the replacement of toluene by xylene as a solvent usually resulted in the formation of the hydrocarbon XXXII instead of the carbinol XXXI. J. Several investigators have reported that dehydration sometimes accompanies reduction of a ketone and that an olefin is obtained as the major product. Chem.28-29'80 Even under these drastic conditions unreduced ketone was present. Soc. BiMS. Zentr. soc.27° It appears that an excess of aluminum isopropoxide has "the desired effect of speeding up the reduction reaction and thus minimizing side reactions in the case of aliphatic aldehydes. 28 Doeuvre and Perret. 38. 77. / .. Dehydration of the Alcohol..
S76 (1938).M However. In the case of d-pulegone (XXVIII)30 the small amount of alcoholic material which was obtained was not d-pulegol (XXXIV). the unreduced ketonic material contained not only pulegone (XXVIII) but also isopulegone (XXXV). 34 Windaus and Kaufmann. In addition. yet in several instances reduction of an unsaturated ketone has resulted in a shift of the double bond as well as reduction of the carbonyl group. but d-reeoisopulegol (XXIX). 218 (1939). 86 Schoenheimer and Evans. Kennedy. R = C9H17). 63. This involves migration of the double bond in the side chain from the a. 542. and was used without purification.. Ber. Spring. R = C8Hi7). However. Chem. Chem.. 567 (1936). and Safir.4-benzpyrene (XXXIII) was reduced with unpurified reagent.M 80% of the product was the alloergosterol derivative (XXXVII. In the reduction of ergostatrienone (XXXVI.. in these special cases in which the alcohols are sensitive to dehydration it is preferable to use distilled aluminum isopropoxide. 1938..to the j8. 114. R = CgHir). 869. / . but with distilled reagent the yield of the alcohol was always in the range 79-90%. Ann. Such an unpurified solution has been used successfully in many instances and excellent yields of the alcohol have been obtained.35 "Baohmann. with respect to the carbonyl group. 597 (1939). with cholestenone (XXXIX) no double-bond migration occurred. 72. and Swain. Carmack. J.MIGRATION OF DOUBLE BONDS 189 In both of the above cases the aluminum isopropoxide was prepared from aluminum metal amalgamated with a small amount of mercuric chloride.fi. 71. Biol. 32 . Heilbron. Soc.7-position. Similar results were observed with A4> v-dehydrocholestenone (XXXVI. 1682 (1941). It has been assumed by many workers that carbon-carbon double bonds are unaffected by aluminum isopropoxide. inconsistent yields and an impure product were obtained when 4'-ketotetrahydro-3. Chem.31 CH8 XXXIII XXXIV XXXV Migration of Double Bonds. Several other examples of this type of double-bond migration have been observed in the sterols. Soc. Am.82. 33 Windaus and Buchholz. Although it is true that these double bonds are not reduced. R = C9H17) and 20% was the ergosterol derivative (XXXVIII. J.. formed by a shift of'one of the nuclear double bonds.
contained sonie of the isopropyl ethers pf the carbinols. dibenzalacetone (XL).5 Carbinols of this type are especially susceptible to ether formation.CfH=CH—C—CH=CH0 XL H XLII " Adkina and Robinson. i V . Even in the case of dibenzalacetone." Similar observations of ether formation with a-halogen ketones will be discussed later..9-Dimethylanthrone-10 (XLI) gave 64% of a material corresponding in analysis to the isopropyl ether (XLII). ether formation is by no means the usual reaction with unsaturated ketones. in most cases no ether was noted in the products. OCH(CH3)2 . the normal product. i.36 9. but it is not a common side reaction.190 REDUCTION WITH ALUMINUM ALKOXIDES xxxvi xxxvn xxxvni XXXIX Ether Formation. It is reported that the reduction products of certain a./8-unsaturated ketones. There appears to be no way of predicting with any degree of certainty when ether formation is likely. has been obtained in 58% yield. for example.e. often recrystallization from an alcohol is sufficient to give the ether. the carbinol. However. private communication. Indeed.
When benzohydrol was treated with aluminum ethoxide under the same conditions. one case "of reduction of a ketone to the hydrocarbon has been observed with aluminum isopropoxide. requiring two days for completion. to avoid formation of the ether (see p. 28% reduction to diphenylmethane occurred.'Was formed from the ethoxide.REDUCTION OF KETO ESTERS 191 Further Reduction to a Hydrocarbon. Soc. Aluminum isopropoxide does not give this type of undesirable reaction. Soe. with this reagent. 38 ' 89 reduction of keto esters by aluminum isopropoxide frequently yields the isopropyl ester of the hydroxy acid. Thus the reduction of the cyclopropane derivative XLIV gave the isopropyl ester of the reduced acid (XLV).12 In these reactions acetic acid. 67. 40 Schenk. •• Baker. 2673 (1938). rather than in isopropyl alcohol. rather than acetaldehyde. Chem. Am. 190). [2] 134.17 When 9. prakt.6-37 However. Fehlandt and Adkins.40 Similarly the substituted methyl /3-keto ester (XLVI) 41 gave upon reduction the isopropyl esters of the stereoisomeric reduced acids (XLVII). CsH 6 -C=O C<jH5— CHOH . unpublished observations. pure benzohydrol is easily obtained in 100% yield from benzophenone. Chem. Am. CH3 CH3 XLIII Reduction of Keto Esters Since aluminum alkoxides function effectively as catalysts for alcohol exchange in esters. 193 (1935).. Chem. J. 9-dimethylanthrone-10 (XLI) was reduced in xylene solution.CH XLIV 87 C COOCH3 CeH 6 . The reduction in either xylene or isopropyl alcohol was very slow. In the reduction of benzophenone with aluminum ethoxide the formation of 7% of diphenylmethane was observed.. J.)s> Wilds. 41 Baohmann and Wilds. J. 215 (1932). the hydrocarbon XLIII was formed in 65% yield. 88 .CH XLV C COOCH(CHj. unpublished observations. 60.
.'upon reduction. and not during the subsequent isolation and purification. Brass. usually give rise to laotones of the hydroxy acids. 42 (1940). A similar reaction was found to occur when the carbon atoms between the ketone and ester groups were included as part of a ring. Moonik. Ether and acetal linkages are not affected. Ann.isomer (XLIV).87 With the cis isomer of the cyclopropane derivative (XLIV) lactone formation occurred to the extent of 52%. Neuroth. Jorde. lactone formation is prevented by steric factors. Thus. the reduction of the acetate (LII) gave a 94% yield of the glycol (LIII). XL VI -CH2CH2COOCH3 YT. Jaoobi.TY Reduction of Esters of Hydroxy Ketones Because of the catalytic effect of aluminum alkoxides on alcohol exchange in esters. It should be pointed out that this formation of a lactone occurs in the reduction mixture in the presence of excess isopropyl alcohol. and Salaer. The methyl ester of /8-(2-naphthoyl)-propionic acid (XLVIII) was converted in almost quantitative yield a into the corresponding butyrolactone (XLIX).102 REDUCTION WITH ALUMINUM ALKOXIDES COOCH8 r^^f-cooc:H(CH3)2 ! xx.42 a Schopf. Methyl l-ketotetrahydrophenanthrene-2acetate (L) gave an 80% yield of the lactone (LI). 644. .vn 7-Keto esters. only a minor portion of .40 With the irans. reduction of esters of hydroxy ketones usually i» accompanied by cleavage of the ester group and the product is a glycol.the reduced material being obtained as the isopropyl ester.
with or without the migration of a methyl or phenyl group. . 3089 (1938).REDUCTION OF a-BROMOKETONES CH 2 COCH 2 OCOCH 8 CH 2 CHOHCH 4 OH 193 !—OCH 2 C 6 H 5 OCH 8 Lii CH 2 C 6 H B OCH 8 Lin Reduction of a-Bromoketones Reduction of <x-bromoacetophenone gave the corresponding bromohydrin in 85% yield. 60. 68. to give the carbonyl compounds LVTI. Allenby. Am. Soc. LXI. / . Sot.6 However. Chm. HOCH •" Stevens. Am. . LV - CH. The main material was a mixture of the carbinols LX. J. the remainder of the product was halogen-free. GH. consisting of a mixture of benzylmethylcarbinol andsome ethers. carbinols through further reduction. LVIII. and DuBois. The occurrence of these products was explained by the fonnation of the oxide (LVI) from the intermediate bromohydrin.. a-bromopropiophenone **• * gave only 35 to * 42% yields of the bromohydrin.. *<0-CH-c/ OH Br CH. 62. 1424 (194g).. and LXII and ethers derived from them. 44 Stevens. The oxide is capable of rearrangement. From a-bromoisobutyropKenone (LIV) **•45 very little bromohydrin (LV) was obtained with aluminum isopropoxide in boiling isopropyl alcohol. Chetn. J.6 Smooth reduction also occurred with chloral2> l6 and bromal. Am. 3264 (1940). and LIX which would give rise to the. 46 Stevens and Aflenby. Soc. Chem.
A similar oxide intermediate explains the formation of benzylmethylcarbinol from abromopropiophenone. but this is rarely necessary and may result in 46 Winstein. if no acetone has been detected after an hour of heating). boiling isopropyl alcohol is generally satisfactory. If reduction still does not occur xylene may be substituted. a-bromoisobutyrophenone gave a bromohydrocarbon as the main product.13 In those reductions for which aluminum ethoxide is satisfactory either ethyl or isopropyl alcohol may be employed as a solvent.44 This was shown to be LXIII accompanied by some of its allylic isomer (LXIV).46 This reaction may involve intermediates similar to those for a-bromoisobutyrophenone. J. O CHS CH 3 V . When aldehydes are reduced. or by direct reaction of the bromohydrin (LV) with aluminum isopropoxide. or when the reduction products are sensitive to air. Certain sensitive aldehydes or ketones may be reduced at room temperature by letting the mixture stand for several days. Curiously enough. SELECTION OF EXPERIMENTAL CONDITIONS Solvent and Temperature For the reduction of aldehydes. This may have been formed from the intermediate oxide (LVI) by the addition of isopropyl alcohol to the oxide ring.CH=C—CH 2 Br LXIII / \—CHBr—C=CH 2 LXIV LXV From 2-bromocyclohexanone (LXV). when the reduction was carried out at 33°. In the few instances in which the temperature must be raised above this point to bring about reduction (that is. In addition to the ethers corresponding to these carbinols. dry toluene may be added and the isopropyl alcohol removed by distillation.194 REDUCTION WITH ALUMINUM ALKOXIDES Of these products the main one was the carbinol LXII. Am. the temperature of boiling isopropyl alcohol is satisfactory for rapid and complete reduction. there was also obtained the monoether of a glycol. Soc. Chem. 61. For most aldehydes. a slow stream of dry nitrogen or hydrogen is frequently employed for reactions requiring long periods of time (including most of the aluminum ethoxide reductions). anhydrous isopropyl alcohol is recommended as the solvent in order to avoid side reactions such as the Tishchenko reaction. In the reduction of ketones. . a 33% yield of cyclohexanol was obtained in addition to a 30% yield of bromohydrin. 1610 (1939).
3. On the other hand. Although the resulting solution is dark because of suspended particles. Excellent yields (90-98%) in -the reduction of piperonal (R2CHO)3A1 + 3O=C(CH3)2 . in many cases it may be used for the reduction without purification.AMOUNT OF ALUMINUM ISOPROPOXIDE 195 dehydration of the product. In general. Although it appears that only a small amount of aluminum isopropoxide is required to catalyze the equilibrium between the alcohol and carbonyl compound. Results with l-keto-l. it is advisable to use distilled aluminum isopropoxide. When the reagent was decreased to two-thirds of one mole (100% excess) for one mole of the ketone.5 This procedure is often convenient where single reductions are to be carried out with letones which are known to be reduced satisfactorily in this manner (see tables at end of chapter). With small runs of ketone (below 0. As the equation indicates. or with those which are known to give anomalous results with unpurified reagent. with ketones at least 100 to 200% excess of the reagent is desirable. CH3" 3R2C=O + Al —OCH CH 3 J 3 Actually.ahydrophenanthrene (LXVI) illustrate this point.4-tetr.1 mole) it may even be well to use as much as three moles of isopropoxide (nine equivalents) to one mole of ketone.2. if the reduction can be carried to completion in twelve to twenty-four hours in isopropyl alcohol it is usually undesirable to substitute a higher-boiling solvent. with aldehydes or ketones which are new or not readily available. one mole of isopropoxide will reduce directly three moles of carbonyl compound. Preparation and Amount of Aluminum Isopropoxide The aluminum isopropoxide is prepared by dissolving cleaned amalgamated aluminum in anhydrous isopropyl alcohol. a six-hour period was required for complete reduction. reduction was complete in fortyfive minutes. since the reaction is cleaner and side reactions are less likely to take place at the lower temperature. in practice it usually is desirable to employ an excess of the reagent. the yield of the reduced carbinol was 100%. This has the advantage of shortening the time required for reduction. with aromatic aldehydes it is preferable not to use excess reagent. However. irrespective of the amount of the reagent.' However. either as the solid or as a molar solution in isopropyl alcohol.41 With three moles (800% excess) of isopropoxide for one mole of the ketone.
" Hahn. Ber. but are unnecessary under other circumstances. 71 (1940). These include various columns sueh as a Vigreux13 or a modified Widmer column. 420 (1910). with only one-half an equivalent of reagent37 an 89% yield of benzyl alcohol is obtained (Procedure II. 544. a two-necked flask may be employed and fresh isopropyl alcohol added at the rate of removal by distillation. 544. p. 3 (adapted from Organic Syntheses). 203). Apparatus The simplest type of apparatus. However. 48 Schopf and Winterhalder. When the distillate no longer gives a test for acetone. If more than half of the solvent distils during the reaction it is advisable to add more isopropyl alcohol to maintain the volume. and one which is quite satisfactory except in the reduction of volatile ketones and aldehydes.. 14 (1940).. . and ethanol is placed in the inner condensing tube. The *' Schopf and Salsser.49 An easily constructed modification is illustrated in Fig. More elaborate means have been described for removing the acetone by distillation with relatively little isopropyl alcohol. 27 (1940). 20. •° Arndt.196 REDUCTION WITH ALUMINUM ALKOXIDES . 201). Syntheses. (LXVII) and benzyl isovanillin (LXVIII) have been obtained with less than one equivalent of aluminum isopropoxide. If a concentrated solution is to be avoided.60 The partial condenser is attached directly to the roundbottomed flask. A reflux condenser maintained at constant temperature by boiling methanol has been suggested.. Ann. Org. 43. the reduction is complete.47-48 With benzaldehyde Wi ' 7 an exoessof reagent gives only 55-65% yields of benzyl alcohol 10 CHO LXVI with considerable benzyl benzoate resulting from the Tishchenko reaction. p.6 More convenient than this is the simple but effective partial condenser designed by Hahn.10 They are to be recommended when the aldehyde or ketone boils within 50° of isopropyl alcohol. attached at the top to another condenser set for distillation (see Procedure IV. Ann. consists of a round-bottomed flask equipped with a short reflux condenser (no water in the cooling jacket).
. This permits easy regulation of the rate of distillation. For this same reason. An apparatus suitable for micro quantities (5 to 50 mg. an electrically heated oil bath is suitable. Especially at the end of the reduction. a burner. while the lower-boiling acetone is permitted to distil.RECOVERY OF ISOPROPYL ALCOHOL 197 top of this tube is connected to a small reflux condenser.) has been described. However. If several reductions are to be carried out this apparatus is highly recommended. hot plate. The outside of the condenser below the side arm is wrapped with cloth or asbestos paper. Instead of a steam bath or a water bath. 3. However. and most of the isopropyl alcohol is returned to the flask. Fia. The refluxing mixture boils the ethanol in the inner condensing tube.if the isopropyl alcohol is to be recov- . or sand bath is not recommended for heating. superheating of the concentrated alkoxide solution may bring about dehydration or other decomposition of the product.22 Recovery of the -Isopropyl Alcohol Because of the low cost of isopropyl alcohol it is usually not economical to recover the solvent. the temperature of the bath should not exceed 95-100° when isopropyl alcohol is the solvent if possible^ dehydration of a sensitive alcohol is to be avoided.
Chem. Am. The flask is attached to an efficient reflux condenser. 1652 (1943). 64. 3049 (1942). Hartung. 2178 (1922-). " Wagner-Jauregg. . 65. The first portion of the distillate is discarded until the test for acetone is negative (p. A. 8111 (1940)]. 200).5 cc. M Wislicenus and Kaufmann. which is protected from moisture by a mercury trap or a calcium chloride drying tube. it may be necessary to clean. A portion of the solution on cooling should no longer give a positive test with acidified potassium iodide even on the addition of starch solution.198 REDUCTION WITH ALUMINUM ALKOXIDES ered. When the liquid is boiling. f EXPERIMENTAL PROCEDURES Aluminum Isopropoxide $ Twenty-seven grams (1 mole) of aluminum wire or foil which has just been cleaned with emery paper and wiped with a clean cloth (if turnings are employed.is dried by refluxing for several hours and distilled. of solid stannous chloride for each liter of recovered isopropyl alcohol and reflux for one-half hour. J. If any iodine is liberated additional 5-g. 447 (1940)[C. Fisher and Baxter. portions of stannous chloride should be added and refluxing continued until the test' le completely negative. 30.. it is still more sensitive if a few drops of 2% starch solution are added to this iodine solution to give the blue-black starch-iodine color. of anhydrous isopropyl alcohol (distilled from calcjum oxide) and 0. Soe. The possibility that the peroxide is trimolecular acetone peroxide has been pointed out by Acree and Haller. Calcium oxide is then added. Peroxides usually redevelop in this purified isopropyl alcohol in several days. 709 (1939). roundbottomed flask containing 300 cc. 2 cc. Chem. 52. Bar. and dry them according to the procedure of Wislicenus) "• 65 is placed in a 1-1. particularly if it had been allowed to stand for several days.. ibid. 44. of dilute (1 : 5) hydrochloric acid. of a 10% potassium iodide solution acidified with 0. the mixture. Any peroxides that are present can be removed conveniently by using stannous chloride M before drying and distilling the recovered isopropyl alcohol.5 cc. of the isopropyl alcohol to 1 cc.. Chem.5 g.*/. and the mixture is heated on the steam bath or a hot plate. Am.. caution must be exercised in working with it. amalgamate. 68 Stannous chloride has been used to remove peroxides from dioxane and ether. and Crossley (reference 13). which is an effective catalyst for the * To test for peroxides add 0. Colo. 61 For the formation of peroxides in pure isopropyl alcohol see Redemann. of mercuric chloride. It is essential to test for the presence of peroxides. 1323 (1895).61' * The literature records 62 a serious explosion during the distillation of a mixture of isopropyl alcohol and acetone (recovered from the reduction of crotonaldehyde) which had aged for a year. 28... Soe. 85 Adkins.. 34. School Mines Mag. Angew. The test is positive if the yellow color of liberated iodine appears in one minute. t Adapted (reference 37) from procedures by Lund (reference 5) and Young. of carbon tetrachloride. t To remove the peroxides add 10 to 15 g. which form readily in the impure isopropyl alcohol-acetone mixture.
or 140-150°/12 mm. The mixture turns gray. A 500-cc. b. This may be kept without deterioration in a glass-stoppered bottle sealed with paraffin. Phya. viscous liquid. yield 185-195 g. The molten aluminum isopropoxide is poured into a wide-mouthed. .p. 67. phymk. Chem. 6S Ulieh and Nespital. In this case it is usually best to prepare just the amount needed for the reduction. refluxing is resumed and is continued until all the aluminum has dissolved (six to twelve hours). w Robinson and Peak. 39. Although aluminum isopropoxide is a solid melting at 118° M> 67 (125° 68). distilling flask. After the reaction has slackened.. of isopropyl alcohol. and a fresh boiling-chip is added.2 cc. it shows a great tendency to supercool. and in a few minutes a vigorous evolution of hydrogen begins. On standing the solution deposits large crystals of the alkoxide. copper bronze (reference 40). A boiling-chip is added. (90-95%).. 180190°) as a colorless. The reagent also is conveniently kept and used as an isopropyl alcohol solution. or a small amount of an aluminum alkoxide (reference 13). of mercuric chloride. Z. Ber..41. For many purposes it is not necessary to distil the reagent. J. glass-stoppered bottle. 1128 (1935). and 0. 130-140°/7 mm. The mixture becomes black because of the presence of suspended particles. the bath temperature is raised to 170° and the pressure is lowered to the full vacuum of the water pump.05 g. which now serves as the receiver. and heating is continued. As soon as the temperature of the distillate rises above 90° the distillation is stopped and the condenser is removed. The molten alkoxide after distillation is weighed and dissolved in sufficient dry isopropyl alcohol to give a 1 M solution. s-butyl alcohol (reference 28). and it may solidify only after cooling at 0° for one or two days. 20 cc. Claisen distilling flask attached to a water condenser with a 250-cc. 298 (1933). the dark solution which results after all the aluminum has reacted is used directly. and the flask is heated in an oil bath at 90° under slightly diminished pressure. The proportions of 1 g. is attached directly to the Claisen flask (since air cooling is sufficient for condensation). and the bottle is sealed with paraffin to exclude moisture. Chem. and frequently the reaction must be moderated by cooling the flask in ice water. It is necessary to discontinue heating. When nearly all the isopropyl alcohol has been distilled. The hot solution is poured into a 500-cc. of aluminum. 936 (1934).*•• * is added through the condenser. M Lund. suction flask as the receiver. A165. but these redissolve slowly when the mixture is warmed to 60-70°. of carbon tetrachloride * Other catalysts which have been used include iodine (referenoe 28).. 0. The aluminum isopropoxide is distilled (oil-bath temperature.ALUMINUM ISOPROPOXIDE 199 reaction of aluminum and dry alcohols.
may deteriorate in the course of several months. After a negative test is obtained. below 150°) Procedure I. of distilled water and 21 cc. For use.200 REDUCTION WITH ALUMINUM ALKOXIDES may be used. For the use of the test with toluene instead of isopropyl alcohol see the note on p. of concentrated hydrochloric acid by warming on the steam bath. The presence of acetone is shown by the formation of a yellow cloudy suspension or precipitate of acetone 2. even though kept in a stoppered bottle.12 g.1% solution of the reagent is prepared by dissolving 0. . of the reagent is added to 5 drops of distillate. employing a Vigreux or a more efficient fractionating column. With aromatic aldehydes. The clear yellow solution is then cooled and diluted to 125 cc. Acetone Test Reagent (2. several drops of the reagent and a few drops of the acetoneisopropyl alcohol distillate are mixed in a small test tube. of 2. old solutions should be checked before use.4-dinitrophenylhydrazine test easily detects 1 part of acetone in 500 to 1000 parts of isopropyl alcohol. The 2. "For higher-boiling aliphatic aldehydes Procedure IV may be followed. Hartung. an excess of aluminum isopropoxide is to be avoided and Procedure II should be used. Since the reagent solution. with distilled water. This procedure indicates complete reduction even with ketones which are reduced very slowly. Reduction of Aldehydes For the reduction of volatile aliphatic aldehydes (b. reduction is complete.4-dinitrophenylhydrazine in 25 cc.p. 204. Otherwise the process is continued until no more acetone can be detected. (1. An equal volume of isopropyl alcohol is added with the ketone to the aluminum isopropoxide solution when the reduction is carried out. which readily undergo the Tishchenko reaction.4-dinitrophenylhydrazone. The test is considered negative if no cloudiness forms within one-half minute when 3 cc. prepared as described above from 47 g. is recommended. it is advisable to reflux the mixture for five to fifteen minutes with complete condensation and then to force over a few drops of distillate for another test. If no acetone is observed. To the undistilled solution of aluminum isopropoxide.74 moles) * From the procedure of Young.4-Dimtrophenylhydrazine)6 A 0. PROCEDURE I * (FOR VOLATILE ALIPHATIC ALDEHYDES AND KETONES) Reduction of Crotonaldehyde. and Crossley (reference 13).
(0. the oil is decanted and fractionated through an 80-cm. (3 moles) of crotonaldehyde and 1 1. In a 1-1. of dry isopropyl alcohol. If the crude crotyl alcohol is dried for several days before distillation the product is 97% pure. and the acetone slowly distils as it is formed. Refractionation through a 110-cm. The aqueous layers are combined and distilled until the distillate no longer gives a test for unsaturation with a dilute solution of bromine in carbon tetrachloride. bead column gives material boiling at 121. After drying over 10 g. t Based (reference 37) upon the procedure of Schfipf and Salzer (reference 47) for piperonal. A 2-1. This procedure permits separation of all the crotyl alcohol from the higher-boiling polymerization products. The oily layer is separated. This material is 93% pure as determined by tiiration with bromine in carbon tetrachloride. of a 1 M solution in isopropyl * Reduced pressure should not be used when low-boiling ketones are reduced and only a email excess of aluminum iaopropoxide is used.5 Equivalent of Aluminum Isopropoxide. Crotyl alcohol distils at 117-122°/76O mm. of anhydrous potassium carbonate. Use of the Hahn Condenser. which is 99. round-bottomed flask is used. of water. The temperature of the distillate is maintained at 60 to 70° (bath 110°).REDUCTION OF BENZALDEHYDE 201 of aluminum and 500 cc. .. weight 130 g. and the oily layer which separates is added to the product obtained by distillation of the oil.* The residue is cooled to 40° and slowly hydrolyzed (cooling as necessary) with 900 cc.2 mole) of benzaldehyde. and distilled at 60-70° while the presBure is lowered slowly from about 275 mm. Vigreux column at atmospheric pressure. to 65 mm. of concentrated sulfuric acid and 790 cc. PROCEDURE II f (FOR AROMATIC ALDEHYDES) Reduction of Benzaldehyde with 0. The distillate is then saturated with potassium carbonate. equipped with an 80-cm. prepared from 145 cc. (60%). since some of the product may be liberated from its aluminura derivative and lost through an exchange with the excess isopropyl alcohol. round-bottomed flask are placed 21 g.7% pure. 7 g.1 to 99. washed once with water. of isopropyl alcohol.2°/760 mm. (0.034 mole) of distilled aluminum isopropoxida (or 34 cc. are added 210 g. Finally the distillation is continued to 100° and 20 mm. of cold 6 JV sulfuric acid. the upper end of which is connected to a water condenser set for downward distillation. The~mixture is heated with an oil bath. Vigreux column. and when the distillate no longer gives a test for acetone (eight to nine hours) most of the remaining isopropyl alcohol is distilled under reduced pressure.
which requires about ten hours. The fraction boiling at 89-91°/7 mm. 197). A Hahn partial condenser (or a reflux condenser or Vigreux column may be used). the time depending to some extent upon the rate of distillation.202 REDUCTION WITH ALUMINUM ALKOXIDES alcohol). layer of ethanol in the inner condensing tube (p. For higher-boiling ketones. and the solution is heated on the steam bath. of water. it is advisable to add more isopropyl alcohol. weight 19 g. The cooled residue is hydrolyzed with cold. and most of the remaining isopropyl alcohol is removed at atmospheric pressure. benzyl benzoate. consists of colorless benzyl alcohol. and the mixture is extracted with three 50-cc. After six hours of slow distillation (2 to 6 drops per minute) the distillate may no longer give a direct test for acetone. PROCEDUBE III. The combined extract is washed once with 50 cc. . A bent glass tube. Hartung. the first portion of the distillate usually contains acetone. the following procedure is satisfactory. and the residue is distilled under reduced pressure from a 50-cc. The benzene is removed at atmospheric pressure. and 450 cc. the yield dropped to 65% and a larger high-boiling fraction resulted). where there is no danger of loss of ketone with the distilling isopropyl alcohol. with a 1-cm. the procedure of Young. during the reduction. is substituted for the Hahn condenser. of concentrated acid and 150 cc. remains in the flask (with a 200% excess of aluminum isopropoxide in 200 cc. and Crossley for crotonaldehyde (Procedure I) is recommended. (If the volume of the mixture should fall below 200 cc. dilute hydrochloric acid prepared from 20 cc. of water.1* Reduction of Ketones For the reduction of low-boiling ketones (below 150°). A small amount of higher-boiling material. Claisen flask. and any suspended droplets of water are removed with 20 g. but after five minutes of total reflux. A larger excess of aluminum isopropoxide may be desirable in small runs. (89%). of isopropyl alcohol. portions of benzene. of dry isopropyl alcohol. attached to a water condenser set for distillation. THE USE OF ALUMINUM ETHOXIDE A procedure for the use of aluminum ethoxide in the reduction of chloral is described by Chalmers in Organic Syntheses. followed by resumption of distillation. is attached. of anhydrous sodium sulfate.) Heating is continued until the acetone test is completely negative.
is attached a small water-cooled condenser set for distillation. (If a clear solution does not result.REDUCTION OF BENZOfHENONE PROCEDTJBE 203 IV * (FOR KETONES BOILING ABOVE 175-200°) Reduction of Benzophenone. * Developed (referenoe 37) from the procedure of Lund (reference 5). of dry isopropyl alcohol should be added to maintain the volume). and the solution is refluxed on the steam bath at such a rate that 5 to 10 drops of distillate are collected per minute (a rate of 1 to 4 drops of distillate per minute is better for ketones which are reduced more slowly). finally in ice. of benzene should be added and the hot solution filtered. A short (25-cm. The water is again removed fromjthe reflux condenser. When a negative test is obtained. In thirty to sixty minutes the acetone test becomes negative (if more than 50 or 60 cc. In a 200-cc. round-bottomed flask are placed a solution of 20 g.4 g. A boiling-chip is added. bent glass tube and cork stoppers. but no water is run through the cooling jacket. The cooled residue is hydrolyzed with cold. 20 cc. and total reflux is maintained for five minutes. of water). (0. weight 18. of isopropyl alcohol distils off. by means of a short. and the first 5 drops of distillate is tested for acetone. then the process is repeated. washed well with cold dilute acid and water. of a 1 M solution in isopropyl alcohol) and 18. (0.1 mole) of benzophenone. most of the excess isopropyl alcohol is removed under slightly reduced pressure. To the top of the condenser. 20 cc. If a positive test is obtained distillation is continued to remove the acetone. Water is then passed through the upright condenser. dilute hydrochloric acid (prepared from 35 cc.1 mole) of aluminum isopropoxide (unpurified reagent is also satisfactory for reduction of benzophenone and many other ketones) in 100 cc.2 g. The crystalline benzohydrol is filtered (it is necessary to extract with benzene or ether if unpurified aluminum isopropoxide has been used). and dried. (99%) of colorless needles of benzohydrol melting at 67-69°. there is obtained 18. of concentrated acid and 175 cc.) Upon cooling. and the cooled aqueous suspension is mixed well by swirling to complete the hydrolysis. .) reflux condenser (a reflux condenser jacketed with boiling methanol 5 or a Hahn partial condenser may also be used) is attached to the flask. For purification the solid is dissolved in 50 cc. of dry isopropyl alcohol (or 100 cc. of hot (60-70°) petroleum ether. Usually the material in the filtrate is negligible unless benzene is used in the recrystallization.2 g.
The following test will easily detect 1 part of acetone in 300 parts of toluene. of 2. Reduction of Acetalsor Enol Ethers Ketones containing these groups may be reduced according to the procedures given above (Procedure I or IV.2.3. The mixture is heated at such a rate that slow distillation occurs (2 to 5 drops per minute^ the volume of solution should be maintained by further addition of solvent as needed).! the toluene solution is cooled and the aluminum salt is decomposed with cold 10% sulfuric acid (from 5 cc.011 mole) of 4-keto-l. When the test for acetone is completely negative.2. .4-dinitrophenylhydrazine reagent solution ie added without shaking.4-tetrahydrochrysene melting at 156-158°. a stream of air should not be used with carbinols boiling below 200°). excess sodium hydroxide solution or a concentrated solution of sodium potassium tartrate 18 should be used to dissolve the aluminum hydroxide. The product is separated with the toluene. of concentrated sulfuric acid and 80 cc.3. of dry isopropyl alcohol is added to facilitate removal of acetone. and then evaporated at room temperature under a stream of air (solutions of secondary alcohols which are susceptible to dehydration should be evaporated at room temperature. in an oil bath. 25 cc. and a water condenser set for downward distillation is attached to the top" by means of a short bent tube (a Hahn partial condenser with a 1-cm. (76%) of colorless 4-hydroxy-l. of dry toluene is refluxed for four hours. then 2 cc.4-tetrahydrochrysene in 25 cc. * From the procedure of Bachmann and Struve (reference 23).4-tetrahydrochrysene (XXII) in Toluene.3. the water is removed from the reflux condenser. and the solution is washed with dilute aqueous ammonia and water. Shaking the toluene-reagent mixture will clarify the cloudy suspension. After the solution has cooled slightly. layer of isobutyl alcohol in the inner condensing tube may be used). A solution of 8. Instead. (0.2 g. There is obtained 2. Five drops of the distillate and 5 drops of water are shaken. acids should be avoided in working up the reaction mixtures after reduction. depending upon the volatility of the compound). of water). In order to avoid cleavage of the acetal or enol ether linkage. Two recrystallizations from a mixture of benzene and petroleum ether bring the melting point to 160-162°. The appearance of cloudiness in the aqueous layer indicates acetone.040 mole) of purified aluminum isopropoxide and 2. t The test for acetone requires Blight modification for use with toluene.2.10 g.204 REDUCTION WITH ALUMINUM ALKOXIDES PROCEDURE V * (FOR KETONES RESISTANT TO REDUCTION) Reduction of 4-Keto-l. (0.75 g.
which have been classified as: (a)-saturated and unsaturated aliphatic ketones. Table II lists the reduction of ketones. REPORTED IN THE LITERATURE 205 The following tables are intended to include all the reductions with aluminum alkoxides which were reported prior to February. (e) ahalogen substituted ketones. which have been subdivided into: (a) aliphatic aldehydes and (6) alicyclic and aromatic aldehydes. (/) diketones. (d) unsaturated alicyclic and aromatic ketones. (c) alicyclic ketones. The yields that have been reported do not necessarily represent the highest that can be obtained. (g) protected diketones. Qi) alcoholic and phenolic ketones (and ethers or esters of these). and (t) keto esters. (6) aromatic ketones. . and it seems probable that some of the lower yields might be improved by making suitable modifications in the^ experimental procedure for the reduction and for the isolation of the product. Table I lists the reduction of aldehydes. although some examples doubtless have been overlooked. 1943.SUKVEY OF ALUMINUM ALKOXIDE REDUCTIONS SURVEY OF ALUMINUM ALKOXIDE REDUCTIONS .
4. D. C refers to clarified aluminum isopropoxide but not distilled.2.3-Dihydroxybutane Crotyl alcohol 2-Chloro-2-butenol-l 2-Bromo-2-butenol-l 2.60 77-90% 5. 221 * If no Bolvent is listed the alcohol corresponding to the alkoxide was used. to an untreated solution of the alkozida (see p.6-Octatrienal-l 2.206 REDUCTION WITH ALUMINUM ALKOXIDES TABLE I REDUCTION OF ALDEHYDES WITH ALUMINUM ALKOXIDES Compound Reduced Product Formed Reagent and Solvent * R in A1(OR)3 Reference (a) Aliphatic Aldehydes Dichloroacetaldehyde Chloral Bromal Butyraldehyde Dichloroethyl alcohol Trichloroethyl alcohol Tribromoethyl alcohol Butyl alcohol i-C3H7(D) C2H6 a. and U./3-TrichIorobutyraldehyde Aldol 1 Crotonaldehyde a-Chlorocrotonaldehyde a-Bromocrotonaldehyde 2.6-Octatrienol-l 2. to distilled reagent.4-Hexadienal-l 2.4.8-Decatetraenol-l Geraniol (24%) Nerol (44%) Citronellol Hydroxycitronellol i-C3H7(C) C2H5 t-C3H7 (benzene) i-C3H7 30-36% (i-C3H7OH) C2H5 6% (benzene) 92% C2H6 C2H6 (25°) i-C3H7(U) C2H6 C2H6 t-C3H7(D) f-C3H7(D) i-C3H7(D) i-C3H7 (U or D) i-C3H7(U) C2H6 C2H6 60% 59 85% 2.15.8-Decatetraenal-l Citral Citronellal Hydroxycitronellal 2.6.3-Trichlorobutanol-l 1.a. .4-Hexadienol-l 2.6.6V 69% 2 19-28% 13 13 13 2 ' 30% 12 60-65% 12. 13 — 12 — 12 64% 62 70% 62 — 62 1 0Q07 ot Do Q CO 32% 60% 78% 13 1 12 (6) Alicyclic and Aromatic Aldehydes As-Tetrahydrobenzaldehyde A3-6-Methyltetrahydrobenzaldehyde A3-Tetrahydrobenzyl alcohol A3-6-Methyltetrahydrobenzyl alcohol NOTE: References 59-80 appear on p.4.4. 199).
.2.4-dimethyltetrahydrobenzyl alcohol Cyclogeraniol Isomer of vitamin A (axerophthol) 5.7 (82°) 75% 74 B. and U. 72) NOTE: References 59-80 appear on p. 12 C2HB 4-Chlorobenzaldehyde 4-Chlorobenzyl alcohol C2H6(2SO) 92% 2 4-Methoxybenzaldehyde 4-Methoxybenzyl alcohol C 2 H 6 (25°) 85% 2 3-Methoxy-6-bromoben...5.4.6-Trimethyltetrahydrobenzyl alcohol As-2.-C3H7(D) t-CsH7(D) i-C3H7 t-C3H7(D) i-C3H7(D) 70% 8P% — ence 64 65 66 64 A3-3.8. (crude) 3.3-Methoxy-6-bromoben.4-Methylenedioxybenzaldehyde 3-Benzyloxy-4-methoxybenzaldehyde 2-Nitrobenzaldehyde 3.10-hexahydro-l-naphthaldehyde thylmethanol Lupenal (a triterpene Pseudolupenol i-C3H7(D) 55% 73 aldehyde) Furfural Furfuryl alcohol C2HB (25°) 88% 2 i-CsB.enzaldehyde Benzyl alcohol i-C 3 H 7 (D) 89% 37 i-C 3 H 7 (benzene) 55% 13 C2H6 (benzene) 28% 13 82-89% 2.6.4-Trimethyltetrahydrobenzyl alcohol A8-2-Phenyltetrahydrobenzyl alcohol s A8-6-Phenyl-3.4-Trimethyltetrahydrobenzaldehyde A8-2-Phenyltetrahydrobenzaldehyde A8-6-Phenyl-3.70 — 66% 71 (cf.i-C3H7(D) 10-hexahydro-l-naph9.8.i-C 3 H 7 (D) benzyl alcohol 2-Nitrobenzyl alcohol i-C 3 H 7 (C) C2H6 90% 93-98% 92% 100% 47 48 5 14 77-93% 67.6.7.^C 3 H 7 (D) zyl alcohol 3-Benzyloxy-4-methoxy. * If no solvent is listed the alcohol corresponding to the alkoxide was used C refers to clarified aluminum isopropoxide but not distilled.9-Triinethyl-5.C 2 H 6 88-100% 16 zaldehyde zyl alcohol. 199).4-dimethyltetrahydrobenzaldehyde Cyclocitral Axerophthal A3-3.68 — 69. to distilled reagent. 221.9.9^11106^1-5.7.4.5.2.5.• REDUCTION OF ALDEHYDES TABLE I—Continued REDUCTION OF ALDEHYDES WITH ALUMINUM ALKOXIDES 207 Compound Reduced Product Formed Reagent and Solvent * Yield ' R in A1(OR)3 ^C 3 H 7 .4-Methylenedioxyben. D.6-Trimethyltetrahydrobenzaldehyde A3-2. to an untreated solution of the alkoxide (see p.
4. 22 — 50% 22 22 Methyl pheophorbide b Trimethyl ester of rhodineffr NOTE: References 69-80 appear on p.~i-C 3 H 7 (D) decapentaenal-1 decapentaenol-1 i-C 3 H 7 2-Styrylbenzaldehyde 2-Styrylbenzyl alcohol i-C 3 H 7 2.4-dimethoxybenz aldehyde Cinnamaldehyde i-C3H7 t!2H6 C6H6CH2 a-Chlorocinnamaldehyde a-Chlorocinnamyl alcohol C2S5 ot-Bromocinnamaldehyde a-Bromocinnamyl alcohol C J H B 2-.4. to distilled reagent. * If no solvent is listed the alcohol corresponding to the alkoxide was used. 3-. 199).2. 3. or 4-Nitrocinnamyl C2H5 alcohol dehyde a-M ethylcinnamaldehyde a-Methylcinnamyl alco. C refers to clarified aluminum iaopropoxide but not distilled.8.i-C 3 H 7 hol ll-Phenyl-2.208 REDUCTION WITH ALUMINUM ALKOXIDES TABLE I—Continued REDUCTION OF ALDEHYDES WITH ALUMINUM ALKOXIDES Compound Reduced Product Formed Reagent and Solvent * Yield R in A1(OR)3 C2H6 (25°) C2H5 xveter- ence 2 14 4-Nitrobenzaldehyde 2-Nitro-3.^•C 3 H 7 (C) 3-methanol Trimethyl ester of rho. to an untreated solution of the alkoxide (see p.10-un. or 4-Nitrocinnamal. 221.ll-Phenyl-2.8.75 45-86% 1.3 80% 3.3-Dimethyl-l-naphthyhnethanol thaldehyde i-C 3 H 7 (D) 9-Pluorenealdehyde 9-Fluorylmethanol i-C 3 H 7 3-Pyrenealdehyde 3-Pyrenylmethanol' i-C 3 H 7 (C) Methyl ester of meaoMethyl ester of mesopyropheophorbide b pyropheophorbide 6-3methanol (15 minutes) or J-CSHTCC) Methyl ester of 9-hydroxydesoxo-mesopyropheophorbide 6-?methanol (2 to 4 hours) Methyl pheophorbide b.63 —. D.10-un.6.j-C 3 H 7 (C) dine ^7-3-methanol 4-Nitrobenzyl alcohol 2-Nitro-3.3-Dimethyl-l-naph2.2.6. and V. .4-dimethoxybenzyl alcohol Cinnamyl alcohol 92% 92-97% 68-80% 13. 12 — 12 — 12 — -90% 95% — 50% 54% — 44 76 77 78 79 80 22.
C refers.-4-Dimethylbenzyl alcohol a-Methyl-4-bromobenzyl alcohol a-Methyl-3-nitrobenzyl alcohol a-Methyl-4-nitrobenzyl alcohol Methyl-4-pyridylmethanol Benzohydrol 4-Nitrobenzohydrol Benzylphenylmethanol Ethyl-4-biphenylmethanol Methyl-1-naphthylmethanol MethyI-2-naphthylmethanol C 93% 52% 86% 76% 74% 75% 92% — 05% 90% 5 36 36 D D C D D 5 38 85 5 86 5 & C. to an untreated solution of the alkoxide (see p.D.5-trimethylhexanone-2 Mesityl oxide CTs-Bepten-3-one-2 1 irons-Hepten-3-one-2 ] PentanoI-3 Heptanol-4 Undecanol-2 3-Neopentyl-5. 221-223. 199) .REDUCTION OF KETONES TABLE II REDUCTION OF KETONES WITH ALUMINUM ISOPROPOXIDE 209 Compound Reduced Product Formed Reagejit and Solvent * Yield Reference (a) Saturated and Unsaturated Aliphatic Ketones Dietbyl ketone Di-n-propyl ketone Methyl nonyl ketone 3-Neopentyl-5. U C D D C C 99-100% 5.5-dimethylhexanol-2 No reduction (4 hours) 4-Methylpenten-3-ol-2 Hepten-3-ol-2 (both gave same isomer) (b) Aromatic Ketones Acetophenone 4-Methylacetophenone 4-Br6moacetophenone 3-Nitroacetophenone 4-Nitroacetophenone 4»Acptylpyridine Benzophenone 4-Nitrobenzophenone Benzyl phenyl ketone 4-Propionylbiphenyl 1-Acetylnaphthalene 2-Acetylnaphthalene a-Methylbenzyl alcohol a.5-dimethylhexanone-2 34-Butyl-3.5. * Unless otherwise stated.36 NOTE: References 81-158 appear on pp.37 80-84% 17. to clarified but undistilled aluminum isopropoxide! D. to distilled reagent. the reduction was carried out with aluminum isopropoxide in boiling Isopropyl alcohol solution. and U.
.93 4-Isopropylcyclohexanols Z-Menthol and neoC.94 Z-Menthone menthol Little reduction (i-CHrOH) — 25 Sabina ketone Borneol and isoborneol C 100% 5 Camphor 2-Morpholinomethyl2-Morpholinomethyl50% 95 cyclohexanone « cyclohexanol 4-Methyl-2-morpholino. 109).4^Methyl-2-morpholinoD 83% 95 methylcyclohexanone methylcyclohexanol r> NOTE: References 81-158 appear on pp. * Unless otherwise stated. D.„ 90% (crade) 100% 78% 95% 90% 88% 93% 68% 87% u U. to distilled reagent.D 90-99% 5. C refers to clarined but undistilled aluminum isopropoxide.210 REDUCTION WITH ALUMINUM ALKOXIDES TABLE II—Continued REDUCTION OF KETONES WITH ALUMINUM ISOPROPOXIDE Compound Reduced Product Formed Reagent and Solvent * D D D D U Yield Reference 86 86 36 36 87 88 89 90 91 80 1-Propionylnaphthalene 2-Propionylnaphthalene 1-Benzoylnaphthalene 2-Acetylfluorene 2-Acetylphenanthrene 3-Acetylphenanthrene 2-Phenanthreheacetone 9-Benzoylphenanthrene 2-Acetyldibenzothiophene 3-Acetylpyrene Ethyl-1-naphthylmethanol Ethyl-2-naphthylmethanol Phenyl-1-naphthylmethanol Methyl-2-fluorenylmethanol Methyl-2-phenanthrylmethanol Methyl-3-phenanthrylmethanol l-(2'-Phenanthryl-) propanol-2 Phenyl-9-phenanthrylmethanol Methyl-2-dibenzothienylmethanol Methyl-3-pyrenylmethanol (c) Alicylic Ketones . 221-223. the reduction was carried out with aluminum isopropoxide in boiling isopropyl alcohol solution. and TJ. to an untreated solution of the alkoxide (see p.D U TJ U Cyclopentanone Cyclohexanone Methylcyclohexanones 4-Isopropylcyclohexanone Cyclopentanol C 33% 5 Cyclohexanol C 95% 5 Methylcyclohexanols C 90-95% 5 a s (5%) and trans (95%) U — 92. .
.9-Hydroxyperhydrophe84% 103 — threne nanthrene l-Keto-4.3.4-tetrahy.3..2.2. 100 drophenanthrene hydrophenanthrene 4-Keto-l.1-Hydroxy-ll-methyl-l.4-tetrahydrochrysene NOTE: References 81-158 appear on pp..4-tetrahydrophenanthrene threne — m-9-Keto-asj/m-octahy.4-tetraU 100% 41.3.3-dimethyl23% 101 u 3.10-dihyD^ 65% / 17 droanthracene (xylene) 1-Keto-l . C refers to clarified but undistilled aluminum isopropoxide.1.4-tetrahydronanthrene phenanthrene 1-Keto-l 1-methyl-l .D 82% 105 4-tetrahydrochrysene 2.6-Methyl-2-mgrpholinoD 95 methylcyclohexanol methylcyclohexanone 8-Methyl-2-hydrindaStereoisomers of 8-meth— 87% 96 none yl-2-hydrindanol 1-Tetralol 1-Tetralone D 86% 17 1-Decalol 1-Decalone C 95% 5 9-Methyl-l-decalone 9-Methyl-l-decalol D 90% 97 1 -Ethyl-7-acenaphthel-Ethyl-7-acenaphD 86% 98 none thenol Fluorenol &. 199).2. * Unless otherwise stated. to distilled reagent. the reduction was carried out with aluminum isopropoxide in boiling isopropyl alcohol solution.3.3.3.l-Hydroxy-4.3.3-Morpholinomethyl-4D 40% 99 chromanone chromanol Xanthydrol C 90% Xanthone 5 9.4-Hydroxy-2.9D 64% 17 dimethyl-1O-hydroxy(i-CaHvOH) 9.9-Dimethyl-9.~D Fluorenone 85-89% 5.9-Dimethylanthrone Isopropyl ether of 9.4-tetrahydropheene-1.4-tetrahydrophenan.4-tetrahy.2.4-tetraU 96-98% 41.3. .3.10 3-Morphoh'nomethyl-4. and U. 100 drophenanthrene hydrophenanthrene 4-Keto-2. D.l-Hydroxy-l.10-dihydroanthracene No reduction (10 hours) D — 17 (benzene) 9.2.REDUCTION OF KETONES TABLE II—Continued REDUCTION KETONES WITH ALUMINUM ISOPBOPOXIDE 211 Compound Reduced Product Formed Reagent and Solvent * Yield Reference _ 6-Methyl-2-morpholino. to an untreated solution of the alkoxide (see p.Mixture of 9-hydroxy102 — drophenanthrene asj/m-octahydrophenanthrenes 9-Ketoperhydrophenan.5-methylene-l .4-Hydroxy-l .3-dimethyl-l .2.5-methylD 87% 104 2.2.2. 221-223.
2-benzanthracene 5-Keto-6-methyl-5. * Unless otherwise stated.5.7.2-benzanthracene 5-Keto-7-methyl-5.6.7.6.2-benaanthracene U (toluene) U (xylene) U — u 'V u u D U D D Nora: References 81-158 appear on pp.8.6.7.7.2benzanthracene 5-Hydroxy-l '-methyl-5 .8.8-tetrahydro-l.6.10-ace-l.8.10o-octahydro-l.7.106.2benzanthracene 8-Hydroxy-7-methyl-5.2-benzanthracene 5-Keto-8-methyl-5.12hexahydrochrysene 7-Hydroxy-4.6-methylene-7.10o-ootahydr6-4.10.8tetrahy dro-1. to distilled reagent.S-tetrahydro-l .8.3.6.6.6.2benzanthracene 4o'-Keto-5.6.212 REDUCTION WITH ALUMINUM ALKOXIDESTABLE II—Continued REDUCTION OF KETONES WITH ALtrMimjM ISOPROPOXIDE Compound Reduced Product Formed Reagent and Solvent * U (I-CSHTOH) Yield Reference 23 23 23 106 107 108 88 88 88 109 88 110 110 4-Keto-l .2-benzanthracene 12-Hydroxy-4.12-hexafiydrochrysene 7-Keto-4.8a.9.7.2-beiu!anthracene 5-Hydroxy-8-methyl-6.2-benzanthracene 6-Keto-l '-methyl-5.8-tetrahydro-l .2benzanthracene 10-Hydroxy-5.5-dimethyl-46.9.8-tetrahydro-l.6.106. .9. and U.7. 221-223.10.8a.6. the reduction was carried out with aluminum isopropoxide in boiling isopropyl alcohol solution.8-tetmhydro-1.7.2-benzanthracene 10-Keto-5.7.8-tetrahydro-l .6. 190).4-tetrahydroohrysene — 0 76% Dehydration — — 99% >90% 98% >79% 93% >89% 82% 97% 12-Keto-4.8.7. D.4-tetrahydrochrysene 4-Hydroxy-l .10-tetrahydrochrysene 5-Keto-5.8a.11.7.10-tetrahydrochrysene 5-Hydroxy-6.5-dimethyl46.2-benzanthracene 8-Keto-7-methyl-5.8-tetrahydro-l. to an untreated solution of the alkoxide (see p.7.2-benzanthracene 6-Hydroxy-6-methyl-5.5-methylene7.10.8-tetraEydro-l .8.2.10o-octahydro-4r 10-ace-1.6.2benzanthracene 4a'-Hydroxy-6.7.6.10o-octahydro-l.8-tetrahydro-l.6.7.7.6.6.3.6.2benzanthracene 5-Hydroxy-7-methyl-5.9.8-tetrahydro-l .10.8o.7.5.11.2.9.6.8-tetrahydro-l.9. C refer* to clarified but undistilled aluminum isopiopojtide.
to an untreated solution of the alkoxide (see p 199) .2'.4-benzpyrene 7-Cholestanone Norlupanone » 4'-Hydroxy-l'.4'-tetrahydro-3.4'-tetrahydro3.2'.and <rans-J-Menthen4-ol-3 (t-C3H7OH) D 84% 24 (i-C4H9OH) d2-Menthen-8-ol-2 — — 116 94% Stereoisomers of menthenD 116 8-ol-2 U 28.114 U Cyclohexen-2-ol-l 4-IsopropylcyclohexenU 73-«8% 92.4benzpyrene 6'-Keto-4'.3'.2'.4benzpyrene 4'-Hydroxy-3'-methyll'.2'.4'-tetrahydro-3.2'.2'.4-benzpyrene 4'-Keto-l'-methyl-l'.3'.2'.4'-tetrahydro-3.63.4-benzpyrene 4'-Hydroxy-2'-methyl-l '.2'. Menthadienes (43%) d48% 30 neo-menthen-8-ol-3 (5%) Stereoisomers of menD.3'.4«benzpyrene 4-Keto-2'-methyl-l '.4-benzpyrene 4'-Hydroxy-l '-methyll'.5-dimethylene-l'.4'-tetrahydro-3. 116.4'-tetrahydro-3.REDUCTION OF KETONES TABLE II—Continued** REDUCTION OF KETONES WITH ALUMINUM ISOPROPOXIDE 213 Compound Reduced Product Formed Reagent and Solvent * D C C C Yield Reference 31 80 80 80 "ill 112 73 4'-Keto-l '.4-benzpyrene 6'-Hydroxy-4'.2'.4benzpyrene 4'-Keto-3'-methyl-l '.117 thadien-6. D.4'-tetrahydro-3. 29.3'.3'.115 2-ol-l D 0 24 cis. U 65-79% 3.8-one-2 4-Ketopinene Nora: References 81-158 appear on pp ^221-223 * Unless otherwise stated.3'.2'.4'-tetrahydro-3.3'.8-ol-2 118 4-Hydroxypinene ftt-Menthen-8-one-2 Z-Menthen-8-one-2 d-Menthen-4 (8)-one-3 d-Menthadien-6.5-dimethylene-1 '.3'. and U.4-benzpyrene 7-Cholestanol Norlupanol 78-90% 91% 100% 94% 98% — 16% u — D (d) Unsaturated Alicyclic and Aromatic Ketones Cyclohexen-2-one-l 4-Isopropylcyclohexen2-one-l J-Menthen-4-one-3 49-74% 113.4'-tetrahydro-3.4'tetrahydro-3. to distilled reagent. the reduotion was carried out with aluminum isopropoxide in boiling ISOpropyl alcohol solution C refers to clarified but undistilled aluminum uopropoxide.3'.3'.
10-dimethyl.A8-l-Hydroxy-5.10-di3-isopropenyloctahymethyl-3-isopropenylocdronaphthalene (eretahydronaphthalene (eremophilol) mophHone) 3-Keto-l.3-Triphenylallyl alcohol A8-l-Keto-5.10.3.2-cyclopentanophenanthrene clopentanophenanthrene Androstadien-3. the reduction was carried out with aluminum isopropoxide in boiling isopropyl alcohol solution. D Yield Reference 119. 190).2.7-ol-3 Cholestadien-4.5-ol-17 Cholesten-4-one-3 Cholesten-4-ol-3 and epicholesten-4-ol-3 Chole8ten-8-ol-7 Cholesten-8-one-7 Cholestadien-4.7-one-3 (35%) ep£-Cholestadien-4.214 REDUCTION WITH ALUMINUM ALKOXIDES -TABLE II—Continued REDUCTION OF KETONES WITH ALUMINUM ISOPKOPOXIDE Compound Reduced Product Formed Reagent and Solvent * D D D D C. and U. * Unless otherwise stated.3. D.10o-hexahydro-l." 1 none Difficult to isolate the Dibenzalcyclohexapure reduced comnone pounds Dicinnamalacetone Cinnamalacetophenone J Benzaldesoxybenzoin 1.120 Axerophthylideneacetone Axerophthylideneisopropyl alcohol Dihydrorhodoxanthin Zeaxanthin Capsanthin Capsanthol Benzalacetone Methylstyrylmethanol Dibenzalacetone Distyrylmethanol Dibenzalcyclopenta. to an untreated solution of the alkoxide (see p. .2-cyhexahydro-1.5-one-l 7 Androstadien-3. 221-223.10.7-ol-3 (49%) Cholestadien-5. C refers to clarified but undistiUed aluminum isopropoxide.9.7-ol-3 (1%) (estimated ratios) Ergosten-8(14)-one-3 Ergosten-8(14)-ol-3 12% 23% 35% 58% 121 122 36 36 (5) • 5 C D D 91% 75% (crude) 80% (crude) 35% 52% 44% — 123.9.124 125 D 126 D D D D 127 35 128 34 • — 129 NOTB: References 81-158 appear on pp.7-ol-3 (15%) ejw-Cholestadien-5. to distilled reagent.2.2.10o3-Hydroxy-l.
1 -Trichloropropanol-2 A1(OCSH8)3 2 67% C 85% 5 nol-1 2.REDUCTION OF KETONES TABLE II—Continued REDUCTION OF RETONES WITH ALUMINUM ISOPROPOXIDE 215 Compound Reduced Product Formed Reagent and Solvent * D Yield Reference 32. C refers to clarified but undistilled aluminum isopropoxide.a-Trichloroacetophenone a-Bromopropiophenone a-Bromoisobutyrophenone 1.7.7. 130 Ergostatrien-4. 129.2.9(ll).45 p.7.1.22ol-3 (35%) Ergostatrien-5. . * Unless otherwise stated.22-ol-3 (19%) epi-Ergostatrien-5.22ol-3 (1%) (estimated ratios) Mixture of ergostatetraenols-3 Mixture of lumistatrienols Zymostenol epi-4-Dehydrotigogenol-3 Lanosterol 100% D D — D D 73% — — 22% 32 32 131 .132 133 (e) a-Halogen Substituted Ketones 1.22-one-3 Lumistatrienone-3 Zymostenone 4-Dehydrotigogenone-3 Lanostenone Ergostatrien-4. to an untreated solution of the alkoxide (see p.7. 221-223.1. 44 panol-1 (and other products—see p. D. 199). 193) • Little bromohydrin (see U (100°) — 44. 193 for products) 42% 44 l-Phenyl-2-methyl-3U (33°) bromopropene-1 (see p.7.33. 194) 2-Bromocyolohexanol U 30% 46 (cyclohexanol 33%) Little bromine in — ' 44 ' u product (2-Bromo-l-phenyletha- 2-Bromocyclohexanone 2-Bromocholesten-4"one-3 Nora: References 81-158 appear on pp. to distilled reagent.22-ol-3 (45%) epi-Ergostatrien-4.1-Trichloroacetone a-Bromoacetophenone a.a. and U.A1(OC2H6)3 2 69% ethanoH 2-Bfomo-l-phenyl-proU 35-42% 43. the reduction was carried out with aluminum isopropoxide in boiling isopropyl alcohol solution.7.2-Trichloro-l-phenyl.22one-3 Ergostatetraen-4.
16-Benzalandrosten-4-olbenzalandrosten-417-one-3 (isolated as.and trans-Androsten.21-ol-l 1one-12 Docosadiene-l. /3-isomer 60%) D 82% 136 NOTE: References 81-158 appear on pp.1 O-Diphenyldecanediol-2.4-Dibenzoylbutane 1.94% u 3. D.4-naphthoquinone Androsten-4-dione-3.17 Hydroquinone 100% c 2-Methyl-2-phytyl-l. and V.3dihydro-l.18-Diphenyloctadecane-diol-2.2.216 REDUCTION WITH ALUMINUM ALKOXIDES TABLE II—Continued REDUCTION OP KETONES WITH ALUMINUM ISOPROPOXIDE Compound Reduced Product Formed - Reagent and Solvent * Yield Reference (/) Diketones Benzil 1. 221-223. 199). to distilled reagent.16-Dibenzoylhexadecane Quinone 2-Methyl-2-phytyl-2.4-tetrahydro-l.21-diol11. * Unless otherwise stated. dione-3.Al(O-t-C4H9)3 70% in «-C4H9OH 4-ol-17-one-3 (g) Protected Diketones Dimethylacetal of phenylglycollic aldehyde 3-Enol ethyl ether of 16.8-Dibenzoyloctane 1.9 — — 1.20-al20-»l-21 21 (isolated as diacetate) Dimethylacetal of phenylglyoxal 5 134 134 134 5 135 21 D D D 55% 33% 68% 17 19 18 (ft) Alcoholic and Phenolic Ketones (and Ethers or Esters of These) Docosadien-1. to an untreated solution of the alkoxide (see p.17 Mesohydrobenzoin C 90% 1.17 acetate) 21-Dimethylacetal of 21-Dimethylacetal of pregnen-5-ol-3-onepregnen-5-diol-3. x .4naphthohydroquinone cis. C refers to clarified but undistilled aluminum isopropoxide.6-Diphenylhexane— — diol-2j5 — — 1.12 (a-isomer 22%. the reduction waB carried out with aluminum isopropoJride in boiling isopropyl alcohol solution.
5-dimethoxyphenylmethanol 90% 95% 81% 38% (crude) 52% (crude) 40% — 43% 69% D D D D D U.20 Ox-norcafestadienol (isolated as acetate) 4-(2'-Hydroxy-l '-naphthyl)-butanol-2 Stereoisomeric equilenin diols Stereoisomeric estradiols 3-Benzyl ether of .5-dimethoxyphenyhnethanol Pentadecyl-2.REDUCTION OF KETONES TABLE II—Continued REDUCTION OF KETONBS WITH ALUMINUM ISOPBOPOXIDB 217 Compound Reduced Product Fonned Reagent and Solvent * C D D D Yield Reference 5 127.17 Allopregnene-16-diol-3. C refers to clarified but undisUlled aluminum isopropoxide. the reduction was carried out with aluminum isopropoxide in boiling isopropyl alcohol solution.estradiol l-Methoxypropanol-2 a-(Methoxymethyl-) benzyl alcohol a-Methyl-2-methoxybenzyl alcohol a-Methyl-3-methoxybenzyl alcohol a-Methyl-4-methoxybenzyl alcohol n-Butyl-3.5-Dimethoxypalmitophenone Mesohydrobenzoin Stereoisomers of androstene-4-diol-3.D D — D D D D D 138 139 139 140 141 92-100% 41.17 (isolated as diacetate) 16-Benzylideneandrostene-5-diol-3.20 Pregnadiene-5. 199).(1 '-Methylpropylidene-) androsten-6-ol3-one-17 16-Benzylideneandrosten-5-ol-3-one-17 Allopregnen-16-ol-3-one20 Pregnadien-5. and U.5-Dimethoxyvalerophenone 2. to an untreated solution of the alkoiide (see p. to distilled reagent.16-oI-3one-20 Ox-norcafestadienone 4-(2'-Hydroxy-l'-naphthyl)-butanone-2 Equilenin Estrone Estrone benzyl ether Methoxyacetone a-Methoxyacetophenone 2-Methoxyacetophenone 3-Methoxyacetophenone 4-Me£&oxyacetophenone 3. 142 "Good" — 40% 72% 82% 80% 52% 66% 143 144 17 17 36 36 36 36 145 D — Nora: References 81-158 appear on pp. D.17 3-Pinacol of androsten-4ol-17-one-3 16-(1'-Methylpropylidene-) androstene-5diol-3. 221-223 * Unleas otherwise stated.137 20 138 Benzoin Androsten-4-ol-17-one-3 3-Pinacol of androstene4-dione-3.16-diol-3.17 16. .
16one-20 3-Acetate 16-(«-acetoxyisocaproate) of pregnene-5-diol-3.20 AlIqpregnanetriol-3.References 81-158 appear on pp 221-223 * TJnless otherwise stated.(4'-methoxyphenoxy-)phenylmethanol 3-Benzyloxy-4-methoxybenzylethylene glycol Ethyl-4'-methoxy-4-biphenylmethanol Ethyl-4-methoxy-l-naphthylmethanol Ethyl-6-methoxy-2-naphthylmethanol 3-Benzoate of estradiols Androsten-5-triol-3.20-Diacetoxypregnanone-3 3-Acetate 16-(w-acetoxyisocaproate) of allopregnanediol-3.16.16-one-20 3-Acetoxycholesten-5one-7 3-ejn-Acetoxycholesten5-one-7 7-Ketocampesteryl acetate Monomethyl ether of hydrobenzoin (stereoisomers) Ethyl-4-phenoxyphenylmethanol Etbyl-4.the reduction was carried out with aluminum isopropoxide in boiling ISOpropyl alcohol solution C refers to clarified but undistilled aluminum isopropoxide. to distilled reagent. 142 146 147 148 Benzoin methyl ether 4-Phenoxypropiophenone 4-(4'-Methoxyphenoxy-) propiophenone 3-Benzyloxy-4-methoxybenzyl acetoxymethyl ketone 4-Propionyl-4'-methoxybiphenyl l-Propionyl-4-methoxynaphthalene 2-Propionyl-6-methoxynaphthalene Estrone benzoate 3.150 Stereoisomers of cholesten-6-diol-3.17-Diacetoxyandrosten-5-one-7 4. to an untreated solution of the alkoxide (see p 199) . D.20 83% — 90% 94% — — — 75% — — — D D D C.7 Cholesten-5-diol-3-ept7^a-(33%).D — D Pregnene-5-triol-3.16.7-^(25%) 7-Hydroxycampesterol (isolated as the dibenzoate) 3-Acetoxysitosten-5-one.4. and U.7 J30 151 152 D NOTE.17 Pregnanetriol-3.Stereoisomers of sitos7 ten-5-diol-3.218 REDUCTION WITH ALUMINUM ALKOXIDE8 TABLE il—Continued REDUCTION OP KETONBS WITH ALUMINUM ISOPBOPOXIDE Compound Reduced Product Formed Reagent and Solvent • D D D D Yield Reference 17 86 86 42 86 86 86 5.20 D D D — — 63% 88% 40% 93% 148 149.7.
to distilled reagent. C refers to clarified but undistilled aluminum isopropoxide. . 221-223.isopropyl esters of hypane-l-carboxylate droxy acid 68% 78%^ (crude) 33% D — C D D D U * 66% 90% — 75% 95% 95% >52% 36 155 5 74 156 36 40 u u u >19% 82% — 40 40 40 Nora: References 81-158 appear on pp.Isopropyl 2-methylcycloanone-2-carboxylate hexanol-2-carboxylate {plus some ethyl ester) Ethyl a-benzyliderieEthyl a-benzylideneacetoacetate 18-hydroxybutyrate (?) Ethyl 0-benzoylpropiY-Phenyl-7-butyrolactone onate Ethyl a-phenyl-0-bena.Lactone of hydroxy acid 3-cts-benzoylcyclopro(19%) (plus isopropyl pane-1-carboxylate ester of hydroxy acid) Methyl 2-trans-phenyl.7-Diphenyl-7-butyrozoylpropionate lactone (after hydrolysis) Isopropyl benzopheIsopropyl benzohydrolnone-4-carboxylate 4-carboxylate Methyl 2-cis-phenyl-3Lactone of 2-ct8-phenylcts-benzoylcyclopro3-cis-phenylhydroxypane-1-carboxylate methylcyclopropane-1carboxylic acid (52%) (plus isopropyl ester of hydroxy acid) Methyl 2-trans-phenyl.22-one-7 mastadien-5.22-diol-3.Stereoisomeric mixture of 3-trans-benzoylcycloisopropyl esters of propane-1-carboxylate hydroxy acid Methyl 2-cts-phenyl-3Stereoisomeric mixture of trans-benzoylcyclopro.7 Chlorogenone # Mixture of chlorogenin and /3-chlorogenin Lupenalyl acetate Lupenediol (i) Keto Esters Ethyl trimethylpyruvate Isopropyl trimethyllactate Ethyl 2-methylcyclohex. and U. the reduction was carried out . to an untreated solution of the alkoxide (see D.Stereoisomers of stig5.REDUCTION OF KETONES TABLE II—Continued REDUCTION OF KETONES WITH ALUMINUM ISOPROPOXIDE 219 Compound Reduced Product Formed Reagent and Solvent * D D D Yield Reference 153 154 73 - 3-Acetoxystigmastadien. D. * Unless otherwise stated.with aluminum isopropoxide in boiling isopropyl alcohol solution. 199).
4-tetrahydrophenanthrene-2-carboxylate 7-(2-Naphthyl-)Y-butyrolactone Isopropyl fluorenol-2carboxylate Isopropyl fluorenol-3carboxylat. and IT.9-Hydroxydesoxomethpheophorbide a ylpheophorbide a Methylpyropheo9-Hydroxydesoxomethphorbide a ylpyropheophorbide a Dimethyl ester of pheo. a isomer = 46%. 199).2.3.4tetrahydrophenanthrene-2-acetate Methyl l-keto-2-methyl1.3.220 REDUCTION WITH ALUMINUM ALKOXIDES TABLE II—Continued REDUCTION or KETONES WITH ALUMINUM ISOPBOPOXIDE Compound Reduced Product Formed Reagent and Solvent * U D D D ' D U Yield Reference 41 36 36 74 37 41 Methyl . to distilled reagent. 221-223. C refers to clarified but uadintilled aluminum isopropoxide. .aTrimethyl ester of 2.3. D.Methyl 3-hydroxycholen11-ate (after remethylaate tion). * Unless otherwise stated.e Isopropyl anthrahydroquinone-2-carboxylate Lactone of 1-hydroxy-l.ahydroxymesochlorin ee c • — NOTB: References 81-168 appear on pp.aketochloroporphyrin e& hydroxy chloroporphyrin 66 D 78% 157 D C C C CN 90% 5% 50% — "Good" 158 2*2 22 22 22 22 Trimethyl ester of 2desvinyl-2-acetylchlorin ee Trimethyl ester of 2.4-tetrahydrophenanthrene-2carboxylic acid (a- 97% 85%71% 55% 80% 91% Methyl 3-ketocholen-ll.2.4-tetrahydrophenanthrene-2-acetic acid Isopropyl esters of stereoisomeric l-hydroxy-2methyl-1.2. to an untreated solution of the nlkocde (gee p.3.2.Dimethyl ester of 9-hyporphyrin OB droxydesoxopheoporphyrin as Trimethyl ester of 2.8-(2-naphthoyl-) propionate Methyl fluorenone-2-carboxylate Isopropyl fluorenone-3carboxylate Isopropyl anthraquinone-2-carboxylate Methyl l-keto-1. the reduction was carried out with aluminum isopf opoxide in boiling ifiopropyl alcohol solution. 0 isomer = 32% Methyl ester of A5-7A6'7-Choladienic acid ketocholenic acid (after hydrolysis) Zinc complex of methyl.
907 (1940) [C. M French and Gallagher. Proc Roy. 36 (1941) 89 Wilds. 64 Blumenfeld. Gen. Dworzak. Chem. 1930) [Chem. 66 Jitkow and Bogert. Soc. 3104 (1930)].281 (Jan. 32 (1926) [C. private communication. 1939.. 67. 760. 1939. 5. 17.ahydroxypheoporphyrin 05 (main product) Methyl ester of 2. / .. 88 Campisell and Chattaway. G. U. 77 Natelson and Gottfried.. and Marsh. pat. Am. 358 (1934). / . Chem. 64. 1556. Am. Chem. No. Chem. / .. 1555 (1936). Soc. 2371 (1932)]. Morrison. Soc. Org. J. 3237 (1941)]. to distilled reagent. 70. Chem. 71 Batty. 63. 64. 1938.a-hydroxymesopheophorbide a (main product) C C — 22 * Unless otherwise stated. "Ponndorf. 35. 1981 (1941). E. 80 Bachmann and Carmack. / . 130B. / . Farbenindustrie A. Batty. Heilbron. and Jones. C refers to clarified but undistilled aluminum isopropoxide.. 72 Barraclough. Soc. J. 529 (1941). Soc. 85 Clemo and Hoggarth.. Ward. Rowland. J. 1941.aketopheoporphyrin as Methyl ester of 2desvinyl-2-acetylpheophorbide o Dimethyl ester of 2. Zentr. 15. 74 Adkins and Elofson. Am. Chem. 69 Haworth. Soc. Soc. Am. 63. J. 62. 15. Zenir. Chem. Chem. J.. 261 (1932). 5. 10. Org. 11. D. 87 Bachmann and Struve. 1249 (1942). Soc. Am. Chem. the reductioa was oarried out with aluminum isopropoxide in boiling isopropyl alcohol solution. 83 Kenyon and Young. Perfumers' J. Soc. 81 Whitmore and Lester. Chem. J. 3. Soc. 199). private communication.954 (Oct. 68 Kuhn and Wendt. 36 (1940). and Jones. London. Org. Soc. 74. 1549. J. 1498 (1942). 1939. Soc. 64. 3256 (1940). 78 Brown and Bluestein. J. Chem. 1333 (1937). Chem. 20. 70 Krauze and Slobodin. 62 Reichstein. 78 Fuson. 1941. Am. 6. J. 32 (1942).S.. and Polya. J. 60 69 . Soc. Am. Soc. 45. 64. Ger. 489. Heh..REDUCTION OF KETONES TABLE II—Continued REDUCTION OF KETONES WITH ALUMINUM ISOPBOPOXIDE 221 Compound Reduced Product Fonned Reagent and Solvent * Yield Reference 22 Dimethyl ester of 2. Chem.. 78 Jones and Meakins. 90 Bachmann and Osborn.R. 698. Am. 88 Bachmann and Chemerda. Ger. 63 Sachs. Chim. Ada. Heilbron. Horning. Chem. 1244 (1942).-G. Monatsh. Soc. 2962 (1942). to an untreated solution of the alkoxide (see p. 435 (1942). 64. Chem. Chem. Soc. Ber.. 61 1. Ber. J. 1429 (1942). (I). 535. pat.. 82 Whitmore and Randall. and U. 7. Royals. Chem.. Chem. 11 (1926). 64. 69. Jones.S. Ber. 1940. J. ' 84 Arcus and Kenyon. 47. Ammann. 128. Heilbron. 1552. Ber. Chem..A. Chem. 2321 (1926)]. 2494 (1941). J.. Soc. 78 Kuhn and Wallenfels.. J. A.. (II). Am.. J. 420 (1940). 1931) [Chem. E. and Trivelli. 67 Kuhn and Hoffer.
1939. and Jones. Org. 72. Chem. 589. 141 MeQuillin and Robinson. 379. J. Chem. Chem. 2600 (1941). "'Bachmann. Soc. and Macbeth. 1941. 1939. 37. J. Am. Laucius. Soc. J.. 1820. and Wendler. Am. Soc. 1939. 2601 (1941). 62. 63. 7.. 64. Zeitschel and Eok. [5] 1. 107 Fieser and Cason. 111 Bachmann and Carmack. 1531. 63. 663. Chem. 3. Soc. J. and Doll. J. 98 Bachmann and Sheehan. Chem. 123 B e r g m a n n . 479 (1935). Helv. 759 (1941). 520. Chem. ^9 (1941) [C. Org. Chim. Soc. 25. Chem. Helv. 97 Elliott and Linstead. J.-Ges. 68. 138 Stodola and Kendall. A. 63. 2936 (1940). prakt. J. 1941. Am. Tscherning.. Am. 786 (1941). 548. Proc Roy. 1938. J. Am. Chem. Plattner. J. 1840 (1937). J. 72. Chem.. J. 1057 (1941). J. 2300 (1940). S. 280 (1939). Soc. 110 Fieser and Novello. J. Macbeth. 116 Gillespie and Macbeth. 113 Bartlett and Woods. Am. 112 Eck and Hollingsworth. Rilegger. 37. Am. Chim. 102 Linstead. Gillespie.. J. Wales. and Wittle. 826 (1942). Am. N. Soc. 59. 613 (1942). 60. Chem. Chem. 1939. and Lions. 120 Heilbron. 63. 128 Eck and Hollingsworth. Hughes. soc chim. Ber. Soc. 142 (1942). 136 Tishler. 137 Butenandt. Whetstone. Chem. Am. 140 Wettstein. 116 Johnston and Read. 114 Whitmore and Pedlow. J. Hunziker. Chem. Am. Chem. 64. Ada. Chem. 363 (1943)]. Chem. Soc. Ada. Soc. 233. 117 Doeuvre. and Widmer. 2972 (1940). 1897 (1938). 119 Karrer. J. Soc. A. Am. Am. 1296 (1940). 126 Gillam. Am. and Levine. J. Soc. Chem. 6. 104 Bachmann and Sheehan. 99 Harradence. Org. 64. 1173 (1938). J. 1941. Helv. Soc. Soc. Am. J. Turner. 122 Karrer and Htibner. Soc. Helv. Am.. J. J. 62. 2020 (1942). 131 Wieland. 96 Burnop and Linstead. Proc Roy. Chem. 854. J. Am. Chem. 802 (1942). 63. Chem. S. Chem. Soc. 106 Bachmann and Safir. Soc. Soc. Soc. 856 (1941). 118 Schmidt. Ann. 367 (1932). 2303 (1926). Am. 1938. and Swanson. Chem. J. Chem. Am. Am. J. 63. 63. J. Bull. 1989 (1940). 101 Fieser and Daudt. Chem. 143 Marker and Rohrmann. Chem. 233 (1939). Soc. Soc. Am. 134 Sohmidt and Grosser. Ber. Chem. 771 (1941). Chim. 126 Robinson and Slater. Lynas-Gray. Soc. 129 Marker. Chem.. 338 (1942). Rath.. Chem. Chem. Johnson. / . 198 (1938). 38 [C. 1940. Kamm. Chim. and Oakwood. Soc N. Ada. 726. 71. Soc. Chem. Wagner. Soc. Soc. J. 439 (1938). and Simonsen. Soc. J. Chem. Am. and Eschinazi. Ada. Crooks. J. Ulshafer. Soc. 63. J. 1934. 66. Fieser. 133 Bellamy and Doree. 93 Cooke. 75. 94 Zeitschel and Schmidt. J. Am. Chem. J. Chem.222 tl 92 REDUCTION WITH ALUMINUM ALKOXIDES Burger and Bryant. 59. 1687 (1941). Soc. 136 Ruzicka. 121 Karrer and Solmssen. 781 (1941). 205 (1941). Soc. 132 Marker and Turner.. [2] 133. and Hanisch. 19. 96 Harradence and Lions. Soc. Chem. 21. Ann. 62. and Benend. 106 Newman. J. Chem. 2927 (1938) . 64. / . 100 Bachmann and Edgerton. Schapiro. J. 201 (1934). 62. 63. Penfold. Chem. 62. 103 Linstead and Walpole.. Soc. 1563. Schimmel & Co. J. J. 6 4 7 (1941). Am. 130 Windaus and Naggatz. 386 (1943)]. 18. 1940.. 60. 2989 (1941). Chem. 139 Marker. Ber. Akt. 1941. J. 142 Marker. 127 Butenandt and Heusner. J. Ada. Soc. J.. 176. Fritzsche. 476 (1936). 560 (1942). Chim. Ber. Chem. Helv. and Miescher. Soc.. 109 Bachmann and Safir.. Schulz. Soc. Chem. and Geiger. 542. 204 (1939). Ber. 124 Bergmann. 349E (1941). Soc. J. Soc. 63.. 63. ' Gillespie. 24. 2100 (1935). Wales.
J.. J. Butenandt and Logemann. 2. A. Heilbron. 267. Turner. v 118 Dane and Wulle. and Wittle. S. J. Am. Lettre. Z. Chem. 34. 166 Robinson and Walker. Krueger. 64. 241. 2455 (1942). 162 Wunderlich. 1940) [C. physiol. 1942. 64. Chim. Am. Chem. Soc. 126 (1936). U. . Rohrmann. Am. . and Lewis.. 6022 (1940)]. Ada. pat. Soc. 1901 (1942). Am. 120 (1936). Soc. J. Helv. Am. 880 (1942). Soc. 5 (1940). and Schenk. Turner.. J. 241. Ulshafer. physiol. 161 Ruigh. J... J. Wittle. 558 (1942).124 (Aug. Eschinazi. 1937. Z. and Ulshafer. 64.. 164 Marker. 63.170.. Soc. 148 Marker.. Chem. 620. Ann.. 1939) [C. Chem. Chem. Plambeck. Chem. physiol.. ' " 6 Bergmann. 149 Windaus. 25. 167 Press and Reichstein. 61. Soc. Soc. Chem. Soc. A. and Wittbecker. Cook. 1133 (1940)].722 (June 19. pat. 661. 774 (1941). Chem. 64. 22. 3319 (1939). Am. 160 Wintersteiner and Ruigh. Chem. 64. 163 Linsert. 34. 842. J. 147 Marker. Wagner. 221 (1942). 103 (1935). Crooks. Fr. Z. Chem.REFERENCES TO TABLES 144 146 146 223 Chinoin.. and Schapiro. Chem..
. . 243 245 245 Diazo Reaction . . . . 246 . BACHMANN AND ROGER A. Procedure Utilizing Sodium Hydroxide 2-Methoxy-4'-bromobiphenyl and 4-Methoxy-4'-bromobiphenyl 224 245 246 . . SELECTION OF EXPERIMENTAL CONDITIONS 230 231 235 236 236 236 237 238 238 239 239 241 241 241 242 242 243 243 Choice of Method Isolation of the Product EXPERIMENTAL PROCEDTJRES '.CHAPTER 6 THE PREPARATION OF UNSYMMETRICAL BIARYLS BY THE DIAZO REACTION AND THE NITROSOACETYLAMINE REACTION WERNER E. HOFFMAN University of Michigan CONTENTS NATURE OF THE REACTIONS PAGE 225 Diazo Reaction Nitrosoacetylamine Reaction MECHANISMS or THE REACTIONS SCOPE AND LIMITATIONS OF THE REACTIONS 225 226 227 230 Types of Compounds Available through the Reactions Derivatives of Biphenyl Terphenyls and Derivatives Arylnaphthalenes Arylthiophenes Arylpyridines Side Reactions Related Reactions Employment of Dry Diazonium Salts Pschorr Synthesis Reaction of Diazonium Salts with Quinones and with Phenols Decomposition of Aromatic Acyl Peroxides OTHER METHODS OF SYNTHESIS OF UNSYMMETBICAL BIARYLS Direct Substitution in Biphenyl Grignard Reaction Diels-Alder Reaction Ullmann Reaction .
403 (1895). 41. 366 (1897). Am.3 the first method involves the following two steps (illustrated by the preparation of 4-bromobiphenyl). for no solvent has been found which will not be attacked by the reactive intermediates which are formed in these reactions (p. " As developed by Gomberg and Bachmann. 28. 1. 247 247 247 247 248 248 248 248 248 248 249 249 251 251 252 252 252 ' NATURE OF THE REACTIONS The amino group of aromatic amines can be replaced by aryl groups with the formation of unsymmetrical biaryls by two general procedures: (1) by reaction of the aryldiazo hydroxide or acetate (obtainable from the diazotized amine) with aromatic compounds. Soc.. . and 7-Phenylpyridine Nitrosoacetylamine Reaction Nitrosation by Nitrous Fumes Nitrous Fumes Method 3-Nitrobiphenyl Nitrosation by Nitrosyl Chloride Preparation of Nitrosyl Chloride . 2339 (1924). Ber. Kiihling. Both reactions owe their origin to Bamberger * and to Kuhling.DIAZO REACTION Procedure Utilizing Sodium Diazotate 4-Methylbiphenyl Procedure Utilizing Sodium Acetate o-Chlorobiphenyl Procedure Utilizing a Stabilized Diazonium Salt a-Phenylnaphthalene " Procedure with Pyridine a-. In general. f)-. and (2) by reaction of the nitrosoacetylamine (obtainable from the acetylated amine) with aromatic compounds. „.2 but it remained for others to develop practical procedures for utilizing them.. 30. / . Diazotization of an aromatic amine in the usual manner. 165 (1896). 28. 231). . . 29. 46. Diazo Reaction. Chem. •NHj + 2HC1 + NaNO2-*Br—i />—N2+C1.the aromatic compound must be a liquid. . Gomberg and Bachmann. . 523 (1895). Ber. Nitrosjd Chloride Procedure p-Terphenyl COMPOTOIDS PREPARED BY THE REACTIONS 225 PAGE ".+ NaCl+2H2O 2^ Conversion of the diazonium salt to the diazohydroxide by means of alkali in the presence of a liquid aromatic compound with which the 1 a 8 Bamberger.. .
A variation in the procedure for certain amines is to add the diazonium salt to sodium hydroxide in an amount sufficient to form the sodium diazotate. 7 Grieve and Hey. Nitrosoacetylamine Reaction. / . or zinc chloride. The overall reaction may be written in the following manner. The diazohydroxide is extracted by the aromatic liquid as it is formed. Haworth.5-disulfonic acid. 1934. Soc. Soc. See also later references. Chem.226 THE PREPARATION OF UNSYMMETRICAL BIARYLS diazohydroxide reacts. 369. explosive diazohydroxides of Bamberger. Soc. In the example given. J. and Hey.' This procedure avoids the isolation of the unstable. Am. Br—i > />—N2+C1. 4-bromobiphenyl is obtained in 35-46% yield.+ (v /) + NaOH -> N2 + NaCl'+ H2O The second step is carried out by adding a 15-40% aqueous solution of sodium hydroxide dropwise to a well-stirred mixture of the cold diazonium salt solution and the aromatic liquid until a slight excess of alkali is present. In this synthesis of unsymmetrical biaryls. salt solution and the aromatic liquid. naphthalene-l. 1940. The biaryl compound is formed when the aqueous solution of the diazotate is stirred with an aromatic liquid. . developed by Grieve and Hey 7 and Heilbron8 and collaborators. three steps are involved (illustrated by the preparation of 3-nitrobiphenyl). and Hey.6 consists in converting the . Soc. Chem.aryldiazonium chloride to a stabilized diazonium salt by treatment wi. the dried salt is then suspended in an aromatic liquid and treated with sodium acetate and acetic anhydride. J.. introduced by Hodgson and Marsden. 48.1 which are formed from the diazonium salt and the alkali.6 Another variation. Chem. 1940. 1940. 1285. 208. 1372 (1926).4 CH3C«H4N2+C1. Chem. 8 France. Chem. The biaryl reaction takes place in the organic liquid and is complete when evolution of nitrogen ceases. / . sodium acetate may be added to the mixture of diazonium.+ 2NaOH > CH3C6H4N=N—ONa + NaCl + H2O CH3C6H4N=N—ONa + C 6 H 6 ^ > CH3C6H4-Cells + N2 + NaOH In place of sodium hydroxide. e Hodgson and Marsden. * Elks.th naphthalene-1-sulfonic acid. 4 Gomberg and Pernert. Heilbron. Soc. J. 1798.
a mixture of NO and NO2 actually is used in the reaction . 2. In the example given. formed by addition of the diazonium salt to an excess of sodium hydroxide. Acetylation of the amine. a yellow solid is precipitated. which are exceedingly unstable and explosive in the * So-called nitrous fumes. or by adding a solution of nitrosyl chloride to the acetylamine and sodium acetate in acetic acid. H N—COCH3 + N0C1 + CHjCOjjNa NO 2 N—COCH3 + NaCl + CH3CO2H NO2 3. such as diazotized p-bromoaniline or p-nitroaniline. The nitroso derivative is precipitated by pouring the solution into ice water and is extracted by the aromatic liquid or filtered and added to the liquid with which it reacts. RNaONa. MECHANISMS OF THE REACTIONS When a dilute solution of sodium hydroxide is added gradually to a solution of an aryldiazonium salt. 3-nitrobiphenyl is obtained from ra-nitroacetanilide in 63% yield. Nitrosation of the acetylamine by means of N 2 O 3 * or N0C1. These products.MECHANISMS OF THE REACTIONS 1. Reaction of the nitrosoacetylamine with a liquid aromatic compound. The same yellow solid can be obtained by adding an acid to the sodium diazotates. NO N—COCH3 + NOJS NO2 N2 + CH3CO2H The nitrosation is carried out by passing nitrous fumes into an icecold solution or suspension of the acetylamine in acetic acid and acetic anhydride. NO —COCH3 + N2O3 NO 2 227 N—COCHs + H2O or.
21. 37. Ann. but also they appear to react according to the same mechanism.+ NaOCOCHg -> R—N=N—OCOCH3 + Ci0H7SO3Na The reaction of the aryldiazo acetates with aromatic compounds to give biaryls was utilized first by Kuhling. Ber. Hantzsch and Wechsler.278 (1940}. is not unexpected in view of the statements that nitrosoacetanilide is a tautomer of benzenediazoacetate. Not only do these substances yield the same products when they react with aromatic compounds. 226 (1902). 1J Discussions of the mechanisms of these reactions may be found in the excellent reviews of Hey and Waters. Repta. and the nitrosoacetylamines are closely related. R—N=N—OCOCH3. and they react in the same manner as the aryldiazo hydroxides.. Revs. The aryldiazo acetates are probably the reactive intermediates also in the procedure in which a stabilized diazonium salt is treated with so_dium acetate and acetic anhydride in the presence of an aromatic compound. Chem.... On the basis of the analysis of one compound of this 'type. R—N=N—ONa + HOH & R—N=N—OH + NaOH R— N=N—OH + R'H -» R—R' + N2 •+• H2O' (R and R' = aryl radicals) The term diazohydroxide will be used to include the so-called diazo anhydrides. in the aromatic liquid with acetyl chloride. The reactions involving the diaaohydroxides. are the reactive intermediates in the diazo reaction and give biaryls when they come in contact with aromatio compounds.228 THE PREPARATION OF UNSYMMETRICAL BIARYLS dry or moist state. 661 (1894). 10 11 - . 27.4 presumably in virtue of hydrolysis to the diazohydroxides and reaction of the latter with the aromatic compound. 325.9-10' u C6H6N(NO)COCH3 +± C6H6N=N—OCOCHj Considerable evidence that all these reactions take place through a free radical mechanism has been accumulated. the diazoaeetates. 914 (1894). foHj]. are probably formed through rearrangement of the aryldiazonium salts initially produced. the diazo anhydride structure. When sodium acetate is added to aryldiazonium salts. perhaps.12 It is considered that 'Bamberger.169 (1937). was assigned to these compounds. v. and of Hey.. Pechmann and Frobenius. 27. aryldiazo acetates. This. Ber. RN2-~0—N2R.1 Solutions of the Bodium salts of the diazohydroxides show a similar behavior with aromatic compounds. Ann.2 who treated a suspension of the potassium diazotate. RN2OK.
in benzene. The reactions are indicated in the following formulation. . Even with nitrobenzene.MECHANISMS OF THE REACTIONS 229 free aryl radicate are produced by decomposition of the diazo compounds and of the nitrosoacetylamines. nitroso-mnitroacetanilide decomposes into wvnitrophenyl and acetate radicals with evolution of nitrogen. / V-N(NO)COCH3 NO2 NOj Similarly. para and ortho derivatives are formed. Substitution usually takes place para and ortho to the substituent in the benzene ring. Another point of interest is that nitrobenzene is attacked more rapidly than toluene.and 4-nitrobiphenyl. Thus. N-nitrosoacetanilide and nitrobenzene give 2. and that the radicals react with the second component to give the biaryl. only the para isomer has been isolated from the reaction mixtures. CH«C0ONO2 NOS CH3COO + HCH3COO CHS H- CH3COOH CH3 • + CO2 CH4 In support of the free radical mechanism is the observation that the usual directive influences are not operative in these reactions. the m-nitrophenyl radical reacts with benzene with elimination of a hydrogen atom and the formation of 3-nitrobiphenyl. irrespective of the nature of the groups. in the few reactions that have been carried out with benzaldehyde and benzonitrile. Thus. which shows also the probable fate of the acetate radical. with ethyl benzoate alT three isomers were obtained.
and iron are attacked when N-nitrosoacetanilide is allowed to decompose in a non-polar solvent such as carbon disulfide in the presence of the metals. Some conception of the types of compounds available by replacement of the amino group of aromatic amines by aryl groups can be obtained from an examination of the following table. which shows the more important amines from which diazo AMINES COMPOUNDS USED FOB COUPLING Aniline Halogenated anilines Nitroanilines Cyanoanilines Alkoxyanilines C-Alkylanilines Bromonitroanilines Bromo-C-alkylanilines Anthranilic esters Aminophthalic esters Phenylenediamines Aminobiphenyls Benzidine Naphthylamines Benzene Toluene Nitrobenzene Methyl benzoate Phenol ethers Thiophene Pyridine .= free aryl radical. R = alkyl group. zinc. antimony.+ RH-> ArH + RAr. SCOPE AND LIMITATIONS OF THE REACTIONS Types of Compounds Available through the Reactions The two general reactions can be used to prepare a variety of compounds in which two aryl groups are linked. In support of the intermediate formation of the acetate radical from N-nitrosoacetanilide is the evolution of carbon dioxide during the reaction. Ar. a behavior similar to that of metals in contact with active free radicals in the Paneth test.+ RX -» ArX + R(Ar. N-nitrosoacetanilide yields benzene in hexane and chlorobenzene in carbon tetrachloride. these are reactions characteristic of active free radicals. The unsymmetrical biaryls are of particular interest since they are not as accessible through other reactions as the symmetrical compounds. X = halogen) ' Thus. metals such as copper.230 THE PREPARATION OF UNSYMMETRICAL BIARYLS In the reactions with aliphatic hydrogen-containing compounds such as hexane. lead. hydrogen and halogen respectively are abstracted from these compounds. Moreover. and halogen compounds such as carbon tetrachloride.
Moreover. and phenylpyridines can be prepared. such as 3-bro. occasionally serve to improve the yield in the diazo reaction. CN. the modifications. Of the solvents which have been tried. which is 5—10° for the diazohydroxide reaction and room temperature or slightly higher for the nitrosoacetylamine reaction. are of particular interest because they cannot be prepared readily from biphenyl. although in some instances they are much lower. a large variety of biphenyl derivatives can be prepared in which only one of the rings is substituted. lying between 40 and 70%. phenylthiophenes. because of the difficulty of finding a suitable solvent. these methods are often the only ones available for preparing substances of definite structure for purposes of identification.mobiphenyl (I). Soc. Cl. with the nitrosoacetyl derivatives the yields are generally higher. . the terphenyls. etc. The last qualification is the most difficult one to satisfy. In these reactions an appreciable amount of the aryl halide (chlorobenzene and p-nitrochlorobenzene) is produced as a by-product. such as the use of sodium acetate or the stabilized diazonium salts. the nitrosoacetyl derivative may give it. 1938.DERIVATIVES OF BIPHENYL 231 compounds or N-nitrosoacetyl derivatives have been prepared and some of the compounds which have been used for coupling. In this manner. 110. J. phenylnaphthalenes. The meta derivatives. Experiments with solid reactants in solution have not been very successful. and from diazotized p-nitroaniline and biphenyl a small amount of 4-nitro-4'-phenylbiphenyl is formed. Chem.13 From diazotized aniline and biphenyl in these solvents. and be inert to the free radicals which result from the diazo compound. OCH3. NO2. The usefulness of the methods for the preparation of compounds of definite 13 Grieve and Hey. With the diazohydroxides the yields usually lie between 15 and 35%. CH3. have a high solvent action and reasonably low boiling point. It is apparent that. derivatives of biphenyl.combination of reagents. the isomeric monosubstituted biphenyls. the yields of products obtained by coupling with reactants in solution are extremely low. some p-terphenyl is obtained. The solvent should be neutral and immiscible with water. In some reactions in which the diazohydroxide fails to give the desired product. and 3-cyanobiphenyl (III). A limitation of both methods is that the second component must be liquid at the temperature of'the reaction. Derivatives of Biphenyl. Even when the yields are low. In general. 3-nitrobiphenyl (II). RCeB^CeHs. carbon tetrachloride and chloroform appear to be the most suitable. have been prepared in which R = Br. By coupling diazo compounds and N-nitrosoacetyl derivatives obtained from substituted anilines with benzene. by the proper ..
4-nitrobiphenyl is obtained in 33% yield.and 4-methylbiphenyl formed from diazotized aniline and toluene.232 THE PREPARATION OF UNSYMMETR1CAL BIARYLS NOj II structure is illustrated by the following five isomeric bromomethylbiphenyls. 4-methylbiphenyl can be isolated readily in pure form from the reaction between diazotized p-toluidine and benzene. since with benzene only a single biaryl compound is produced. Thus.+ •Ni+Cl" + However. For the preparation of biphenyl compounds with substituents in only one ring. isolation of the product or products formed by coupling with nitrobenzene and certain other compounds has been successful. and from o-ni^ro- . it is usually advisable to employ a substituted aniline and couple with benzene rather than to use aniline and couple with a benzene derivative. •N 2 +C1. From nitrobenzene and diazotized aniline (in the form of the stabilized diazonium salt). but not from the mixture of 2. which have been prepared from the corresponding bromotoluidines and benzene.
J. F r o m diazotized p-bromoaniline a n d anisole a 2 0 % yield of 4-bromo-2'-methoxybiphenyl and a 7 % yield of 4-bromo-4'-methoxybiphenyl are obtained. .5'dimethoxy-4'-n-amylbiphenyl (VII). I n connection with their studies on Cannabis Indica. 1940.4'-dinitrobiphenyl (VI) in 6 9 % yield from p-nitroaniline and nitrobenzene. Pascall. PascaU. Ghosh. I t is of interest t h a t in the latter reaction coupling takes place para to the nitro group r a t h e r t h a n para t o the methyl group. a n d T o d d w prepared t h e highly substituted biphenyl compound. 1118.DERIVATIVES OF BIPHENYL 233 toluene a n d N-nitrosoacetanilide. T h e structure of t h e compound follows from i t s formation from t h e nitrosoacetyl derivative of 3-methyl-4-nitroaniline a n d benzene. i n 2 7 % yield from t h e nitrosoacetyl derivative of 2-cyano-5-methylaniline a n d 2. N(NO)COCH 3 N(NO)COCH 8 T h e stabilized diazonium salt procedure h a s given 3. 2-cyano-5-methyl-2'. Chtm. NO2 NOJS NO2 VI Alkoxy derivatives of biphenyl can be obtained either from alkoxyanilines or b y coupling with alkoxybenzenes. Soc.4'-dinitrobiphenyl (V) in 5 4 % yield from m-nitroaniline and-nitrobenzene a n d 4.5-dimethoxy-ra-amylbenzene. CH8 •N(NO)COCH 3 + CN 0CH 3 CH 3 CE^O \ \ » Ghosh. 4-nitro-3-methylbiphenyl (IV) is obtained in 1 5 % yield. and Todd.
113. By this procedure. or (c) diazotized anthranilic acid and benzene are used as components in the reaction. ethyl 4-phenylphthalate (VIII) is formed in 37% yield. which can be cyclized to fluorenone. and from the products the acids can be obtained by hydrolysis. the reaction proceeds normally if methyl benzoate is used in reaction (a) or when methyl anthranilate replaces the anthranilic acid in (b) and in (c).234 THE PREPARATION OF UNSYMMETRICAL BIARYLS It is* not possible to prepare biaryls containing a free carboxyl group directly by the diazo reaction. and Wilkinson. No biaryl is formed when (a) diazotized aniline and sodium benzoate. Hydrolysis affords 2-biphenylcarboxylic acid. esters and nitriles can be prepared from esters of aromatic amino acids and cyanoanilines and also by coupling with esters of aromatic acids. .4 However.and 3-substituted fluorenones have been prepared. 1938.-COOCH Cl .13 On the other hand.COOCH. VIII The products obtained from esters of anthranilic acid and substituted anthranilic acids are of interest because fluorenones can be prepared from them. . . From diazotized methyl anthranilate and benzene. 2-carbomethoxybiphenyl is obtained in 24% yield. "HeUbron. J Chem Soc . Hey. 3-chlorofluorenone was prepared from methyl 4-chloroanthranilate and benzene through the following steps. (6) diazotized anthranilic acid and aqueous sodium benzoate. By coupling N-nitrosoacetanilide with ethyl phthalate. The success of the diazohydroxide reaction appears to lie in the ability of the nonaqueous liquid to extract the reactive diazo compound from the aqueous layer. a number of 2.16 Thus.
4-phenylenediamine was treated with nitrous fumes. Derivatives of m-terphenyl and pterphenyl can be prepared from the substituted aminobiphenyls. for the product obtained by treating the nitroso compound with benzene was 3-nitro4-acetamidobiphenyl (X. By coupling the bis-nitrosoacetyl derivative of benzidine with ben/ene. CH3CONH . the preparation of o-terphenyl by these methods has not been reported.TERPHENYLS AND DERIVATIVES 235 Fluorenonecarboxylic acids are accessible from the products formed by coupling diazotized esters of methyl 3-aminophthalic acids with benzene and benzene derivatives. From diazotized methyl 3-aminophthalate and benzene. and (b) from the 6is-nitrosoacetyl derivative of p-phenylenediamine. COOCH3 COOCH3 Terphenyls and Derivatives. methyl 3-phenylphthalate (IX) is obtained in 35% yield. When the diacetyl derivative of 3-nitro-l. the acetamido group ortho to the nitro group was not nitrosated. 32% yield). I(NO)COCH. only a mononitroso derivative was formed. quaterphenyl (XI) is obtained in 17% yield. + CH3C0(N0)N- -N(NO)COCHS + m-Terphenyl can be prepared by analogous reactions from 3-aminobiphenyl and from m-phenylenediamine. The yields by both routes are about the same (50-60%). p-Terphenyl can be prepared satisfactorily in two ways: (a) from the nitrosoacetyl derivative of 4-aminobiphenyl.
An example is 5-nitro-6-methoxy-2phenylnaphthalene (XII).. 18 and from the nitrosoacetyl 14 Gomberg and Bachmann. The product obtained from diazotized m-cyanoaniline and thiophene 3 in 19% yield appears to be the a derivative (XV). unpublished results. 26%) are formed. J. 3 by treatment of the sodium diazotate in pyridine with acetyl chloride. which can be obtained in 19% yield Irom the nitromethoxy-j3-naphthylamine and benzene. but /3-phenylnaphthalene is obtained readily by several procedures. A considerable number of derivatives of /3-phenylnaphthalene have been prepared. Soc. Forsyth and Pyman. 16 xv Arylpyridines. The amino group of aromatic amines can be replaced by the pyridyl group by the normal diazohydroxide reaction. 26. 1924. a-Phenylnaphthalene can be prepared satisfactorily only through the stabilized diazonium salt method.17 by adding the dry diazonium salt to pyridine. N0 2 CH3O XIII XIV Arylthiophenes. » 17 . Chem.236 THE PREPARATION OF UNSYMMETRICAL BIARYLS Arylnaphthalenes. From the reaction between diazotized /8-naphthylamine and nitrobenzene and sodium acetate. Thiophene couples with the diazohydroxides 3 and with N-nitrosoacetylamines 1 to give phenylthiophenes and derivatives. > Mohlau and Berger. The position taken by the aryl groups in the thiophene nucleus has not been determined in all instances. 1926. /S-(2-nitrophenyl)-naphthalene (XIII. Ber. 14%) and jS-(4-nitrophenyl)naphthalene (XIV. Aryhiaphthalenes can be prepared "by replacement of the amino group of naphthylamines by aryl groups. 1994 (1893). 2912.
Heilbron. N 2 +C1- N Excess N By this procedure a considerable number of arylpyridines have been prepared.and -y-pyridyl derivatives of biphenytcan be prepared. which may be considered to be formed by further reaction of the biaryl initially produced. / . no nitrogen is evolved until after one equivalent of pyridine has been introduced. Thus. Pyridine derivatives can be prepared also from amines containing the pyridyl group. the yields of products vary from 20 to 80%. and alkali. Side Reactions One of the side reactions is the formation of linear polyaryls. . 349.19 The best procedure is to add an aqueous solution of the diazonium salt to an excess of pyridine at temperatures ranging from 20° to 70°. From benzenediazonium chloride and pyridine a 40% yield of phenylpyridines is obtained from which a-phenylpyridine (9%). 1940. Soc . if the pyridine is added to the solution of the diazonium salt.SIDE REACTIONS derivative and pyridine. J. and Hey. 1940. for. benzene. Heilbron. Chem. •N(NO)COCH3 + XVI Similarly. the nitrosoacetyl derivative of m-a-pyridylaniline can be coupled with benzene to yield 3-a-pyridylbiphenyl (XVI). and Hey. the 0. and in the mixture formed in the" preparation of 4-methylbiphenyl a hydrocarbon was found 19 20 Haworth. pterphenyl * and quaterphenyl 16 have been isolated. Chem. and 7-phenylpyridine (4%) can be isolated in pure form. (3-phenylpyridine (4%). formed from diazotized aniline. Soc. From the high-boiling residue remaining after the removal of the biphenyl.20 Apparently the pyridine plays the role of sodium hydroxide in liberating the reactive intermediate diazohydroxide. A mixture of isomers results which can be separated either directly or through the picrates. 373 Haworth.
m-Bromotoluene was isolated in 6% yield from the reaction between the sodium diazotate from 2-bromo-4-methylaniline and benzene. The source of the hydrogen effecting the reduction has not been determined.21 XVII XVIII Another side reaction which occurs is reduction. the limitations to coupling with liquid aromatic compounds. indicating that.4 It is of interest that the decomposition of benzenediazonium formate in acetic acid in the presence of copper yields quinquiphenyl (XVII) and sexiphenyl (XVIII) in addition to biphenyl. In addition Do these types^of compounds. Related Reactions Employment of Dry Diazonjum Salts. . 250). in the reaction the —N2C1 or —N(NO)COCH3 group is replaced by hydrogen. Mohlau and Berger. in this particular instance at least.4 Some nitrobenzene is obtained in the preparation of 3-nitrobiphenyl from nitroso-m-nitroacetanilide (p. 739 (1924). Ber. nitrogen is evolved in addition to hydrogen chloride. 11 2a Gerngross and Dunkel. 57. and the difficulty of separating isomers when more than one compound is formed. the difficulty in some instances of getting the product out of-the mixture containing the high-boiling by-products.238 THE PREPARATION OF UNSYMMETRICAL BIARYLS which appeared to be a di-p-tolylbenzene. Of interest is the reaction between dry diazonium salts and aromatic compounds in the presence of anhydrous aluminum chloride. CH3C6H4N=NC6H4CH3. was isolated.18-22 The reaction resembles a Friedel and Crafts reaction.. Ber. 26. The disadvantages of the methods are the low yields in many of the reactions. azo-ptoluene. ' Azo compounds are formed to some extent in the biaryl reactions. 1198 (1893). the azo compound was derived entirely from the diazonium compound. From the reaction between diazotized p-toluidine and benzene.. and quaterphenyl. and in 10% yield in a similar reaction from 2-methyl-4-bromoaniline. p-terphenyl. a considerable amount of high-boiling material is usually formed in the reactions.
Reactions. Am. this volume. 9-phenanthroic acid is obtained. Org. The method has been employed only to a limited extent 23 since its discovery. . 363 (1943). .24 COOH Ring closure of m-o-aminostilbene (XIX) to phenanthrene. and aluminum chloride. probably because it involves the isolation of the dry diazonium salts and because a number of aryldiazonium salts (from o. Org. Reactions. benzene. Am. biphenyl is obtained in 33% yield. u See Kornblum. Chem.and ptoluidine and /3-naphthylamine) gave no biaryls but only the corresponding aryl halides. In this synthesis of phenanthrene derivatives. 24 See Johnson. •N 2 +C1. I. ••• Lothrop and Goodwin. 896 (1921). By treatment of diazotized a-phenyl-o-aminocinnamic acid with copper.REACTION OF DIAZONIUM SALTS 239 From dry solid benzenediazonium chloride. J. Soc. Pschorr Synthesis. Chem. 43. 246 (1942). Aryldiazonium salts couple with quinones in the presence of sodium acetate to " Knowles..2Ba CH=CH • XXI Reaction of Diazonium Salts with Quinones and with Phenols. and o-aminodiphenylmethane (XXI) to fluorene can be effected likewise through the diazonium reaction.25 A number of substituted fluorenones have been prepared by this method. 66..10-dihydrophenanthrene. one of the steps involves the union of two aryl nuclei through a diazotization reaction.+ HC1 Similar reactions have been carried out with naphthalene and thiophene. o-aminobibenzyl (XX) to 9. J. Soc.
1066 (1939).'and Corse. 29. 390. Am. and phenols if no alkali is added. 118 Hirsch. a good yield of a mixture of 2. 121 (1903). Am. O C«H 6 N 2 +C1NaOAc- 0 + N2 + NaCl + AcOH The phenylquinone can be made to react further to give 2. Farbenind. Chem... 2478 (1934). Maclntire. Chem. Chem. 410.3 2 From a solution of diazotized aniline in a large excess of-phenol. 284. phenylquinone is obtained. G.. Ind. 2 8 ' 2 9 ' 3 0 ' 8 1 . . / . 23. Brit. 81 Chatterjee.5-diphenylquinone. with the latter compound it yields 2-(p-carboxyphenyl)-l. 1.. 306 (1895). 30 Norris. J.26 By means of this reaction a number of arylquinones (and the corresponding dihydroxybiphenyls by reduction) have been prepared in 55-85% yields.4-Naphthoquinone reacts readily only with reactive diazonium compounds such as diazotized p-aminobenzoic acid. 56. 12.O OOH XXII Hydroxy derivatives of biphenyl can be prepared from diazonium salts.4»naphthoquinone (XXII).. J. Soc. 690 (1935). Ber.and 4-hydroxybiphenyl is obtained in addition to diphenyl ether. Chem. followed or preceded by the addition of an excess of sodium acetate. such as the chloride or sulfate. G. 32 Huntress and Seikel. 29 Graebe and Schestakow. 61. Soc.27 The solid diazonium salt is added to a solution of the quinone in alcohol..029 (1933). " Kvalnes. A.240 THE PREPARATION "OF UNSYMMETRICAL BIARYLS give arylquinones. pat. N2+C1- HC1 16 1 . . 3705 (1890). J. Soc. Ann. Am. From diazotized aniline and benzoquinone.
Direct nitration. 36 OTHER METHODS OF SYNTHESIS OF UNSYMMETRICAL BIARYLS Direct Substitution in Biphenyl.. Eng.. 58. 58. / ..and 4-nitrobiphenyl. 313. and bromination of biphenyl can. Ind. Gelissen and Hermans. chlorination. In certain substitution reactions it is sometimes difficult to separate the mixture of 38 34 36 Borsche. The decomposition of aromatic acyl peroxides in liquid aromatic compounds is similar to the decomposition of nitrosoacetylarylamines and appears to involve the intermediate formation of free radicals. '•Gelissen and Hermans. and small amounts of phenyl benzoate. 1966. Ber. Ber. When dibenzoyl peroxide is heated in benzene. 37 Direct nitration is probably the most satisfactory method of preparing large quantities of 2. McCullough. 984 (1925).DIRECT SUBSTITUTION IN BIPHENYL 241 Prom diazotized aniline and p-nitrosophenol Borsche 83 obtained 2-hydroxy-5-nitrosobiphenyl (XXIII) in 8% yield. . 31 (1930). A 29% yield of p-terphenyl can be obtained by careful decomposition of benzoyl peroxide in molten biphenyl at 95°. and quaterphenyl are produced. Ann. 285. C6H6—<^\ C6H Decomposition of Aromatic Acyl Peroxides. benzoic acid.. 1934. Chem. Soc. 476. biphenyl. Hey.be used to prepare certain derivatives. p-terphenyl. 37 See Jenkins. 764 (1925). 211 (1900). and Booth. 34 That the second component enters into the reaction is shown by the formation of 4chlorobiphenyl from the decomposition of di-p-chlorobenzoyl peroxide in benzene Si and of dibenzoyl peroxide in-chlorobenzene^3B ClC6H4C0-O—O-COC6H4C1 + C6H6 -> C1C6H4—C6H6 + CO2 + C1C6H4COOH CH 6 CO • 0—0 • COCeUs + C6H6C1 -» C6H5—C6H4C1 + C0 2 + C6H6COOH Similar results have been obtained with other peroxides and benzene derivatives. 22.. Chem. and with 2-methyl-4-nitrosophenol he obtained 2-hydroxy-3-methyl-5-nitrosobiphenyl (XXIV).
Am. Chem. By addition of an arylmagnesium halide to a eyclic ketone. 591 (1835). o-Terphenyl has been prepared from the adduct of maleic anhydride and 3.28 Grignard Reaction. 1337 (1932). J. 39 88 . By means of the Diels-Alder reaction a considerable number of hydrobiphenyls have been prepared. Am. J. J. itls difficult or impossible to prepare many compounds by direct substitution.. Diels-Alder Reaction.Moreover.242 THE PREPARATION OF UNSYMMETRICAL BIARYLS isomers formed. Weiss and Woidich. 1365 (1942). Chem. Short. When applicable. Soc. a carbinol is formed which can be dehydrated and dehydrogenated to a biaryl compound. Ind. Monatsh. only those biaryls can be prepared which contain. >3b See Table 2 of the review by Norton.. Braun. 295 (1935). *** Lohaus.39-40-41-42-43-43a For example.38 . 453 (1925). m-tolylmagnesium bromide and cyclohexanol yield 1-m-tolylcyclohexanol. Am... which on dehydration and dehydrogenation gives 3-methylbiphenyl. 65. this method is excellent. 31. 66. 516. Revs. However. 12. Soc. Chem. 1471 (1933). Chem. Irmisch. CoUins. Soc. 46. 58. 1251 (1936).. 10 Mayer and Schiffner. Ann. 62. *'r Allen and Pingert. and Stansfield. « Chatterjee. **• Arnold. Soc. / . Only a few of the adducts have been converted to the completely aromatic compounds.4-diphenylbutadiene. Chem. Ber. « v .436 from which it should be possible to obtain unsymmetrical biaryls by dehydrogenation. 1832. 1932. Soc 64. Certain compounds which are not available through direct substitution in biphenyl itself have been prepared by deamination of substituted ammobiphenyls and benzidines... J. Ber. 41 Sherwood. 3M (1942). 983 (1940).43d + CH3OOC—C=C—COOCHg CH—CH CH3OOC \ COOCH3 Case. Chem. and Nelles.43k and p-terphenyl has been obtained in practically quantitative yield from the adduct of the methyl ester of acetylenedicarboxylic acid and l. and Zenk.4-diphenylcyclopentadienone.substituents that do not enter into reaction readily with Grignard reagents and that can withstand the conditions of dehydrogenation.
the yield -of the biaryl was improved by using sodium acetate.and nitro-anilines. Am. Chem. See Adams and Teeter. 2188 (1940).CHOICE OF METHOD 243 DUmann Reaction. chlorobenzene. in connection with the preparation of symmetrical biaryls. Some comparative studies have been made of the use of sodium acetate in place of sodium hydroxide in the diazo reaction. and previous papers of this series. Grieve and Hey 7 found little difference in the yields of biaryls obtained by the two procedures when they coupled diazotized aniline with six different components: benzene. Thus. mxylene. toluene. Chem. the diazo reaction has been employed frequently. Where it is applicable. The particular method to be used depends to some extent on the compound to be prepared. SELECTION OF EXPERIMENTAL CONDITIONS Choice of Method.Ullmann reaction is considered usually. However. it has been employed also to prepare unsymmetrical biaryls. J. 62. Soc. The Ullmann reaction appeared to be the only satisfactory method for preparing certain highly substituted unsymmetrical biphenyl derivatives which were required by Adams and coworkers 45 in their study of the stereoisomerism of biphenyl compounds. nitrobenzene. probably because it is less troublesome to carry out. the N-nitrosoacetyl method is generally to be preferred. 2089 (1927). 48 44 . J. Better yields were obtained by this variation with the following Baohmann and Clarke. Although the . Soc.44 biphenyl and 2. this modification offers the advantage that the dropwise addition of alkali is eliminated.6 In five out of twelve reactions. Am. Gomberg and Pernert 4 recommended the use of the sodium diazotates for the preparation of biaryls from aniline and from p-toluidine and the normal diazo method for negatively substituted amines such as the bromo. On "the basis of yield.2'-diphenylbiphenyl were by-products of the reaction.. oterphenyl has been synthesized by heating a mixture of iodobenzene and 2-iodobiphenyl with copper. 49. and ethyl benzoate.
Am. All the reactions were with benzene. The use of stabilized diazonium salts is a recent modification. 49. then NaOH Diazohydroxide Diazotate Diazohydroxide Diazotate Diazohydroxide Diazohydroxide 22% 24 29 22 33 35 Grieve and Hey 13 obtained no markedly improved yields of biphenyl when they tried various reagents under different conditions. and the exact limits of this reaction have not yet been established. It has been found to be particularly good for nitroanilines (4-nitrobiphenyl is obtained in 70% yield from p-nitroaniline) and for coupling with nitrobenzene. Soc . naphthalene. biphenyl. as shown in the following table. Chem. Coupling of the stabilized salt of aniline failed with toluene.244 ' THE PREPABATION OF UNSYMMETRICAL BIARYLS amines: the nitroanilines. 236 (1927). COMPARISON OP YIELDS USING SODIUM HYDROXIDE AND SODIUM -ACETATE Amine Aniline o-Nitroaniline wi-Nitroaniline p-Nitroaniline o-Chloroaniline m-phloroaniline p-Chloroaniline p-Toluidine p-Bromoaniline p-Anisidine p-Phenetidine jS-Naphthylamine Product Biphenyl 2-Nitrobiphenyl 3-Nitrobiphenyl 4-Nitrobiphenyl 2-Chlorobiphenyl 3-Chlorobiphenyl 4-Chlorobiphenyl 4-Methylbiphenyl 4-Bromobiphenyl 4-Methoxybiphenyl 4-Ethoxybiphenyl jS-Phenylnaphthalene NaOH 22% 21 18 26 25 25 40 22 44 25 29 16 Yields CH8COONa 16% 45 45 60 38 13 35 11 12 4 11 25 The effect of various other reagents on the yield of biphenyl from diazotized aniline and benzene has been studied. This modification allows the use of components which are solid at the lower temperature but liquid at the higher one (30°). and 1-nitronaphthalene. . The following yields of biphenyl were obtained from one mole of aniline under the conditions noted. They did observe that the yield of biphenyl is just as good in the sodium diazotate method when the reaction is run at 30° as at 5-10°. o-chloroaniline. and the stabilized salt of (3-naphthyIamine gave no /3-phenylnaphthalene when coupling with ben46 Gomberg and Baohmann.16'46 REAGENTS METHOD YIELD OP BIPHENYL NaOH NaOH Ca(OH)4 Ca(OH)2 Mg(0H) 2 MgSQ*. and 0-naphthylamine. / .
l-nitro-2-naphthylamine. Blakey and Scarborough. is to distil the mixture under reduced pressure. the base. but one which gives a less pure product. The usual method of working up the reaction mixtures is to remove the excess of benzene derivative by distillation or steam distillation and then obtain the biaryl by steam distillation by means of superheated steam or by keeping the reaction flask in a hot oil bath.48 In one instance. for continued distillation is necessary in order to get the product out of the high-boiling tarry by-products. Isolation of the Product. This is a tedious process. "Aromatic Diazo Compounds. Little work has been done with very weakly basic amines in the diazo reaction. Chem. The volume of water is kept at a minimum since the success of the reaction depends in part on the efficiency with which the unstable intermediate is extracted from the aqueous layer by the organic liquid. Soc. but the product obtained is fairly pure. 1936. 374.47 EXPERIMENTAL PROCEDURES Diazo Reaction The diazotization of the amines is carried out in the usual manner.6 The nitrosoacetyl method usually gives good yields of biaryl compounds. Chem.49 For the very weak bases. Soc. 1940. in 2 cc. 1927. J.DIAZO REACTION 245 zene was attempted. the nitrosoacetyl reaction is recommended. It has the disadvantage that oxides of nitrogen must be generated and that unless the nitrosation is carried out carefully the yield suffers. Either the previously prepared amine hydrochloride is employed or a paste of the hydrochloride is prepared by dissolving the amine in concentrated hydrochloric acid and then cooling rapidly with stirring. A recent innovation employing nitrosyl chloride has eliminated the objections of the older nitrosation procedure and promises to be the best method. 48 47 . since it is carried out entirely under anhydrous conditions. J. London.. In the preparation of 3-nitrobiphenyl good results were obtained by precipitating the tar from: the benzene solution by means of petroleum ether and then recrystallizing the product. 49 Hey and Lawton." Edward Arnold and Co. Interesting data on the relative merits of various stabilizing agents and reagents for bringing about coupling with aromatic compounds may be found in the original paper. of water) is used. 3000. benzene was added and then sodium hydroxide until the mixture was slightly alkaline. For diazotization a nearly saturated solution of sodium nitrite (1 g. For a discussion of the diazotization of weakly basic amines see Saunders. was diazotized by means of nitrosylsulfuric acid in sulfuric acid. A more rapid method.
113. of anisole are cooled in ice and stirred vigorously as 280 cc. The layers are then separated and the product is isolated from the organic liquid.. and the whole is cooled rapidly to 0° with stirring. a third fraction. Usually the mixture is stirred for an hour or two at this temperature after the addition has been completed. When. the mixture is then allowed to warm up to room temperature and stirring is continued for a few hours longer. Coll. . Prolonged steam distillation is required to obtain a good yield of the latter compound.6i! A mixture of 215 g. of 5 N sodium hydroxide solution is added during the course of one hour. chemical means may be employed. however.60 2-Methoxy-4'-bromobiphenyl and 4-Methoxy-4'-bromobiphenyl. occasionally. of p-bromoaniline and 100 cc. and -it is then followed by crude 2-methoxy-4'-bromobiphenyl. 68 Harley-Mason and Mann. Syntheses. Chem. Soc.. such as a large wide-mouthed bottle. Ginsberg. Chem. of concentrated hydrochloric acid is then added. Vol. Unchanged anisole comes over rapidly at first. should be used for the diazo reaction in order to provide for the increase in volume thrpugh foaming of the mixture. 2nd ed. which is kept at 5-10° throughout the reaction. J. 4-methoxy-4'-bromobiphenyl. The intermediate fraction of 2-methoxy-4'-bromobiphenyl is crystal"Gomberg and Bachmann. of sodium nitrite in 200 cc. which solidifies in the chilled receiver. crystallization starts in the condenser. of water is heated until the amine melts. I. Colorless 4-bromobiphenyl was obtained by treating an alcoholic solution of the yellow product with a little zinc dust and hydrochloric acid. since it is only slightly volatile with steam even at 220°. 77 (1939). the flask being heated ultimately to 220°. the crude reaction mixture was shaken with portions of concentrated sulfuric acid until the red color of the solution was removed. the heavy brown oil which has separated is removed and steam-distilled. 61. 61 Marvel. When it is difficult to remove traces of azo compounds from the biaryl by distillation or recrystallization. J. Am. 1940. 1941.246 THE PREPARATION OF TINSYM METRICAL BIARYLS A fairly large container. is collected. 250 cc. The aqueous solution of sodium hydroxide (or sodium acetate) is added dropwise to the vigorously stirred mixture of the diazonium salt and aromatic liquid. and Mueller. After twelve hours of continued stirring. 1383.61 Procedure Utilizing Sodium Hydroxide (A-l) A detailed procedure for the preparation of 4-bromobiphenyl by this method is described in Organic Syntheses. Org.60 In the preparation of 3-bromobiphenyl. The clear solution of the diazonium salt and 500 cc. A solution oT 90 g. of water is added slowly with cooling and agitation. Soc.
m. . and the solution becomes yellow. yield. steam is passed into the residue (flask in oil bath at 150-175°). pressure. of 10 N sodium hydroxide. the fraction boiling at 150-155°/10 mm. and ice sufficient to keep the temperature. After recrystallization from ethanol the product melts at 34°. of hydrochloric acid (sp. (38%). (7%). 1.p. of concentrated hydrochloric acid (sp. * Procedure Utilizing Sodium Diazotate (A-2) 4-Methylbiphenyl.p. 18 g.4 One hundred and seven grams (1 mole) of ptoluidine is dissolved in 185 cc. 109 g. Procedure Utilizing Sodium Acetate (A-3) o-Chlprobiphenyl. When all the diazonium solution has been added. The o-chlorobiphenyl is then distilled under reduced pressure. Vacuum distillation is recommended forrrorking up larger quantities. and the benzene removed by distillation. 267-268°). and the mixture is cooled to 0° and diazotized in the usual manner. gr. The solution is added during the course of two to three minutes to a vigorously stirred mixture of 275 cc. Direct distillation of the mixture lowers the yield.2). After the removal of the benzene by distillation. washed with water.at 5°. of sodium acetate trihydrate in 200 cc. no more ice is added after the first hour. (20%). of water is added dropwise. The fraction boiling at 145-153° is nearly pure 4-methylbiphenyl. after the first three hours. and melts at 63-64°. the reaction is allowed to proceed at room temperature. A small part of the benzene is kept frozen by the ice. The filtered diazonium salt solution is stirred vigorously with 500 cc.traces of the less volatile 4-methoxy isomer. the solution is cooled by the addition of ice and diazotized by the addition of a solution of 76 g.16) and 45 cc. The product from three runs (321 g. being collected. The 4-methoxy-4'-bromobiphenyl is recrystallized from benzeneethanol.o-CHLOROBIPHENYL 247 lized from ethanol and then distilled under reduced pressure to remove . of sodium nitrite in 150 cc. 600 cc. (22%) and melts at 47°. (21%). yield. After distillation at atmospheric pressure (b. Stirring is continued for five hours. throughout the addition the temperature is kept at 5-10°. 144-145°. The benzene solution is separated. yield. 1. The 4-methylbiphenyl which comes over solidifies readily. nitrogen is evolved. of benzene. gr. yield. of water. of p-toluidine) is distilled at 20 mm. of benzene as a solution of 80 g. Stirring is continued for forty-eight hours. a vigorous reaction ensues. 64 g.6 Thirty-two grams of o-chloroaniline is added to 80 cc. it weighs 38 g. 22 g. of water. It boils at 200-201 °/18 mm.
weight.6 a-Naphthylamine (14. the mixture is heated to 80° until nitrogen ceases to be evolved. /3-. the mixture of phenylpyridines is distilled under reduced pressure.4 g. -y-phenylpyridine melts at 69-70°. Procedure Utilizing a Stabilized Diazonium Salt (A-4) a-Phenylnaphthalene. 1.p. yield. of pyridine with stirring at 30°. 159-160°) of /S-phenylpyridine. Procedure with Pyridine (A-5) a-. and the a-phenylnaphthalene"is isolated (no details given). and 5 g. and the ether extract is dried over potassium hydroxide. of the picrate (m.5-disulfonic acid. of water. cooled.p. . 5 g. the benzene layer is separated. of benzene. 20 g. Frequently some acetic anhydride is used with the acetic acid in order to lower the freezing point and thus permit a lower temperature for the reaction. of acetic anhydride. The mixture is separated through the picrates and yields 12 g. The pyridine layer is separated and poured into water. 175-176°) of a-phenylpyridine. and 7-Phenylpyridine.. from which the pure bases can be generated. and the diazonium salt solution is treated with 16 g. 195-196°) of 7-phenylpyridine. gr. the product is extracted with ether. After forty-eight hours. Nitrosoacetylamlne Reaction Nitrosation by Nitrous Fumes. are added 3 g. (30%). After removal of the ether. and treated with concentrated sodium hydroxide. Some stabilized diazonium salt separates immediately.16) and 150 cc. To 10 g. of anhydrous sodium acetate and 1 g. The salt is then filtered and dried. of the picrate (m.248 THE PREPARATION OF UN8YMMETRICAL BIARYLS i . The addition of a small quantity of phosphorus pentoxide often serves to speed up the reaction and give a slightly higher yield of product. of the dry salt. 1. 170-190°/10-20 mm. of the pure picrate (m.) is diazotized at 0° in a mixture of 24 ccv of hydrochloric acid (sp.20 • A solution of benzenediazonium chloride prepared in the normal manner from 30 g.3 g. of aniline is added dropwise in the course of two hours to 300 cc. at room temperature. the mixture is treated with water. of finely powdered naphthalene-l. b.p.and /3phenylpyridines are liquids.p. the solvent is removed. The mixture is then warmed on a steam bath for one hour. but the mixture is stirred for one hour to complete the precipitation. The general procedure consists in passing nitrous fumes into a solution or suspension of the acetylamine in glacial acetic acid at about 10° until a clear green solution is obtained. The a. well agitated with 30 g.
J Chem. the acetamido group submits to nitrosation. Hoffman. and Hey. Directions for generating nitrous fumes by means of the reaction between arsenious oxide and nitric acid are given in Organic Syntheses. it may be filtered and dried on a porous plate. others. 2. Heilferon. among them o-chloroacetanilide. Coll. a third group.6-dichloro-4-nitroacetanilide. 1288. which includes p-nitroacetanilide and a. nitrite and nitric acid appears to be more rapid and convenient. In this preparation the acetyl derivative of the amine is prepared in the mixture used for nitrosation. Unfortunately. France. A considerable number of acylarylamines. such as 4-dimethylamino-4'-acetamidoazobenzene. A connection is made from the trap to a tube passing through the stopper in the generating flask. 63 M M Haworth and Hey. and diacetyl-l. . form abnormal nitroso compounds with nitrous fumes..) ' Through a three-hole rubber stopper in the neck of a 1-1. Chem. If the product is an oil. Soc. I. A.3-phenylene diamine. O g . 1940. there is no simple way of determining exactly when nitrosation is complete. Soc. 361. 266. 1939. flask containing 125 g.6* The preparation of nitrous fumes by means of solid sodium. do not yield nitroso compounds with nitrous fumes. and l-acetamido-2-methylanthraquinone. Most of the solid nitrosoacetylarylamines can be kept at room temperature for over a day without appreciable decomposition. the yield is reduced considerably and the product is tarry. long-stemmed dropping funnel containing 125 cc. Dox. and Hey 66 revised and augmented by R. which serves as a bubble counter. Heilbron.3-NITROBIPHEN'YL 249 If the passage of nitrous fumes is continued after the dark green solution stage. 1941. Syntheses. 2nd ed. The outlet tube of the flask is connected to a drying tower packed with 4-mesh calcium chloride. and the solution is washed rapidly with water and then kept over a drying agent. benzene-ptoluidide. J.63 In general. it is dissolved in the aromatic liquid (Component B). (Procedure of France. whereas the benzoyl and benzenesulfonyl and toluenesulfonyl derivatives of amines are resistant to the action of nitrous fumes. of sodium nitrite is placed a 250-cc.and /3-acetarnidoanthraquinone. one side of which leads to the top of the dropping funnel (to overcome the back pressure of the gas) and the other side to a mercury trap. A compressed air outlet is connected to a T-tube. Vol.. if the nitrosoacetylamine is solid. The nitrosoacetylamine is precipitated when the solution is poured into a large volume of ice water.68 Nitrous Fumes Method (B-l) 3-Nitrobiphenyl. is recovered unchanged after the same treatment. of concentrated nitric acid.
of anhydrous sodium carbonate. of cold 2% sodium hydroxide. The volume of the clear light-yellow solution is brought up to 2. of m-nitroaniline. The center neck is fitted with a stirrer passing through a glycerol seal. Syntheses. In a few minutes evolution of nitrogen and carbon dioxide commences. Org. The addition of nitric acid is continued until all the white m-nitroacetanilide goes into the dark green solution (forty-five to sixty minutes). the rate varies from one to three bubbles per second through the mercury trap.5-1. The residue is transferred to a 125-cc. reduced pressure is necessary toward the end in order to bring the volume down to about 75 cc. by the addition of benzene. after a 3-5 cc.5 1. the product distils 66 Kyrides.6* and the other neck holds a calcium chloride tube. the nitrous fumes are then passed in for an additional fifteen minutes. 250 cc.01-0. flask. separately funnel (made by sealing a stopcock to the bottom of a round-bottomed flask). three-necked flask are placed 50 g. and the benzene is removed by distillation on a steam bath. of ice water and finally with 11. fore-run of nitrobenzene. The compressed air is adjusted so that there is no nitric oxide (which turns into the brown nitrogen dioxide as it comes in contact with air) escaping from the calcium chloride outlet tube. of acetic anhydride. and a light-yellow solution is obtained. The water layer is separated and extracted with an additional 500 cc. and the solution is stirred in order to precipitate the wwiitroacetanilide as a fine powder.02 mm. At 0. After this period the solution is dark brown in color. The solution of the nitroso compound is poured into 1. of ice water in a 5-1. The light brown oil which separates immediately is extracted with 1. nitric acid is allowed to drip on the sodium nitrite in the generator at the rate of 1-2 drops per second. 40 (1941). and the mixture is stirred to keep the salts suspended throughout the solution.250 THE PREPARATION OF UNSYMMETRICAL BIARYLS In a 1-1. . The flask containing the hot solution is immersed in an ice bath. 21. and after preliminary removal of the benzene the 3-nitrobiphenyl is distilled under reduced pressure. The benzene layer is separated carefully and run into a 3-1. The outlet tube from the drying tower is attached to a tube which passes through a stopper in one neck of the flask and extends below the surface of the solution. of anhydrous sodium sulfate and 50 g. and the benzene extracts are combined in the large funnel and washed twice with 1. When the mixture is at 5°. becoming increasingly vigorous during the first hour. of glacial acetic acid.5 1. of thiophene-free benzene.5 1. and 125 cc. The flask is warmed on a steam bath for about an hour with occasional swirling. The filtered solution is placed in a 5-1. beaker containing 75 g. The solution is stirred for about six hours and then allowed to stand for about eight hours more.. of benzene. Claisen flask. the solid mnitroaniline dissolves.
4. Lillis. of methanol yields 38-40 g.3-phenylenediamine can be prepared. and hydrogen chloride is given in Inorganic Syntheses. One hundred cubic centimeters of fuming nitric acid (sp. fuming nitric acid. SO2 + HN03 -»• N£>-SO4H NO-SO4H + NaCl . with the flask immersed in an oil bath at 170-190°. distilling flask under an efficient hood. France. after about two and one-half hours. Recrystallization from 35 cc. About 40-43 g.However. of 3-nitrobiphenyl from 10 g. The use of nitrosyl chloride in the presence of sodium acetate 8 as a nitrosating agent shows much promise. Nitrosation by Nitrosyl Chloride.67 The following adaptation employing sodium chloride was found to be much simpler. The flask is then immersed in a beaker of water and air is passed through the mass for about three hours while the temperature of the water is raised gradually to the boiling point. Sulfur dioxide is bubbled into the nitric acid at the rate of four to eight bubbles per second until no more is absorbed (about four hours). (56-60%) of product. 55 (1939).• NOC1 + NaHS04 Preparation of Nitrosyl Chloride.6) is placed in a 500-cc.4-phenylenediamine have resisted nitrosation even by this method.. 54-56°. gr. Normal nitroso derivatives which cannot be prepared with nitrous fumes from certain compounds can be formed by means of nitrosyl chloride. (53-56%) bi large yellow crystals of 3-nitrobiphenyl melting at 58-59°.5-diethoxydiacetyl-l. is obtained.PREPARATION OF NITROSYL CHLORIDE 251 at 136-138°. gave a 40% yield of biphenyl. Syntheses. .avoided.8 Addition of a benzene solution of nitrosyl chloride to a benzene solution of acetanilide in the presence of fused potassium acetate at 5°. a yellow solid separates. 2. the nitroso derivatives of p-nitroacetanilide and of diacetyl-l. A method for preparing nitrosyl chloride from sulfur dioxide. and Goheen. and the time required for the reaction is reduced from hours to minutes. Inorg. I. followed by warming at 30° for two hours. superior to those resulting from the action of nitrous fumes. since a liquid (NOC1) or a solution of the liquid is employed.6trinitroacetanilide and 2. A procedure which dispenses with the isolation of the nitroso derivative has been employed in one instance. and Hey 6* obtained 7 g.p. In this way. In particular. 1. the reaction can be put on a quantitative basis. Moreover. m. Heilbron. of m-nitroacetanilide. the solid melts to a light yellow " Coleman. Both the yield and the quality of the nitrosoacetylamines prepared by this method are. the detrimental results due to an excess of the nitrosating agent can be .
J. yield. 3-. (69%).4phenylenediamine in a mixture of 150 cc.4'-. on the acetylamine or on the nitrosoacetylamine. (c) disubstitution products with a group in each ring (2. COMPOUNDS PREPARED BY THE REACTIONS The compounds which have been prepared by replacement of the amino group of aromatic amines by aryl groups are listed in the table.8'" To a stirred solution of 10 g. The biphenyl compounds are listed in the following order: (a) monosubstitution products (2-. After no more nitrouB fumes are evolved. in the nitrosoacetylamine reaction. etc. of anhydrous potassium acetate and • 1 g. arylthiophenes.252 THE PREPARATION OF UNSYMMETRICAL BIARYLS liquid. and the yellow 6zs-nitrosoacetyl-l. (d) polysubstitution products.4-phenylenediamine is filtered and dried. Nitrosyl Chloride Procedure (B-2) ^-Terphenyl.3-.. Heilbron. Chem.5°. of phosphorus pentoxide at 8° is added dropwise a solution of 8 g. 1364. " France. After these the terphenyls. The red liquid NOC1 which is collected weighs 60 g. 11. 1938. O. and the water bath is warmed slowly to about 80° and kept there until no more yellow-ora. The yield of p-terphenyl is 7 g.). of glacial acetic acid and 75 cc. . Cl. The mixture is poured onto ice and water.4'-. 2. The side arm of the flask is connected to a tube running down to the bottom of a 10-inch test tube immersed in an acetone-dry ice mixture.). Pure nitrosyl chloride boils at —5. I). during this time the solid passes into solution with evolution of nitrogen.nge fumes of nitrosyl chloride come off from the mixture. 2. m. and Hey. (b) disubstitution products with both groups in one ring (2. 124° dec. Br. indicated by a double dagger (J). of acetic anhydride containing 12 g. and then 4-derivatives) arranged according to the elements in the groups (order: C. of benzene is stirred at 35° for twelve hours. etc. A dagger (f) indicates that the yield refers to a mixture of isomers. The yields in the diazo reaction are based on the amines. of the nitroso compound and 300 cc.4-. The residue obtained on removal of the solvent is distilled at 110-120°/10~3 mm.5-. of diacetyl-1. A mixture of 11 g.p. Soe.3'-. the flask is cooled to 40° and 150 g. After recrystalh'zation from acetic acid it melts at 210212°. N. of dry sodium chloride is added. and arylpyridines are given in the order mentioned. 3.. of nitrosyl chloride in acetic anhydride.4 g. 2. arylnaphthalenes. The top of the distilling flask is closed with a rubber stopper.
'Nitrosoacetylamine reaction (NOC1).COMPOUNDS PREPARED BY THE REACTIONS TABLE 'OP COMPOUNDS PREPARED BY THE REACTIONS 253 The procedures are designated by letters and numbers. Nitrosoacetylamine reaction (N2O3).5 5 9-16%f 4 . 5. Sodium acetate modification. 51 25% 3. 7 — 3 12% 3 7 26% t * References 59-76 appear on p. Stabilized diazonium salt procedure. 261. 5 5 4.47 lS-28% 3. Sodium diazotate procedure. A-1 A-2 A-3 A-4 ' A-5 B-l B-2 Diazohydroxide reaction (NaOH). Pyridine method. 2-Methyl 2-Carbomethoxy 2-. 3-. t The product was a mixture of isomers. and 4-Carboethoxy 2-Nitro o-Toluidine Methyl anthranilate Aniline o-Nitroanih'ne o-Nitroacetanilide o-Chloroaniline m-Toluidine TO-Cyanoaniline m-Nitroaniline m-Nitroacetanilide 3-Bromo 3-Chloro 4-Methyl avMethyl 4-Carbomethoxy 4-Carboethoxy 4-Aldehydo m-Bromoaniline m-Chloroaniline p-Toluidine Aniline Aniline Ethyl j>-Aminobenzoate Acetanilide Benzene Benzene Ethyl benzoate Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Toluene Methyl benzoate Benzene Benzaldehyde A-2 A-1 A-1 A-1 A-3 A-^t B-2 A-1 A-3 A-2 A-1 A-1 A-3 A-4 B-l B-2 A-1 A-1 A-3 A-2 A-3 A-2 A-1 A-1 B-l 8% 24% 1214% t 20% 45% 35% 60% 25% 38% 28% 19% 45% 56% 63% 64% 13% 22% 11% 4 13 7 5 5 6 8 5 5 4 3 5 6 53 8 2-Chloro 3-Methyl 3-Cyano 3-Nitro 15-18% 3. . Reference • Product Component A Component B Method Yield Monosubstitulion Products of Biphenyl.
5 5 6 3.Methyl 5-nitroanthran4-nitro ilate * References 59-76 appear on p. t The produot was a mixture of isomers.4-Dimethyl Methyl.3-Dicarbomethoxy 2.7 6 7 -t 60% 8 40% 5 35% 5 34% 6 7 13-15% — 7 3 4 ^ 6 % 3.A-4 A-1 Nitrobenzene A-4 B-l Nitrobenzene B-2 Benzene A-1 Benzene A-3 A-i Chlorobenzene A-1 Chlorobenzene B-l A-1 Benzene A-3 Bromobenzene A-1 B-l Benzene Benzene Cyanobenzene Benzene 3 3 5 5 6 53 5 5 53 3.50 5 12% — 3 — 53 15% 10% 25% 4% 26% 55% 29% 11% 50% 30% 60% 70% — 33% Disubstitution Products of Biphenyl. 261. 3-aminophthalate Aniline Acetanilide 2-Methyl-4-chloro 2-Methyl-4-chloroaniline 2-Methyl-4-bromo 2-Methyl-47-bromoaniline 2-Carbomethoxy.R'CeH3-C^Hs 2.254' THE PREPARATION OF UNSYMMETRICAL BIARYLS TABLE OP COMPOUNDS PREPARED BY THE REACTIONS—Continued Product Component A Component B Method Yield Reference * 4-Cyano 4-Methoxy p-Cyanoaniline Aniline p-Anisidine p-"Methoxyacetanilide p-Phenetidine p-Ethoxyacetanilide p-Nitroaniline Aniline Acetanilidep-Nitroacetanilide p-Chloroaniline Aniline Acetanilide p-Bromoaniline Aniline p-Benzamidoacetanilide 4-Ethoxy 4-Nitro 4-Chloro z-Chloro 4^Bromo as-Bromo 4-Benzamido A-1 A-1 A-1 A-3 A-4 B-l Benzene Benzene A-1 A-3 B-l Benzene Benzene A-1 A-3 . Benzene wi-Xylene ?n-Xylene Benzene Benzene Benzene A-1 A-1 B-l A-1 A-1 A-1 35% 9% 45% 14% 7% 7% 59 7 7 60 4 15 .5. R.
z'-Dicarboethoxy 3-Methyl-4-nitro — 9% 15% 19% 0 32% 20% 65 22-30% 38.4-Dicarboethoxy Component A Methyl 5-chloroanthranilate Methyl 5-bromoanthranilate 2.4^ amido phenylene diamine 3-Chloro-4-nitro 3-Chloro-4-nitroaniline 3-Bromo-4-methyl 3-Bromo-4-methylaniline 3-Bromo-4-nitro 3-Bromo-4-nitroanUine * References 59-76 appear on p. 261. J Based on the nitrosoacetylamine.4-Dinitroaniline 2-Bromo-4^methylaniline 2. z.4-Dibromoaniline Methyl 4-chloroanthranilate Methyl 4-bromoanthranilate 2-Cyano-5-methylacetanilide 2-Nitro-5-methylacetanilide 2-Chloro-5-methylaniline 2-Bromo-5-methylaniline 2-Bromo-5-nitroaniline Methyl 4-aminophthalate Ethyl 4-acetamidophthalate Acetanilide Aniline Component B Method Yield Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Ethyl phthalate Ethyl phthalate Benzene o-Nitrotoluene •o-Nitrotoluene Benzene Benzene Benzene Benzene Benzene Benzene A-1 A-1 B-l A-1 A-1 A-1 A-1 B-l B-l A-1 A-1 A-1 A-1 B-2 B-l A-1 A-1 A-1 B-l A-1 A-1 B-l A-1 A-1 A-1 29% 29% 10% 25% 22% 25% 25% 45% 51% 15% 16% 30% 37% — 37% ft 12% t Reference * 15 15 S 4 61 15 15 14 55 62 62 38 59 8 59 59 63 7 7 38 64 58 3-Methyl-4-nitroaniline Aniline Acetanilide 3-Methyl-4-bromo 3-Methyl-4-bromoaniline 3-Nitro-4-methyl 3-Nitro-4-methylaniline 3-Nitro-4-acet2-Nitrodiacetyl-l.COMPOUNDS PREPARED BY THE REACTIONS TABLE OF COMPOUNDS PREPARED BY THE REACTIONS—Continued 255 Product 2-Carbomethoxy4-chloro 2-Carbomethoxy*4-bromo 2.4-Dicarbomethoxy -3. 65 30% 66 .4-Dibromo 2-Carbomethoxy5-chloro 2-Carbomethoxy5-bromo 2-Cyano-5-methyl 2-Nitro-5-methyl 2-Chloro-5-methyl 2-Bromo-5-methyl 2-Bromo-5-nitro 3.4-Dinitro 2-Bromo-4-methyl 2. t The product was a mixture of isomere.
RCtHi • 2-Methyl-4'-nitro 2-Methyl-4'-chloro 2-Carbomethoxy4'-chloro 2-Carbomethoxy4'-bromo 2-Methoxy-4'bromo 2-Methoxy-4'-iodo 2-Nitro-4'-methyl 2.4.6-Trimethylaniline Benzene 2.'-Dinitro 2-Bromo-a.Methyl 4-aminoAnisole oxy-s'-methoxy phthalate * References 59-76 appear on p.4'-Dinitro 3-Bromo-4'-nitro 4-MethylVmethyl 4-Methyl-4'-nitro p-Nitroaniline p-Chloroaniline Methyl anthranilate \ . 26}.4.and p-Toluidine 4'-bromo 4-Methoxy-4'p-Anisidine benzoyl 4-Methoxy-4'p-Bromoaniline bromo 4-Methoxy-4'-iodo p-Iodoaniline 4. 69 — 69 — 69 32% f 59 .'-methyl 3.4.6-Trimethyl A-1 B-1 A-1 B-1 A-1 10-15% 69 10-42% 7.4.6-TrimethylacetBenzene anilide 3.4'-Dinitro p-Nitroaniline 4-Bromo-x'-methyl p-Bromoaniline Polysubstitution Products of Biphenyl Aniline Mesitylene Acetanilide Mesitylene 2. 2.4-Dicarbometh.2&8 THE PREPARATION OF UNSYMMETRICAL BIARYLS TABLE OF COMPOUNDS PREPARED BY THE REACTIONS—Continued Product Component A Component B Method Yield Reference * Disubstitution Products of Biphenyl. t The product was a mixture of isomere. Methyl anthranilate p-Bromoaniline p-Iodoaniline p-Toluidine o-Nitroaniline o-Bromoaniline m-Nitroaniline TO-Bromoaniline p-Toluidine Toluene Toluene Chlorobenzene Bromobenzene Anisole Anisole Nitrobenzene Nitrobenzene Toluene Nitrobenzene Nitrobenzene Toluene Toluene Nitrobenzene Toluene Bromobenzene Benzophenone Anisole Anisole Nitrobenzene Toluene A-1 A-1 A-1 A-1 A-1 A-1 A-2 A-4 A-1 A-4 A-1 A-2 A-1 A-2 A-1 A-1 A-2 A-1 A-1 A-1 A-4 A-1 9% — 17% f 13% t 20% — — 30% 54% 2% 23% t 4% — — 22% f 2% 7% — 69% 28% 67 15 15 15 52 52 64 6 58 6 68 4 67 64 15 58 4 13 52 52 6 4 -t p-Nitroaniline p-Toluidine 4-Methyl-4'-chloro p-Chloroaniline 4-Methyl-2'.
4-phenylene diamine. t The product was a mixture of isomers.B Method Yield Reference * 50 3.3-phenylene diamine Benzene Benzene B-l B-2 B-2 24% 32% 21% 55 8 8 p-Terphenyl p-Aminobiphenyl Aniline Acetanilide •4-Acetamidobiphenyl Diacetyl-1. X Based on the nitrosoacetylamine.5'-diethoxy 2-Cyano-5-methyl2'.5'-dimethoxy 2-Cyano-5-methyl2'. 2-Methyl-4'-acetamidobiphenyf 2-Nitro-4'-acetamidobiphenyl 4-Acetamidobiphenyl 4-Acetamidobiphenyl 4-Acetamidobiphenyl Benzene Biphenyl Biphenyl Benzene Benzene A-1 A-1 B-l B-l B-l B-2 3 13 58 50% J 8. 5'-dimethoxy4'-w-amyl Methyl 4-aminophthalate 2-Cyano-5-methylacetanilide 2-Cyano-5-methylacetanilide 2-Cyano-5-methylacetanilide Chlorobenzene p-Dimethoxybenzene p-Diethoxybenzene 2. 3-.4-Dicarbomethoxy-s'-ehloro 2-Cyano-5-methyl2'. 58 558 60%: 5560%: 17% 58 67 58 2-Methyl 2-Nitro 2-.Benzene biphenyl * References 59-76 appear on p. . and 4bromo 4-Methyl Benzene Benzene Nitrobenzene Chlorobenzene Bromobenzene B-l B-l B-l B-l B-l B-l 25% 33% t 31% t 54% 58 58 58 67 4-Methyl-4'-acetamido. 3-.COMPOUNDS PREPARED BY THE REACTIONS TABLE OP COMPOUNDS PREPARED BY THE REACTIONS—Continued 257 Product Component A Component. and 4chloro 2-. 261.5-Dimethoxy-n-amylbenzene A-1 B-l * B-l B-l 43% f 4 1 % % 14 24% 14 27% % 14 Terphenyls and Derivatives m-Terphenyl 3-Acetamidobiphenyl Diacetyl-l.
4-phenylmethoxy ene diamine 2.5"-Tetra. 261. Benzene Benzene Nitrobenzene 2-Methylnaphthalene 2-Methoxynaphthalene A-1 A-4 B-1 A-4 A-1 A-1 Low 30% — 39% — — 13 6 53 6 71 70 .2".4"-Dinitro Diacetyl-l. t Based on the nitroeoacetylamine.258 THE PREPARATION OF UNSYM METRICAL BIARYLS TABLE OF COMPOUNDS PREPARED BY^THE REACTIONS—Continued Product Component A Component B Method Yield Reference * 67 13 53 58 58 58' 67 67 67 58 58 67 •67 58 53 52 52 4-Methexy 4-Nitro 4-Bromo 4-Iodo s>-Methyl z-Methoxy 2.5.Diacetyl-1.5-Dimethoxy 4.4-phenylene diamine methyl 2.4'-Dinitro-4-acetamidobiphenyl 4.Diacetyl-l.5.4-phenylchloro ene diamine Quaterphenyl Diacetylbenzidine Dimethoxy Benzidine Diacetylbenzidine Arylnaphihalenes 1-Phenylnaphtha.3'-Dinitro 4-Methoxy-4'-acetamidobiphenyl p-Nitroaniline 4^Acetamidobiphenyl 4-Nitro-4'-acetamidobiphenyl 4-Bromo-4'-acetamidobiphenyl 4-Iodo-4'-acetamidobiphenyl 4-Acetamidobiphenyl 4-Acetamidobiphenyl 4-Acetamidobiphenyl Benzene Biphenyl Nitrobenzene Benzene Benzene Benzene Toluene Anisole p-Dimethoxybenzene Benzene Nitrobenzene p-Xylene p-Dimethoxybenzene p-Dichlorobenzene Benzene Anisole Anisole B-1 A-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 A-1 B-1 58% — 22% t — — 25% ft 15% — 5% 10% 7% 6% 17% 0% 0% 3.5"-Tetra.Methyl anthranilate • carbomethoxy * References 59-76 appear on p.2". t The product was a mixture of isomers.2".Diacetyl-l.ot-Naphthylamine lene * a-Acetamidonaphthalene 4'-Nitro a-Naphthylamine 2-Methyl-2'Methylanthranilate carbomethoxy 2-Methoxy-2'.5"-Tetra.4-phenyl-ene diamine 2.5.
13 0 6 25% 5 25.Methyl anthranilate z'-phenylnaphthalene a>-(2'-Carboamyl.49.5-Nitro-6-methoxy-2oxy acetamidonaphthalene 8-Nitro-7-meth. — . 53 30% t 2549 30% f 49 — 29% 29% 42% t 31% 18% 31% 46% f 14% 0 14% 26% 19% 22% — 49 49 49 49 49 49 49 5 6 49 5 72 72 13 73 /3-Acetamidonaphthalene /3-Naphthylamine 4'-Nitro 5-Nitro-6-meth. t Based on the nitrosoaoetylamine. 261.a-Acetamidonaphthaoxynaphthyllene 1-naphthalene * References 59-76 appear on p.COMPOUNDS PREPARED BY THE REACTIONS TABLE OF COMPOUNDS PREPARED BY THE REACTIONS—Continued 259 Product Component A Component B Method Yield Reference * 2-Phenylnaphtha./3-Naphthylamine lene /3-Acetamidonaphthalene 1-Nitro ' 5-Nitro 6-Methoxy 6-Nitro 6-Bromo 7-Phenyl 7-Methoxy 8-Nitro 2'-Nitro l-Nitro-2-naphthylamine 5-Nitro-2-acetamidonaphthalene 6-Methoxy-2-acetamidonaphthalene 6-Nitro-2-acetamidonaphthalene 6-Bromo-2-acetamidonaphthalene 2.7-Diacetamidonaphthalene 7-Methoxy-2-acetamidonaphthalene 8-Nitro-2-acetamidonaphthalene /3-Naphthylamine Benzene Benzene A-1 A-3 B-l ~^B-2 Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Nitrobenzene Nitrobenzene Nitrobenzene Benzene Benzene Naphthalene Amyl 2-Naphthoate A-1 B-l B-l B-l B-l B-l B-l B-l A-3 A-4 B-l A-3 >B-1 B-l A-1 B-l 16% 5.8-Nitro-6-methoxy-2acetamidonaphthaoxy lene 2-Carbomethoxy.
Pyridine Pyridine Pyridine Pyridine Pyridine Pyridine Pyridine Pyridine Pyridine Pyridine Pyridine Pyridine Pyridine Pyridine Pyridine A-5 B-1 A-5 A-5 A-5 A-5 A-5 A-5 A-5 A-5 B-1 A-5 A-5 A-5 A-5 40% f 60% ft 50% f 35% f 30% t 35% f 83% f 54% j 36% f 70% t 13% f 36% f 17% t 26% f 21% t 20 19 75 20 75 20 74 75 74 20 19 74 74 75 75 X Based on the nitrosoacetylanune.3-Nitro-4-methoxyoxy aniline 4-Nitro-2-meth.4-Nitro-2-methoxyoxy aniline * References 59-76 appear on p.-(l'-Carboamyl. ./9-Acetamidonaphthaoxynaphthyllene 2-naphthaIene s.4-pheny 1ene diamine p-Chloroaniline 4-Chloro p-Bromoaniline 4-Bromo 3-Nitro-4-meth.-(2'-Carboamyl. 261.0-Acetamidonaphthaoxynaphthyllene 2-naphthaJene Amyl 2-naphthoate Amyl 1-naphthoate " B-1 B-1 — 73 Arylthiophenes Phenylthiophene 8'-Cyano 4'-Nitro 4'-Chloro 4'-Bromo Aniline Acetanilide m-Cyanoaniline p-Nitroaniline p-Chloroaniline p-Bromoaniline Thiophene Thiophene Thiophene Thiophene Thiophene ThiopEene A-1 B-1 A-1 A-1 A-1 A-1 U% — 15% 23% • 3 1 3 3 24% 20% 3 3 Arylpyridines Phenylpyridines Aniline Acetanilide o-Anisidine 2-Methoxy o-Nitroaniline 2-Nitro 3-Methoxy m-Anisidine 3-Nitro ro-Nitroaniline 4-Carboxy p-Aminobenzoic acid 4-Methoxy p-Anisidine 4-Ethoxy p-Phenetidine p-Nitroaniline 4-Nitro 4-Amino Diacetyl-1.260 THE PREPARATION OF UNSYMMETRICAL BIARYLS TABLE OF COMPOUNDS PSEFABED BY THE REACTIONS—Continued Product Component A Component B Method Yield Reference * 73 a. t The produot was a mixture of isomers.
67 France. 60 89 . and Hey. Soc. Chem. Chem. Chem. Am. J. 1216 (1933). Chem. Soc. Soc. 78 Haworth. 1939. Soc. . 1938. Chem. Am. Soc. 68 Case. J. Soc. Soc. 365.1386. Butterworth.. 700. Chem. Chem. Hey. 69. •» Grieve and Hey. 1933. Soc. 2381 (1937). M Grieve and Hey. J. 1888. » Hey. Chem. Chem. J. 1941. Heilbron. J. Chem. Soc. 1279. M Cook and Cook. Soc. J. J. Soc. Chem. J. 1932. 1932. / . 78 Hey and Lawton. 1940. J. Chem. 1940. Chem. Chem. J. 61. / . / . 1283.COMPOUNDS PREPARED BY THE REACTIONS TABLE OF COMPOUNDS PHEPARED BY THE REACTIONS—Continued 261 Product Component A Component B Method Yield Reference 75 76 76 76 76 76 76 76 ' 76 5-Nitro-2-methoxy 3-a-Pyridylbiphenyl 3-|8-PyridyIbiphenyl 3-T-Pyridylbiphenyl 3-Pyridylbiphenyls " 4-a-Pyridylbiphenyl 4-0-Pyridylbiphenyl 4-7-Pyridylbiphenyl 4-Pyridylbiphenyls 5-Nitro-2-methoxyaniline 3-a-Pyridylacetanilide 3-/3-Pyridylacetanilide 3-y-Pyridylacetanilide 3-Aminobiphenyl 4-a-Pyridylacetanilide 4-j3-Pyridylacetanilide 4-Y-Pyridylacetanilide 4-Aminobiphenyl Pyridine Benzene Benzene Benzene Pyridine Benzene Benzene Benzene Pyridine A-5 B-2 • B-2 B-2 A-5 B-2 B-2 B-2 A-5 20%* 36% 33% 36% 39%* 40% 38% 38% 35%* * The product was a mixture of isomers. 78 Swain and Todd. Soc. Heilbron. and Wilkinson. 74 Butterworth. Soc. Heilbron. 61. 1941. 2247. 166 (1939). n Suter and Smith. 1938. Am. 820 (1939). 59. Soc. J. 55. Hey. 358. Chem. J. Soc.. Am. 65 Schoepfle and Truesdail. 1940. Soc. 677. J. 384. J. 310. M Case and Sloviter. 2636. J. Chem. Soc. 424 (1938). Chem. and Wilkinson. and Lambert. and Hey. Huntress and Seikel. ™ Badda]. Heilbron. Hey. 7 « Heilbron. Am. and Hey. 375 (1937). 60. 1940. Am. Chem. 70 Heilbron. Soc.
. Purdue University. Catalysts. . 264 271 273 274 277 277 282 285 286 287 288 289 290 294 Ethanol Deaminations Hypophosphorous Acid Deaminations m-Nitrotoluene from 3-Nitro-4-aminotoluene Toluene from o-Toluidine 7-Chlorohydrindone-l from 4-Amino-7-chlorohydrindone-l 1.5-Trinitrobenzene from 2. . and Other Substances Temperature REDTTCTION WITH HYPOPHOSPHOROUS ACID REDUCTION WITH ALKALINE FORMALDEHYDE USE OP STABILIZED DIAZONIUM SALTS TREATMENT WITH SODIUM STANNITE CONVERSION TO THE HYDRAZINE FOLLOWED BY OXIDATION MISCELLANEOUS REDUCING AGENTS COMPARISON OF THE VARIOUS DEAMINATION PROCEDURES APPLICATIONS OF THE DEAMINATION REACTION EXPERIMENTAL PROCEDURES *" . Present address. . 1942-1943./ .CHAPTER 7 REPLACEMENT OF THE AROMATIC PRIMARY AMINO GROUP BY HYDROGEN NATHAN KORNBLUM Oberlin College* and Harvard University * CONTENTS INTRODUCTION USE OF ALCOHOLS . 263 264 Influence of Substituents Acid Used for Diazotization Nature of the Alcohol Influence of Water.. . . .3-Dimethyl-5-bromobenzene from l..5-Diaminotriptycene Alkaline Formaldehyde Deamination 4-Methyldiphenyl Ether from 4-Methyl-4'-aminodiphenyl Ether .3-Dimethyl-4-amino-5-bromobenzene • • • • * National Research Fellow.3. . Sodium Stannite Deamination l.6-Trinitroaniline . .4. . Triptycene from 2. 262 294 294 294 295 295 296 297 297 297 298 298 .
2 Griess... Ber. Alcohols. 115-152. J. "Unit Proaesses in Organic Synthesis.5 5. Alkaline formaldehyde. Sodium Stannite Deaminations Table VI. 4 Brewster and Poje. 1938. Trans. The more important of these processes involve reduction by: 1. Deaminations via the Hydrazine INTRODUCTION 300 324 334 336 339 The replacement of an aromatic primary amino group by hydrogen is usually effected by reduction of the diazonium salt derived from the amine. 587 (1889). pp. Stannous chloride or sodium sulfite. 1936..INTRODUCTION EXAMPLES OP THE DEAMINATION REACTION 263 PAGE 299 Table II. Hypophosphorous Acid Deaminations Table IV. • Friedlander. p. Fortunately. Gilman and Blatt. Stabilization of the diazonium salt with naphthalene-l.. "Organic Syntheses. 2418 (1939).5-disulfonic acid followed by treatment with zinc or copper. Hypophosphorous acid. 163 (1902)...7 Saunders. Soc.-* ArH + N2 + HX It is evident that the success of the deamination process is a function of the completeness of diazotization as well as of the reduction. 683 (1864).6 6..~558.3 3. revised. 1940.1 Diazonium compounds have been treated with a great variety of reducing agents." 2d ed. 35.. Phil. 6-12. The conditions for this reaction are comparatively standard and are fully described in monographs on the diazo compounds. For some recent examples of the technique of diazotizing weakly basic amines. Lothrop. Cain. 22. J. 1550 (1941). Ethanol Deaminations Table III." pp. Ber. 1—27.. Soc. practically any primary aromatic amine is susceptible of diazotization. "Chemistry and Technology of the Diazo-Compounds. reduction to the hydrazine from which the hydrocarbon is obtained by oxidation. Chem. Chem." Collective Volume I. Ber.4 4. 6 Hodgson and Marsdeii. London." pp. 63. John Wiley & Sons. see de Milt and van Zandt. 207. 61. ibid. 154. J. New York. Am. 1941. usually in yields approaching the theoretical. Alkaline Formaldehyde Deaminations Table V. some of which have become incorporated into procedures for replacing the diazo group by hydrogen. Edward Arnold and Co. Soc. ArNH2 ->• ArN2+X. "The Aromatic Diazo-Compounds and Their Technical Applications. McGraw-Hill Book Company. London. New York. Edward Arnold and Co. 2044 (1936).. 90 (1885). Am. Niemann and Redemann. 8 Mai. Groggins. 7 Haller. 725 (1938). 18. Sodium stannite. 60.. 1920. ibid. 58. Chem.. 1 .2 2.
the reaction with alcohol may result in replacement of the —N2X group by —H or —OC2H5. gave the corresponding ethyl ethers. led to the suggestion that the normal products of reaction between diazonium salts and ethanol are the ethers.. 3.+ CH3CHaOH -» C6H8 + CH3CHO + Ns + HX The reaction came to be regarded as a general one. Ber. Actually.11 The remainder of Wroblewsky. and very often both types of products result. the presence of water and catalysts.2 C6H6N2+X. and the reaction temperature. The first irregularity appeared in 1870. upon treatment with boiling ethyl alcohol. 8 - .. 11 Hantesch and Jochem. Ber. 8. J. 247 (1886). Chem. Am. 10 Remsen and Orndorff. Am. 288-289). 387 (1887). 3337 (1901). various diazonium salts obtained from aniline have proved that phenetole is the main product. 98 (1870).• ArOCHsCH3 + Na + HX Later it was found that the decomposition of benzenediazonium salts with ethanol actually yields phenyl ethyl ether contaminated with a little benzene. coupled with the fact that a number of instances of ether formation had been recorded. J. Chem.. the alcohol employed in the reduction. • Remsen and Palmer. for example. results in a 61% yield of phenetole and a -5% yield of benzene. It was found that two chlorotoluidines. ArN2+X. 34.+ CH3CH2OH . along with a very small quantity of benzene. 9..' This. Influence of Substituents Careful studies of the action of absolute ethyl alcohol on. The character of the products is also affected by the acid used for diazotization. yield benzene. The most important factor in determining the course of the reaction is the nature of the substituents in the diazonium salt. a variety of other reducing agents have been employed (see pp. 8 the reaction of a diazonium salt with ethyl alcohol had taken an alternative course. USE OF ALCOHOLS In 1864 Griess reported that benzenediazonium salts. in spite of the fact that evidence to the contrary soon began to accumulate. when diazotized and boiled with ethanol.264 THE AROMATIC PRIMARY AMINO GROUP' In addition.10 The decomposition of benzenediazonium chloride.
an 80% yield of biphenyl is obtained without any evidence of ether formation.. Rec. C(C 6 H 6 ) S C(C6H6)3 C(C e H 6 ). "Winston... Am. the yield of hydrocarbon falls to zero.H5)S IV i VI v "1. In some instances only slight losses are thus incurred. C(C. appreciable amounts of diazonium salt are resinified. OC2H6 CH. * The decomposition of a-naphthalenediazonium acid sulfate in absolute ethyl alcohol yields both naphthalene (40%) and a-ethoxynaphthalene (23%). 153 (1891). trav.14 * Tar formation is observed in the reduction of most diazo compounds and is not peculiar to the use of alcohol as the reducing agent. chim. J. Am. " Raiford and Oberst. 36. 16 ' 16 While 4aminotetraphenylmethane (III) is converted to the hydrocarbon (IV) in 46% yield. o-toh'dine yields approximately equal quantities of ether and hydrocarbon. 242 (1933). and /3-ethoxynaphthalene is obtained in 30% yield. 13. Extreme care is necessary to prevent the reaction from occurring violently. . Am. 10 ' 1S CH 3 CH 3 CH 3 CH 3 Nj+HSOr OC2H6 N 2 +HSO 4 - An interesting example o{ the deleterious effect of an ortho methyl group is to be found in the tetraphenylmethane series. With the beta isomer much less naphthalene (7%) results. A methyl group ortho to each of the amino groups in benzidine again exerts a definite effect in favor of ether formation.12-13 Upon heating the tetrazonium chloride derived from benzidine with ethanol. Chem.INFLUENCE OF SUBSTITUENTS 265 the diazonium chloride is converted into tarry non-volatile substances. 31. 603 (1927). M Van Alphen. NH2 NH 2 CH. in others. whereas benzidine gives only biphenyl. Ber. for. respectively).. 46.. Pharm. the homolog (V) gives only the ether (VI). J. J. "TJUmann and Milnzhuber. 107. 119 (1904). only ethers (I and I I ) are isolated (in 50% and 40% yields. Chem.14 When a methyl group is introduced into the orlho or meta position of aniline. 408 (1903). 12 Orndorff and Kortright.
a substantial fraction of p-toluidine can be converted into toluene (45% yield). Chem.. Am. Chem. *> Shober.19 and from p-aminobenzenesulfonic acid the only product isolated is benzenesulfonic acid.266 CH 3 Cl-N8+- THE AROMATIC PRIMARY AMINO GROUP CH 3 The influence of an ortho methyl group does not completely determine the course of a deamination. 18 . the ether is also obtained (20% yield). 10 ' 13 A para methyl group apparently facilitates replacement of the diazo group by hydrogen. 3359 (1904). OCsHg . 19 Shober and Kiefer. One of the early and important examples of the utility of the deamination process^in determining structures involved an amino group adjacent to a methyl. 1 8 the meta isomer yields a mixture of m-ethoxybenzenesulfonic acid and benzenesulfonic acid (the ether predominates). 455 (1898).. namely.. and not the ethyl ether (37%) . J. 105 (1893). 16.. 17 CH 3 NH 2 In contrast to the ortho and meta isomers. Chem. 379 (1893). the conversion of the leuco base of fuchsine to the diphenyltolylmethane. Thus. the main product is o-toluenesulfonic acid (59%). Ber.SO3H CH3 I . J. The influence of the sulfonic acid group upon the course of ethanol deaminations somewhat resembles that of the methyl group. 20. 37. Am. in which a methyl group is -para to the amino group. Chem. 0aminobenzenesulfonic acid gives only the ether.21 • CH 3 . J. 11 Remsen and Dashiell. 15. Am. 17.. J. 454 (1895). Am.SO3H CHS I SO3H NH 2 VII " Fischer and Fischer. 18 Franklin.20 With the~aminosulfonic acid (VII).
* but the smoothness of the reaction cannot be estimated from the available experimental data. J. 769 (1939).**•22 Finally. The influence of carboxyl and nitro groups as well as chlorine and bromine atoms has been the subject of systematic investigations. it appears that. 1941. J. Vol I. is diminished somewhat in the meta position. Syntheses. Org. Though the data do not lend themselves to broad generalizations. This gradation is illustrated by the results obtained with the diazonium salts from the isomeric aminobenzoic acids. 19. and ethyl ra-ethoxybenzoate. of 2. * See Table II. Chem. it is by no means a common occurrence.4. 319 (1889). Chem.24. 13. When the orthQ diazonium nitrate is treated with absolute ethanol only reduction occurs. All these groups promote the replacement of the diazonium group by hydrogen.26 Apparently iodine also favors the reducing action of alcohols. Coll.. 61. Syntheses.. 20. Soc. 57 (1939). 21 Weida. Chem. 22 Remsen and Graham. It has been demonstrated that the presence of chlorine or bromine in the nucleus facilitates replacement of the diazo group by hydrogen. 26. 80% yield).. Am. 547 (1897). 42.26'27 No attempts to deaminate fiuorinated amines are recorded. 10 Wallingford and Kreuger. esterification takes place during the reduction. 978 (1888). in the main. and is weakest in the para position. Am. J. 317-319. 28 Jackson and Behr. f The diazonium acid sulfate derived from Mi-aminobenzoic acid is converted into a mixture of ethyl benzoate. 19. « Wheeler and Liddle.22> M from the nitrate the yields of p-ethoxybenzoic acid and ethyl benzoate are 50% and 12%. . 2t Cgleman and Talbot. Am.. Org. 28 Griess. Chem. 96 (1933). Chem.. 45% yield). « Case. little or no ether formation occurs. Representative of the efficiency with which ethanol reduces diazonium salts derived from halogenated amines are the deaminations of m-chloroaniline 26 (87% yield). with the p-diazonium salts the ether reaction is the favored one.. and Sandborn. J. 441 (1909). Org. 133. Am. the former preponderating. J.6-tribromoaniline 29 (ca. and a few other instances. t In this. Johnson. Am. respectively. in the biphenyl series the deamination of VIII in 53% yield31 may be cited. J. 21. 25 Cameron. 88 Bigelow. Ber. and of 2-carboxy-4iodoaniline80 (ca. 58 (1901). Am. **•M ethyl benzoate is obtained in 53% yield. 11. 2d ed. pp. Syntheses.. the effect is at a peak when the group is situated ortho to the diazo group. Chem. but this point has not been investigated carefully. of 2-bromo-4-methylaniline28 (57% yield).INFLUENCE OF SUBSTITUENTS 267 Aminosulfonic acids of the naphthalene and biphenyl series also have been deaminated. 229 (1898).
36 Other typical examples are the deaminations of 2. 510 (1941). 1933. "Orndorff and Cauffman.5-dinitro-4-aminotoluene is converted to 3. 84 Clarke and Taylor. 14. * ether is formed. Chem. Chim. Vol. 415. "Ruggli and Dinger. Chem. Syntheses. . Helv. Ber. m-nitrotoluene could not 82 Hantzsch and Smythe. 45 (1892). Chem. I. Instead.. J. 1941. Hi.34 p-nitroaniline gives nitrobenzene in approximately 70% yield. on treatment with water. 63. Soc.. J. the presence of a nitro group tends to decrease the amount of tar produced. J. 8.* With ethyl alcohol little. J.87 and of the dinitrodimethylbenzidine (X) in 53% yield. 1271 (1905). if any..39 despite repeated attempts. Am. 505 (1900). this is especially true when several nitro groups are present. 3-nitro-4-aminotoluene is converted to mnitrotoluene in 67% yield. Org. Coll. Consequently nitro substituted amines are frequently susceptible of deamination in excellent yields.88 NO8 NOj C=C H \ IX NO* One of the rare instances of failure to deaminate a nitroamine was reported in 1875. Am..268 THE AROMATIC PRIMARY AMINO GROUP NOj NO* •NH 2 VIII It is significant that. part of the salt is converted into pentabromobenzene and part is resinified. 87. 182 (1941). " L&denburg. Ber. 86 Hodgson and Walker. 86 Cohen and McCandlish. Chem. pentabromobenzenediazonium acid sulfate does not yield the expected phenol.22 and 3.4-dinitro-l-naphthylamine (50% yield).5dinitrotoluene in yields approaching the theoretical.83 In addition to minimizing ether formation.*2 The nitro group exerts a powerful influence in facilitating the reduction of diazonium salts by alcohols. Soc. 1212 (1875).22. Thus. 88 Case and Koft. 1620. Soc. 33.36 of the trans dinitroaminostilbene (IX) in 56% yield. Aeta.
m-.4-diamino-5-nitrotoluene (XI). Cameron himself states that "the'experiments with the diazophenols here recorded are to be regarded as indecisive. the alcohol-soluble portion gave a small quantity of 2-ethoxy-5-nitrotoluene (XII). (See references 40. Ethers could not be detected. CH3 OC2HS O2N I NH2 XI ' 02N XII The effect of hydroxyl groups upon the reactions of diazpnium salts with ethyl alcohol appears not to be established. London. therefore. .. that in this case the primary decomposition product is phenol and that by coupling with undecomposed diazonium salt it is converted into the azophenol. He merely reports that the diazonium chlorides derived from 0-. J. 50-55% yield).and p-aminophenols change * The literature oontains statements which lead to the Conclusion that the presence of a phenolic hydroxyl is generally conducive to replacement of the diazonium group_ by hydrogen. "The Aromatic Diazo-Compounds and Their Technical Applications.. amorphous material from which no definite product could be isolated. 41 Hodgson and Foster. (See reference 25. 1940.) However. careful scrutiny of this article reveals that the generalization is clearly not warranted by Cameron's results." p." 40 Saunders. p'-azophenol (ca.26'40'41-* Very recently it has been shown that treatment of the double salt of zinc chloride and p-hydroxybenzenediazonium chloride with ethyl alcohol leads to phenol (38% yield) and p. Soc.41 N2+C1Ho/ OH \—N=N—< x />OH It appears. 1936. Hydroxydiazonium salts derived from o. Addition of zinc oxide to the reaction mixture raises the yield of phenol to 60% while that of the azo compound falls to approximately 30%. 145. and p-aminophenol give phenol (yield unstated) and tar when decomposed with methyl or ethyl alcohol. 1150. Chem. Tetrazotization converted most of the diamine into alcohol-insoluble. 41. Edward Arnold and Co.) The sole authority cited for this claim is a paper by Cameron published in 1898.INFLUENCE OF SUBSTTTUENTS 269 be obtained from 2.
" Morgan and Porter. m Apparently. very few attempts have been made to apply the ethanol deamination procedure to amino ethers. Hdv Chim." revised by Taylor and Baker.* XIV Replacement of the diazo group by hydrogen has been reported for a number of diazo oxides. 14. 652 (1915). * For a discussion of the structure of the diazo oxides (diazophenols) see Sidgwick. . XIV) will be used in this chapter.44 NH 2 N2 . 47. the first of the two resonance structures (XIII.** and that from 1anuno-2-hydroxy-6-bromonaphthalene-4^sulfonic acid gives XV in approximately 50% yield. 107. XIV). "The Organic Chemistry of Nitrogen.. 1937. Ber. either spontaneously or under the influence of alkali.—OH SO3H Once again. J.42. Oxford University Press.. For example. the data are so sparse that generalized statements are not justified. 422-423. pp. Soc. I t is of interest to note that. 781 (1941). Ada.270 THE AROMATIC PRIMARY AMINO GROUP into compounds known as diazo oxides or diazophenols (XIII. " JQemenc. "Ruggli and Michels. For convenience. 1413 (1914). the diazo oxide from 2-nitro-4aminophenol yields o-nitrophenol in 5 3 % yield. Chem.
3'-dimethoxybenzidine takes place in but 24% yield.* In the deamination of polybromoamines.6-dibromobenzenediazonium chlorides. sulfuric acid has been used rather than hydrochloric or nitric acid. "Hantzsch. in certain cases.. 46 Starke. Ber. 2334 (1897). diazotization with hydrochloric acid involves a risk that the deamination product may contain chlorine in place of a bromine atom or a nitro group originally present in the aromatic amine.and 2.46 Acid Used for Diazotization In most of the recorded deaminations with ethanol. however. respectively.. after one hour at 0°. but dibromodiazonium chlorides do so readily. nuclear bromine is exchanged for chlorine. Bromine atoms meta to the diazo group are not affected. Thus.32-46 B N2+C1- N2+Br- Monobromodiazonium chlorides do not isomerize. that a number of satisfactory deaminations have been effected via the diazonium chlorides. of the * It must be emphasized. Chem. J.14 the desmination of 3. in H^6 normal methanol solutions of 2. 221 (1899). prakt.2% and 21. As a general practice this appears to be a good choice since.ACID USED FOR DIAZOTIZATION 271 whereas benzidine is converted to biphenyl in 80% yield. . even at low temperatures. [2] 59. 6. 30.4-dibromo.4%. if the bromine atoms are ortho or para to the amino group and if the diazotization is carried out with hydrochloric acid.
4. the reaction becomes exceedingly slow..29 Even pentabromoaniline suffers no loss of bromine when deaminated via the diazonium acid sulfate.6-tribromobenzenediazonium fluoride. 81. After two hours at + 5 ° . Thus. or temperatures close to the boiling point of the alcohol. Apparently halogen exchange is restricted to the diazonium chlorides of polybrominated amines. the nitro group is not eliminated when sulfuric or nitric acid is used in the diazotization.2% of ionic chlorine. by treating the diazonium acid sulfate of tribromoaniline with boiling ethanol.272 THE AROMATIC PRIMARY AMINO GROUP ionic halogen is bromide ion. the diazonium chloride of a polybromoamine should not be used in this reaction. In general.32 No interchange occurs with 2.47 Chlorine sometimes replaces a nitro group ortho to a diazonium group. Tribromobenzenediazonium chloride in 90% ethyl alcohol isomerizes at a rate less than one-twentieth that in absolute ethanol. When 2.6-triiodobenzenediazonium chloride or 2. raising the temperature causes a striking increase in the rate of isomerization. The diazonium chloride obtained from symmetrical tribromoaniline exchanges with great rapidity. On the other hand. pure tribromobenzene is obtained in about 80% yield. Soc. 2069 (1903). Diazotization in the presence of sulfuric acid affords a simple means of avoiding the exchange reaction since diazonium acid sulfates do not rearrange. . 988 (190?). loss of nuclear bromine is considerably faster. a 3^8 normal ethanol solution contains only 4. Meldola and Eyre. Chem. the remainder having displaced nuclear bromine atoms. 2-nitro-3-chloroanisolc is obtained 48 in unspecified yield. J.4. NE N 2 +C1- OCH OCH3 On the other hand. Diazotization of l-nitro-2-naphthylamine in hydrochloric acid results in replacement 47 48 Hantzsch. in pure water. In ethanol.3-dinitro-4-methoxyaniline is diazotized in the presence of hydrochloric acid and then treated with ethyl alcohol. The presence of water cuts down the speed of the halogen exchange. The same interchange occurs in the naphthalene series. the interchange takes place more rapidly as the number of bromine atoms in the ring increases. 36. and since alcohol deaminations almost invariably involve reflux conditions. Ber.
Chem..). 1930.+-f V .NATURE OF THE At-COHOL 273 of the nitro group49> 80 with the formation of l-chloro-2-naphthalenediazonium chloride. / .61 The use of diazo nitrates instead of the acid sulfates offers no advantage and may result in nitrated products. Am. \—i \—NH2 -* NO2 Br BF«-N. / .p'-dimethoxybiphenyl and a trace of the hydrocarbon. Soc. 410 (1940)]. 68 Morgan and Evens. 53 Hodgson and Kershaw. 960 (1936). 69. 1377 (1902). Gen. 522 (1939) [C.S. Soc.. J. The use of methanol greatly increases the probability that ethers will be formed. 1933. 5X8 (1893).26'18> 63 The higher aliphatic alcohols have been employed in the deamination reaction with the hope that the increased yielde of hydrocarbon noted in passing from methanol to ethanol would continue as the series was ascended. Soc. a 26% increase over that obtained by employing the tetrazonium acid sulfate.62 NO8 Br H2N—i . diazotization with sulfuric acid prevents the lose of the nitro group. 15. it is never superior to and rarely as good as ethanol for this purpose. A convenient method involves preparation of the dry bisdiazofluoborate and decomposition in absolute ethyl alcohol. 2785.R. Here again. 66 Hantzsch and Vock. J.. Soc. The yield of pure product is 78%.25 Deamination of large quantities of 2-nitro-3'-bromobenzidine by the sulfuric acid procedure proves tedious. For example. 1590. and Traykin. U S . whereas decomposition with absolute methanol gives a 65% yield of p. Chem. Schiemann and Ley. 34.S. (U. This expectation has not been realized. J. Chem. Ber.A. Chem. biphenyl is obtained in 80% yield. . Ber.14 Although methanol has been known to bring about replacement of the diazo group by hydrogen. V-N a +BF 4 Nature of the Alcohol All alcohols do not produce the same result with a given diazonium salt. 81. 36. Chem.f . 60 48 9.. Chem.66 The results Morgan. 64 Orndorff and Hopkins.63' M ' 66 . Keriov. 62 Lesshe and Turner. " Vororiitsov. J. 2061 (1903). if the tetrazonium chloride derived from benzidine is treated with absolute ethyl alcohol. 1126 (1919).
69 Apparently the nitro group undergoes hydrolytic cleavage.63-66 Influence of Water. if any. NH2 N2+HSO4OCH3 . 67 68 .68 Certain diazonium salts. Catalysts. but this by no means has been clearly demonstrated. Many successful deaminations take place with alcohol containing as much as 15% of water and. 1202 (1905).69 * See p. smooth replacement of a diazo group does not depend upon perfectly anhydrous conditions. 74. are unstable in the presence of water.274 THE AROMATIC PRIMARY AMINO GROUP are far from conclusive.5-dinitro-4-methoxyaniline rapid and complete conversion to the diazo oxide occurs upon diazotization with sulfuric or hydrochloric acid. Beeson. J. Soc. 235 (1894). Muller and Tiete." Although general practice does not require rigid exclusion of moisture. a diazo oxide * (XVII). Benzyl alcohol may be superior to ethanol in reducing diazonium salts. in some instances. and Other Substances Water.14-28.. 823 (1941). 10 .. Chem. Am. 16. a hydroxybenzenediazonium salt (XVI) being intermediate in the diazo oxide formation.OCH3 NO2 NOj N 2 +HSO 4 OCH8 . / . Thus.5-dinitroaniline when diazotized in sulfuric acid containing an equal volume of water gives. 270.OCH3 With 3. however. Ber. 2-methoxy-4. In the main. the amount of' water should be limited to about 5-10%.**•21. a still larger proportion. 87. in addition to the expected diazonium salt. but apparently there is little. Chem. advantage in replacing ethanol by the higher aliphatic alcohols. M Meldola and Stephens.
Helv. New York.61-62. the deamination of N 2 +HSO 4 - NO2 2-nitronaphthylamine-l and 2.60 Picramide is diazotized by treating a solution of the amine in. 432. Chim. 780 (1925).61 Addition of ice-cold water to the diazonium solution results in immediate decomposition of the diazonium salt. 1938." p.. in addition. 1474 (1907). Chem. Chim. Ada. ! 82 Blangey. 61 Misslin. 60 Meldola and Hay.6-dinitrobenzenediazonium ion is produced. Nordemann Publishing Co. Misslin implies (reference 61) that the 2-hydroxy-4. whereas it readily occurs with 2. a nitro or methoxyl group becomes sufficiently mobile to be eliminated during the course of diazotization only when ortho or para to the diazo group and. 8. and in the light of Blangey's results (reference 62) the course of the reaction must be regarded as an open question. adjacent to a nitro group. The elimination of a nitro group from 2.INFLUENCE OF WATER NH 2 N2 275 An extensive study of the methoxypolynitroanilines has shown that. 3. and again it is an ortho nitro group that is removed. Thus. a view that is accepted by Karrer.* ' Nitronaphthalenediazonium salts are more susceptible of hydrolytic cleavage than the corresponding benzenoid compounds.4-dinitronaphthalene-l-diazonium acid sulfate.4-dinitronaphthylamine-l requires diazotization with nitrosylsulfuric acid. 91. in this series. * The nature of the degradation products has not been established.36 Diazonium salts derived from nitro-/3-naphthylamines also undergo hydrolysis.glacial acetic acid with nitrosylsulfuric acid (prepared by dissolving sodium nitrite in concentrated sulfuric acid). J.36166 Because the diazonium salts are unstable in the presence of water. 626 (1920).4-dinitrobenzene-l-diazonium acid sulfate is not effected merely by dilution with water. Soc. Ada. Hdv. followed by direct decomposition with ethanol. . "Organic Chemistry. There does not appear to be any experimental basis for this deduction.
* Metals. M Parsons and Bailar. Am. however. 72 Iddles and Hussey. 80 Ruggli and Welge. Chetn. "Helle.276 i THE AROMATIC PRIMARY AMINO GROUP when l. 34. Chim.63' M In consequence of hydrolytic cleavage. 68.. Ber. Am. 666 (1915). Soc. _ " Kuggh and Staub. 27. a number of metals. However. 7i. In an effort to facilitate the reduction of diazonium salts by ethanol. Chem. so that anhydrous conditions are unnecessary. 70 Witt and TJermenyl.6-dinitronaphthylamine-2 is diazotized in concentrated sulfuric acid and then diluted with ice-cold water. elimination of the nitro group is a comparatively slow reaction so that treatment with ethanol gives. 6. J. Ber. Chim. Here..8-dinitronaphtha-. M Gaess and Ammelburg.8-dinitronaphthylamine-2. a diazo oxide also is obtained from the isomeric l. and salts are added to the reaction mixture. Soc. 71 Schlenk and Brauns. Chim. In this connection it is significant that diazotized picramide. . Helv. Metallic Oxides. "Scheid. ffefo.68'44> 69> f and cupric sulfate80'70 are often employed. 2769 (1941).. 60 (1937). 88.. 748. Hodgson and Turner. Ada. 166 (1923). 586 (1932). 20. Zinc "• 4i. Finely divided copper. 48. 15.61-82 is converted to trinitrobenzene in 60-65% yield upon treatment with 50% aqueous hypophosphorous acid. it appears that in many instances the reaction is a comparatively slow one. Helv. Ber. 306 (1013). 68 Sandmeyer. 1816 (1901). 363 (1892).6-dmitronaphthalene. Ada. oxides. N2+HSO4- The reaction occurs so rapidly that attempts to deaminate by the usual procedures give little or no 1. Soc. 28> "• 6 6 ' 6 6 ' 6 7 cuprous oxide.. J. but this beneficial 2 effect is frequently offset by the heightened production of tars and * Detailed directions for this deamination are given on p 296 t It is claimed that a deamination procedure employing cuprous oxide in conjunction with ethanol appears to be of general application. a satisfactory yield of 1. 46. 7 inhibits the formation of ethers. Chem.63-64 * A dearth of quantitative information about the rate of diazo oxide formation makes it impossible to generalize about the importance which is to be attached to this side reaction. 1942. 269 (1936). which is reported to be very unstable in the presence of water.. Ada.. the diazo oxide is precipitated. lene. and Salts. J. 270. Ber. 2211 (1894). Ann.
however. 42.. J. 19. sodium hydroxide. J. 298 (1898). moderation by external cooling may be necessary. the addition of zinc dust is reported to overcome the influence of substituents..21-68 this. 77 Pfeiffer. Am. 631 (1897). especially when the diazonium salt is isolated and dried before reduction.67> 68-73-74-79 Temperature Very few quantitative data concerning the effect of temperature on the deamination reaction are available. 78 Moale. J.41 Aluminum powder is sometimes added to advantage.REDUCTION WITH HYPOPHOSPHOROUS ACID 68 74 76 277 biaryls. 19. 80. and the encouraging results that had been obtained did not give rise to widespread use of hypophosChamberlain. Griffin. J. or sodium carbonate. respectively. 48. 2494 (1882). Am. Soc. 581. Chem. Ber. Benzene. J.14.. 67. In several instances. . in fact.. p-toluidine. Ind..66 The use of these substances is unquestionably beneficial in many instances. Chem. lowering of the temperature favors replacement by hydrogen at the expense of the ether reaction.. is not always true. Am. 1942. 78 Mohlau. if any.14-28-34 REDUCTION WITH HYPOPHOSPHOROUS ACID In 1902 Mai discovered that aniline. 1793 (1915). There is.62-77-78 In the presence of sodium ethoxide. once it is started. From a-naphthalenediazonium chloride. naphthalene was produced very slowly and in unstated yield. Ber. toluene. and biphenyl were obtained in 40. 15. a marked increase in the yields of biaryJs and tars so that these bases are of no real value in bringing about deaminations.. only reduction occurs. Chem. certain reductions are adversely affected by the addition of promoters. 163 (1897).3 The reaction was not investigated further. 97T (1923). n Morgan and Jones.73-l4 Very often reduction of diazonium salts by ethanol requires temperatures in the neighborhood of the boiling point of the alcohol. little. Chem. SocTChem. however.**• In the ethanol decompositions of zinc chloridediazonium chloride double salts. Concentrated sulfuric acid is sometimes added to the alcohol. and benzidine could be deaminated by reducing their diazonium chlorides with 10% aqueous hypophosphorous acid.79 Zinc oxide is helpful in the deamination of hydroxybenzenediazonium salts. but the utility of most of them is limited. 76 Hodgson and Foster. and 60% yields. ether formation occurs. The reaction may take place with violence so that. 74 73 .66-76'66 Acids and Bases.
then one molecule of hypophosphorous acid will be required for the reduction of each diazo group. and with 15 moles. In practice. Org. and with the more difficultly reduced diazo salts this ratio should be 15 to 1. ArN2+X. 80 Adams and Komblum. pure toluene is obtained in 27% yield. Only recently has it been demonstrated that the reduction of diazonium compounds by hypophosphorous acid is an excellent and general method for replacing the diazo group by hydrogen.81'82> * Since hypophosphorous acid is not an expensive reagent.278 THE AROMATIC PRIMARY AMINO GROUP phorous acid in deaminations. however. Am.76 mole of hypophosphorous acid does not increase the yield of m-nitrotoluene (reference 84). 5 moles of this reducing agent usually give excellent results.75 moles of hypophosphorous acid.76 mole gives a 70% yield of m-nitrotoluene. 8 * Kornblum.81-82 If it is assumed that hypophosphorous acid undergoes oxidation to phosphorous acid. Reduction is usually complete within twenty-four hours. much tar. Soc. the yield is increased another 5 to 15%. Can. Some tetrazonium salts of the benzidine series may be deaminated either at * In the case of 3-nitro-4-aminotoluene the use of more than 0. 20B. it is advisable to use 5 moles of hypophosphorous acid per mole of diazonium compound. however. and no toluene. unpublished work. . when amines that are deaminated smoothly with only 5 moles of hypophosphorous acid are treated with 15 moles. unpublished work. 133 (1942). Ten moles of hypophosphorous acid give a 63% yield. a 50% yield of pure toluene is obtained. 194 (1941).13'80'81-82' M The yield depends upon the molar ratio of hypophosphorous acid to diazonium salt. and. 21.+ H3PO2 + H2O -» ArH + H3PO3 + HX + N 2 ..in the case of 3-nitro-4-aminotoluene. this is by no means generally true.75 moles t>f hypophosphorous acid per mole of diazonium chloride gives some o-cresol. J. the use of more than 5 moles is justified when a valuable amine is to be deaminated. Marion. and the use of 15 moles results in the production of pure toluene in 70-75% yield.13 with 5 moles.82 Similarly. and the reaction is allowed to proceed at 0° to 5°.82 Although 10 or 15 moles of hypophosphorous acid may be required for the successful deamination of some amines. Treatment of o-toluenediazonium chloride with only 2. m-toluenediazonium chloride cannot be converted to toluene by using 2. 8S Kornblum and Dorn.13 With 5 moles of acid. Syntheses. and Leger. 30 (1941). 84 Manske. as little as 0. Research.84 In general. 81 Komblum. The hypophosphorous acid procedure is notable for its simplicity of operation\ Ice-cold 50 or 30% aqueous hypophosphorous acid is added to the diazonium solution. J. 63. the yield is 51-62%. Chem.
Pt. the yields of nitrobenzene are essentially the same (60-80%).M As has already been noted in the section on ethanol deaminations. pura applicata.. hypophosphorous acid reduction gives a deaminated product containing chlorine in place of the nitro group. For example. a diazonium salt is obtained in which the nitro group has been replaced by chlorine (pp. 2442 (1942).88 NH2 88 Bellavita. 31.85 Hydrochloric and sulfuric acids have been employed with about equal frequency in hypophosphorous acid reductions. I.81 Although deaminations have been carried out at the boiling point of the reaction mixture it does not appear that such a high temperature is to be recommended. The striking results obtained with the tqluidines are recorded in Table I. 3901 (1937)]. with certain exceptions discussed below. J. A. M Keilen and Cass. when 5-amino-8-nitroisoquinoline (XVIII) is diazotized with hydrochloric acid and then treated with hypophosphorous acid. Consequently.REDUCTION WITH HYPOPHOSPHOROUS ACID 279 refrigerator or room temperature. chim. 272-273). Chem.. 5th Congr.82 so that. with either hydrochloric or sulfuric acid. 64. nazl. in "general.. Soe. upon diazotizing some nitroamines in hydrochloric acid. Atti congr. - . 1935. diazotization with hydrochloric acid is advisable. 8-chloroisoquinoline (XIX) is obtained in 60-70% yield instead of 8-nitroisoquinoline. 294 (1936) [C. Rome. Recent work has shown that. the reaction goes more smoothly with the diazonium chlorides. Am. The isomeric nitroanilines TABLE I DEPENDENCE OF THE YIELD OF TOLUENE ON THE ACID USED FOB DIAZOTIZATION Toluidine oriho Acid Used for Diazotization HCl H2SO4 HCl H2SO4 HCl H2SO4 Yield 70-75% 12-23% 51-62% 5-12% 77-83% 27-29% meta para do not display this sensitivity to the acid used for diazotization.
upon treatment with aqueous hypophosphorous acid. while the hypophosphorous acid reduction of the diazonium chloride derived from 2. l-nitro-2-aminonaphthalene gives 1-chloronaphthalene in 69% yield and only a trace of 1-nitronaphthalene when diazotized in hydrochloric acid solution and reduced with hypophosphorous acid. Chem.4. S..5-diaminotriptycene (XX).3. been accomplished in 40-45% yield by diazotizing with sulfuric acid.83 The same type of side reaction occurs when 2.5diaminotriptycene (XX) is diazotized in hydrochloric acid solution and then reduced with hypophosphorous acid.87 Cl xx Conversion of this diamine to triptycene has. and Cohen. the diazonium chloride of 2. 88 Oberst. 275).6-tribromoaniline when treated with hypophosphorous acid gives 1. 87 . p. In aqueous solution at 0° to +5°. however. 2. State University of Iowa. J. 271-272) does not occur. * l-bromo-2. thesis. * This deamination is described in detail oh p.83 NH2 The successful deamination of l-mtro-2-aminonaphthalene. and l-bromo-2.83 Upon diazotization with sulfuric acid. 1928. Ryan.3. 2649 (1942). 297. however. a 61% yield of a-nitronaphthalene is obtained. exchange of nuclear bromine for chlorine (pp.83' f is of considerable interest inasmuch as this diazonium salt is immediately decomposed by ice water "• 62 alone (p.5-diaminotriptycene (XXI) suggests that 5-amino-8-nitroisoquinoline (XVIII) also could be deaminated to 8-nitroisoquinoline if the diazotization were carried out in sulfuric acid. t Described in detail on p. Am. 29.5diaminotriptycene (XXI) has also been deaminated by this procedure. Thus.4. Bartlett.5trinitrobenzene in 60-65% yield.5-tribromobenzene in 70% yield. M.6-tribromo-3methylaniline is productive of the corresponding tribromotoluene in 91% yield.88-13 The conversion of diazotized 2. 296. 64.6-trinitroaniline (picramide) to 1. Soc.280 THE AROMATIC PRIMARY AMINO GROUP Similarly.4.
82 treatment with ethanol gives o-ethoxytoluene in approximately 50% yield. 50%) and o-(|3-phenylethyl)-phenol (23%). Gazz. us.4-diethyl-6-bromoaniline (70%). 42 (1931).. Chem. chim.M In the last case. 94 Finzi. Adams.t. w. 65%). ital. and Mclntosh. 90 .10'13 And while reduction of the diazonium salt of p-aminophenylarsonic acid by hypophosphorous acid yields phenylarsonic acid (ca. Ber. aqueous sodium hypophosphite containing copper •• Snyder. when ethanol is used dibenzyl is not obtained. M Failure of the hypophosphorous acid procedure has been reported in a rather special case. when diazotized in sulfuric acid and treated with ho. Ber.13 3. Ber... whereas deamination of o-toluidine by the hypophosphorous acid procedure affords toluene in 70-75% yield. 295. 3103 (1912). 50%).80-81 4-amino-7chlorohydrindone-1 (85%). Am. Described in detail on p. Bertheim and Benda. 63. For example..92 ethanol gives p-ethoxyphenylarsonic acid (ca. the yield with hypophosphorous acid is 66-78% 80 ' 81 as compared to approximately 20% when ethanol is used. 61. 1855 (1908).46 These data.89 3-nitro-4-aminophenylarsonic acid (45%).13' si. in conjunction with other results. 3282 (1941).3'-dimethylbenzidine (76-82%). M. Soc. private communication. 45. 44. instead the products are 9. cw-o-aminostilbene. •• Bertheim. 41. " Fieser and Berliner.M CH2—CH2 xxn This is not the only instance where hypophosphorous acid is more effective than ethyl alcohol.3'-dimethoxybenzidine may be deaminated by either procedure. J. 87. Although 3.. 93 Stoermer and Heymann. 3298 (1911).91 5-methyl-8-aminoquinoline (72%) M o-(J3phenylethyl)-aniline (XXII) (47%). and that it is usually effective in deaminations which cannot be carried out with ethanol.90 3-amino-6-bromobenzoic acid (75%).REDUCTION WITH HYPOPHOSPEOROUS ACID 28X The yields obtained on deaminating the following amines further illustrate the wide utility "of hypophosphorous acid: 2.10-dihydrophenanthrene (ca. lead to the conclusion that hypophosphorous acid is at least equal to ethanol as a reagent for deaminating an aromatic amine.
the Pschorr reaction is not possible.84 In hypophosphorous acid reductions varying amounts of phenols and tars are obtained.66' * With the trans isomer. deamination might be achieved by treating the diazonium chloride with hypophosphorous aoid at 0° to +5° in the absence of copper. .66 Deamination of 4.4 The method is simple in practice. no difficulty is experienced in isolating products of excellent quality. In general.4 The deaminations of 2.and aryloxy-amines. however.282 THE AROMATIC PRIMARY AMINO GROUP powder.5-dimethylquinoline. Although there are comparatively few examples of deaminations employing alkaline formaldehyde. and it is particularly effective where the ethyl alcohol procedure is of little or no value.66 Ethanol also yields phenanthrene instead of cts-stilbene.5-dimethyl-8-aminoquinoline by hypophosphorous acid gives only a 6% yield of 4. with alkoxy. several generalizations can be made. Aromatic amines and their homologs are converted to the corresponding hydrocarbons in 60-80% yields. conversion to the stilbene takes place whether ethanol or hypophosphorous acid is employed. that the diazotization takes an abnormal course. however. There is some evidence. REDUCTION WITH ALKALINE FORMALDEHYDE The reduction of diazonium salts by alkaline formaldehyde affords good yields of deaminated products in a number of instances. the yields range from 50 to 75%.4-dimethyl* It would be of interest to attempt this reduction under somewhat modified conditions. gives phenanthrene in 80% yield.
796 (1903). "Bamberger and Kraus. This instability is merely an extension of the hydrolytic cleavage reaction previously noted (pp. 39. Alkaline formaldehyde is also useful in removing the amino group of ortho. 67.. diazo oxide formation is facilitated. Chem.and trichloro-benzenediazonium salts are rapidly transformed into the diazo oxides by ice-cold aqueous sodium hydroxide. while 2.and paro-chloroanilines. J.66 The reaction is not quantitative. o-ethoxyaniline (75% yield). and with the meta and para isomers the yield drops to 10%.. 50-55% yields of chlorobenzene are obtained. J. Only a 20% yield of nitrobenzene is obtained from o-nitroaniline.5-dichloroaniline. Ber. 83. should not be applied. and finally on the alkaline side many diazo compounds that are stable in acid media undergo hydrolytic cleavage. 96 15 .Saunders. or any other deamination process requiring alkaline conditions.* There is a substantial group of diazonium salts to which the alkaline formaldehyde method.4-dinitrobenzenediazonium acid sulfate is stable to dilute aqueous sulfuric acid. As the acidity of the solution is decreased. Soc. a poorly defined insoluble product is also formed in 14 to 20% yields. Comparatively few diazonium salts are converted to the diazo oxides in aqueous mineral acid. ' . "The Aromatic Diazo-Compounds and Their Technical Applications. the yield falls to 10%. . and 4-amino-4'methyldiphenyl ether (50% yield) are indicative of the possibilities. Soc. London. NO2 NO2 NO2 Symmetrical tribromo." pp. 274-276). 908 (1895). With 2. Chem. 56-59. however. •• Orton. however.97-98 Meldola and Streatfeild. 1936.REDUCTION WITH ALKALINE FORMALDEHYDE 283 aniline (80% yield).96' 96 Thus.. Alkaline formaldehyde and hypophosphorous acid are about equally valuable in deaminating such compounds^ ethanol is not satisfactory here. Edward Arnold and Co. in neutral or slightly alkaline solution it readily yields the diazo oxide. 4249 (1906). The formaldehyde procedure cannot be applied to nitroamines inasmuch as reduction of the nitro group occurs. inasmuch as they are unstable in the presence of alkali.
96-10° NHj N2 Cl O NH2 . J. 91. I O.284 THE AROMATIC PRIMARY AMINO GROUP Na+X- OH N2+X- KJ Br Br Br N 2 +XB Br OH The para halogen atoms are less labile than those in the ortho positions." The more highly halogenated diazonium salts are more likely to undergo hydrolytic cleavage. A great many of the diazonium salts that undergo hydrolytic cleavage in alkaline solution are probably stable to very concentrated alkali. 39. 1555 (1907).98 The pH at which the reaction proceeds with maximum velocity has not been established and in all likelihood will vary from compound to compound.N SO 3 H NH. although alkaline formaldehyde is an excellent 100 '• Orton and Reed. about 20% of the molecules that yield diazo oxides lose an atom of bromine from the para position. Even if these diazo salts were usually stable in strongly alkaline solution. it is needless to run the risk of exposing them to alkali inasmuch as either hypophosphorous acid or ethanol is effective in reducing them. Consequently.. Noeltmg and Battegay. whereas approximately 80% lose an ortho bromine. Ber. Soc . Cleavage is apparently more rapid in dilute than in concentrated alkali.100 The generality of the hydrolytic cleavage reaction in alkaline media is illustrated by the following examples. Chem. . 79 (1906).
Clara Deasy of Oberlin College. chloroform.8 a.) t In an attempt to repeat certain of these experiments.) 101 Arnold and McCool. 1315 (1942). and carbon tetrachloride. In most cases the stabilized diazo salts require slight variations in technique for their preparation in optimum yield.6 o~. The following compounds are reported to have been deaminated by decomposing their stabilized diazonium salts: aniline. 64. m-. 748).6 benzidine. nitrobenzene.USE OF STABILIZED DIAZONIUM. a-ethoxynaphthalene. and ptoluidine. and p-nitroaniline.1943. Nor was it possible to deaminate m-chloroaniline by this method.6 m-tolylenediamine. acetaldehyde.5disulfonic acid or 2-naphthol-l-sulfonic acid.6 p-aminophenol. Chtm.* The dry salt is reduced at room temperature in ethanol containing zinc or copper. (Private communication from Dr. Arnold of the University of Minnesota. its utility appears to be largely restricted to these substances.6 o-. whereupon the stabilized diazonium compound is precipitated. insoluble intermediate products were isolated. the purity of the product is not specified. naphthalene. In the absence of metals. Overall yields of the order of 90% are reported.. benzene.+ | II " 1 -> SO3H f I I +HX ArN 2 + SO 3 - Conversion of stabilized diazo compounds to hydrocarbons does not depend upon the reducing action x)f ethyl alcohol.. ether. No acetaldehyde is produced when ethanol is the solvent.101 m-phenylenediamine. however. m-. SALTS 285 deaminating agent for unsubstituted amines. however.and jS-naphthylamine. / .6 An aqueous solution of the diazotized amine is treated with the molar quantity of naphthalene-1. Arnold and ittcCool were unable to deaminate 5-amino-4-nitro-2-methylooumaran by this method because it was not possible to isolate any insoluble stabilized diazonium salt. T. Deasy was unable to obtain any toluene from o-toluidine and only a 15% yield from p-toluidine. (Private communication from Professor R. Am. Chem. their homologs. when the stabilized salts of diazotized a-naphthylamine are treated with ethyl alcohol. and p-anisidine. for the reaction takes place smoothly in acetone. and tar are obtained.'' f * Very recently Hodgson and Turner have pointed out that "preparation of the stabilized diazonium salt may be easy or difficult" (J.b o-. USE OF STABILIZED DIAZONIUM SALTS A deamination procedure for which general application is claimed has been described by Hodgson and Ma^sden. and ethers.6 2-methoxy-4-nitro-5-aminotoluene. m-. . SO3H I ArN2+X. Soc. iSoc. In all three cases.
38%) in the case of the nitroaminostilbene XXIII.. 10 » Bigelow. 380 (1942). previously discussed in connection with the * The first of these compounds is successfully deaminated either by ethanol or hypophosphorous acid.108-109 The danger of hydrolytic cleavage in alkaline media. Soc. A detailed description of this deamination will be found on p. hypophosphorous acid is effective in bringing about the desired reaction. 1M Koenigs and Carl.. and phenylhydrazine. thesis.D. 41. 298. " 104 Fieser and Heymann. with the last two.106 NH2 TYTTT In the following instances. Harvard University. 103 von Auwers.6 Few sodium stannite deaminations are to be found in the literature. 96 (1919). Ber. Ber.3-dimethyl-5-bromobenzene occurs in 73% yield.4. 106 Pfeiffer and Monath.107. Heymann. Chem. aniline gives phenol. .3-dimethyl-4-amino-6-bromobenzene to 1. 36. 23. Ber. the reaction proceeds rapidly. J. phenyl azide. 39. 64.1M. Ph. J.. J. 2672 (1890). 1305 (1906). the temperature being kept in the neighborhood of 0°. 108 Bamberger and Meimberg. benzene is obtained from aniline in 60% yield. Soc.106 p-aminophenylarsonic acid. 419. 26. In addition to benzene.104 but the yield is considerably lower (ca.286 THE AROMATIC PRIMARY AMINO GROUP TREATMENT WITH SODIUM STANNITE In this reduction aqueous stannite is added to an alkaline solution of the diazo compound. Am.. [2] 40.102-1S and the hydrocarbons derived from 2. failures have been recorded for sodium stannite: 3-nitro-4-aminotoluene. 1566 (1919). 497 (1893).3-dimethylaniline and 2. 1941.5-trimethylaniline are produced in "satisfactory yields" and in a high state of purity.92 transo-aminocinnamic acid. Chem. azobenzene. praM. Thus. Ber. l07 Eibner..93.103 The conversion of l.. Ann. 813 (1903). and of these a substantial fraction concerns unsubstituted amines and their homologs. 108 (1889). Chem.* A number of by-products may be isolated from sodium stannite reductions. 109 Culmann and Gasiorowski. Am.
117 5-bromo-6-aminoquinoline ("satisfactory yield"). 116 Chattaway. D." 22nd ed."°. a chlorine atom may replace the hydrazine group. Ber.. "Organic Syntheses.. 283-284). 1508 (1915)." Collective Volume I. Chem. or potassium chromate. 111 Zincke.. J. Soc. John Wiley & Sons. Hopper.. Soc. 117 Wynne. 908 (1915). 2nd ed. New York. therefore. 1042 (1892).CONVERSION TO HYDRAZINE FOLLOWED BY OXIDATION 287 alkaline formaldehyde method (pp. 715 (1922). 118 Gattermann and Holzle. 270 (1908). 2329 (1884). 116 Chattaway and Vonderwahl.* * Table VI. stannit© should be employed only after failure of the procedures already noted.-> ArNHNH2 -> ArH Although sodium sulfite and stannous chloride are used with about equal frequency in this process. Soc. J Chem. Ber. J. 1932. These compounds may be oxidized to the hydrocarbons. 1M McPherson and Stratton. pp. ferric chloride.7. 107.116 p-toluidine (55-65%). Van Nostrand Co.110. contains a number of additional examples of deaminations via the hydrazine. aqueous cupric sulfate. thus providing a deamination sequence. but this is not a reliable reaction. 25. pp. Ber.. a preference for sodium sulfite is sometimes expressed.m Phenylhydrazine hydrochloride is converted to chlorobenzene in 86% yield when treated with a solution of cupric sulfate containing hydrochloric acid.m .. Macmillan Co. J. if this is not done. 285-289.1U ." 2nd ed. 178180.121. 18.7 ArNH2 . 111 Coleman. New York. 1931. Soc.. . and Wheeler. Chem. IIJ Davies. 110 Gattermann and Wieland.. J. "Systematic Organic Chemistry. Soc. pp. 37.118 Some idea of the utility of the hydrazine procedure may be inferred from the yields obtained on deaminating the following compounds: aniline (45-75%).* ArN2+X.. 1941. 61. 249 (1906). Am. it is advisable to convert them to the free bases before carrying out the oxidation. 121 Meigen. 339-340.120-116 3-chloro-4-aminotoluene (40%). "Laboratory Methods of Organic Chemistry. J.117-11S. 119 Cumming. New York. prakt. 787 (1885). also exists with sodium stannite. [2] 73. Chem. Chem. 121. 17. p.. 1074 (1892).112 Stannous chloride occasionally brings about direct replacement of the diazonium group by hydrogen. 118 Effront. 93. 442. Chem. It appears. CONVERSION TO THE HYDRAZINE FOLLOWED BY OXIDATION Reduction of diazonium salts by sodium sulfite or stannous chloride usually produces hydrazines.uo> 114> 116> 1U Although hydrazines often are isolated from reduction mixtures as hydrochlorides...118-7-48-114 The hydrazines usually are converted to hydrocarbons by treatment with hot.
36. 122 Ferrous hydroxide. Ephraim. Soc. and Berger. 123 Jolles and Busoni. Soc. a solid solution or an "interstitial" compound. e.102-13i Stannous chloride. "Inorganic Chemistry.126 Copper hydride. Qazz.116 MISCELLANEOUS REDUCING AGENTS The literature contains references to deamination procedures involving a number of other reducing agents: a. h. 320. 6269 (1941)]. 560 (1898). /. Ber. 31. 6947 (1941)]. 2.. 186 Ullmann and Schalk. p.. Ber. Mineral. g. Nordeman Publishing Co. «8'Neogi and Mitra. 62. 126 yon Pechmann and Nold. 23. 1646 (1913). No.. * The existence of copper hydride (C11H2) as a chemical compound has been questioned. pat. 14B. Ber. 132 ' S6 Hydrazines and hydroxylamine. 93. Keller. Ber. 127 Vorlander and Meyer. 40. 388. b. d. 1631 (1890).107. Ann.130-119' m Formic acid. 123 ' 124 Glucose in the presence of alkali. A. secondary reactions take place to a varying extent. p-nitroaniline. Arkiv Kemi. 1117 (1941). h.1 W Potassium cuprocyanide. 858 (1907).. Chem. and symmetrical tribromoaniline have been deaminated by reducing their diazo compounds with hydroquinone.Sodium arsenite.791 [C.. Aniline. The remaining processes either possess some small utility or might be found useful upon investigation. j. (1941) [C. 128 Orton and Everatt. 2065 (1903). Chem. 1160 (1932). traces of azo compounds. 134 Gutmann. 1939. 1332. It may actually be an adsorption mixture.. 46. . Geol. J. 182 Tobias. in this category may be placed methods /. i. Hydrocarbons of the biphenyl series may be formed. chim. / .230. Hydroquinone. 45. 865. 1021 (1908). 1928.128 ' 129 Sodium hydrosulfite. Soc. Chem. Ber. 186 Benade. 7 pp.. 822 (1912). 183 Hantzsch and Vock. Ann. S. A. ital. 698. pat. i.... J. 131 Modlin and Burger. g. and small amounts of phenols result..136'186 m For some of these no merit whatsoever appears to have been demonstrated. 3268 (1941)].288 THE AROMATIC PRIMARY AMINO GROUP In the oxidation of hydrazines. 129 Fredga and Anderson.." third English edition. New York.. c. 35.318 (Cl 12 q. m Berger.. Ger. Am. 185 Terres. 38. 35. 35. and j . 1 1 3 ' 7 ' 4 6 . 203 (1912). 180 Grandmougin.m . U. 63.*' 126 . 143 (1902)... frequently a little tarry material. A. Ber. 23) \C.
The treatment of diazo compounds with copper hydride affords an• other means of deamination. the utilization of sodium hydrosulfite in deaminations apparently has received little attention. the diazo oxide * XXIV is converted to the phenol XXV in 95% yield (crude product. . the product.COMPARISON OF VARIOUS DEAMINATION PROCEDURES 289 Although yields were not given. carboxyl. 9096% yields of the naphtholsulfonic acid are reported.119 a statement supported solely by reference to the work of Grandmougin. the reaction is not very efficient.122 It is claimed in a recent patent that ferrous hydroxide is a reagent of considerable value for the deamination of certain aminonaphtholsulfonic acids. Upon reduction with hydrosulfite. Aniline gives not only benzene but also phenyl azide and biphenyl in unspecified yields.126' m > m > 129 Though the hydrocarbon may be produced in some cases.123 Alkaline glucose converts the diazonium salts of l-amino-2-hydroxynaphthalene-4-sulfonic acid and its halogen. or sulfonic acid derivatives into the corresponding 2-hydroxynaphthalene-4-sulfonic acids. however. the yields are nearly quantitative. is not isolated. nitro. the method was recommended for the replacement of amino groups by hydrogen. These are noted in the table below.126 According to this patent.)131 0 ' ^ C H S CHs XXIV Further than this. COMPARISON OP THE VARIOUS DEAMINATION PROCEDURES Certain generalizations are possible regarding the effectiveness of the various deamination procedures with a particular type of amine.124 From 3-hydroxy-4-aminonaphthalenesulfonic acid.130 Actually he obtained only a small yield of benzene from benzenediazonium salts but suggested that on further study the process might prove to be useful. *Seep 270.128 It is reported that alkaline sodium hydrolumte (Na2S2O4) is effective -in converting certain diazo compounds to the hydrocarbons.
3. which may be deaminated to 1. pp. therefore. . Oxford Press. 285. j.62 * For an account of this subject see Sidgwick's "Organic Chemistry of Nitrogen. ortho-oiientiag effect of the amino group. 1937. Aminocarboxylic acids 4 6. Aminophenols * See. bromination of aniline gives symmetrical tribromoaniline. Ethanol useful Alkaline formaldehyde Unpromising 6. conversion to the ammonium salt produces a meio-directing group.5-tribromobenzene in an over-all yield of 65-72%. Thus.* Advantage is taken. Aminoethers 3. . however.. 1. footnotes on p. 69-70. -1 t Useful Sodium stanmte j Ethanol Poor 2. the. An amino group may be useful in a synthesis because of its effect on the position assumed by an incoming substituent. Hypophosphorous acid Preferred Ethanol Stabilized diazonium salts * Fails Alkaline formaldehyde 4.29 This appears to be the only practical method of preparing 1. Similarly. c . Stabilized diazonium salts ' Promising APPLICATIONS OF THE DEAMINATION REACTION The deamination reaction is of considerable value both in synthesis and proof of structure. Its utility is best demonstrated by a consideration of several specific examples.5-tribromobenzene. of the directing influence of this group in synthesizing compounds otherwise difficult to secure. Hypophosphorous acid Preferred Alkaline formaldehyde Stabilized diazonium salts * 3.290 THE AROMATIC PRIMARY AMINO GROUP AMINE DEAMINATION PROCEDURE 1. Halogenated amines 5. Nitroamines ^ 4. Hypophosphorous acid 1 Preferred Ethanol Useful Oxidation of hydrazine Unpromising Alkaline formaldehyde Sometimes 5. and finally deaminating. Hypophosphorous acid 1 Alkaline formaldehyde [ Preferred Stabilized diazonium salts *J Oxidation of hydrazines 1TT .3. The free ann'no group and its acyl derivatives are strongly ortho-para orienting. Unsubstituted amines and their homologs 2." revised by Taylor and Baker. 2-nitro-3'-bromobiphenyl is obtained from benzidine in good yield by utilizing the meto-orienting influence of the ammonium ion.
APPLICATIONS OF THE DEAMINATION REACTION NO2 291 H2N Certain primary aromatic amines that are available as a consequence of their use in the manufacture of dyes serve as convenient starting points in the preparation of organic compounds.2'-dinitro5.3'-dihydroxybiphenyl from o-dianisidine 80 are examples.5'-dicarboxybiphenyl from o-tolidine 38 and of 3. Their range of utility is increased by the deamination reaction. The syntheses of 2. CH 3 NO2 NOss CH 3 CH3 COOH COOH NO 2 NO 2 I I OCH H2N OCH3 OH .
1. which cannot be obtained by direct chlorination of resorcinol. the nitro group may be introduced into an aromatic nucleus for the purpose of closing a position to other groups in subsequent steps of a synthetic sequence. ""Bogert and Mandelbaum. 544 (1941). D r a k e . the so-called thio-p-to. . 1 0 5 (1942). 45. 3052 (1923). I t was shown to be fo's-(2-amino-5-methylphenyl) sulfide by deamination and subsequent oxidation to the crystalline sulfone^140 137 188 MUligan and Hope. For example. finally. This blocking effect is utilized in the preparation of 2-chlororesorcinol.137 COOH COOH COOH H O2NO2N OH COOH COOH HssN—' Any radical that may be converted to an amino group is capable of replacement by hydrogen. Am. the following are typical. rather than by the customary zinc dust fusion. 189 Private communication from Professor M. Soc. Chem. Soc. In certain instances such an indirect procedure may be of value. the nitro group is replaced by hydrogen. A large number of illustrations might be cited. Org. 63. Since polynuclear phenols are transformed into amines by the Bucherer reaction. and. I .139 Deamination affords an excellent method of degrading an amine of indeterminate structure to a known compound or one having fewer possible isomers. Am.292 THE AROMATIC PRIMARY AMINO GROUP Ready conversion of nitro compounds to amines further extends the applicability of the deamination process. Chem. Upon heating p-toluidine with sulfur at 140° in the presence of" litharge. Reactions.luidine is formed. J. J. Newman of Ohio State University. 138 it has recently been suggested that the preparation of condensed ring hydrocarbons from the hydroxyl derivatives might best be achieved through the amines. S.
NH2 OjN O2N COCH.141 NHCOCH.5-dinitrophenol. By the condensation of a molecule of aniline with one of o-toluidine and one of p-toluidine..The position of the incoming nitro group was demonstrated by the following degradation. 17 NH2 H2N 4. The action of nitric acid on diacetylated p-aminophenol yields a dinitro derivative for which four structures are possible. Ber. Nitration of 2-methoxy-4-nitrobenzoic acid produces a dinitro compound. 38. 1593 (1905). 2.APPLICATIONS OF THE DEAMINATION REACTION 293 CHg CH CH3 CH3 CH3 CH3 NH2 NH2 . O2N •NOj 3. . COOH COOH O2N COOH O2N COOH 141 Reverdin and Dresel. The structure was determined by conversion to the diphenyltolylmethane. NHCOCH. Hydrolysis followed by deamination gives the known 3. thus proving that substitution occurs ortho to the acylated amino group. the leuco base of fuchsine is obtained. .
n%° 1.5468. Hypophosphorous Acid Deaminations The deaminations of 3. and directions for deaminating 2-amino-5-iodobenzoic acid are given on p. and the solution is then pladed in a refrigerator (held at or close to 0°) for approximately twenty-four hours. 592 (1943). 142 Goldstein and Jaquet. Stirring at a temperature of —5° to 0° is continued for another hour. of water.4 g.d dropwise in the course of one-half hour. and the filtrate is extracted with two 125-cc. Ada. p. of water is added from a dropping funnel over a period of approximately one hour. . 100-102°..5 g.5-tribromobenzene is described in Collective Volume II. and the mixture is stirred mechanically. while a temperature of —5° to 0° is maintained. round. b. the benzene is removed and the residue is distilled at 10 mm. (0. Chim.3'-dimethoxybenzidine and 3. 24. of concentrated hydrochloric acid (sp. the flame is removed and an additional 50 cc. (0. Helv. of concentrated hydrochloric acid is added. To the orange-yellow diazonium solution. 2nd ed.p. portions of benzene.2 mole) of 3-nitro-4-aminotoluene is added. 1941.0 mole) of 50% aqueous hypophosphorous acid (precooled to 0°) is adde. 415). 133) and 3nitro-4-aminotoluene (p. The conversion of 2. In a 1-1. The mixture is placed in an ice-salt bath. contains directions for the deamination of 3-bromo-4-aminotoluene (p.4. Collective Volume I. and.204 mole) of 97% sodium nitrite in 35 cc. (1. the temperature being held at —5° to 0°.bottomed flask are placed 45 cc.294 THE AROMATIC PEIMARY AMINO GROUP Inasmuch as the known 2-methoxy-5-nitrobenzoic acid is formed. When the amine is completely dissolved. The solution is heated to boiling. Nitrogen is evolved. 1.19) and 90 cc. The combined orange crystals and benzene extracts are washed with 10-20% aqueous sodium hydroxide and then with water. 30. 104 cc. the dinitro acid must be 2-methoxy-4. and crystals of m-nitrotoluene form. 353 of the same volume. a solution of 14.*1 m-Nitrotoluene82 from 3-Nitro-4-aminotoluene. 33 (1941). After drying over calcium chloride. The orange solid is isolated by nitration.142 EXPERIMENTAL PROCEDURES Ethanol Deaminations A number of carefully worked out ethanol procedures are available in Organic Syntheses. (80%) of m-nitrotoluene. gr. There is obtained 22.5-dinitrobenzoic acid.3'-dimethylbenzidine are described in Organic Syntheses.4 g.3.6-tribromoaniline to 1.
55 mole of hypophosphorous acid gives some o-cresol. (3. the mixture becomes more fluid and the nitrite may be added somewhat more rapidly. Stirring is continued for an additional five minutes. . a 50% yield of pure toluene is obtained. a 70% yield of m-nitrotoluene is obtained. however. b.8 g. A me- chanically stirred suspension of 5. 1:19). and dried over potassium carbonate. and no toluene. on using only 0.9-13.204 mole) of 97% sodium nitrite in 35 cc. then with water. after which it is allowed to remain overnight before being worked up.45 g. one-half to three-quarters of an hour is required for diazotization.) of acid. While a temperature of —5° to 0° is maintained. a solution of 14. While a temperature of —5° to 0° is maintained. (70-75%). of concentrated hydrochloric acid. In all likelihood a much smaller quantity of reducing agent would prove equally effective. is 12.4962. portions of ether.84 Toluene^82 fronK)-Toluidine.82 If sulfuric acid is substituted for hydrochloric acid.0 mole (104 cc. The flask is immersed in an ice-salt mixture and is fitted with an efficient stirrer. If necessary. Reduction with 0. As the reac' tion proceeds.13 With 1. The reaction product consists of an orange oil floating on the aqueous phase. the flask is then stoppered loosely and placed in a refrigerator (at or close to 0°) for approximately twenty-four hours. The combined oil and ether extracts are washed with 20-30% aqueous sodium hydroxide. the yield falls to 12-23%. and then 100 cc. of water.84 Another departure from the above directions consists in permitting the cold reaction mixture to come to room temperature in six hours. suffices). much tar. and then a solution of 2. of water is added over a period of thirty minutes.HYPOPHOSPHOROUS ACID DEAMINATIONS 295 Doubling the amount of hypophosphorous acid does not increase the yield of m-nitrotoluene.2 mole) of o-toluidine.82 It has recently been found that. Moderate stirring and a temperature of —5° to 0° are continued for an additional hour. and 25 cc. of wateris cooled to 3°. and 15 cc. After separation of the oil. ng1" 1. of water is slowly added from a dropping funnel.4 g. (0.M „ 7-Chlorohydrindone-l91 from 4-Amino-7-chlorohydrindone-l.2 g. of concentrated hydrochloric acid (sp. the aqueous solution is extracted with three 125-cc. of 50% hypophosphorous acid * (precooled to 0°) is run into the diazonium * No attempt was made to use less hypophosphorous acid.p. of sodium nitrite in 10 cc. The ether solution is then distilled through a small modified Widmer column. a few grams of ice is added to maintain the temperature (usually 2-4 g.0 moles) of 50% hypophosphorous acid (precooled to 0°) is added to the diazonium solution in the course of ten to fifteen minutes.5 g. In a 1-L flask are placed 21. 312 cc. The yield of toluene. gr. (0. 75 cc. of 4-amino-7-chlorohydrindone-l. 12 cc.76 mole of hypophosphorous acid per mole of 3-nitro-4-aminotoluene. 109-110°.
01 mole) of 2. a decrease in the amount of acetic acid and sulfuric acid will not lower the yield . a solution of 2. 1. Finally. undried benzene. (90%). After one recrystallization from aqueous ethanol (charcoal).4. and then.3 g. the flask is then stoppered loosely and placed in a refrigerator for approximately twenty hours. (0. m. efficient stirring is instituted. of glacial acetic acid is run in over a period of one-half to three-quarters of an hour.by nitration.8-95.2 cc.6v trinitroaniline (picramide) in 100 cc.37 g.* The column is developed with ordinary. and the solvent is removed. copious evolution of nitrogen occurs. is reached and the resulting deep-red solution is passed through a 12 by 2 cm. (0.296 THE AROMATIC PRIMARY AMINO GROUP solution in about five minutes.83 With gentle stir- ring.25 g. Nor was the effect of adding small amounts of water. The resulting solution is cooled to —5° to 0°.p. which might prove beneficial. and 5.028 mole) of sodium nitrite is added to 55 cc. After being stirred at ice temperature for two hours.p. The solution that follows is collected. Benzene is then removed by distillation until a volume of 25-50 cc. Essentially the same result is obtained when hypophosphorous acid is added after the picramide has been diazotized. of sulfurlc acid (sp.6-Trinitroaniline. very possibly. the mixture is kept in an ice chest for about twenty hours and the yellow precipitate is then isolated.3.4. and a pale yellow crystalline mass is obtained upon removal of the solvent. studied. An eightfold increase in the amount of hypophosphorous acid did not raise the yield.05 mole) of 50% hypophosphorous acid (precooled to —5° to 0°) is added rapidly. and the benzene solution washed with water. The filtrate is extracted with ether. 1. 94. The product is poured into ice water. the reaction mixture is kept in the ice-salt bath for another hour. The possibility that a large excess might increase the yield was not investigated. with reversion to gentle stirring. 92-93°. 2 g. Recrystallization from ethanol gives 1. then dried over sodium sulfate. there is obtained 4.) is also very satisfactory. The crystalline product weighs 4. (85%) of white needles. t Excess sodium nitrite is used in this preparation.5 g.f * Aloreo activated alumina (Aluminum Company of America) and Celite Analytical Filter-Aid (Johns-Manville Co.).7-123. portions joi a. after addition of the yellow solid. While a temperature of —5° to 0° is being maintained. thoroughly extracted with benzene.2° (cor.8°. (0. column of aluminum oxide. and that portion of the eluate which runs through before the strawberry-red zone reaches the bottom of the tube is discarded.84).5-Trinitrobenzene from 2. Brockmann's aluminum oxide (Merck and Co.) in approximately equal volumes. gr. 10% sodium hydroxide^ solution. and.241. the ether solution is washed twice with 50-cc. (60-65%) of pale yellow crystals that sinter at 119° and melt at 122. m. it should be noted that.
extracted with benzene. Triptycene8Si * from 2.20.83 indicate that either the diazotization or the reduction (or both) does not take place smCothly unless an appreciable amount of water is present. The pale yellow crystals so obtained are dissolved in bejizene.9 g. and 200 cc. § This procedure was furnished through the courtesy of Professor R Q. and a bath temperature of 160-190°. A solution of 100 g. aqueous sodium hydroxide. 50 cc.5-diaminotriptycene in 30 cc. and similar observations. This is followed by a solution of 0. and finally with water. and the mixture is stirred to effect complete solution.} Removal of the solvent gives 0. gave but a trace of impure triptycene. After removal of the solvent. 50 cc. of water is chilled in ice and diazotized in the usual manner with 7 g. (0. After cooling to —5° to 0°. Stirring is continued for an additional ten minutes. of concentrated hydrochloric acid.23 g. of sulfuric acid (sp. and the solution is passed through a short column of aluminum oxide. the residue is sublimed at 1 mm. The presence of chloride ions should be avoided. after'which 100 g. The product is then poured into ice water. with vigorous stirring. of commercial sodium hydroxide in 600 cc. of 2. of sodium nitrite dissolved in a little water.5-Diaminotriptycene. over a period of ten to fifteen minutes. t See footnote on p. A solution of 19.87 A parallel experiment. approximately ten minutes being required for the addition. This result. of glacial acetic acid. Diazotization with hydrochloric acid produces 2-chlorotriptycene. and washed with water. Brewster of the University of Kansas.84). One-half 297 gram of sodium nitrite is added to 50 cc. . 296. t The use of a smaller amount of hypophosphorous acid was not studied.ALKALINE FORMALDEHYDE DEAMINATION . Alkaline Formaldehyde Deamination ' ^Methyldiphenyl Ether 4> § from 4-Methyl-4'-aminodiphenyl Ether. of ice in a 5-1. of 50% hypophosphorous acid f (precooled to —5° to 0°) is added in about ten minutes. flask fitted with a mechanical stirrer. of ice. 1. of glacial acetic acid.57 g. * See p 280 for formulas.1 mole) of 4-methyl-4'-aminodiphenyl ether in 50 cc. of water is then prepared and placed with 500 g. differing only in the omission of the 100 g. of crushed ice is added. A temperature of —5° to 0° and gentle stirring are maintained for another three hours. (40-45%) of white crystals which begin to sinter at 245° and melt at 252-254° (cor. and the reaction mixture ^(loosely stoppered) is placed in the refrigerator for twenty-four to thirty-six hours. gr.).
of concentrated hydrochloric acid is diazotized with 7 g. The escaping nitrogen causes considerable frothing.3-dimethyl-4-amino-5-bromobenzene hydrochloride in 60 cc. and 75 cc. the solvent is removed and the residue distilled at 12 mm. and the resulting solution is dried over calcium chloride. A suspension of 23. of water at 5-6°. After all the diazonium chloride solution has been added. After standing for an hour at room temperature the reaction mixture is steam distilled. The oily 4-methyldiphenyl ether is collected by the addition of a lAtle carbon tetrachloride and separated from the aqueous solution.: 145-150/7 mm. The clear diazonium solution is then added in portions to an ice-cold solution of sodium stannite prepared from 40 g. The yellow oil is separated from the aqueous phase. about five to ten minutes is required for the addition.3-Dimethyl-4-amino-5-bromobenzene. of sodium nitrite in 30 cc. of l.3-Dimethyl-5-bromobenzene m from l. the stirring is continued for five minutes. There is obtained 13. added. of stannous chloride. of formalin (37% formaldehyde) is. of sodium hydroxide. the mouth of the flask covered with a watch glass. and the reaction mixture allowed to stand with occasional shaking for thirty to forty minutes. .p. and the aqueous phase is extracted with ether. The ether extract is added to the yellow oil.2 g: (73%) of a colorless product boiling at 88-89°. Sodium Stannite Deamination l. After the carbon tetrachloride has been removed by distillation. (54-60%). The diazo solution is then poured in a slow stream into the rapidly stirred alkaline solution of formaldehyde. b.6 g. of water and 15 cc. 50 g. 275-278°/744 mm. of water. After separation from the water and drying. and 260 cc. at a bath temperature of 120°. the product is distilled. and the 4-methyldiphenyl ether is purified by distillation in a current of superheated steam. the flask containing the crude product is heated to 150° in an oil bath. The results are essentially the same when the diazonium salt solution is made alkaline before reduction^but the yield is lower when the stannite solution is run into the acidic solution of the diazotized base instead of carrying out the reduction as described above.298 THE AROMATIC PRIMARY AMINO GROUP The stirrer is started. The yield is 10-11 g. after which the stirrer is removed.
within a given table. inasmuch as the deamina• tion reaction has often been employed in a synthesis or structure proof without any indication of this fact in the title of the paper. . that the list is extensive enough to afford a real cross section of the results obtained for the various reducing agents. Aminoarsonic acids. Aminocarboxylic acids. Aminophenols. Heterocyclics. and their homologs. For example. Aminoazo compounds. a bromonitroaniline will be found under halogenated amines. the amines are listed in the following sequence: Amines. The tables are unquestionably incomplete.EXAMPLES OF THE DEAMINATION REACTION EXAMPLES OF THE DEAMINATION REACTION 299 Each of the Tables II-VI is concerned with a single reducing agent. "The principle of latest position" has been invoked. It is believed. Aminosulfides and sulfones. Diazo oxides. however. Where the yield is not given. the product was reported in the literature without any information about the yield. Aminosulfonic acids. and. polyamines. Aminoethers. Halogenated amines. Nitroamines.
13 10. H3PO2 gives a 45% yield of pure toluene. 13 Amine Aniline Benzidine «-Naphthylamine j8-Naphthylamine o-Toluidine o 10 10.TABL£ II ETHANOL DEAMINATIONS 1 o CO © • Product. H3PO2 gives a 60% yield. NasSnC^. Alkaline HCHO gives 80% of pure toluene. AlkaUne HCHO gives an 80% {ca. 50%) H3PO2 gives pure toluene in 70-75% yield. 18%) yield of pure toluene. Reference* 11. lene (7%) o-Methylphenetole (ca. and HsPOj all give benzene in 60% yield. . Yield Phenetole (61%) + benzene (5%) Biphenyl (80%) Naphthalene (40%) + a-ethoxynaphthalene (23%) • /S-Ethoxynaphthalene (30%) + naphtha. Remarks Alkaline H2CO. 45%) + p-methylphenetole H8PO2 gives 80-85% of pure toluene.H3PO2 gives naphthalene in 35-45% yield. 40%) Toluene (ca. 10 14 12 12.13 m-Toluidine p-Toluidine ' m-Methylphenetole (ca.
3'-dimethyl.2. 94 144 145 17 2.4'.4"-Triaminotriphenylmethane CH3 NH2 4-Aminotetraphenylmethane NH. crude) Used only enough HNO2 for one amino group. 81 4.4'-Diaminotriphenylmethane 4.4'-Diaminobiphenyl 4. H3PO2 gives 76-82% yield equal amounts" of hydrocarbon.In the presence of Zn dust only the 14.5-DimethyIanilme 3.5-Dimethylphenetole 143 3. 4-Aminobiphenyl Triphenylmethane Triphenylmethane (25%.4'-diethoxybiphenyl ' 'approximately hydrocarbon is isolated (58% yield).3'-Dimethylbiphenyl + 3. .72 * References 143-195 appear on p 323. 15 16. 71.4'-diaminobiphenyl (o-Tolidine) I 2. pure) In the absence of Zn dust only the ether is obtained.3'-Dimethyl-4. Tetraphenylmethane (46%.
66 66 . NHCOCH. Zn dust added. pure) Cu powder added. 282) Stilbene (62%. 282) cis-o-Aminostilbene (p. an 80% yield of pure phenanthrene resulting. incompletely purified) Phenanthrene (64%.TABLE II—Continued ETHANOL DEAMINATIONS Amine Product. Reference* 72 -NH 2 (60%) CH. Yield Remarks Tin dust added. 72 \J~Fr\J -NHCOCHa (21%) tran«-o-Aminostilbene (p. Cu powder is added. NaH2PO2 also v fails here.
10-Dihydrophenanthrene (co. Zn dust added. pure) Qu powder added. Cu powder added. Diazonium salt stabilized with ZnClj. H3PO2 gives 66-78% yield (pure). 23. 281) 9. 60%) + o-(/3-phenyl ethyl)-phenol (23%) Phenol Phenol Phenol (60%) Anisole ZnO added.3'-Dimethoxybiphenyl (12%. pure) Ethyl benzoate (53%) Ethyl benzoate (main product) + ethylm-ethoxybenzoate 45 22. Used methanol.4'-diaminobiphenyl (odianisidine) o-Aminobenzoic acid m-Aminobenzoic acid 3.H w H Phenanthrene (18%. 323. 37 NH2 o-03-Phenylethyl)-aniline (p.3'-Dimethoxy-4. .22 • * References 143-195 appear on p. 66 o-Aminophenol m-Aminophenol p-Aminophenol p-Anisidine 25 25 41 41 3.23 24. NaHaPOs gives crude CeHijCItCI^CeHB in 47% yield.
Yield p-Ethoxybenaoic acid (50%) + ethyl benzoate (12%) 3-Methyl-4-ethoxybenzoic acid "quantitative conversion" Remarks Reference* 22.23 146.3'-Dicarboxybiphenyl 2-Carboxynaphthalene (/S-naphthoic acid) Cu powder added. 23 148 37 _l NH 2 (18%) .TABLE II—Continued ETHANOL DEAMINATIONS Amine p-Aminobenzoic acid 3-Methyl-4-aminobenzoic acid COOH H2N—r^V-COOH Product.4'-diaminobiphenyl 2-Carboxy-3-aminonaphthalene H / ~ \ COOH 3.10 147 • COOH f^Si—COOH • k v JL-OCH 3 OCH3 k^J—OCHs "Forms easily" 3.3'-Dicarboxy-4. COOH Cu powder added.
152 NO2 NOj .3-Dimethyl-5-nitrobenzene (62%. 22 22 22 39 H3PO2 gives 75-80% of pure mnitrotoluene.3-Dimethyl-4-nitrobenzene "very good yield" l.3-Diamino-4-nitrotoluene 3-Nitro-4-aminotoluene 2-Nitro-4-aminotoluene 2.o-Nitroaniline m-Nitroaniline p-Nitroaniline l. 333 Nitrobenzene (ca. 70%) 2-Ethoxy-4-nitratoluene. pure) o-Nitrotoluene (ca. H3PO2 gives 55-60% yield of pure nitrobenzene.3-Dimethyl-2-nitrobenzene "very good yield" l. 34 149 150 150 151 Only a little nitrogen was evolved. pure) CH3 H—C=N H3PO2 gives 75-80% 01 pure nitrobenzene. 50%) l. 66%) Nitrobenzene (ca. 82%) Nitrobenzene (ca.4-Dimethyl-3-nitroaniline 2.4-Dimethyl-6-nitroaniline CH 3 O2N—(T^N—NH2 NO* •References 143-195 appear on p. small amount rre-Nitrotoluene (62-72%.4-Dimethyl-5-nitroaniline 2. H3PO2 gives 60-70% pure nitrobenzene.
306 THE AROMATIC PRIMARY AMINO GROUP I p o 1 3 g £ 4 .
323. A nitro group iff replaced by Cl upon diazotizing in HC1. With H2SO4 the nitro groups remain intact. 48 * References 143-195 appear on p. . pure) 3. 43 42 141 141 165 NO* NH.5-Dinitrophenol 2.6-Dinitro-4-hydroxyaniline 3. o-Nitrophenol o-Nitrophenol (33%. 154 N02 3-Nitro-4-hydroxyaniline 3-Nitro-4-methoxyaniline 2.S-Dinitro-4-hydroxyaniline OCH.CH.6-Dinitrophenol DCHS Diazotized at 70-80°.
3'-Dinitrobiphenyl "good yield" 157 . NH. 3.3'-Dinitro-4.TABLE II—Continued ETHAN OL. DEAMINATIONS Amine Product. O2N 156 NH 8 COOH COOH 142 O . Yield Remarks Reference* 1S6 O2NNOs 02N •N0 2 OCHjCOOH OH NO. i.4'-diaminobiphenyl 3.
160 may be used.3-Dinitro-4-aminonaphthalene 1. -v- H (45%.33 36 64 Either ethanol or "amyl alcohol" 159.4'-dinitrobiphenyI 2.3'-Dinitrobiphenyl 1-Nitronaphthalene (ca.4'-I>initrobiphenyl 2.2. 268) 3-Amino-4-nitrobiphenyl 3-Amino-4. Sodium stannite gives a 38% yield (pure).2'-Dinitro-4.4'-diainino-5>5'-dimethylbiphenyl (p. 52%) 1-Nitronaphthalene (ca.3-Dinitronaphthalene (50%) 1.3'-Dinitro-4.8-Dinitronaphthalene "satisfactory yield" 38 158 31 158 33 33 36. 57%) 2-Nitronaphthalene (50-80%) 1. 323.4'-diaminobiphenyl l-Nitro-2-aminonaphthalene l-Nitro-4-aminonaphthalene l-Amino-2-nitronaphthalene l. "Amyl alcohol" and Cu powder are the preferred reagents.8-Dinitro-2-aminonaphthalene 2. pure) * References 143-195 appear on p.5'-dimethylbiphenyl (53%) 4-Nitrobiphenyl 4.2'-Dinitro-5. .
(ca. 37 NH. 65 . (56%. pure) -NH. Yield Remarks Reference* 77 !H=CH- )CH3 H=CH(15%. 50%) \ = / Cu bronze added. pure) 5 Cu powder added.TABLE II—Continued ETHANOI* DEAMINATIONS i—• o Amine Product. H 8 i >\ NO.
H3PO2 gives a 50% yield. 50%) o-Chloroaniline m-Chloroaniline p-Chloroaniline 2. 323.NHj A-N=N.3-Dichlorobenzene (46%) 1.6-Trichloroaniline 3. 25 25 25.4-Dichloroaniline 2.4'-diaminobiphenyl 2-Amino-5-chlorotoluene 3-Chloro-4-aminotoluene Chlorobenzene (86%) Chlorobenzene (87%) Chlorobenzene (87%) 1.4.5-Trichlorobenzene (92%) 3. . CH3 (ca.3.3'-Dichlorobiphenyl m-Chlorotoluene (49%. pure) m-Chlorotoluene (60%) Via hydrazme get 66% yield of crude. Via hydrazine get 40% yield of pure product.3'-Dichloro-4. Cu bronze added. 65 NHS Cu bronze added.11 13 161 162 163 164 * References 143-195 appear on p. 50%) H. 65 (co.
6-Trichlorophenol Remarks Reference* 165 57 166 167 25 2.TABLE II—Continued ETHANOL DEAMINATIONS CO to Amine Product. • 25 25. Yield 2. H3PO2 gives 70% (pure).3.5-Dichloro-4-aminomethyl benzoate 2-Amino-4r4utro-5-ehk»rotoluene 2-Nitro-6-chloroaniline • o-Bromoaniline m-Bromoaniline p-Bromoaniline 2. HCl should not be used in the diazo tization.11 168 13.3-Dibromo-5-chlorobenzene JA5-Tribromoben8ene (72-80%. pure) Sodium added. pure) HCl should not be used in the diazotization.5-Trichloro-4-hy<Iroxyaniline 3.29 Pentabromoaniline Pentabromobenzene 32 . HCl should not be used in the diazotization.5-Dichloro-methyl benzoate {60%.3.6-Dibromo-4-chlon>aniline 2. 3-Chloro-4-nitrotoluene (30-50%) m-Chloronitrobenzene Bromobenzene <72-80%) Bromobenzene (65-69%) Bromobenzene (68-80%) l.&-Tribromoaniline 3.4.
67Tetrabromo-5-aminobiphenyl • References 143-195 appear on p.4'-Dibromobiphenyl 3.5'-Tribromo-6-aminobiphenyl 2.2'-Dibromobiphenyl 3.added.4'. pure) ro-Bromotoluene (52%) 3-Nitror5-bromotoluene 3-Nitro-5-bromotoluene 2.6'-Tribromobiphenyl (52%) 3.5.3-Bromo-4-aminotoluene 2-Amino-5-bromotoluene 3-Nitro-4-amino-5-bromotoluene 2-Amino-3-nitro-5-bromotoluene 3.6'-Tribromo-4-aminobiphenyl 3.169 169 78 • 13 13 170 170 * 170 170 170 31 170 170 .2'-Dibromo-5-aminobiphenyl 3.3'-Dibromobiphenyl 2.4'.5.4'.4.enyl 2.5-Tribromobiphenyl 3.5-Tribromo-4-aminobiphenyl 3. 28 13 .4'-Dibromo-5-aminobiphenyl 3.3'-Dibromo-6-aminobiphenyl 2. m-Bromotoluene (54-69%.5.5'-Tribromobipb. 323.6-Tetrabromobiptenyl Cu powdra.3'-Dibromo-4'-aminobiphenyl 2.3'-Dibromobiphenyl 2.5.4.5-Dibromo-4-hydroxyaniline 2-Amino-5-bromobenzoie acid 2-Bromo-5-aminobenzoic acid 2.4'.6-Dibromophenol m-Bromobenzoic acid (32%) o-Bromobenzoic acid (34%) 2.
B p^a (ca. If the diazonium acid sulfate is used the yield of pure product falls to 52%. 52 l.4.4'-diamino-5-nitrobiphenyl 3. 50%) 26 .6-Triiodoaniline kT^ . pure) Br 1.4r-diaminobiphenyl (p.4.5-Dibromo-3'-nitrobiphenyl (46%) 2-Nitro-3'-bromobiphenyl (7§% pure) (p.6-Tribromo-2-aminonaphthalene 0 NH 2 1.5-Dibromo-3'-nitro-4-aminobiphenyl 2-Nitro-3'-bromo-4.6-Triiodobenzene (co. 70%.4.3.6-Tribromonaphthalene 171 172 I^YlfT" B r Br/ 2. 273) Remarks Reference* 31 170 31 Reduction of the bis-diazoborofluoride gives a 78% yield of pure product. Yield 2-Nitro-3'-bromobiphenyl (53%) 3-Bromo-5-nitrobipheayl 3.TABLE II—Continued ETHANOL DEAMINATIONS co Amine 2-Nitro-3'-bromo-4'-aminobiphenyl 3-Bromo-4. 273) Product.
4rdisulfonic acid 2-Methyl-5-aminobenzenesulfonic acid 3. 323.3. CuSO4 added.4-disulfonic acid Benzene-l.3-disulfonic acid 2-«Methylbenzenesulfonic acid (59%) + 2methyl-5-ethoxybenzenesulfonic acid (37%) 3-Methylbenzenesulfonic acid 3-Ethoxy-4-methylbenzenesulfonic acid CuSO4 added. pure) 2-Nitrd-3-iodotoluene o-Ethoxybenzenesulfonic acid (only product) m-Ethoxybenzenesulfonic acid (main product) + benzenesulfonic acid Benzenesulfonic acid (only product) 2-Ethoxybenzene-l. 60%) 3. 176 177 .5-Diiodbbenzoic acid (42%) 3. It appears to be of value in this instance.5-Diiodotoluene (ca.5-Diiodo-4--aininotoluene 3.4-disulfonic acid l-Aminobenzene-2.5-diiodobenzoie acid 2-Amino-5-iodobenzoic acid 2-Nitro-3-iodo-6-aminotoluene o-Aminobenzenesulfonic acid m-Aminobenzenesulfonic acid p-Aminobenzenesulfonic acid 2-Aminobenzene-l. 70.5-Diiodobenioic acid wt-Iodobenzoic acid (45-50%.5-Diiedo-4-aminobenzoic acid 2-Amino-3. 27 27 173 30 174 18 18.19 20 175 175 21 2-Amino-5-methylbenzenesulf onic acid 3-Amino-4-methylbenzenesulfonic acid * References 143-195 appear on p.
5-dimethylbenzenesulfonic acid Product.3-disulfonic acid 2-Amino-3.(/JL CH(CH. CH(CHs)j .) 8 ' CHs • C.3-disulfonio acid 2-Ethoxy-3.5-dimetIiyIbenzenesuIfonic acid (63%) CHs Remarks Reference* 178 179 180 CHs |pV-S°.00 TABLE II—Continued ETHANOL DEAMINATIONB Amine 4-Ammo-5-methylbenzene-l .H CH(CH.H. Yield 4-Ethoxy-5-methylbenzene-l.)J o a 181 CHs CAO-ij^HSOjfl I CH(CH S ).
6-Tribromo-3-aminoben?enesulfonic acid 3-Chlorobenzenesulfonic acid 3-Chlorobenzenesulfonic acid 3-Iodobenzenesnlfonic acid 2. 4. 182 3-Chloro-5-aminobeazenesulfonic acid 3-Chloro-6-aminobenzenesulfonic acid 3-Iodo-4-aminobenzenesulfonic acid 2.3'-disulfonic acid 4. Cu powder added.2'-disulfonic acid Biphenyl-3.4.4.N CH.5'-dimethylbiphenyl-2.6-Tribromobenzenesulfonic acid 183 184 185 188 187 -N=NBiphenyl-2.2'disulfonic acid * References 143-196 appear on p. •H.5'-Dimethylbiphenyl-2. 323.CH.2'-disulfonic acid 4. 188 1S7 67 CO .4'-Diamino-5.4'-Diaminobiphenyl-3.3'-disulforiic acid 5. •NO.2'-disulfonic acid Cu powder added.4'-Diaminobiphenyl-2.
Cu2O added. CujfO added. 69 .)r-N—/y-Vc—H 1 NH. Yield Remarks Reference* 68 a HOsS NH. H 68 f (CH.CO TABLE II—Continued ETHANOL DEAMINATIONS 00 Amine Product.
HCOOH + Cu much inferior to Al + ethanol. 8 Al powder added. 323.N . Cu + HCOOH gave a better yield (58%). Replacement of ethanol by butyl alcohol lowers the yield considerably.6-disulfonic acid Naphthalene-l.H.6-disulfonic acid (41%) Cu2O added.H NH. . (53%) NO. 56 75 .H co * References 143-195 appear on p. Cu2O added. Here ethanol alone is superior to ethanol + Al or Zn. 8-Aminonaphthalene-l. Cu or Zn somewhat less effective. 132 42.43 NO.
Remarks Reference* 189 SO8H (ca.TABLE II—Continued ETHANOL DEAMINATIONS Amine Product. 60%) CH. 90% ethanol is used in preference to absolute alcohol. 90%) CusO added.H {ca. 1 3 g SO. Yield CusO added. CH. CHs 84 I a .
Added Cu bronze. O O.N NH. 323.N 193 (43^4%) p-Aminophenylarsonic acid 2-Amino-5-nitrophenylarsonic acid * Befereaces 143-195 appear on p. 65%) m-Nitrophenyl&raonic acid 92 194 00 K5 . H3PO2 gives ca.NH. 190 Br Br 191 "Excellent yield" Acridine 192 O. 60% of deanunatod product. ) p-Ethoxyphenylaraonic acid (ca. o Na2SnC>2 alao fails.
Cu added.TABLE II—Continued ETHANOL DEAMINATIONS 8 Remarks Only 1 mole of HNOj used. Reference 90 140 Amine 2. 70 H.5-Diaminophenylarsonic acid Product. Cu powder added. Yield m-Aminophenylarsonic acid CH. CH. "Very good yield" . CH (18%) CuSO4 added.N IH.
. Ada. 39... 1300 (1901).. 157 Mascarelli and Vinsintin.. 159 Ruggli and Schmid. 1694 (1909). Chem. 3489 (1939). 2794 (1914). chim.. Ann. 3005. 182 Zincke a n d M a u e . 2665 (1885).. Helv. Am.. m H a s s e . Chem. MonaUh. Am. Scholl. 1042 (1929). 99. chim. Ann. 2754 (1901). 8 (1879).. J. Ber.. 168 Hurtley. Ann. Witt. Chim. Chem. a n d Zimmermann. Fischer. 193 (1878). 163 Feitler.. 79. 16 (1870).. 46. 43. J. Chem. 364 (1932). 44.. 146 Remsen and Broun.. 179 J u n g h a h n . 173 Wheeler and Johns. 1 5 . Hal. 192. 148 Mohlau. 160 Stoermer and Prigge.. Eberle.. 185 Boyle. Chem. 230. 85. Chem. O. / . 374 (1882). Chim. Ann. 161 Noyes. CH. proM. Chem. 409. 406 (1910). prakt.. 238 (1894). Gazz. Am. chim. m Cain. and Forel. J. Ann. P a r t 1 (1891).. prakt. Z. 189 Ruggli. Am. Ann. 17. 800 (1898). Chem. News. 189 Wroblewsky. and O... 191. Rec. 171 175 170 CO . 138 (1910). 183 Claus a n d Bopp. [2] 87. 191 Claus a n d Schnell. 117 (1896). J. 17 (1898). Ann. 1927. Fischer. 2683 (1906). 187 Lobry de Bruyn. Ber. 667 (1896). 7 (1904). 146 E. Ann. 36. 217. trav. 161 Jackson and Lamar. 190 Claus a n d Howitz. 152 (1880). Ber. 177 Hayduck. prakt. 162 Brand and Eisenmenger. Ber. [2] 50. Helv. 270 (1878). 4. 12. 2303 (1886). Chem. 15. 61. 198. Ber. Soc. 4. 1M Wibaut. 160 Grevingk. 327 (1891). 1232 (1935). Merz. J. J. 293 (1885).. 18. 62. 18. J. J..... Ber. 2186 (1882). 339. 375 (1886). 2349 (1911). 206. 1932.NH. 2429 (1884). 174 Wheeler. 2367.. ital. Ann. 164 Wroblewsky. 200 (1873). chim. 98 (1891). [2] 33.. 186 Langfurth. 95. 172. Soc.. 2 1 . J. 194. Chem... Chem. 184 Paal. / . Chem. 75 (1889).^247 (1886).. 35. 292 (1913). M4 Bertheim and Benda. Am. 195 N < Noelting. 186 Lampert. Ber.. K n a p p . Soc. Ann. Chem. 2 6 1 . 180 Widman... J. J. 215 (1874). 181 Errera.. 69. Chem. Claus and Jack. 47.. 18. 83. / . 197 (1883). and Tritsch.... 138 (1916). 3433 (1913). 32. J. Ber. J. Soc. Chem. Chem. Iran. 20. 154 Blakey and Scarborough.. l9 » Cullinane. 19. prakt.. 176 Metcalf. Ada. Chem. 265. 147 Grtae. Ber. 192 Grandmougin and Smirous. 44. 176 Zander. Ann.. 1M Crossley and Morrell. J. Chem. 34 (1915). 3299 (1911). Am. Soc. Chem. 498 (1913). 166 Meldola and Eyre. Chem. 3099 (1895). 155. Ann. 144 143 Case. 285 (1901)... Gazz. Ann.. 203 (1878). 163 Staedel. Soc. Rec. 34. 215 (1905). 19. 168. CH3 CuSO4 added. 32. Ann. Ber.. J. 3762 (1902). Am. 1M Reverdin and Bucky. Ber. 149 Beilstein and Kuhlberg. physik. 196 Witt and Truttwin. [2] 67. 1065 (1911). 3 0 5 (1893).. 187 Griess. Ber. 88. 188 Limpricht. Soc. [2] 53.
TABLE III HYPOPHOSPHOROUS ACID DBAMINATIONS Amine Product. Yield Remarks Reference 3. Q 3 I § Must diazotize with HC1. 13. pure) Diazotize with HC1.biphenyl (small amount) Na2SnO2 or alkaline HCHO also give 60% yield of benzene. see is used yield falls to 12-23%. 82 Toluene (51-62%. 3 used yield is 27-29%. 295 Alkaline H2CO gives pure toluene in 80% yield. p. Alkaline H2CO gives an 80% yield of pure toluene. If HjSO4 is used yield is 5-12%. Ethanol gives a 7% yield of naphthalene. 1 Diaaotiae with HG1. If H2SO4 is 82. Biphenyl (60%) Naphthalene (35-45%) Toluene (70-75%. 13 3 82. pure) Toluene (77-83%. . pure) Ethanol gives an 80% yield of biphenyl. If H2SO4 82. 13 Aniline Benzidine jS-Naphthylamine o-Toluidine / wt-Toluidine p-Toluidine Benzene (60%) -f.
4'-4iaminobiphenyl 2-Hydroxybiphenyl 3. "H3PO2 was the best of the various reducing agents tried.3. 81. NaH2PO2 used. NaH2PO2 used. 281) Dibenzyl (47%) 66 2-Hydroxy-4'-aminobiphenyl 3. 83. pure) a CO o-(jS-Phenylethyl)-aniline (p.4'-diaminobiphenyl (oTolidine) NH 2 3. Triptycene (40-45%. 50% yield.3'-Dimethoxy-4.3VDimethyl-4. a 64% yield of pure phenanthrene resulting. 280) ^VY^V-NHCOCH. 282) fetons-Stilbene (40-^50%) Phenanthrene (80%.81 1 on 8 ea ." Ethanol gives a 12% yield of pure product. 9. pure) Ethanol gives a 58% yield.80 94 4~V-\}—NHCOCH. Ethanol and sodium stannite fail here.3'-Dimethoxybiphenyl (66-78%.10-dihydrophenanthrene being obtained in ca. 2.3'-Dimethylbiphenyl (76-82%. Ethanol also fails here. 282) cts-o-Aminostilbene (p. see p. NaH2PO2 used.5-Diaminotriptycene (p. 297 66 66 iran-8-o-Aminostilbene (p. Ethanol fails here. pure) 94 80. pure) Must diazotize with sulfuric acid.
pure) Nitrobenzene (55-60%. 70%. H3PO2 was the only reducing. 82% yield. OCH. H—G—COOH o-Nitroaniline m-Nitroaniline p-Nitroaniline ll S Nitrobenzene (75-80%. agent which succeeded. pure) Nitrobenzene (60-70%.N H . Ethanol gives ca. pure) "93 82 82 . pure) C—H H3PO2 was the only reducing agent which succeeded.CO TABLE III—Continued HTPOPHOSPHOBOUB ACID DEAMINATIONB Amine - Product. Ethanol gives a yield of ca. 82 93 NH. Remarks Reference 80 !H3 (80%. 66% yield. Yield OCH. H—O—COOH Ethanol gives nitrobenzene in ca. H IOOC—C—H €—H > .
296 83 82 NO. pure) 1-Nitronaphthalene (61%. pure) CH. see p. When HCl is used get a 69% yield of 1chloro naphthalene and but a trace of 1-nitronaphthalene.4. pure) Diazotize with H2SO4. CH. NH> 82 02N (70-75%. pure) CH. pure) . Ethanol gives a 62-72% yield of pure product.6-Trinitroaniline (picramide) l-Nitro-2-aminonaphthalene 1.2. (55-60%. 82.5-Trinitrobenzene (60-65%. Must diazotize with H2SO4.3. 83.84 (75-80%.
4'-Diamino-3'.2'-Diniteobiphenyl 2.4'-Knitrobipheiiyl 196 196 Used only one mole HNO2. Product. 197 196 198 198 198 196 2-Hydroxy-4-nitro-4'-aminobiphenyl 2-Hydroxy-4-nitrobiphenyl .4-Diamino-3-nitrobiphenyl 2.4'-dinitrobiphenyl NO. OCH.4'-Diamino-4-nitrobiphenyl 2'.4-Dinitrobiphenyl 4.TABLE III—Continued HTPOFBOSFHOROTTS ACID DEAMINATIONS 09 to 00 Amine OCH.4-Dinitrobiphenyl 2.2'-Dinitro-4-amiiiobiphenyl 2. pure) 3-Nitrobiphenyl 4-Nitrobiphenyl 3-Nitro-4-aminobiphenyl 3'.ro-4'-amin6biphenyl 2-AiniDO-4. Yield Remarks Reference* 82 v • NO* 3-Nitro-4'-aminobipbenyl 2.4-Dinit. r65-70%.4-dinitrobiphenyl 2.
6-DibromoaniIine 2.4-Dibromoaniline 2.5-Tribromobenzene (70%. 295 S (85%. 333.2. pure) Ethanol gives a 46% yield. 13 82 82 91.4-Dichloroaniline 2-Nitro-4-chloroaniline 2-Chloro-4-nitroaniline m-Dichlorobenzene (50%) m-Nitrochlorobenzene (65-70%. pure) m-Nitrochlorobenzene (65-70%. pure) o-Bromotoluene (79%) Ethanol gives 72-80% (pure). .3.6-Tribromoaniline 3-Ammo-6-bromotoluene m-Dibromobenzene (73%) p-Dibromobenzene (69%) m-Dibromobenzene (49%) 1.5-Dibromoaniline 2. 13 13 13 13 13 13 CH. * References 196-201 appear on p.4. p. pure) 2.
4-Dibromo-4'.6-diaminobiphenyl (70%. 13 83 85 85 I .TABLE III—Continued HYPOPHOSPHOBOTTS ACID DEAMINATIONS s o AmiBe Product. pure) o-Bromobenzoic acid (75%) 1-Bromotriptycene 3. 280) 3.5-diamino tnptycene (p. Yield CHs Remarks Reference* 13 CH.4-Dibromo-4'-aminobiphenyl 3.4-Dibromobiphenyl Must diazotize with sulfuric acid. NH* 3-Amino-6-bromobenzoic acid l-Bromo-2. (91%) C2H6 89 Br—IIJ—CJI.4-Dibromobiphenyl 3. Br—it^V-Br Br—||^W-Br ILJ-NH.
4-Dibromo-2. 333.4-Dibromobiphenyl 3.4'-diaminobiphenyl 3.3. I^JLJ-CH8 (60%.4-Tribromo-4'-aininobiphenyl ' 2-Amino-3. 3.4-Dibromo-4'-nitrobiphenyl 2-Nitro-4. * References 196-201 appear on p.5'-diaminobiphenyl \ CH. CH 3 84 LJ-^J-CH.3'.5.4'-diaminobiphenyl 3.4'-Diiodo-5.4'-Tribromo-6-aminobiphenyl 2. pure) CH.4'-Tribromobiphenyl 2.4-dibromo-4'-nitrobiphenyl 2-Nitro-4. (72%.S'-Tetrabromo-2.3'5.3.3.6-dibromo-4'-aminobiphenyl 2.5'-Tetrabromobiphenyl 3.4-Tribromobiphenyl 3.4'-Diiodobiphenyl CH a i 85 85 85 85 85 85 199 84 N NH.5-dibromobiphenyl 2.4.4. pure) .
CH. 84 NH.04 00 to TABLE III—Continued HTPOPHOSPHOEOTJS ACID DBAMINATIONB Amine CH. Product. Yield • Remarks Reference o 84 i CH 8 CH. <€%) 5-Amino-8-nitroisoquinoline (p. 86 . 279)' 8-Chloroisoquinoline (60-70%) Diazotized with HC1. There is some evidence that the diazotization takes an abnormal course.
/ . 85 (1938). 1M Finzi and BeUavita. ital. 68. Soc. 64. Gazz. Chem. 671 (1932). J. *• Cass. 101 W NO* NH2 NO2 3 Is 92 p-Aminophenylarsonic acid Phenylarsonic acid (ca. Oazz. pure) 201 Stabilized diazonium salt procedure fails here. 345 (1934). 1189 (1932).... Gazz. 64. 1 en CO . Chem. chim. 785 (1942). ital. 62. Am.. a 90 3-Nitro-4-aminophenylarsonic acid "» Finri and Mangini. 50%) 3-Nitrophenylaxsonic acid (45%) Both Na2SnO2 and ethanol failed here. in Find and Mangini. Soc.. 64. "" Rosenbaum and Cass. Oazz. chim. chim. chim. m Finzi and BeUavita. itdt.. 62. 2444 (1942). Am.200 2-(o-Aminophenyl)-oxazole 2-(p-Aminophenyl)-oxazole "Satisfactory yield" 2-phenyloxaaole 2-Phenyloxazole (34%. ital.
H3PO2 gives 77-83%.TABLE IV ALKALINE FORMALDEHYDE DEAMINATIONS Amitie Aniiinft Product. Yield Benzene (60%) Toluene (80%) Toluene (80%) m-Xylene (80%) Anisole (75%) Anisole (72%) Phenetole (75%) Phenetole (65%) Diphenyl ether (60%) Remarks NassSnOj! or H3PO2 also give a 60% yield. . Reference 4 4 4 4 4 4 o-Toluidine p-Toluidine 2. < H3PO2 gives 70-75%.4-Dimethylaniliiie o-Anisidine p-Anisidine o-Ethoxyaniline p-Ethoxyaniline 4 4 4 \\—O-/~~V-NHj Diphenyl ether (60%) 4 NH.
OH,-/
(50%) -NHS Detailed directions on p. 297.
o-Aminobenzoic acid o-Nitroaniline m-Nitroaniline p-Nitroanihne * o-Chloroamluie p-Chloroaniline 2,5-Dichloroaniline
Benzoic acid (25%) Nitrobenzene (20%) Nitrobenzene (10%) Nitrobenzene (10%) Chlorobenzene (55%) Chlorobenzene (50%) p-Dichlorobenzene (10%) Ethanol gives ca. 82% nitrobenzene, H3PO2 75-80%. Ethanol gives co. 66% nitrobenzene, H3PO2 60-70%. Ethanol gives ca. 70% nitrobenzene, H3PO2 55-60%.
TABLE V
SODIUM STANNITB DEAMINATIONS
Amine
Product, Yield
Remarks
Reference*
Aniline
Benzene (60%),+ azobenzene (ca. 10%)+ Alkaline H»CO and H3PO2 also give 13, 102, phenol + pnenyl azide + phenyl hya 60% yield of benzene. 107,108, drazine 109 Naphthalene o-Xylene "pure and in satisfactory yields" m-Xylene "pure and in satisfactory yields" 1,2,4-Trimethylbenzene "pure and in satisfactory yields" "Could not be deaminated" Only H3PO2 succeeded.
i
a-Naphthylamine 2,3-Dimethylaniline 2,4-Dimethylaniline 2,4,5-Trimethylaniline
6 103 103 103 93
ksj/L-NHj
H—C—COOH "Unsuccessful"
1
o
3-Nitro-4raminotoluene
HsPOj gives 75-80% of jn-nitrotoluene. With ethanol the yield is 62-72%.
106
H
\ N0 2
"Amyl alcohol" and Cu powder give a 45% yield of pure product.
105
(38%, pure) COOH COOH K^SnOj is actually used. 137
H,N
JH COOH
)H
COOH is actually used.
202
H,N
JH l,3-Diinethyl-4-ainino-5-bromobenzene Sulfanilic acid
* References 202 and 203 appear on p. 338
l,3-Dimethyl-5-bromobenzene (73%, pure) Detailed directions on p. 298. Benzene sulfonic acid
104
QO
TABLE V—Continued
SODIUM STANNITE DEAMINATIONS
Amine CH 3 CH 3
Product, Yield
Remarks
Reference 203
(ca. 35%) p-Aminophenylarsonic acid
108
"Could not be deaminated"
H3PO2 is successful, ca. 50% yield.
• " Koemgs, Ber., 83, 2672 (1890).
92
von Hemmelmayer, Monatsh., 35, 3 (1914).
I
TABLE VI
DEAMINATIONS VIA THE HYDRAZINB
Amine Aniline p-Totaidine 2,4,5-Trimethylaniline 2-Amino-6-chlorotoluene 4-Amino-3-chlorotoluene 3,5-Dibromoaniline 2-Amino-6-bromotoluene 4,4'-Diaminobiphenyl-2,2'-disulfonic acid l-Aminonaphthalene-4,7-disnlfonic acid
* References 204-206 appear on p 340.
Product, Yield Benzene (46-75%) + biphenyl (very small amount) Toluene (55-65%) 1,2,4-Trimethylbenzene m-Chlorotoluene (66%) m-Chlorotoluene (40%, pure) m-Dibromobenzene m-Bromotoluene Biphenyl-2,2'-disulfonic acid Naphthalene-2,5-disulfonic acid -
Remarks
Reference* 110, 111, 116 120, 116
I
Na2SnO2 gives a pure product in "satisfactory yields." Ethanol gives a 49% yield of pure product. Ethanol gives a 60% yield. -
7 117 117 204 205 188 206
TABLE VI—Continued
DEAMINAMONS VIA THE HTDRAZINE
o
Amine CH 8 CH 3
Product, Yield
Remarks
Reference 207
O
208
H4
I
Ethanol is not satisfactory here. H,N
B
121
o
"Satisfactory yield"
•M Chattaway and Ellington, J. Chem. Soc., 109, 588 (1916). »• Chattaway and Hodgson, / . Chem. Soc., 109, 582 (1916). m Armstrong and Wynne, Proc. Chem. Soc., 6, 17 (1890).
M7
Byvanok, Ber., 31; 2150 (1898). *» Besthorn and Byvanok, Ber., 31, 799 (1898).
CHAPTER 8
PERIODIC ACED OXIDATION
ERNEST L. JACKSON
National Institute of Health, U. S. Public Health Service
CONTENTS
PAGE THE NATURE OF THE REACTION THE SCOPE OF THE REACTION EXPERIMENTAL CONDITIONS EXPERIMENTAL PROCEDURES 341 344 357 361
Preparation of an Aqueous Solution of Periodic Acid Analysis for Periodic Acid Qxidation of Methylglycosides Oxidation of N-Acetyl-D-glucosylamine Oxidation of Alginic Acid Oxidation of 9,10-Dihydroxystearic Acid. The Use of Aqueous Ethanol as the Solvent Oxidation of Starch. Oxidation in Aqueous Suspension Oxidation of the a-Benzyl Ether of Glycerol. The Use of an Emulsifying Agent .' Degradation of the Side Chain of A4-Pregnene-ll,17,20,21-tetrol-3-one. Small-Scale Oxidation ,
SURVEY OF PERIODIC ACID OXIDATIONS. TABLE
361 361 361 362 362 363 363 363 364
364
THE NATURE OF THE REACTION Periodic acid oxidation* is applicable to compounds having two hydroxyl groups or a hydroxyl and an amino group attached to adjacent carbon atoms and is characterized by the cleavage of the carbon-carbon bond, as illustrated by the following equations. RCHOHCHOHR' + HIO4 -> RCHO + R'CHO + H20 + HIO8 RCHOHCHNH2R' + HIO4 -> RCHO + R'CHO + NH8 + HIO3
1 Periodic acid, as a reagent for glycols, was introduced in 1928; Malaprade (a) Bull soc. chim., [4] 43, 683 (1928); (6) Compt. rend., 186, 382 (1928). 341
342
PERIODIC ACID OXIDATION
If the hydroxyl groups or a hydroxyl and an amino group are not attached to contiguous carbon atoms no oxidation takes place.2 This selectivity, which is the outstanding characteristic of periodic acid oxidation, adapts the reaction to testing for the presence of contiguous hydroxyl groups 3 and hydroxyl and amino groups. Carbonyl compounds in which the carbonyl group is adjacent to a second carbonyl or hydroxyl group are oxidized also. Thus, aketols,26- *•6 a-diketones,4 and a-ketonic aldehydes4 react as illustrated by the following equations. CHsOHCOCHjOH + HIO4 -+ HCHO + CH2OHCOOH + HIO3 CH3COCHOHCH3 + HIO4 -» CHSCHO + CH3COOH + HIO8 C6H5COCHOHC6H6 + HIO4 -> C6H6CHO + C6H6COOH + HIO8 CHsCOCOCHs + HIO4 + H2O -> 2CIJ3COOH + HIOS CH3COCHO + HIO4 + H2O -» CH3COOH + HCOOH + HIO8 Oxidation of carbonyl compounds was interpreted by Malaprade6 as conforming to the a-glycol type by the assumption that the reaction proceeds through the hydrated form of the carbonyl group, >C(OH) 2 . This hypothesis is useful in interpreting the results of the oxidation of some complex compounds, intermediates of the type RCHOHCHO being oxidized like the a-glycols. Concerning the mechanism of the periodic acid oxidation of a-glycols, the suggestion has been made,7-8 through analogy with lead tetraacetate oxidation, that the splitting of the carbon chain results from a series of three reactions, the first being the esterification of a hydroxyl group by paraperiodic acid (H5IO8 or HIO4-2H2O).
The discovery that the reaction of glycols is limited to 1,2-diols was made by Fleury; (o) Fleury and Courtois, Compt. rend., 209, 219 (1939); (b) Fleury and Lange, ibid., 195, 1395 (1932); (c) Fleury and Paris, ibid., 196, 1416 (1933); (d) Fleury and Paris, J. pharm. chim., [8] 18, 470 (1933); see also (e) Bailly, Compt. rend., 206, 1902 (1938); (/) Bailly and Gaume, Bull. soc. chim., [5] 2, 354 (1935); (,g) Yokoyama, / . Agr. Chem. Soc. Japan, 15, 499 (1939) [C. A., S3, 8570 (1939)]. * For an example of the use of the reaction as a test see Marvel and Denoon, / . Am. Chem. Soc., 60, 1045 (1938). * Clutterbuck and Reuter, J. Chem. Soc., 1935, 1467. 6 Fleury and Lange, J. pharm. chim., [8] 17, 409 (1933). ' Malaprade, Bull. soc. chim., [5] 1, 833 (1934). T Criegee, Sitzber. Ges. Bef&rder. ges. Naturw. Marburg, 69, 25 (1934) [C. A., 29, 6820 (1936)]. 'Criegee, Kraft, and Rank, Ann., 507, 159 (1933).
s
THE NATURE OF THE REACTION —COH —COIO6H4 j + H6IO6 - » | + H2O —COH ' —COH
343
(a)
—COIO6H4
—COv
(6)
|
—COH —CCk | >IO 4 H 3
-^
I >
—CCK
- (c)
—ccx
This mechanism has been considered 9> 10 in relation to the rates of the periodate oxidation of cis- and trans-glycols, and in connection with the effect of the pH of the reaction solution on the rates of oxidation of ethylene glycol, pinacol, and cis- and 2ra«s-cyclohexene glycols. In reactive compounds containing the amino-alcohol structure, the amino group may be primary or secondary.11-12> 13 The reaction has not yet been tested extensively on compounds possessing a secondary or tertiary amino group. Oxidation, would be expected to occur generally in the case of secondary amino derivatives, —CH(OH)—CH(NHR)—, but tertiary amino compounds, —CH(OH)—CH(NB.2)—, should not react. In agreement with this, view, diethanolamine, HN(CH2CH2OH)2, has been oxidized to produce four moles of formic acid, whereas diethylaminoethanol, (C2H5)2NCH2CH2OH, showed virtually no reaction. Acyl derivatives n> 14/1B of serine have been reported to react extremely slowly, a result which suggests that acylated derivatives, —CH(OH)—CH(NHCOR)—, generally are substantially stable in the presence of periodic acid. Oxidation has been reported to occur with a number of compounds which contain nitrogen but possess no a-amino-alcohol structure.11- u - 16 Thus, cystine, methionine, and tryptophan are oxidized, though without
• Price and Knell, J. Am. Chem. Soc., 64, 552 (1942). Price and Kroll, J. Am. Chem. Soc., 60, 2726 (1938). • Nicolet and Shinn, / . Am. Chem. Soc., 61, 1615 (1939). 12 Shinn and Nicolet, / . Biol. Chem., 138, 91 (1941). 18 Van Slyke, Hiller, MacFadyen, Hastings, and Klemperer, J. Biol Chem., 133, 287 (1940). " Nicolet and Shinn, J. Biol. Chem., 142, 139 (1942). 16 Posternak and Pollaczek, Hdv. Chim. Ada, 24, 1190 (1941). 11 Van Slyke, Hiller, and MaoFadyen, J. Biol. Chem., 141, 681 (1941).
10 11
. J. Chem. Soc. where R is H or a substituent other than acyl. Compt. The reaction also has provided an improved method for Martin and Synge. histidine. and glutamic acid also react. some of them are available at the present time only through this type of oxidation. rend. 21 Reeves. Soc. certain analytical procedures12> 18-19-20-21 have been based on the determination of the aldehyde produced in the reaction. acetaldehyde results from the oxidation of compounds having the groupings CH3CHOHCHOH—. Am. J. at 100° in aqueous solution the acetone molecule is split to produce acetic acid and formaldehyde. Periodic acid oxidation of a-glycols or a-amino alcohols containing the structure ck 2 OHCHOH—. THE SCOPE OF THE REACTION Although the widely applicable reaction has gained recognition chiefly' through its use in analysis and determination of constitution.344 PERIODIC ACID OXIDATION the production of ammonia. " F l e u r y and Boisson.. «» Nioolet and Shinn. and pyruvic acid yields acetic acid and carbon dioxide. acetaldehyde is oxidized to formic acid and methanol. Nioolet and Shinn. Chem. 1456 (1941).11. Chem. pharm. " Nioolet and Shinn. 139.. 35. asparagine. Am. Bid. 21 Fleury and Boiason. [8] 30. Glycine. M Fleury and Boisson. 294 (1941). The reaction with cystine and methionine apparently is due to oxidation of the sulfur. CH2OHCHNH2—.18 Since the oxidation reactions are quantitative. chim. diethyl ketone yields propionic acid and probably ethanol. 307 (1939). J. lactic acid gives acetaldehyde and carbon dioxide. The estimation of the formic acid derived from the oxidation of secondary alcohol groups in certain types of compounds also has provided procedures for analysis as well as evidence on constitution. J.22-23-24-25 Thus. Certain compounds which show no substantial reaction with periodic acid at room temperature can be oxidized at elevated temperature. Oxidation of compounds of the types thus far discussed proceeds readily at room temperature. 63. Soc. Such analytical data also have afforded useful evidence on the structure of the reacting compound. The data now available are insufficient to establish the nature of these reactions. aspartic acid. Similarly. 24 Fleury and Boisson. which is converted into formaldehyde. Am. CH3CHOHCHNHR—. 1509 (1939)." but at a markedly slower rate than compounds having the a-amino-alcohol structure. 1264 (1937). 687 (1941). 204. 63.. tyrosine. chim. 18 17 . Biochem. J.. Chem. pharm. 1476 (1941). rend. 1486 (1941). J.. J. 208. Compt. or CH3CHNHRCHOH—.. or CH2OHCHNHR— converts the terminal primary alcohol group into formaldehyde. many compounds have been prepared for the first time by this method. alanjne. [8] 30. 145 (1939). 63..
as well as oxalic acid. " Jackson and Hudson. Chem. J. Chem. Am. 0 . Ada. Periodic acid. 65. Ber. have been reported8 to oxidize a-glycols in the same manner as lead tetraacetate.. such as permanganate and nitric acid. A disadvantage for large-scale operation is the relative expense of the reagent. 321 (1940). at' room temperature. M Karrer and Hirohata. 27 Criegee. Ber. 30 Criegee.THE SCOPE OF THE REACTION 345 the preparation of some compounds that usually-have been obtained in other ways. Ber. The more common oxidizing agents. Angew. Am. 1060 (1923). Angew. Ann.. 994 (1937).. 56. and cerio sulfate. . Chem. since the reaction of the former was not limited to the a-glycol group in the mannoside molecule. The two oxidants. does not react with oxalic acid and oxidizes a-hydroxy acids only tilowly even at •• B*er. Only Criegee's reagent.. 59.. Chim. 18 Criegee. Soc. lead tetraacetate. thallic acetate. CHjOHCHCHOHCHOHCHQHCHOCHs but the product that was isolated was a xjarboxyl derivative I2OHC CH2OHCHCOOH HOOCCHOCH. manifest a marked difference in their action upon a-hydroxy acids and upon oxalio acid. 1770 (1932). 378 (1936). 260 (1931). such as manganic acetate. 16. instead of the corresponding dialdehyde which was obtained by periodic acid oxidation.7' *«• "• 28«2«-so. usually cannot be substituted for periodic acid. An advantage in most periodic acid oxidations is the absence of side reactions and the consequent high yield. since they are not selective in their action. 959 (1933). Also these reagents oxidize many of the compounds obtained as products of periodic acid oxidation. Am. Also the yield was markedly lower with barium hypobromite than with periodic acid. 50. 153 (1937). * M Jackson and Hudson. however. Chem. 53. cobaltic acetate. The same cleavage of the carbon chain as produced by periodic acid resulted from the reaction of barium hypobromite **••*• IB with a-methyl-D-mannopyranoside . J. 211 (1932). 68. Hdv. 62. Other reagents.. Soe. J. 64. 1597 (1940). 15 Bergmann and Wolff.. on the other hand. and the rate of oxidation by each reagent is more rapid for cisthan for fo-ans-glycols. 19 Criegee. 81 Criegee.«*•M has thus far had sufficiently extensive and successful application to merit consideration as a substitute for periodic acid.. but they are inferior to th'at oxidizing agent. Soc. Chem. 495. Periodic acid and lead tetraacetate react similarly with simple aglycols. Lead tetraacetate readily oxidizes a-hydroxy acids.
. « Voris. soc. chim. Chem. chim. Anal. Grosheintz. 48 Fleury and Fatome. 1. Am. the reaction with these compounds has no preparative value.38> 39> 40 a mixture of water and acetic acid is suitable. BvU.45 eiythritol. 313 (1933). 40 Criegee and Bttchner. chim. provided that the rate of oxidative cleavage of the glycol exceeds the velocity of hydrolysis of lead tetraacetate. Ada. pharm. Mikrochim. 117 (1941) [C. and Coleman. and Fischer. Ind. to form glyoxylic acid. although it has analytical uses. 906 (1937). 73... Eng. chim. rend. 2. chloroform.. Biol. 61.. [5] 4. is best adapted to organic solvents. Soc. nitrobenzene. CH2OH(CHOH)nCH2OH. 51 Palfray.61-62 ROCH2CHOHCH2OH -» ROCH2CHO + HCHO Fleury and Bo. Ellis. 457 (1937). 2607 (1939).26-86> 37 for example... 85 (1936). The complete degradation of the molecule in these polyhydroxy alcohols is pre^nted by appropriate substitution of the hydrogen atom of one or more hydroxyl groups. J. 61. [8] 17. chim. Ed.«• « and sorbitol. 765 (1940). 247 (1935).346 PERIODIC ACID OXIDATION elevated temperature. 35. 42.. pharm. 44 Malaprade. Reifer. 47 Joly. pharm. Ber.. since it is hydrolyzed by water. are oxidized to ethers or esters of glycolaldehyde. 44. J.. Baer. can be carried out in the presence of water. 1. J.. Ada. pharm. [8] 21. The a-monoethers or a-monoesters of glycerol. and Weinmann.. chim. The two reagents differ also with respect to the kind of solvent in which they function best.4s. J.. 563 (1940). Ann. [8] 26.M Since the oxidation of simple polyhydroxy alcohols. as for 'the determination of ethylene glycol. 60 Fleury and Joly. is oxidized quantitatively to formic acid. The molecule of tartaric acid.«• « erol) 4i. 210. soc. 42 Fleury and Fatome. Halasz. 133. « Palfray and Sabetay. Water is the most suitable solvent for periodic acid oxidation. Am..46-47. 41 Rappaport. Chem. 285 (1935). [8] 23..47. 290 (1937). benzene. while lead tetraacetate cleaves tKe carbon-carbon bonds in two ways: (a) as an a-glycol and (6) as an a-hydroxy acid. 37 60 Inositol. BvU. / . Fleury and Lange. 12.. 3379 (1939). [8] 25. J. such as glacial acetic acid. J. Lead tetraacetate. 23.. The use of organic solvents in periodic acid oxidation will be discussed later. Chem. and di. results in the complete degradation of the molecule.n-Bernatets. J.7*28. is split as an a-glycol rapidly and quantitatively at room temperature by periodic acid. Soc. 6214 (1941)]. 384 (1940).and tetra-chloroethane. 41 Allen. 950 (1937). however. 87 88 36 . Chem. Charbonnier. 397 (1937). 4 «Fleury and Courtois. 341. Ann. pharm. chim. appl. ' a cyclic polyhydroxy compound. chim. 88 Grosheintz. and Rovira. for example.A. Compt. Mikrochim. chim. 273 (1937). Oxidation with lead tetraacetate. and Maynard. [5] 4. 491 (1940). 48 Rappaport and Reifer.*1 glyc44 mannitol. anal. Fermentations. Further comparison of the two reagents may be found in the literature.
Soc. J. In some cases it is possible to protect selected portions of the molecule by substituents which can be removed subsequent to cleavage of the carbon chain at the desired point. .THE SCOPE OF THE REACTION 347 -A convenient method for the determination of a-glycerophosphoric acid 2c~gi M> 64 alone or mixed with 0-glycerophosphoric acid is based upon oxidation by periodic acid. Soc. Soc. 752. Ada. Chem. 1934.5-monoacetone-Dgalactose dimethylacetal 66 (I) to produce 2. 66 Fischer and Dangschat. 67 Fischer and Dangschat. Chim. Hdv. 448. . Am. Chem. 705 (1937). 1200 (1934).66>67 /OCH3 HC< |X OCH 3 HCOH OCH i CHO OCH OCH i 7C(CH3)2 HCO' CH 2 OH 1 /OCH H( ^OCH CHO in HC(X CH^OH n COOH COOH C=O HCH f 1 c=o HCH- COOH HO—C / \ HOCH HCH • * 1 1'~ 0—CH HCOH W CH 0 IV HOCH 1 HCO | >C(CH 3 ) 2 *± V "BCQr | OCH | HCO V I >C(CH3)2 > HCO HC=O COH H 1 «• Gulland and Hobday. Chim. This is illustrated by the periodic acid oxidation of 4. Chem. 61. J. and Green. « Pacsu. Melt.. one of the a-glycol groups being masked by the easily hydrolyzed isopropylidene group.3-monoacetone-D-threose (II) and glyoxal dimethylacetal (III).. Trister. / . 64 Pyman and Stevenson.. Ada. 20. 2444 (1939). Similar protection of an a-glycol group was necessary in the oxidative cleavage of the ring of the shikimic acid derivative (IV). 17. 1940.
yielded the a-hydroxy acid XI. 1107 (1939). and v. Hdv. The course of the reaction is thus preferential to the production of a cyclic ketoneby way of the pair of hydroxyl groups attached to carbon atoms 17 and 20. Chim. Hdv.5-dihydroxy-2-carboxybenzoyl methyl ketorie4 (VI) produced 3. Ada. Hdv. In the periodic acid oxidation of the pregnene derivative VIII. Hdv. 22. the side chain was degraded completely to vn OH CHOHCH2OH CH3 HO Vlil IX !H3 COCH2OH OH yield the cyclic ketone IX. The diversity of cyclic derivatives accessible in this way is apparent from the following examples of oxidations that have actually been accomplished. 24.(1941). Chim. 61 Fuehs and Reichstein. 88 Oxidation of X. Ada. 60 ' 61 which was formed through reaction with the hydroxyl groups at carbon atoms 20 and 21.348 PERIODIC ACID OXIDATION If the a-glycol or other reactive group forms the side chain of a nonreactive ring. Chim. 69 . 418 (1941). The oxidation of 3. 804. Ada. Euw and Keichstein. By the reaction of one molecular equivalent 68 Reichstein. which has a reactive hydroxyl group attached to carbon atom 17 of the ring. M v. the type of product resulting from periodic acid oxidation varies with the structure of the side chain. Meystre. 978 (1937). 24. 69 In the case of XII the product was the a-ketol XIII. Reichstein. the side chain of which is an a-ketol instead of an a-glycol as in VIII.5-dihydroxyphthalic acid (VII). Ada. Euw. Chim. 20.
. must be carried out under selected conditions. Helv. like tartaric acid. Heh.THE SCOPE OF THE REACTION 349 of periodic acid with XIV the a-hydroxyaldehyde XV has been prepared 62' M in 65% yield. 396 (1941).63 With increasing aromatic substitution the a-glycol molecule is reported 7> 28 to become less reactive toward periodic acid.26'S7 CH2OH(CHOH)4COOH + 4HIO4 -» OCHCOOH + HCHO + 3HC00H + H2O + 4HIO3 HOOC(CHOH)4COOH + 3HIO4 -> 20CHC00H + 2HC00H + H2O + 3HIO3 62 63 Prins and Reichstein. diphenylacenaphthenediol (XVII). Prins and Reichstein. Chim. Ada. Ada. for example. yield glyoxylic acid. since a-hydroxy-aldehydes are oxidized by periodic acid. 945 (1941). 24. Chim. The preparation of this unusual type of product. 24. Gluconic and saccharic acids. XV yields the cyclic ketone XVI. does not react. only a few examples of which have been reported.7 CH20H(2l) CH3COH(20) !H3 OH XII xm CH3 CHOHCH2OH CHO XIV xv XVT xvn Polyhydroxy acids are split in the characteristic way by periodic acid.
857 (1939). Lactones react like substituted hydroxy acids. Chem. and Jones. 1939. 664 (1939). the carbon chain of the 3. Jones. J. 66 Reeves. 67 Schmidt and Gunthert. the oxidation of 2. Chem. 493 (1938). Am. Soc. COOH | H3COCH 1 COOH HCOH COOH H3COCH . Thus. 71. which is an ester of glyoxylic acid with L-threuronic acid (XXII). J. H3COCH H—C=O XIX H3COCH HCOH HCOH COOH XVIII -CH HCOH 0 HCOH -C=O xx COOH HCOH 1 H—C=O ?H H—C=O COOH 1 qooH HCOH HOCH COOH XXIII HCOH 1 HOCH 1 XXI H—C=O XXII 1 Periodic acid has proved to be a useful reagent for the analysis of certain wa-hydroxyamino acids. and Jones.. Jones. Soc. The hydrolysis of XXI and subsequent oxidation of the products with calcium hypobromite produced in high yield D-tartaric acid (XXIII) and oxalic acid. provided that the lactone ring is sufficiently stable to resist hydrolysis during the oxidation reaction. 66 ^ . 1880.350 PERIODIC ACID OXIDATION Since etherification of one or more of the alcohol groups arrests the degradation process. Ber. Hirst. Since the oxidation produces one mole of ammonia the determination of the ammonia generated provides a M Hirst.6-monolactone (XX) of D-saccharic acid 66-_67 is cleaved between carbon atoms 4 and 5 to yield XXI. Nature..3-dirnethylrnannosaccharic acid (XVIII)64'66 yields besides glyoxylic acid the dimethoxyaldehydo acid (XIX). 143.. 61.
26-6> •• 46 ' 49> 82~84 galactose. 5396 (1937)]. Biol. Moore.ffl>8B and mannose ffi produce one mole of formaldehyde and five moles of formic acid per mole of aldohexose. Chem. Biol. Biol. 88 Rappaport. Chim. Glucose. J. J. J. Macara.. [8] 20. J. Bioehem. 31. Chem.. 187 (1941). A. Biol. Folch and Schneider. arid Saidel. and Berg. 140. 140. 36. and Bergmann. periodic acid oxidation has bad many important applications. Ada. 299 (1942). 81 Nicolet. / . J.. 137. 73 Stein. The reaction with the ketose fructose follows two courses: ib . / . A . Chem. Biol.. / . and of primary alcohol groups J1> 84i 86 in carbohydrates... Fleury. Bioehem. 171 (1941). 461 (1942). 77 Brown. 72 Macara and Plimmer. Nature. 315 (1941). 263 (1938). 766 (1934). Compt.69 88 . 142. Ada. 212. Biol. Chim. 17.» CH3CHO + OCHCOOH + NH 3 + NaIO3 Procedures have thus been provided for the determination of serine and threonine in protein hydrolysates14~17v74"81 and of the hydroxyamino acids of insulin.19 Among the sugars and their glycosidic derivatives. 357 (1937) [C. Am. 139. CH2OHCHNH2COOH + NaIO4 =^ HCHO + OCHCOOH + NH 3 + NaIO3 CH3CHOHCHNH!!COOH + NalO* . 265 (1938). J. 86 Ariyama. 82 Herissey. 697 (1942). 85 K h o u v i n e a n d Arragon. xcviii (1941). 685 (1941). Chem. 79 Nicolet and Shinn. Mikrochemie. 481 (1941): 74 Martin and Synge. Biol. and Plimmer. 142. and Piersma..... Bioehem. J. 149 (1934). Totter.. 17. "Hotchkiss. 609 (1942). Biol. Biol. Mikrochemie. The methylpentoses yield acetaldehyde and formic acid. 146. and Joly. pharm. 83 Karrer and Pfaehler. 76 Borchers.68~73 of these acids in the presence of other types of amino acids. J. Chem. 142. 1018 (1942)]. J. 26. Chem. 25. 167 (1941) [C. Chem.. Chem. Chem. Biol. and Kitasato. The estimation of the acetaldehyde or formaldehyde generated by periodate oxidation has provided methods for the determination of methylpentoses 18 in the presence of pentoses and hexoses. . 141. 78 Nicolet and Saidel. 84 Karrer and Pfaehler. chim. Japan. Chem.. rend. 142. 25. 80 Nicolet and Shinn. Chem. Proc. Chem.. 76 Winnick. Soc.6> •• 48> 86' S7> 88 one (a) (like that of Christensen.. Biol. 34. 71 Lowndes.. Since the degradation of the molecule is complete. 35.THE SCOPE OF THE'REACTION 351 simple method for the quantitative estimation 16~17. 51 (1941). 141. 139. / . the reaction is limited to analytical applications. Shinn. 363 (1934). Methods for the determination of serine 17 ' 20 and threonine 12> "• 74> 76 are based on the estimation of the formaldehyde or acetaldehyde resulting from periodate oxidation. J. 477 (1941).49. Biol. Helv. 87 Fleury.. Helv. Edwards. 491 (1940). 1431 (1940). J.
3507 (1939). gives dimethylglyceraldehyde. Periodic acid oxidation is applicable to glycosides34' 82> u< "• 91 of various groups of sugars.352 PERIODIC ACID OXIDATION dihydroxyacetone) to yield glycolic acid. •o Jackson and Hudson. Am. Soc.6-Dimethylglucose. 61. and the other (6) (like that of tartaric acid) to yield glyoxylic acid. J. Am.• 2HCH0 + 2HC00H + OCHCOOH + H2O + 4HIO3 Periodic acid oxidation "of non-glycosidic derivatives of the aldoses yields various products.. which apparently is derived by further oxidation of the expected three-carbon atom cleavage product (XXV). (a) CH2OH(CHOH)3COCH2OH + 4HIO* . CH2OHCH(CHOH)3CHOCH3 + 2HIO4 Methylaldohexopyranoside CH2OHCHCHO OHCCHOCH3 + HCOOH + H2O + 2HIO3 Dialdehyde Salmon and Powell. Soc. l-phenyl-4benzeneazo-5-pyrazolone (XXVI). 2669 (1939). 61. Chem. the identity of which depends upon the nature of the substituent and its position in the molecule. 91 Pacsu. 5. Chem.89 for example. Am. 61. as shown by the following equations. Chem. J. Glucose phenylosazone (XXIV) 84 yields an unusual type of product. 1530 (1939). 88 » . sugars. HC=N—NHC 6 H 6 C=N—NHC«H 6 HOCH HCOH HCOH CH2OH XXIV XXV XXVI C6H8 "HC=N—NHC6H 5 ' -> C=N—NHCsH 6 _HO=0 N /' -> o=c I \ N II I 1 C II Many compounds of types not otherwise available are accessible through application of the cleavage type of oxidation to the glycosidic derivatives of the. Soc. reaction (a) predominates.* HCHO + 3HC00H + CH 2 OHC00H + 4HIO3 (6) CH2OH(CHOH)3COCH2OH + 4HIO4 . J.
and its optical antipode (XXXV) from the /3-methyl-D-pentopyranosides.91 . XXXIII from the a-methyl-D-pentopyranosides. and the other (XXXI) is derived from the eight /3-methyl-D-aldohexopyranosides.84. as illustrated by the oxidation of a-methyl-D-glucopyranoside (XXVII) and /3-methylD-glucopyranoside (XXX). indirect evidence has been obtained for the formation of the dialdehyde shown in the above equation from a-methyl-L-sorbopyranoside. the preparation of XXVIII from a-methyl-D-arabinofuranoside actually has been accomplished. Consequently.39 The same dialdehydes should result from oxidation of the methy!-D-aldopentofuranosides as from the methyl-D-aldohexopyranosides. The methylpentopyranosides (see table) can yield only two products. only two products can be obtained from the periodic acid oxidation of the sixteen possible methyl-Daldohexopyranosides.34 Although the product of the oxidation of a methyVketohexopyranoside has not been isolated. One of these (XXVIII) is the product from the eight a-methyl-D-aldohexopyranosides. and oxidation of a pentopyranoside eliminates all except carbon atom 1.THE SCOPE OF THE REACTION 353 CH2(CHOH)3CHOCH3 + 2HIO4 Methylaldopentopyranoside CH2CHO OHCCHOCH3 + HCOOH + H2O + 2HIO3 Dialdehyde CH2OHCH(CHOH)2CHOCH3 + HIO4 Methylftldopentofuranoeide CH2OHCHCHO OHCCHOCH3 + H2O + HIO3 Dialdebyde CH2(CHOH)3C(OCH3)CH2OH + 2HIO4 Methylketohexopyranotside CH2CHO OHCC(OCH3)CH2OH + HCOOH + H2O + 2HIO3 Dialdehyde It will be noted that the oxidation of a methylaldohexopyranoside removes all the asymmetric carbon atoms from the molecule except carbon atoms 1 and 5.
XXXIX. 61. 92 Maelay. 1660 (1939) . have yielded four dialdehydes: XXXVII. XXXVIII. and Hudson. Chem. Am. J. and XL. H3CO \ H H3CO \ H 0=C—H 0 Sr r 0—c=o 0 0==C—H 0 0=C—H XXXIII L0—c=o CH2—I XXXIV Sr r o—c=o 0=C—H CH2—• XXXV L0—c=o CH2XXXVI o The methylaldohexomethylopyranosides34'92 (see table).Soc.354 H \ HCOH HOCH HCOH HC CH2OH XXVII PERIODIC ACID OXIDATION OCH3 H \ OCH3 H \ OCH8 O=C—H 0 O=C—H HC XXVIII . which have a hydrogen atom in place of the hydroxyl group at carbon atom 6 of the corresponding methylaldohexopyranoside molecule.—O—C=0 O Sr U)-C=O 1 HCCH"2OH XXIX CH2OH H H 3 CO H3CO H H3CO H C HCOH HOCH HCOH HC CH2OH XXX \ Q / 0=C—H 0 1 0 p-O—C=O Ba 0 0=C—H Hi I—O—'C = 0 HC CH20H XXXII CH2OH XXXI H OCH3 H \ OCH.. Hann..
34 D-glyceric.and L-lactic acids..34 • illustrated by formulas XXIX. Periodic acid oxidation of the glycosides proceeds quantitatively. the possibility of applying the reaction to other glycosides with various alkyl or cyclic groups in place of the methyl group should be noted. 96 alginic acid. are acetals and consequently are readily hydrolyzed.CH 3 XXXVIII CH3 XXXIX Although the methylglycosides predominate among the examples.THE SCOPE OF THE REACTION H3CO H H c OCH3 1 H3CO c H 1 1 355 H OCH3 \ / 1 °\ . which is composed of the /3-D-mannuronic acid units.. A number of crystalline strontium and barium salts. 90 the galacturonide unit of polygalacturonide methyl ester (XLVII or XLVIII) from citrus pectin produces XLIX or L.92 the identity of the product depending upon the glycoside subjected to oxidation. have been prepared in good yields by oxidation of the dialdehydes with bromine water kept neutral with the appropriate metallic carbonate. Chem. 120. Soc. Chem. it will be noted. "Jackson and Hudson.34 and D. Sdt. The dibasic acids derived from these salts. M levoglucosan (XLIII). / . The principles outlined for the periodic acid oxidation of the methylglycosides apply also to the oxidation of other classes of carbohydrates having the glycosidic type of structure. gives XLVI. J.a-trehalose (XLV). Chem. With the exception of the four crystalline dialdehydes from the methylaldohexomethylopyranosides the products have been obtained as syrups. •» Niemann and Hayu. The reaction thus provides the best way at the present time for the preparation in pure condition of the stereoisomeric glyceric and lactic acids. 62. Am. a non-reducing disaccharide. By virtue of their aldehydic structure they are capable of yielding a variety of derivatives. 2960 (1940). XXXII. 1 H—C=O 0 I H—C=O L CH CH3 XXXVII O=C—H 1 0 O=C—H I O=C—H 1 HC 1 0 O=C—H 1 1 1 H—C=O 0 j H—C=O HC i 1 1 CH CH3 XL . Am. BM. . J. and the dialdehydes produced can be isolated in high yields. and XXXVI. XXXIV. 95 Levene and Kreider. u a. From the products of hydrolysis have been prepared glycolic. 591 (1937). N-Acetyl-D-glucosylamine (XLI) is oxidized to XLII. Also a variety of products is possible from the oxidation of glycosides appropriately substituted at the alcohol groups.. 958 (1940). yields XLIV. an example of the sugar anhydrides. 62.
Am. produces oxidized starch.97' 98 With the exception of CH3COHN \ CH3COHN \ H OOH XL VII XLVI 96 Lucas and Stewart. Soc. Chem. Chem. Soc. Am. yields the polymeric dialdehyde (LIII or LIV). the molecule of which is built principally of the unit LV. J. " Jackson and Hudson. Soc. 88 Jackson and Hudson. J. the chief unit of which is LVI. 1792 (1940). 60. 62.. 2049 (1937).356 PERIODIC ACID OXIDATIOM LI or LII. COOH XLVIII . 59.989 (1938). »' and starch. Am. Chem.. J.
H LVI the product from N-acetyl-D-glucosylamine. for which no data are available. preferably after oxidation by hypobromite. and the dialdehyde and corresponding dibasic acid from levoglucosan. the oxidation product from a.EXPERIMENTAL CONDITIONS \ 357 0 \ C HOCH HOCH H < HC—O— COOH LII H / o COOH LIII COOH LIV CH2OH • LV CH2O. . Thus. the derivative of polygalacturonide methyl ester produced L-tartaric acid.a-trehalose yielded D-glyceric acid. which are exceptionally resistant to acid hydrolysis. and the selection of the solvent and'the temperature. and oxidized starch yielded D-erythronic acid. these oxidation derivatives are known to yield simpler scission products through hydrolysis. the polymeric dialdehyde from alginic acid gave mesotartaric acid. EXPERIMENTAL CONDITIONS Important considerations in carrying out periodate oxidations are the choice between periodic acid and a suitable salt of the acid as the oxidant.
which through reaction with an equivalent amount of sulfuric acid yields a solution of pure periodic acid. \Ba2I2O9. 101 Hiokling and Richards. J. "'Fleury and Lange. is commercially available. 5 0 .." In connection with this preparation of trisodium paraperiodate from sodium iodate. Chem. " 100 89 . The reaction in the presence of a boric acid-borax buffer is shown by the following equation.. which is hygroscopic and readily soluble in water. An aqueous solution of periodic acid free from metals can be prepared from commercial potassium metaperiodate. with standard sodium arsenite solution..»»-10° it has been prepared also by the electrolytic oxidation 101> 102 of iodic acid. Most of the salts of periodic acid are characterized by their slight solubility in water. 1949.. 2 5 6 102 Willard a n d R a l s t o n . Chem.3% at 20° and 12. Soc. anal. J. 239 (1932). The periodate content is readily determined by titrating. J. pharm. Am. / .." Sodium metaperiodate is commercially available and also can be obtained readily from the slightly soluble trisodium paraperiodate. Z. Chem. 35. Soc. the iodine liberated from iodide in neutral solution. [8] 21. Lange and Paris. 6 2 . this salt can be converted in high yield to the slightly soluble barium dimesoperiodate. is the most suitable salt because of its solubility in water (9.6% at 25°). Trans. chim.. Paraperiodic acid has been prepared in about 93% yield from trisodium paraperiodate. 2678 (1928). chim. 758 (1913). For oxidation experiments sodium metaperiodate. 1M -\ Miiller and Friedberger. of concentrated nitric acid to 100 g. NaIO4 + 2NaI + 4H3BO3 -> NaI03 + I2 + Na2B4O7 + 6H2O Oxidation by sodium metaperiodate resembles that by periodic acid except with regard to the rate. 2869 (1938).34 Solutions of periodic acid and of sodium metaperiodate in water are quite stable at room temperature. Soc. pharm. Ber. it should be noted that in the usual periodate oxidation reactions the periodate is converted quantitatively into iodate. 2655 (1902). [8] 17. J. NaIO4. pharm. J. 60. 106 Willard and 'Greathouse. Chem. since in neutral solution periodate is reduced by iodide to iodate.100 It is also produced in 80% yield by the oxidation of sodium iodate with chlorine in aqueous sodium hydroxide solution. 62." Trisodium paraperiodate is formed in 90% yield by the reaction of bromine and sodium iodide in aqueous sodium hydroxide solution at 8O0. Na3H2IO6.. of water and 45 cc. 107 Miiller and Weglin.. 196 (1933). Electrochem. Soc. of salt. chim.358 PERIODIC ACID OXIDATION Crystalline paraperiodic acid. 107 (1933). 104 Fleury and Lange. 403 (1935). a dilute aqueous solution of Hill. H5IO6.49' 103-107 Periodate also may be determined accurately in the presence of iodate.6 The salt. [8] 17. Am. by crystallization from nitric acid in the ratio of 150 cc.
Chem. J. In the case of certain methylhexosides M which were oxidized by periodic acid formed from potassium metaperiodate and an equivalent of sulfuric acid in aqueous solution. and cellulose. 11! MieheU and Purves. is used instead of periodic acid in applications to a-glycol derivatives that show extreme ease of hydrolysis by acids..18'21 the reaction is carried out in the presence of excess sodium bicarbonate. Am. Soc.0. For the estimation of the ammonia produced in the periodate oxidation of a-ammo alcohols the oxidation solution is kept alkaline with sjodium hydroxide of selected concentration. the effect of the presence of metal ions on the yield should be considered. the presence of metal ions should not reduce the yield. 61. If the product is volatile or slightly soluble. 64£ 585 (1942). Soc. J. has been used frequently as a substitute for pure periodic acid. Oxidation by pure periodic acid. the presence of potassium ions was found to cause a low yield of the crystalline strontium salt prepared by the strontium hypobromite oxidation of the dialdehyde resulting from the periodic acid reaction. Soc. / ..aldehyde generated in the periodate oxidation of threonine12> 17' n-76 and the methylpentoses. Am. 1290 (1939). 64. J. Periodate oxidations usually are carried out in aqueous solution at or below room temperature. 589 (1942). J. or one of the potassium periodates. Starch.109"113 In analytical applications involving the determination of the acet.. 15 (1942). Am. 118 Michell and Purves. Soc.13'16 With an excess of free periodic acid the reaction with hydroxylysine and serine was slow and incomplete but proceeded rapidly to completion in the presence of excess sodium bicarbonate. 61.B6-108 Oxidation by sodium metaperiodate is preferable when the formic acid 44> 90 generated in the oxidation reaction is to be determined as the increase in the acidity of the reaction solution. Chem. 2432 (1939) Grangaard. Oxidations also have been carried out with an aqueous solution of trisodium paraperiodate buffered to pH 4. Soc. Michell. or is isolated either as a slightly soluble derivative or by extraction with organic solvents. Chem. Mahoney and Purves. a solution of which is prepared either from crystalline paraperiodic acid or by the previously mentioned method from potassium metaperiodate. 110 . Am. 6i. Am. Soc. and Hudson. Although water is the solvent commonly employed.2 with acetic acid. 64. 111 Mahoney and Purves. 9 (1942). Chem. Maclay. it is emphasized that periodate oxidation is not limited to water-soluble compounds. Chem. is desirable when the presence of difficultly removed metal ions affects the yield adversely. and Purvea.EXPERIMENTAL CONDITIONS 359 which has a pH near 4. trisodium paraperiodate. Am.16 An aqueous solution of sulfuric acid and a salt of periodic acid. sus108 109 Hann. starch formate. Chem. When the product of the oxidation reaction is to be isolated. J.
King. Myers. J. Ada. and Kendall. y the normal oxidation product. J. Soc..122 The reaction solution normally shows no color change due to liberation of iodine. Ada.89 The procedure for the isolation of the various kinds of oxidation products must be adapted to the properties of the particular substances.. Chem. the heterogeneous reaction in the case of starch being substantially complete within a few hours. Helv. 24. T109 (1941) . show appreciable reaction in the course of a number of hours. Chim. 118 v. Chem. Ada. 62. An emulsifying agentB2 was employed in the oxidation of the a-benzyl ether of glycerol. In the oxidation of optically active compounds the end of the reaction usually can be determined by observing the time when the rotation of the reaction solution becomes constant.7-32 dioxane. however. Chem. periodate reactions is determined readily by means of the arsenite method. T81 (1940). Euw and Reichstein. 31. Anal. may not affect materially the preparation of. Soc. J. T25. Biol. J. 267 (1936).116 glucose phenylosazone. Euw and Reichstein. 122 Davidson. 3342 (1940). 1938. 29.10dihydroxystearic acid. Chim. Usually the oxidation products are substantially stable in the presence of periodate and iodate. Am. This analytical procedure also provides a convenient method for establishing the completion of the reaction. 114 116 Gottlieb. 116. Glyoxylic acid is oxidized36 by periodic acid to formic acid and carbon dioxide. 137 (1941). 117 Mason. but the rate of the reaction at room temperature is exceedingly slow compared with the rate of its formation from the polyhydrbxy acids. 1826. Chem. 120 v. 13. have been oxidized "• M>1U at room temperature.84 and other compounds. 1114 (1940). the excess of the periodate preferably being small. Chim."»"W> and methanol68 also have been used.m Mixtures of water with acetic acid.4. though oxidized by periodic acid only slowly at room temperature. 119 v. Soc. Ind....61. 1140 (1941). 24. Chem. An example of a somewhat reactive product is glyoxyKc acid. Euw and Reichstein. 118 King. 1936. Helv.121 The consumption of^the oxidant in. Eng. A mixture of water and ethanol was a successful solvent in the oxidation of 9. the formation of which indicates the presence of a substance capable of reducing the iodine compounds beyond the iodate stage.360 PERIODIC ACID OXIDATION pended in aqueous periodic acid solution. Caldwell. which results from the periodic acid oxidation of certain polyhydroxy acids. Textile Inst. The development of iodine color in some cases.116. 2-Butyl alcohol and a mixture of ethanol and ethyl acetate (ethanol being more resistant to oxidation by periodic acid when mixed with ethyl acetate) have been suggested as possible solvents. J. 121 WiHard and Boyle. and Hixon. Hdv. 23. 32. T195 (1938). Ed. 1788. 401 (1941). Formic acid and formaldehyde. the proportion of organic solvent in some instances exceeding 90% of the mixture.
Helv. When this procedure is followed.1 N sodium arsenite solution containing 20 g. Although the known compounds of this type are stable in dilute aqueous solutibn of iodic acid at room temperature. The sample of periodic acid solution. the excess of sodium arsenite is titrated in the usual way with 0.5 g. The concentration of the periodic acid solution is calculated from the amount of sodium arsenite consumed: 1 cc. The same procedure is used for the analysis of oxidation solutions where excess periodate is to be determined in the presence of iodate. of crystalline paraperiodic acid per liter of solution at 20°. of the solid or its equivalent as a saturated aqueous solution being required. 5 cc.'of NaI0 4 .) of 0. Silver acetate and hydriodic acid also have been used to remove iodic acid. An excess (25 cc. for approximately 0. Barium hydroxide and strontium hydroxide have proved to be advantageous bases for neutralization of the reaction solution. Analysis for Periodic Acid.1 N sodium arsenite solution is equivalent to 0.5 g.5 M solution. for 0.2 M or 2 cc.1 N sodium arsenite solution is added.54 M is usually found by analysis for a solution prepared with 124. heating the acid solution would be expected to cause hydrolysis..34 The following directions for the oxidation of a-methyl-D-glucopyranoside apply generally to the methylpyranosides of the aldohexoses and aldopentoses. of 0. of 20% aqueous solution of potassium iodide. After being kept at room temperature for ten to fifteen minutes. "'Fischer and Dangschat.010696 g.123 EXPERIMENTAL PROCEDURES Preparation of ah Aqueous Solution of Periodic Acid. the solution should be kept for twenty-four hours and filtered before analysis and use in oxidation experiments. 1196 (1934).10*"105 Standard 0. then 1 cc. Chim. Acta.1 N iodine solution are required. 17. some of the products of periodate oxidation.0095965 g. since iodate and excess periodate are largely removed at the Same time as the slightly soluble barium or strontium salts. of HIO 4 or 0. Aqueous solutions of periodic acid prepared from commercial paraperiodic acid frequently deposit a small precipitate upon standing at room temperature. especially the mixed acetals from the glycosidic derivatives of the sugars. the reaction solution customarily is neutralized to a pH of 8-9.1 N iodine solution. Oxidation of Methylglycosides. a concentration near 0.EXPERIMENTAL PROCEDURES 361 As already pointed out. are readily hydrolyzed by acids. of sodium bicarbonate per liter and 0. The solution is neutralized with sodium bicarbonate. . 1. is diluted with water to about 10 cc. If this occurs. Before isolation of these oxidation products.
54 M aqueous periodic acid solution (2. which requires about one and onehalf hours. The mixture is kept at room temperature for twenty to twenty-four hours. df strontium carbonate. Oxidation of N-Acetyl-D-glttcosylamine.380 M periodic acid solution until peptized. can be converted into the corresponding barium salt (see reference 93). of 0. and the filtrate evaporated to dryness in vacuum. The solid is extracted with 100 cc. filtered to Temove strontium carbonate. The residue is extracted six times with 25>cc. and the reaction mixture is maintained at 25° for four and one-half hours. The rotation of the reaction solution should correspond to [a]o = +121° calculated for the dialdehyde XXVIII. The solution. during which time periodic acid is reduced (1. The solution is exactly neutralized with barium hydroxide. the solution is concentrated in vacuum with the water bath at 50° to a volume of about 50 cc. 40°) continued to dryness. The product. is kept at 20-25° for about twenty-four hours. and the solution is centrifuged and again evaporated to dryness. of 0.027 mole) of N-acetyl-D-glucosylamine (XLI) in 100 cc. of pure a-methyl-D-glucopyranoside (XXVII) in distilled water is added to 250 cc. (0.93 Six grams (0. the residue taken up in ethanol. the ethanol extract evaporated to dryness. If desired. Addition of 1600 cc. the precipitate removed. After the addition of 1 g.081 mole) of paraperiodic acid in 100 cc. which separates the dialdehyde completely from slightly soluble strontium salts.362 PERIODIC ACID OXIDATION A solution of 12. of <-butyl alcohol throws down an amorphous precipitate. of water.96 Fifteen grams (0. The precipitate of strontium iodate and strontium periodate is filtered and washed with cold water. the excess periodic acid can be determined by the arsenite method. portions of cold absolute ethanol. The solution is neutralized to phenolphthalein with hot strontium hydroxide solution with care to avoid any excess. which is known from analytical data obtained in small-scale experiments to be sufficient time for completion of the reaction with the consumption of two moles of the oxidant.085 equivalent) of dried alginic acid (LI or LII) is stirred vigorously with 425 cc. as shown by the lack of optical activity of an aqueous solution of these salts. The dialdehyde XXVIII is recovered from the ethanol solution as a colorless syrup in quantitative yield by distillation of the solvent in vacuum with the bath at 40-45°. Oxidation of Alginic Acid.1 mole per equivalent of alginic acid).5 g. of absolute ethanol.1 molecular equivalents).5 g. of water is added to 18. after being diluted with water to 500 cc. and the concentration (bath. the dialdehyde XLII. The oxidation proceeds comparatively rapidly during the first two hours. This i& centrifuged down and washed four times with 50-cc portions of aqueous f-butyl alcohol .
and the aqueous solution reduces Fehling's solution. After ten minutes the clear solution is cooled to 15° and diluted with sufficient water to dissolve the precipitated potassium sulfate. and 200 cc. weighs 13 g.) of non-volatile products from the steam distillation is cooled to room temperature. of potassium periodate in 300 cc. yields 1.533 M aqueous periodic acid solution. This material is easily peptized when added to water. 0. 40-60°) in which all but 0.. dried. the resulting fluffy white residue. and then cooled in ice water. Extraction of the distillate with ether yields 3. When the petroleum solution is cooled in ice-salt mixture. 6. After being shaken thoroughly.1" The Use of Aqueous Ethanol as the Solvent. of 0.p.p. and dried at 40-50°..10-Dihydroxystearic Acid. or 76%) which separates is collected. Mff = +36.5 g. the mixture is kept at 20-25° for twenty-four hours. previously dried at 100° for about twenty hours.10-dihydroxystearic acid (m. CH3(CH2)nOSOsNa. The yield is quantitative. 132°) in 400 cc. Oxidation of the a-Benzyl Ether of Glycerol.EXPERIMENTAL PROCEDURES 363 (1 part of the alcohol to 3 of water). A mixture of 10 g.). of 9. of the a-benzyl ether of glycerol. . of pure azelaic aldehyde acid as colorless rhombic plates melting at 38°. The somewhat impure azelaic half aldehyde (3. Extraction with ether gives an oily product.2 g. of alcohol at 40°. Sodium metaperiodate can be substituted for periodic acid as the oxidant.97' 98> u* Oxidation in Aqueous Suspension. Over 99% of the substance dissolves in forty parts of water at 100° during two hours. The aqueous solution (about 180 cc.3%).7° (c. of pure pelargonaldehyde as a colorless oil boiling at 76-77° (11 mm. or 89%. [a]g = +9°.62 The Use of an Emulsi- fying Agent. identified as the trimer of the aldehyde acid. which is submitted to steam distillation. of water is shaken mechanically at room temperature for thirty minutes and then extracted with ether. of boiling light petroleum (b. filtered to remove a little insoluble material. of potassium metaperiodate. which corresponds to reaction product LIII or LIV. The product is filtered. Oxidation of 9. After being dried at 30 mm. Ten grams of cornstarch or potato starch. 2 g.5 g. Oxidation of Starch. is suspended in 290 cc. 15 g. of sulfuric acid. About one mole of periodic acid per C6H10O5 unit of starch reacts to yield cnadized starch (LVI). after several recrystallizations from 50 parts of warm water. the semialdehyde separates as plates which. washed free from iodic acid and excess periodic acid with cold water. and extracted with 400 cc.. of Gardinol.6 g. dissolves. of N sulfuric acid at 20° is added rapidly to a solution of 8 g. A solution of 6 g.33 g. over sulfuric acid.
(8) miscellaneous compounds. fine needles of A*-androstene-ll-ol-3. have been reported for a number of compounds without isolation of the products. obtained by evaporation of the solvent.20. The Roman numerals appended to the names of some of the compounds refer to the structural formulas given in the text..17-dione (IX) melting at 189-191° (cor. of A4-pregBene-ll. The yields recorded for the products of the oxidation of some of the glycosidic derivatives of the sugars are based on analytical and rotatory data. (4) hydroxyamino compounds. After twenty hours the solution is diluted with water and freed from methanol in vacuum.01 mm. then sublimed at 160° and 0. or 60%. The benzyloxyacetaldehyde thus obtained boils at 115°/15 mm. and the residue distilled in vacuum. The yield of hygroscopic. of methanol is added a solution of 40 mg. is recrystallized from ether. . Degradation of the Side Chain of A4-Pregnene-ll. (5) polyhydroxy and hydroxyketo acids. Analytical data.3 cc. 1941. the substances are listed alphabetically in the following groups of related compounds: (1) carbocyclic compounds. In such cases the products were isolated in unspecified amounts as intermediates in the preparation with high yields of the corresponding crystalline strontium or barium salts. the solvent evaporated. The extract is washed with water and sodium carbonate solution.21-tetrol3-one (VIII) by Periodic Acid Oxidation. although their identity in many instances is apparent from the analytical data. In these cases the substances oxidized are listed but the products are omitted. To a solution of 25 mg.) is 12 mg. (6) polyhydroxy alcohols. and then dried over anhydrous sodium sulfate.68 Small-Scale Oxidation. of periodic acid in 0.. (2) carbohydrates. The crystalline neutral product.17. such as the consumption of the oxidant or production of formic acid.17. of water. 1942) to show cleavage oxidation by periodic acid are recorded in the table.20. were unavailable for the survey. French journals after May.5 cc. 1940.21-tetrol-3-one in 1. and the majority of other foreign publications after June.364 PERIODIC ACID OXIDATION The ether extract is washed thoroughly with sodium bicarbonate solution. and finally recrystallized from a mixture of ether and pentane. (3) a-diketones and a-ketols. The residue is extracted with ethyl acetate and ether. SURVEY OF PERIODIC ACID OXIDATIONS REPORTED IN THE LITERATURE Most of the compounds that had been reported (before March. (7) steroids.
3-Dimethylgalactose Not isolated Not isolated Acetone-D-mannosan 85% — 88% 85% — — _ — — 126 93 96 127 128 128 111 97. Carbohydrates L '-Oxy-b-methylenediglycolic aldehyde N-Acetyl-D-glucosylamine (XLI) . 122. 113.9 124 56 57 7 37 123 123 125 4 — — — — — — — 80% 75%.6-dialdehyde methyl ester Aldehydo keto acid (V) Not isolated Formic acid Citric acid dialdehyde methyl ester Citric acid dialdehyde .SURVEY-OF PERIODIC ACID OXIDATIONS PRODUCTS AND YIELDS OBTAINED IN PERIODIC ACID OXIDATIONS 365 1.5-isopropylidene-shikimic acid (IV) Dimethylacenaphthenediol. 2.6-Dihy droxy-4. cis Inositol Quinic acid methyl ester Quinic amide^acetone Shikimic acid methyl ester Tetrahydroterrein Not isolated Not isolated Not isolated Tricarballylic acid 1.9^ 7. — — * References 124-171 appear on pp. 129 130 131 7. 374-375 . 98. Acetamino-D-hydroxymethyl diglycolic aldehyde (XLII) Alginic acid (LI or LII) Polymeric dialdehyde (LIII or LIV) D-Altrosan L'-Oxy-D-methylenediglycolic aldehyde a-Amylose Not isolated Not isolated /3-Amylose Cellulose methyl and ethyl Not isolated ethers Cotton cellulose Oxycelluloses Dextrins 2. trans Dihydroshikimic acid Dihydroshikimic acid methyl ester 1. Carbocyclic Polyhydroxy Compounds Cyclohexanediol. cis Cyclohexanediol.amideacetone Aconitic acid dialdehyde methyl ester Aldehydocarboxyl deriv.
15-20% zolone (XXVI) — 134 Not isolated — Not isolated 48 L'-Oxy-D-methylenediglycolic 94 85% aldehyde (XLIV) 126X L'-Oxy-D-methylenediglycolic 85% aldehyde Formaldehyde 100% X 82 — Formic acid 84 35% Formaldehyde — ' 96 Methyl ester of polymeric dialdehyde (LIII or LIV) D'-Methoxy-D-hydroxymethyl100% 135 diglycolic aldehyde 34 D'-Methoxy-D-hydroxymethyl. 82.366 PERIODIC ACID OXIDATION PRODUCTS AND YIELDS OBTAINED IN PERIODIC "ACID OXIDATIONS—Continued Substance Product Yield Reference* 21.6-Dimethylglucose Dipotassium D-glucopyranose-1phosphate (Cori ester) Ethylated ethylglucosides from ethylcellulose a-Ethyl-D-galactopyranoside a-Ethyl-D-glucopyranoside /3-Ethyl-L-sorbopyranoside Fructose Formaldehyde Dimethylglyceraldehyde Not isolated Not isolated Not isolated Not isolated Not isolated Formaldehyde Formic acid Glycolic acid Glyoxylic acid Acetaldehyde Not isolated Formaldehyde Formic acid Formaldehyde Formic acid See Hydroxyamino Compounds Formaldehyde 100% — — — — — — 86% — — — 26.co.3-Dimethylglucose 5. 5. 374-375.5>/3<1.6> Galactose Glucoheptose Glucosamine Clucose Glucose phenylosazone (XXIV) Glucose-6-phosphoric acid Glycogen Levoglucosan (XLIII) D-Mannosan Mannose Mannose phenylhydrazone Methyl alginate a-Methyl-D-altropyranoside a-Methyl-D-arabinofuranoside 100% — 100% 100% — — 100% Formic acid Formaldehyde • l-Phenyl-4-benzeneazo-5-pyra. . 21 85 Fucose in seaweed D-Galactosan <1. 86 89 132 110 82 82 91 2. 86. 100% 6. 21 18 133 49.84 84 93% * References 124-171 appear on pp.5. 90% diglycolic aldehyde 26. 21.
6-Monoacetone-/3-ethylgalacto. 374-375.92 33.34 34 86 86 86 34 137 138 34.34 136 139 91 34 34 131 . a-Methyl-D-arabinopyranoside 100% 100% 95% 95% 100% 100% 34.136 — 95% 95% 100% 100% 81% 51% — 100% 100% 95% 100% 100% 100% — 100% 100% — 131 92 92 33.Not isolated furanoside * References 124-171 appear on pp.SURVEY OF PERIODIC ACID OXIDATIONS PRODUCTS AND YIELDS OBTAINED IN PERIODIC ACID OXIDATIONS—Continued 367 Substance Product Yield Reference* 34 34 92 92 34 D'-Methoxydiglycolic aldehyde (XXXIII) P-Methyl-D-arabinopyranoside L'-Methoxydiglycolic aldehyde (XXXV) a-Methyl-L-galactomethyloii'-Methoxy-L-metbyldiglycolic pyranoside aldehyde (XXXVII) /3-Methyl-L-galactomethyloD'-Methoxy-L-methyldiglycolic pyranoside aldehyde (XL) a-Methyl-D-galactopyranoside D'-Methoxy-D-hydroxymethyldiglycolic aldehyde jS-Methyl-D-galactopyranoside L'-Methoxy-D-hydroxymethyldiglycolic aldehyde 6-Methylgalactose Not isolated a-Methyl-D-glucomethyloD'-Methoxy-D-methyldiglycolic pyranoside aldehyde (XXXVIII) L'-Methoxy-D-methyldiglycolic 18-Methyl-D-glucomethyloaldehyde (XXXIX) pyranoside a-Methyl-D-glucopyranoside D'-Methoxy-D-hydroxymethyl(XXVII) diglycolic aldehyde (XXVIII) jS-Methyl-D-glucopyranoside li'-Methoxy-D-hydroxymethyl(XXX) diglycolic aldehyde (XXXI) 2-Methylglucose Formaldehyde Formaldehyde 3-Methylglucose 6-Methylglucose Not isolated a-Methyl-D-gulopyranoside D'-Methoxy-D-hydroxymethyldiglycolic aldehyde a-Methyl-D-lyxopyranosid& D'-Methoxydiglycolic aldehyde /J-Methyl-D-lyxopyranoside L'-Methoxydiglycolic aldehyde a-Methyl-L-mannomethyloL'-Methoxy-L-methyldiglycolic pyranoside aldehyde a-Methyl-D-mannopyranoside D'-Methoxy-D-hydroxymethyldiglycolic aldehyde 0-Methyl-D-mannopyranoside L'-Methoxy-D-hydroxymethyldiglycolic aldehyde L'-Methoxydiglycolic aldehyde jS-Methyl-D-ribopyranoside a-Methyl-L-sorbopyranoside Not isolated «-Methyl-D-xylopyranoside D'-Methoxydiglycolic aldehyde /3-Methyl-D-xyIopyranoside L'-Methoxydiglycolic aldehyde 5.
374-375.D'-Oxy-bts-(D-hydroxymethyl. 130 100% 114 Monoformyl oxidized starch D'.4-Trimethylglucose Xylose — 48 100% 18 100% 134 61% — 134 90% 85 — — — 100% 97.21 Formic acid 3. methyl ester 2. a-Diketones and a-Ketols Acetoin Benzil Benzofuroin Benzoin Diacetyl Acetaldehyde Acetic acid Benzoic acid Benz aldehyde Pyromucic acid Benzaldehyde Benzoic acid Acetic acid — 4 * References 124-171 appear on pp.3. .100% 90 diglycolic aldehyde) (XLVI) 86 Formaldehyde 5% Formaldehyde 100% 18. 112. 98.5-Monoacetone-D-gaJactose dimethylacetal (I) Monoacetoneglucose Pentose-phosphoric acid from cozymase Polygalacturonide.a-Trehalose (XLV) 2.3-Monoacetone-D-threose (II) Glyoxal dimethylacetal (III) Not isolated Not isolated Methyl ester of polymeric dialdehyde (XLIX or L) Not isolated Acetaldehyde Formic acid Formaldehyde Not isolated Formaldehyde Formic acid Glycolic acid Glyoxylic acid Polymeric dialdehyde (LVI) 97% 70% — — — 55 21 134 95 (XLVII or XLVIII) Raffinose Rhamnose Ribose-3-phosphoric acid Ribose-5-phosphoric acid Sorbose Starch Starch monoformate a. 113.368 PERIODIC ACID OXIDATION PRODUCTS AND YIELDS OBTAINED IN PERIODIC ACID OXIDATIONS—Continued Reference* Substance Product Yield 4. 109.
.i>/3-Hydroxyglutamic acid Hydroxylysine 3-Methylglucosamic acid Serine Threonine See Carbohydrates Not isolated" Acetaldehyde Not isolated Formic acid Not isolated Not isolated Not isolated Not isolated Not isolated Formaldehyde Formaldehyde Formic acid Formaldehyde Glyoxylic acid Acetaldehyde Glyoxylic acid 90% 84% — — — 100% 98% — 70% — 140 17 140 100% 11 — 16 — 140 — 140 — 16 — 13. Polyhydroxy and'Hydroxyketo Acids 9. 17 100% 141 100% 98% 11. / 20 5.irAllothreonine N-Benzoyl-a-methylglucosaminide Diethanolamine Ethanolamine Ethyl N-benzoylglucosamate Glucosamic acid Glucosamine D. 74. 374-375. 16.SURVEY OF PERIODIC ACID OXIDATIONS PRODUCTS AND YIELDS OBTAINED IN PERIODIC ACID OXIDATIONS—Continued 369 Substance [ Product Yield Reference* 26.Acetic acid acetylearbinol 6-Aldehydo-2.5 4 4 4 Formaldehyde Glycolic acid 3.10-Dihydroxystearic acid (m.14 100% 13.4-dihydroxybenzoic acid p-Toluoylphenylcarbinol Benzaldehyde p-Toluic acid Dihydroxyacetone 4.p. Hydroxyamino Compounds N-Acetyl-D-glucosylamine N-Acetyl-a-methylglucosaminide D. — 12.5-Dihydroxy-2-carboxyphenyl. 132°) Nonaldehyde Azelaic aldehyde-acid 89% 76% 115 * References 124-171 appear on pp.20 100% 17. 12. — 11.5-Dihydroxyphthalic acid (VII) 3.5-Dihydroxy-2-carboxybenzoyl "Acetic acid methyl ketone (VI) 3. 17.
6 98% 18 100% la.3-Dimethylmucic acid 1 100% 100% 143 — ^108 — 108 — 144 — 5. 6 100% 16 100% la.3-Dimethyl-D-mannosaccharic acid (XVIII) 2.36.3. 135°) (XX) s L-threuronic acid (XXI) Methyl ester of XXI Saccharolactone methyl ester Tartaric acid Glyoxylic acid D-Tartaric acid ester meso-Tartaric acid ester 2.6-monolactone Glyoxylic acid ester of (m.p.6-Trimethyl-D-galactonic acid Not isolated Not isolated Not isolated 6.370 PERIODIC ACID OXIDATION PRODUCTS AND YIELDS OBTAINED IN PERIODIC ACID OXIDATIONS—Continued Substance Product Yield 89% 76% — — — — 89% — — 75% 62% 63% 91% — — — 100% — — — Reference* 115 64.5-Dibenzyldulcitol Dulcitol Erythritol Ethylene glycol L-Fucitol Glycerol a-Glyce£A benzoate Formaldehyde Formic acid Acetaldehyde Not isolated Not isolated Not isolated Not isolated Formaldehyde Formic acid Formaldehyde Acetaldehyde Formaldehyde Formic acid Glycolaldehyde benzoate 9. 108 100% la. 16. 374-375.10-Dihydroxystearic acid (m.3-Butanediol 1. 100% 16 — 51 • References 124-171 appear on pp.L-galactitol 2. Polyhydroxy Alcohols Adonitol 2.p. ' 37 7 7 55 Nonaldehyde Azelaic aldehyde-acid Glyoxylic acid meso-Dimethoxysuccinic acid semialdehyde (XIX) Glyoxylic acid D-Dimethoxysuccinic acid semialdehyde Gluconic acid Formaldehyde Formic acid Glyoxylic acid 9-Hydroxy-lO-ketostearic acid Nonanoic acid Azelaic aldehyde-acid 10-Hydroxy-9-ketostearic acid Nonaldehyde Azelaic acid Formic acid Saccharic acid Glyoxylic acid D-Saccharic acid 3.4-Dibenzoyl-D. 95°) 2.65 142 37 116 116 37 67 66 6.37. 6.6-Diacetyldulcitol 1. .
20/3.11diol Formaldehyde t-Androsterone 17-Formylandrostane-3/3.22-triol Allohomo-(oj)-pregnane-3|8.22-pentol Allopregnane-3|8. 84. 100% 1b.8. d — — 7 34% 32 3% 100% la.20/3-diacetoxy17(?-ol-21-al Not isolated t-Androsterone 3/3.11.21a.17/3-diacetoxy21-ol-20-one Allopregnane-3.2-dimethylethyleneglycol Mannitol l-Methyl-2-p-methoxyphenylethyleneglycol l-Phenyl-2. 9.17|8.22-triol Allohomo-(&))-pregnanepentol Allohomo-(w)-pregnane-3/3.2-dimethylethyleneglycol Pinacol Sorbitol Volemitol Product Benzyloxyacetaldehyde Glycolaldehyde butyrate Glycolaldehyde nonanoate Glycolaldehyde phenylacetate Formaldehyde Phosphoglycol aldehyde Not isolated Isovaleraldehyde Isovaleric acid Formaldehyde Formic acid Not isolated j Yield Reference* — 52 — 51 — 51 — 51 84% 2a.20. 48.8.21.10 100% 47.37 Benzaldehyde Benzoic acid Not isolated Formaldehyde Formic acid Not isolated 7.20.2Q/Sdiacetoxy-17(3.SURVEY OF PERIODIC ACID OXIDATIONS PRODUCTS AND YIELDS OBTAINED IN PERIODIC ACID OXIDATIONS—Continued 371 Substance Glycerol &-benzyl ether a-Glycerol butyrate a-Glycerol nonanoate a-Glycerol phenylacetate a-Glycerophosphoric acid Hydrobenzoin l-Isobutyl-2.20/3diacetoxy-17/3.21/?.20/9. 21 — 7 83% 32 2% — 7.147 — — 60% 35% 148 149 62.21tetro1 Allopregnane-3/3.ll. 100% 49 — — 5.21pentol (Reichstein's compound A) Allopregnane-3.17^diol 45% 53% — — 73% 119 119 119 119 145 64% 146. c.17(3-Diacetoxyetioallocholanic acid 11-Hydroxyandrosterone 17-Formyletioallocholane-3.21-tetrol Allopregnane-3.21-tetrol Allopregnane-3.20.17. 374-375 .20/3-diacetoxy170-ol-21-al v Allopregnane-3/3.17/3. Steroids Allohomo-(w)-pregnane-3/3.17. 6.63 • Inferences 124-171 appear on pp.
17.21^.17^-DihydroxyetioalIocholanic acid Formaldehyde 3-Keto-l l-hydroxy-4-etiocholenic acid Formaldehyde 3.21/3.20/3diacetoxy-17(9.22-triol Homo-(a>)-A6-pregnene-3/3.21a.20-triol Allopregnane-30.372 PERIODIC ACID OXIDATION PRODUCTS AND YIELDS OBTAINED IN PERIODIC ACID OXIDATIONS—Continued Reference* 150 149 151 152 148 150 \ 153 Substance Product Yield Allopregnane-3.20/S-diol-21al-3-one 100% 84% — — — 19% 35% 90% 84% 99% 85%' — 154. 70% 155.17.20/3-diacetoxy17/3-ol-21-al A4-Pregnepe-17/3.20a-triol Allopregnane-3|S.17-Pregnadiene-3/3-ol-21-al A6'17-Pregnadiene-3/3-ol-21-al A6-Pregnene-3^. 155. 61 61 61 61 120 * References 124-171 appear on pp.21/3.20/3-triol Allopregnane-3..17-diol-ll-one 3/3. 156.lldione Hydroxy-3-ketoetiocholenic acid A4-Androstene-3.17-dione A6.21 -tetrol20-one Allopregnane-3.5-Dihydrocorticosterone 4.17-dione (XVI) A*-Androstene-3.20-dione Allopregnane-3.22-triol Homo-(w)-A6'17-pregnadiene-3/3. 17a. .21-triol Allopregnane-3.17a.20^-diacetoxy17/3-ol-21-al A6-Pregnene-3/3.22-triol Homo-(«)-A4-pregnene-l 7^.156 100% 83% 154.22-triol Homo-(w)-A6-pregnene-3/3.11.21-triol-ll.21-triol20-one Corticosterone Dehydrocorticosterone (Kendall's-compound A) 4.11.17.22-tetrol-3-one Formaldehyde Etioallocholane-17-carboxy-3.157 60% 156 82% 80% — 72% 66% 80% 81% 34% 53% — 156 158 63 ' 63.20/3.17-triol Acetaldehyde t-Androsterone i-Androsterone Acetaldehyde <-Androsterone 17-Formyletioallocholane-3-ol Formaldehyde Etioallocholane-17-carboxy-3.ll-Diketo-4-etiocholenic acid Formaldehyde Etiocholane-17-carboxy-l l-ol3-one Etiocholane-17-carboxy-3. 374^375.21a.20.5-Djhydrodehydrocorticosterone Dihydroxyprogesterone 17-Formy1-4-androst ene-17a-ol3-one (XV) 17-Formyl-4-androstene-l 7/3-ol3-one Homo-(oj)-AB' 17-pregnadiene-3|8.20|Sdiacetoxy-17/3.17.
SURVEY OF PERIODIC ACID OXIDATIONS PRODUCTS AND YIELDS OBTAINED IN PERIODIC ACID OXIDATIONS—Continued 373 Substance 20-Hydroxymethylallopregnane3/3.20.21-diol-ll.164 156 165 71% 58% 59.17/3-diol-20-one A5-Pregnene-30-ol-2O-one A6-Pregnene-3/3-ol-20-one 3.17diol-3-one 17-Formyl-4-androstene-17a-oI3-one (XV) .20.20/3.21-diol-3.11-dione A4-Androstene-1 l-ol-3.17/3.20a.17.20trione (Kendall's compound E) "A4-Pregnene-ll. 17-Formyl-4-androstene-l 7j3-ol3-one Yield Reference* 159 — 79% — —' — — — 93% 100% — — 82% 159 160 161 60.20-dione (Kendall's compound H) Pregnane-3a.20/3.17/3.17.17-diol-21-al A6-Pregnene-3^.20dione A4-Pregnene-17a.22-triol-20acetoxy-3-one A4-Pregnene-ll.11.21-tetrol (XII) 21-Methylol-A4-pregnene-17.21.21 -diol-3.21-triol Pregnane-3.17-dione (IX) A4-Pregnene-17-ol-20-acetoxy21-al-3-one Fornwddehyde 4-Etiocholene-17-carboxy-l 1.21-triol 20-Methyl-A6-pregnene-3j3.8.17. 167 83% 117.21-tetrol3-one (VIII) A4-Pregnene-17.20.159 159 159 163.12-diacetoxy-21-al20-one Pregnane-3.21-tetrol (postulated) 20-Methylallopregnane-3/S.20.12-Diacetoxyetiocholanic acid Formaldehyde Etiocholane-17-carboxy-3-ol11-one Etiocholane-3a-ol-l 7-one 3-Keto-l 7^-hydroxy-4-etiocholenic acid (XI) Formaldehyde 4r-Etiocholene-17-carboxy-17-ol3.17.21-triol-3one (XIV) A4-Pregnene-17j3.21-triol 17-Isodesoxycorticosterone 20-Methylallopregnane-3/3.21-triol 2O-Methyl-A6-pregnene-3/3.20-triol • A4-Pregnene-17. 17.21diol-3-one 21-Methylol-A6-pregnene-3«.20.21-triol 20-Hydroxymethyl-A6-pregnene30.159 162 162 61.20.20dione (X) A4-Pregnene-17.21-tetrol 20-Methyl-A6-pregnene-3/3. 166.16.21-triol-3.21-triol3-one \ Product 3-Hydroxy-etioallocholanic acid 3-Hydroxy-5-etiocholenic acid 17-Iso-3-keto-4-etiocholenic acid Not isolated Allopregnane-3/3.17/3-diol-20-one (XIII) A4-Pregnene-17-ol-3-one-21-al AB-Pregnene-3«.63 • References 124-171 appear on pp 3 '-375 ™ .168 70% 60% 76% 80% 68% 66% 52% 58 118 150 63 62.
374
PERIODIC ACID OXIDATION PRODUCTS AND YIELDS OBTAINED IN PERIODIC ACID OXIDATIONS—Continued
8. Miscellaneous Compounds Dihydroxydihydrobetulin Glyoxylic acid Heparin (inactivated) Lactoflavin (riboflavin) Leucodrin methyl ether Methylglyoxal Formaldehyde Dihydroxynorlupanone Formic acid Not isolated Formaldehyde Formaldehyde Anisylsuccinic acid Formic acid Acetic acid 57% — — — 60% — — 76% """" 169 36 170 134 171 4
"* Fischer a n d D a n g s c h a t , Helv. Chim. Ada, 1«, 1206 (1935). 126 Fischer a n d D a n g s c h a t , Helv. Chim. Ada, 1 8 , 1204 (1935). 126 Knauf, Hann, -and Hudson, J. Am. Chem. Soc, 63, 1447 (1941). 127 R i c h t m y e r a n d H u d s o n , J. Am. Chem. Soc., 6 2 , 9 6 1 (1940). 128 Pacsu and Mullen, / . Am. Chem. Soc., 63, 1168 (1941). 129 D a v i d s o n , J. Soc. Dyers Colourists, 5 6 , 58 (1940). 130 Caldwell and Hixon, J. Biol. Chem., 123, 595 (1938). 131 Pacsu and Trister, J. Am. Chem. Soc., 62, 2301 (1940). 132 Wolirom and Pletcher, J. Am. Chem. Soc., 63, 1050 (1941). 133 H a n n a n d H u d s o n , J. Am. Chem. Soc., 6 $ , 1484 (1941). 134 v . Euler, K a r r e r , a n d Becker, Helv. Chim. Ada, 19, 1060 (1936). 135 Richtmyer and Hudson, J. Am. Chem. Soc, 63, 1727 (1941). 136 Jackson and Hudson, J. Am. Chem. Soc., 61, 959 (1939). 137 Maclay and Hudson, J. Am. Chem. Soc, 60, 2059 (1938). 138 Isbell and Frush, J. Research Natl. Bur. Standards, 24, 125 (1940). 139 Jackson and Hudson, J. Am. Chem. Soc, 63, 1229 (1941). 140 Neuberger, J. Chem. Soc, 1941, 47. 141 Neuberger, J. Chem. Soc, 1941, 50. 142 Beaven and Jones, Chemistry & Industry, 58, 363 (1939). 143 Birkinshaw, Charles, and Clutterbuck, Biochem. J., 25, 1527 (1931). 144 Haskins, Hann, and Hudson, J. Am. Chem. Soc, 64, 132 (1942). 146 Reichstein and Montigel, Helv. Chim. Ada, 22, 1212 (1939). 146 Reichstein, Helv. Chim. Ada, 19, 402 (1936). 147 Reichstein, Helv. Chim. Ada, 19, 979 (1936). 148 Steiger and Reichstein, Helv. Chim. Ada, 21, 161 (1938). 149 Steiger and Reichstein, Helv. Chim. Ada, 21, 546 (1938). >" Mason, Hoehn, and Kendall, J. Biol. Chem., 124, 459 (1938). U1 Reich, Sutter, and Reichstein, Helv. Chim. Ada, 23, 170 (1940). "•2 Prins and Reichsstein, Helv. Chim. Ada, 23, 1490 (1940). 168 Reichstein and Gatzi, Helv. Chim. Ada, 21, 1185 (1938). 164 Kendall, Mason, Hoehn, and McKenzie, Proc. Staff Meetings Mayo Clinic, 12, 136 (1937). '
SURVEY OF PERIODIC ACID OXIDATIONS
166
375
Kendall, Mason, Hoehn, and McKenzie, Proc. Staff Meetings Mayo Clinic, 12, 270 (1937). 166 Mason, Hoehn, McKenzie, and Kendall, J. Biol. Chem., 120, 719 (1937)> 167 Reiehstein and Fuchs, Helv. Chim. Acta, 23, 676 (1940). 168 Ehrhart, Ruschig, and Aumuller, Ber., 72, 2035 (1939). 1M Hegner and Reiehstein, Helv. Chim. Acta, 24, 828 (1941). 160 Shoppee, Helv. Chim. Acta, 23, 925 (1940). 1(1 Lardon and Reiohstein, Hdx. Chim. Acta, 24, 1127 (1941). 162 Miescher, W e t t s t e i n , a n d Soholz, Helv. Chim. Acta, 2 2 , 8 9 4 (1939). 163 Hoehn and Mason, / . Am. Chem. Soc., 60, 1493 (1938). 184 Reiehstein and v. Arx, Helv. Chim. Acta, 23, 747 (1940). m Hirschmann, / . Biol. Chem., 140, 797 (1941). 166 Kendall, Mason, and Myers, Proc. Staff Meetings Mayo Clinic, 11, 351 (1936). 187 Reiehstein, Helv. Chim. Acta, 19, 1107 (1936). 168 Mason, J. Biol. Chem., 124, 475 (1938). 169 Ruzicka and Brenner, Helv. Chim. Acta, 23, 1325 (1940). 170 Charles and Todd, Biochem J., 34, 112 (1940). 171 Rapson, J. Chem. Soc., 1940, 1271.
CHAPTER 9
THE RESOLUTION OF ALCOHOLS
A. W. INGEESOLL
--»
VanderbiU University CONTENTS
o INTRODUCTION
'
•
P A Q B
377 377 379
RESOLUTION BY SEGREGATION OF ANTIPODES BY CRYSTALLIZATION RESOLUTION BY FRACTIONATION OF DIASTEREOISOMEHIC DERIVATIVES . . . .
Resolution through Simple Esters Z-Menthyl Isocyanate . . . . ? . ' " d-Camphoric Acid d- and Z-Mandelic Acid ' d- and Z-Camphorsulfonyl Chloride Z-Menthoxyacetic Acid Z-Menthylglycine d-Tartranilic Acid Resolution through Salts of Acid Esters Acid Sulfates Acid Phthalates and Succinates Resolution through Ethers and Coordination Complexes
RESOLUTION BY D I F F E R E N T I A L INTERACTION WITH AN ACTIVE A G E N T
'. . . .
380 381 381 381 381 381 382 383 384 384 385 387
388
. . . .
Fractional Reaction with an Optically Active Agent Fractional Decomposition on an Optically Active Catalyst Fractional Adsorption on an Optically Active Surface Asymmetric Biochemical Reaction Biochemical Resolution ' • Controlled Asymmetric Biosynthesis '
EXPERIMENTAL CONDITIONS IN RESOLUTIONS THROUGH SALTS OF ACID E S T E R S .
388 389 389 390 390 392
393
Preparation of Acid Esters Formation and Separation of Salts Solvents Resolving Agents Fractional Crystallization Purification of Both Active Forms^ Isolation of Active Acid Esters . " . . . « Purification of Active Acid Esters Hydrolysis of Active Acid Esters 376
. . _
393 394 394 394 394 396 397 397 397
PASTEUR'S FIRST METHOD
EXPEBIMENTAL P B O C E D U B E S
377
PAGE! 398.
Preparation of 2-Menthoxyacetic Acid Resolution of c&-Menthol Resolution of (K-2-Octanol Preparation of <K-OctyI Hydrogen Phthalate Resolution with Brucine in Acetone Decomposition of the Brucine Salts . . . . Purification of the Crude Active Hydrogen Phthalates Recovery of the Active Alcohols Resolution of s-Butyl Alcohol
TABLES OF OPTICALLY ACTIVE ALCOHOLS AND PHENOLS
.
398 399 400 400 401 401 402 402 403
404
INTRODUCTION
The resolution of nearly one hundred and fifty alcohols and phenols is recorded in the literature. Practically every known method of resolution has been applied to these classes of substances, and several methods of considerable utility have been developed. It is the purpose of this chapter to describe and evaluate the results thus far, obtained. Methods of resolution seldom possess the scope and generality of application associated with purely synthetic processes. The worker in this field therefore is obliged to place more than the usual reliance upon knowledge of underlying principles and upon patient and resourceful experimentation guided by extensive acquaintance with the literature. For this reason, a brief statement of the underlying principles and the main steps in the experimental procedure for all the important methods of resolution are included.*
RESOLUTION BY SEGREGATION OF ANTIPODES BY CRYSTALLIZATION
(Pasteur's First Method)l A solution of a solid racemic substance under suitable conditions may deposit individual crystals each of which is composed chiefly or exclusively of one or the other of the two active components. The crystalline deposit as a whole contains equal weights of the two active components and is commonly known as a racemic mixture or conglomerate: The
* The reader is assumed to be familiar with the elements of stereoohemical theory and terminology and with at least the main features of the more common general methods of resolution. An excellent treatment of these subjects is contained in the chapter on stereoisomerisnvby Shriner, Adams, and Marvel in "Organic Chemistry—An Advanced Treatise," edited by Gilman, John Wiley & Sons, New York, 1938, 1943. 1 Pasteur, Compt. rend., 26, 535 (1848); Arm. ctnm. phvs., [3] 24, 442 (1848).
378
THE RESOLUTION OF ALCOHOLS
individual crystals often exhibit enantiomorphism in external form or show dissymmetrical optical or electrical properties by which the dextro and levo formamay be distinguished. When such distinction is possible a resolution may be effected by sorting out mechanically the crystals of each antipode. Alternatively, it may be possible to induce the partial crystallization of one component alone by inoculating the supersaturated solution with a crystal of that component2> 3 or with some other suitable material.4 In this case the second component remains in solution, at least temporarily, for lack of a suitable nucleus for crystallization. The initial deposit is removed before crystallization of the other antipode is permitted to occur. Usually the mother liquor then may be made to deposit the second antipode by suitable concentration and seeding. The two antipodes thus may be crystallized more or less alternately until the solution is exhausted. _^ Both modifications of the method depend upon a natural segregation of the molecules of each active component into their individual crystal lattices. Experience has shown that such segregation, though common for dissimilar solutes, seldom occurs in the solution of a racemic substance and then usually in a narrow range of conditions that cannot be predicted or attained readily. In the great majority of instances the molecules of both active components combine in equal numbers to form one species of crystals known as a racemic compound or combine in variable proportions to form a series of solid solutions. Also, when segregation does occur, the experimental procedure necessary to produce distinguishable crystals or a uniform deposit of one variety is usually troublesome and slow. Hence the method has assumed practical value only in a few instances in which all the circumstances are especially favorable. Thete have been few attempts to apply this method to the resolution of alcohols. Le Bel,6 following earlier experiments of Pasteur,6 failed to resolve racemi& s-butyl carbinol by crystallization of the barium salt of the racemic hydrogen sulfate. dJ-Erythritol7 was found to be a racemic mixture, but the active crystals were too poorly formed to permit separation. It has been stated 8 that dZ-cis-jS-decalol shows indications of being a resolvable racemic mixture, but no resolution has been described. The only recorded clear-cut resolution by this method is that of the
Gernez, Compt. rend, 63, 843 (1866); Ann., 143, 387 (1867). Ruff, Bar., 34, 1362 (1901). 4 Ostromisslenski, Ber., 41, 3035 (1908). 6 Le Bel, Compt. rend., 87, 213 (1878), Bull. soc. chim , [2] 31,104 (1878). 6 Pasteur, Compt. rend., 42, 1259 (1856). 7 Maquenne and Bertrand, Compt. rend , 132, 1565 (1901). "Huckel and Kuhn, Ber., 7<J, 2479 (1937).
8 2
PASTEUR'S SECOND METHOD
379
glycol, dWsohydrobenzoin. Erlenmeyer,9 following earlier observations of Bodewig,10 found that crystallization of this substance from ether gave optically active hemimorphic crystals with rotations of the order of ±8°. Read and co-workers "• 12 have shown that the resolution in ether ••13 is sometimes incomplete, since the rotations of the pure active forms are ±92°. Crystallization from ethyl acetate or chloroform,12- w however, readily gave both of the pure active forms. Perhaps the most that can be said for this method is that it has been neglected in favor of more reliable methods and that it might at least be tried when other methods have failed. Many phenols and alcohols are crystalline or form a variety of crystalline derivatives that could be tested without great difficulty. RESOLUTION BY FRACTIONATIOIT OF DIASTEREOISOMERIC DERIVATIVES (Pasteur's Second Method) 16 The most useful and general of all methods of resolution is that which involves combination of a racemic substance with an optically active reagent (a so-called resolving agent) to give two diastereoisomeric derivatives, one derived from each of the two active components. These diastereoisomers often may be separated by conventional fractional crystallization. Each isomer then is treated to regenerate the pure active component. No satisfactory method has yet been devised for separation of such diastereoisomers if they are liquids, since the vapor pressures are so nearly alike. Bailey and Hass 16 effected for the first time partial separations of certain diastereoisomeric esters, including the lactates of 2-butanol and 2-pentanol and related esters by fractional distillation through an efficient column. In the customary use of the method, the first step is the formation of a semi-permanent linkage between the resolving agent and the two components of the substance to be resolved. This step obviously should be as convenient and as nearly quantitative as possible. The linkage must be stable enough to remain intact during the subsequent operations in9 Erlenmeyep, Ber., 30, 1531 (1897). "Bodewig, Ann., 182, 279 (1876). 11 Read and Steele, J. Chem. Soc, 1927, 910. " Read, Campbell, and Barker, J. Chem. Soc, 1929, 2305. 13 Ott, Z. anorg. Chem. (Schenck-Festschrift), 188, 47 (1930). 14 Reis and Schneider, Z. Krist., 69, 62 (1928). "Pasteur, Compt. rend., 3fi, 176 (1852); 37, 162 (1853). 16 Bailey and Hass, J. Am. Chem. Soc, 63, 1969 (1941).
380
THE RESOLUTION OF ALCOHOLS
volved in the fractional crystallization process, yet it must also be capable of being broken readily in the final step without causing racemization or other damage to the desired active component or to the resolving agent, and without requiring conditions that interfere with the ready recovery of both products. For the resolution of an alcohol or phenol, the most common type of linkage that meets these requirements is that formed by esterification with an acid or acid derivative. In practice, the method takes two principal forms: (a) The racemic alcohol is esterified with an optically active acid. The acid is chosen, if possible, so that the two resulting diastereoisomeric esters are soh'ds capable of separation. After the separation, the active alcohol and resolving agent are recovered from either (or both) of the pure active esters, usually by alkaline hydrolysis. (6) The racemic alcohol is esterified with a diacid (such as phthalic acid) so that the corresponding acid ester is produced. The ester is then resolved as an acid, the resolving agent usually being an optically active base, such as an alkaloid. When either or both of the salts derived from the two active forms of the acid ester have been purified, the resolving agent is removed and the corresponding active acid ester is saponified to regenerate the active alcohol. Although the two procedures just outlined, especially (6), actually have been used for more than 90% of all recorded resolutions of alcohols, neither is invariably successful or convenient. The scope and some of the limitations of the various methods are indicated in the following sections. Resolution through Simple Esters Frankland and Price " were the first to attempt the resolution of alcohols (and acids) by fractional crystallization of their solid esters. The isomeric solid esters formed from i-s-butylcarbinol and dJ-dibenzoylglyceric acid failed to separate on crystallization; the corresponding dlalcohol-Z-acid ester was liquid. Marckwald and McKenzie 18> 19 effected partial resolutions of dJ-mandelic acid and related acids with Z-menthol and d-borneol, and of a7-2-octanol with d-tartaric acid, but did not develop a satisfactory method for resolving alcohols. Later investigators, however, have employed the following resolving agents in several more or less successful resolutions of certain alcohols: (a) i-menthyl isocyanate, (b) d-camphoric acid, (c) d- or ^-mandelic acid, (d) d- or
Frankland and Price, J. Chem. Soc , 71, 253, 696 (1897). Marckwald and McKenzie, Ber., 32, 2130 (1899); 34, 485, 1419 (1901). 19 Marckwald and McKeuzie, Ber., 34, 469 (1901).
18 17
Z-MENTHOXYACETIC ACID
381
3-camphor-lG-sulfonyl chloride, (e) J-menthoxy- and d-bornoxyacetic acids, (/) J-menthylglycine, and (g) d-tartranilic acid. Z-Menthyl Isocyanate. Pickard and Littlebury 20 ' 21 found that lmenthyl isocyanate forms crystalline esters (urethanes) with many alcohols and phenols. The two diastereoisomeric urethanes from dJ-1-phenyl1-p-hydroxyphenylethane and from d£-ac-tetrahydro-/$-naphthol were separated readily.20 The method has not been applied widely. Z-Menthyl isocyanate is the most readily available resolving agent of this type but is difficult to prepare. The urethanes are not easily hydrolyzed, and the isocyanate is not recovered in the hydrolysis but is converted to the amine. x {/-Camphoric Acid. Mascarelli and Deliperi 22 obtained only partial resolutions of several alcohols by the use of d-camphoric .acid or its anhydride. Most of the pairs of hydrogen camphorate esters formed from this acid could not be separated by crystallization. d- and Z-MandeHc Acid. Active mandelic acids have been used successfully in the resolution of d^-menthol.23'24 This method suffers the disadvantage of almost complete racemization of the rather costly resolving agent during the final hydrolysis of the diastereoisomeric esters. d- and 7-Camphorsulf onyl Chloride. dZ-Menthol was resolved readily by fractionation of the crystalline esters formed from d- and Z-camphor10-sulfonyl chloride.25 The yield of active menthols was unsatisfactory, however, because the drastic conditions necessary for the hydrolysis of tije sulfonates caused extensive dehydration of the alcohol. Z-Menthoxyacetic Acid. In order to overcome most of the disadvantages of the reagents mentioned above, Read and his associates!6 introduced a new class of resolving agents, typified by J-menthoxyacetic acid, CioHieOCH2C02H. Acids of this type meet many of the requirements of satisfactory resolving agents. Thus they are prepared easily from chloroacetic acid and the sodium derivatives of various readily available active alcohols, such as i-menthol and d-borneol. The alcohol to be resolved is esterified readily by means of the corresponding acid chloride and pyridine. The esters have convenient rotation values and often crystallize well enough to permit satisfactory resolutions. The resulting
'"Piokard and Littlebury, J. Chem. Soe., 89, 467, 1254 (1906). !1 Pickard, Littlebury, and Neville, J. Chem. Soc, 89, 93 (1906). 21 Mascarelli and Deliperi, Atti acad. Lincei, 26, (i) 43 (1916); Qazz. chim. Hal., 46, (i) 416 (1916). M McKenzie and Luis, J. Chem. Soe., 1934, 715. "Findlay and Hiokman, J. Chem. Soc, 91, 905 (1907). ra Read and Grubb, / . Chem. Soc., 1931, 188. " Read and Grubb,' J. Soc. Chem. Ind., Bl, 329T (1932); Brit, pat., 397,212; Ger. pat., 600,983.
382
THE RESOLUTION OF ALCOHOLS
active esters may be hydrolyzed easily so that both the pure active alcohol and the resolving agent are recovered. Although not yet widely used, resolving agents of this type have proved to be remarkably versatile. Both active antipodes of the menthoxy- and bornoxy-acetic acids have been used, thus facilitating the purification of both active forms of alcohols. Thus d£-menthol26 and di-neomenthol27 were completely resolved by the successive use of Vand d-menthoxyacetic acids, and crude d- and J-borneol were purified through use of d- and Z-bornoxyacetic acids,28 respectively. Also, lmenthoxyacetic acid has been used successfully for resolving dl-transcyclohexane-l,2-diol29 into both active forms. The resolution of glycols is usually difficult by other methods. _ ' 30 The success of Knauf, Shildneck, and Adams in adapting iknenthoxyacetic acid to the resolution of phenols is especially useful since only one member of this class had been resolved previously by other methods.20 Fujise and Nagasaki31 extended the method to the resolution of 7-hydroxyflaVanone and demethoxymateucinol, but perhaps the most interesting example is the complete resolution of cK-equilenin by Bachmann, Cole, and Wilds.32 The attempted resolution of di-isoequilenin 32 was unsuccessful. The method thus appears to be particularly promising for the resolution of phenols, glycols, and alcohols of high molecular weight. Esters of menthoxy- and bornoxy-acetic acids with lower alcohols tend to be liquids, and in some instances83 diastereoisomeric esters cannot he separated even when crystalline. It appears probable that active alkoxyacetic acids derived from other highly crystalline terpenoid or steroid alcohols might prove useful in overcoming these difficulties and in extending the scope of the method. The preparation of Z-menthoxyacetic acid and its use for the resolution of d£-menthol are described in a later section (p. 398). Z-Menthylglycine. Clark and Read 34 also have introduced still another type of agent for resolving alcohols. The method of application is essentially similar to that just described but has additional features making for greater range and flexibility. The racemic alcohol is first esterified with chlordacetic acid and the product is then caused to react with an optically active amine, such as Z-menthylamine. The resulting
17
Read and Grubb, J. Chem. Soc., 1933, 167. Clark and Read, J. Chem. Soc, 1934, 1773. Wilson and Read, J. Chem. Soc., 1935, 1269. 80 Knauf, Shildneck, and Adams, J. Am. Chem. Soc, 56, 2109 (1934). 81 Fujise and Nagasaki, Ber., 69, 1893 (1936); J. Chem. Soc Japan, 57, 1245 (1936). 82 Baehmann, Cole, and Wilds, / . Am. Chem. Soc, 62, 824 (1940). 88 Read, Grubb, and Malcolm, J. Chem. Soc, 1933, 170. '* Clark and Read, J. Chem. Soc, 1934, 1775.
28 29
and the active alcohol is recovered from each form by hydrolysis. Org. J. 1935. being employed directly for esterification of the alcohol to be resolved. Soc. Chem. / .d-TARTRANILIC ACID 383 diastereoisomeric J-menthylglycine esters are separated by crystallization.34 Recovered Z-menthylglycine or its N-acyl derivatives may be used again. which are then fractionated instead. (cH)RO—CO—CH2C1 + H2NR* -*• (d)RO—CO—CHz—NHR* . Syntheses. 89 Ingersoll and Burns.35 thujyl-. 54. 1934. Thus J-menthyl-Z-menthylglycine was purified as the sulfate and d-menthyl-Z-menthylglycine as the p-nitrobenzoyl derivative. » Diokison and Ingersoll. 40 Barrow and Atkinson. 80 (1937). Moreover. 1939. 226. 61. The esters are formed by heating the alcohol with d-tartranil in the presence of an acid HOCH—CO HOCH—CONHC6H6 C NC6H6 + ROH -^—* / HOCH—CO 85 HOCH—COOR Read and Johnston.• (d)ROH . 2-hexanol. 2477 (1939). 274 (1932). should the fractionation of the esters themselves be unsatisfactory. Chem. Am. Soc. Am. Am. .. and/or + ©RO—CO—CH2—NHR* -> (QROH HOOC—CH2—NHR* It was found that the majority of Z-menthylglycine esters. Barrow and Atkinson 40 have investigated the use of the esters of d-tartranilie acid for resolving certain lower alcohols. 1138. 54.36 and fenchyl-amines 38 as "well as simpler amines like a-phenylethylamine 37 and its analogs. The method so far has been applied only to the" resolution of dlmenthol. 87 Ingersoll. Soc. 2-pentanol. they may be converted to their crystalline N-acyl derivatives or to the salts of ordinary acids.. 638. / . even those of the lower aliphatic alcohols. Soc.38'39 d-Tartranilic Acid. 88 Ingersoll and White. They succeeded in obtaining pure active 2-octanol. / . Chem. 76. and menthol from the racemic modifications but were unsuccessful in resolving 2-butanol and 2-methyl-l-butanol because of the formation of mixed crystals. Chem. are highly crystalline and stable enough for satisfactory fractionation. 17. The procedure was also unsuccessful in resolving methylphenylcarbinol and a-terpineol because of the ease of dehydration of these alcohols.34 Its range doubtless can be extended still further by replacing J-menthylamine with other readily available terpenoid amines such as the active carvomenthyl-. Chem. J. 4712 (1932).. Soc.
1233 (1934). Basic resolving agents are sufficiently numerous and accessible so that it usually is possible to find some combination of active base and solvent that will yield separable crystalline salts with nearly any type of acid. Ber. 26. Resolution through Salts of Acid Esters In this method the alcohol is converted to an acid ester.. It was developed because of the relative ease and certainty with which racemic acids may be resolved by means of their salts with active bases. but its preparation is easy and cheap. 315 (1939). and Richaud. 41. 1203 (1893). rend..42 after failures in other instances. trav. 312 (1922). Compt. 394). A list of basic resolving agents is given later (p. Meth.. Ber. Japon. 47 Godchot. and the active esters are recovered from the salts and saponified to yield the corresponding active alcohols. 42 48 41 .. 198.46'46> 47 The glycol is converted to the dihydrogen sulfate by reaction at —15° with excess concentrated sulfuric acid. The acid ester is then resolved by crystallization of its salts with active bases. 44 Griln. 52. presumably still other common amines could be substituted for aniline in forming the original tartranil. finally effected a partial resolution of s-butyl hydrogen sulfate as the brucine salt. The resolving agent is not recoverable after the final hydrolysis. 27. 260 (1919). Ber. that the method is particularly useful for resolving certain glycols such as propylene glycol u and various cycloalkanediols. The method has proved to be impracticable for most altfohols43 because the majority of alkyl hydrogen sulfates are unstable and inconvenient to handle.. phthalate.. such as strychnine. The method has been by far the most generally applicable.384 THE RESOLUTION OF ALCOHOLS and are separated by crystallization. and the product is obtained as a solution of the barium salt. Compt. 40. Folia pharm. u Godchot ana Mousseron. rend. It has been shown. 48 D e n . or succinate. usually the sulfate. Bee. 695 (1907). Kriiger 41 failed to resolve the alkaloid salts of the hydrogen sulfate of ethyl-n-propylcarbinol but Meth. Acid Sutfates.40 p-Bromotartranilates also were used with moderate success. Mousseron.. Pasteur 6 and also Le Bel 4 fractionated the cinchonine salts of the mixture of amyl hydrogen sulfates derived from fusel oil and effected a partial separation of the structurally isomeric alcohols. 837 (1934). Krilger. This is treated with two equivalents of the sulfate of some active base. 199. however. Hano. chim.
Acid Phthalates and Succinates. Chem. moderately strong acids that usually can be resolved with active bases. Soc. or-) . 49 48 . J. Chem. 106.48 These are easily prepared from nearly all types of primary or secondary (but not tertiary) alcohols by reaction with the corresponding acid anhydride.ACID PHTHALATES AND SUCCINATES 385 After removal of barium sulfate and fractionation of the alkaloid salts. 101. 101. 45 (1911). 2677 (1914). 99. but it may be noted that the glycols cannot be resolved by the phthalic ester procedure described below because they tend to form polymeric esters instead of simple hydrogen phthalates when treated with phthalic anhydride. 105. Soc.COOR iCOOBase (+ or . 1115 (1914). 620 (1912). / . and of the active alcohols from the acid esters. 9 1 . 63 Pickard and Kenyon. 1923 (1913). Chem. 103. 9 1 . Chem. 60 Pickard a n d Kenyon. J. 830 (1914). 105. 1973 (1907). Soc. may be accomplished easily and in excellent yield. 1427 (1912). Soc. Chem. Soc. Chem. / . 2058 (1907). 62 Pickard and Kenyon. J.and Jborneol and for the resolution of dUsoborneol by crystallization of the Z-menthylamine salts of the hydrogen phthalates. J. M Pickard and Kenyon.48-46 The method is tedious and not yet well developed. the glycol sulfate ester is recovered as alkali -salt and saponified with alkali. The resulting acid esters are stable. Chem. J. * Pickard a n d Kenyon.48 The method was then extended. Soc. After the resolution the recovery of the active acid esters from the salts.. Soc. Piekard a n d Kenyon. The resolution of alcohols through acid esters was given especially useful form when Pickard and Littlebury introduced the use of hydrogen phthalates and hydrogen succinates. Chem. particularly by Pickard and Kenyon 48~B6 and by Levene Pickard a n d Littlebury. Soc. J. The • procedure for the use of phthalates is outlined'in the following scheme.) The method was used first for the purification of crude d. "Pickard and Kenyon.
. 66 Levene and Harris. and K u n a .. J. 2304 (1924).. Chem. J.. 591 (1929). / . 78 Levene and Stevens. 80 Paolini. 67 _ . (ii) 226 (1914). 100. Chem. Phenols also usually form phthaleins or other condensation products instead of simple acid esters. J. 355 (1926). Soc. Chem. Levene and Haller. " to many series of simple secondary alcohols and eventually to alcohols of nearly all types.. Science. M -« and CH 2 =CHC5 2 CHOHR. Biol. 55 (1936). 812.66 in which R represents normal or variously branched alkyl radicals ranging from methyl to pentadecyl.. Lincei. The 3-nitrophthalates. Chem. 589 (1933). Chem. 173 (1934). 65. Biol. 579 (1929). • "*» Levene and Haller. J. 77 Levene and Stevens. M ' Levene and Haller. 60 Levene and Haller... 47 (1929). A few tertiary alkyl phthalates. Chem. Biol. quinine. Chem. Chem.« (CH3)2CHCH2CHOHR.. Biol. J. Biol. 91. 759 (1937). 83. have been pre«• Levene and HaUer... 89 Levene and Marker. 81.M. / . 69. 405 (1931). 106. 379 (1932). 90. Chem. Rothen. 375 (1930). Biol. Biol. 475 (1928). phthalic anhydride has been much the most widely used reagent. 507 (1925). J. Chem. Biol. have been prepared and resolved by first converting the alcohols to sodium or potassium salts and allowing these to react79> 80 with phthalic anhydride. 61 Levene and HaUer. 77. 7J Levene and Mikeska. In the great majority of these resolutions the alkaloids brucine. 669 (1931). 818 (1925). 6S (CH3)2CHCHOHR. J. 88 Levene and Marker. J.. 777 (1937). 83. Chem. J. For these resolutions... 74 Levene and Mikeska. 89. 555 (1928). 425 (1929). Marker. Biol. Biol..67 C6H5CHOHR. Chem. J. 804.. 76. 79 Fuller and Kenyon. 55. Biol. 113.7". 83. This modification has been apph'ed successfully to dlra. 471 (1930).. Chem. and K u n a . 415 (1928).. however. 185 (1929).. Biol. 79. 65 Levene and Haller.6°. 71 Levene.. 81 Paolini and Divizia. and/or cinchonidine were used instead of the Z-menthylamine originally employed. 587 (1927). Chem. J. J. 76 Levene. 70 Levene and Marker. J. Chem.386 66 78 THE RESOLUTION OF ALCOHOLS and others. Biol. Bwl. 703 (1929).. Chem. J. 180. Biol. J. •• CH 2 =CHCHOHR. Biol. The procedure usually is unsuitable for tertiary alcohols since the reaction with phthalic anhydride or succinic anhydride either fails or results* in dehydration of the alcohol. 81. 87. Gazz. Biol. 68 Levene and Haller. J. Chem. Among the series that have been most completely studied are -CHsCHOHR. ital. Chem. 7J Levene and Mikeska. 120. Biol. Biol. Chenu. Chem. 68 Levene and Haller.60. strychnine. Chem. J. J. 78 Levene. however. Atti acad.6°. Biol. J. " C2H5CHOHR.. chim. Biol. 67 Levene and Marker. Chem. Biol. 83.7S CeHnCHOHR. Chem. and Rothen.«. 97. 82 Levene and Haller. 70. 75. glycols cannot be resolved by this procedure because they form polymeric esters when heated with phthalic or succinic anhydride.81 As already mentioned. J. Rothen..177 (1929). J. 125.and /3-santalols 81 and dWinalool. [5] 23.
Thus dUtranscyclopentane-l. /3-phenylpropyl alcohol. but the products were not suitably crystalline.60. 588 (1937).42 The hydrogen succinates also have been employed in the resolution of menthol. Biochem. Z.ETHERS AND COORDINATION COMPLEXES 387 pared in a few cases 82' n and proved more suitable for resolving s-butylcarbinol. 109 (1912). 126. preferably. "Helferich and Hiltmann. 26.2-diol was converted to the acetylated monoglucoside (or. The tetrachlorophthalates were unsatisfactory. and Woodman." (CH3)2CHCHOHR..61 and C2H5CHOHR. ^ . and dZ-methylethylacetic acid indicate that no specific functional group is necessary for the coordination process. Soc. J.Sobotka and Goldberg 86 have resolved dM-phenyl-2-butanol by fractional crystallization of the solid coordination complex formed with desoxycholic acid. / . J. 905 (1932). Weinhold.60. TJie less soluble fractions. and. 70. Chem. 887 (1915). 308 (1923). The method failed with cK-carvomenthol and di-methylphenylcarbinol and with the majority of 81 Cohen. Chem. Marshall. 7-phenylbutyl alcohol than the corresponding phthalates. 308. Chem. but has been insufficiently studied as yet. Chem. Ber. Similar resolutions of di-camphor.60 or for completing resolutions only partly effected by means of the phthalates. The method would appear to have considerable promise for resolving glycols.60 phenylethylcarbinolB0 and various members of the series CH3CHOHR. after deacetylation and subsequent hydrolysis with the aid of emulsin. 53.. dWimonene. and possibly phenols. the diglucoside) by reaction with d-/3-acetobromoglucose and silver carbonate. Jnd.. physiol. . 86 Sobotka and Goldberg. including alcohols that are not readily esterified. 107..87 who found that digitonin precipitates the digitonide of one (partially) active form of a-terpineol and oc-tetrahydro-/3-naphthol when added to a solution of the racemic form. and Klanhardt.63-83 Resolution through Ethers and Coordination Complexes Walker and Read 84 attempted to resolve alcohols through ether formation with d-hydroxymethylenecamphor. 299. " Piokard and Littlebury. and Klanhardt.. Weinhold. J. 53T (1934). The method deserves further study as a possible means of resolving various types of compounds. 101.". Soc. 87 Windaus. Helferich and Hiltmann 86 recently have been more successful with a method employing glycoside formation. Soc. 44 Walker and Read. A method employing a similar effect is that of Windaus.63 The succinates are superior to the corresponding phthalates when more soluble or more stable salts are required. gave the pure deatfro-glycol in moderate yield.83 phenylmethylcarbinol.
A partial resolution of the antipodes therefore can be effected by separating the combined and the uncombined portions of the system. when a mixture of equal amounts of the two diastereoisomeric esters was partially hydrolyzed. The process has been extended to the resolution of acids and amines through the formation and hydrolysis of amides. the rates of the reversal usually are different for the two products. Ber .388 THE RESOLUTION OF ALCOHOLS other alcohols and phenols studied. Also. 1005 (1938). Eisenlohr and Meyer 8S likewise were unsuccessful in the attempt to use numerous other molecular compounds. RESOLUTION BY DIFFERENTIAL INTERACTION WITH AN ACTIVE AGENT When the two active components of a racemic substance are brought into contact with an optically active agent with which some form of slow or reversible combination may occur. after the interaction has continued for a time but has not gone to completion. Also.. Several methods of stepwise resolution have been based upon the effects just described. 801 (1905). Marokwald and Meth. after combination has taken place. The two effects may operate simultaneously when the process is reversible. S8. . Ber. one antipode alone will enter into combination or one diastereoisomeric combination only will undergo decomposition'. Thus When e#-mandelic acid was heated with less than one equivalent of J-menthol. Presumably the difference in rates in either direction is the result of steric factors that influence the chemical or thermal stabilities of the two combinations concerned. then more of one active component and less of the other will be found in combination. 71. In any event. at the other extreme the antipodes will show no significant dif88 89 Eisenlohr and Meyer. Fractional Reaction with an Optically Active Agent The principles outlined above were applied by Marckwald and McKena e 18 for the partial resolution of a racemio acid with an active alcohol. At one extreme. the degree of separation obtainable in processes of this kind will depend on the differential rate coefficient of the two competing reactions. the resulting ester contained somewhat more ?-menthyl-dmandelate than Z-menthyl-Z-mandelate and the unesterified acid contained a corresponding excess of Z-mandeh'c acid.89 In general. the regenerated acid and that still combined in the residual ester contained unequal amounts of the two antipodes. it usually i» found that the two antipodes do not combine at the same rate.
pharm. These results have not been explained fully. Naturwiasenschaften. J. 363 (1932). " Schwab and Rudolph. 141. 29. Usually the difference in rates is comparatively small. The method is not practical in its present form. Hence. Similar results were noted after partial catalytic oxidation on the same surfaces. 19S9. but a few instances are recorded in which partial resolutions were effected. J. Fractional Adsorption on an Optically Active Surface Henderson and Rule 9S separated dJ-j>-phenylenebisiminocamphor into its active forms by passing its dilute petroleum ether solution through a column containing powdered d-lactose. Chem. 92 Henderson and Rule. it is possible that each of the two active forms of the alcohol is adsorbed momentarily on the quartzcopper interface. 91 .91 The alcohol recovered after partial thermal dehydration upon a film of copper supported on powdered d. No very useful resolutions of alcohols have been based upon this method.or Z-quartz was faintly active in the same sense as the quartz. it would appear to have little practical value.ADSORPTION ON AN OPTICALLY ACTIVE SURFACE 389 ference in rates.. Thus Marckwald and McKenzie 18 partially esterified rft-2-octanol with d-tartaric acid. ehim. the Worm' was carried toward the bottom. The d-form was more strongly adsorbed and hence collected near the top of the column. Nature. The procedure was similar to that commonly used in chromatographic analysis. Theoretically. unless means can be found to operate the process continuously. the substantially pure antipodes might result from enough repetitions. in proportions of the two antipodes can be increased by repeating the procedure upon either or both portions of the system obtained in the first treatment. VI. Several repetitions of the <> Pozzi-Escot. that recovered from the ester was slightly dextrorotatory. Pozzi-Escot90 obtained similar results with the d-tartrates of dJ-2-butanol. 917 (1939). 20. 57 (1909). Soe. Unfortunately each repetition at the same time increases the number and decreases the size of fractions beyond practical limits. Fractional Decomposition on an Optically Active Catalyst A method apparently fundamentally related to the above is illustrated by the fractional catalytic dehydration of dZ-2-butanol observed by Schwab and Rudolph. according to the countercurrent principle. The disparity.. The unesterified portion of the alcohol was slightly levorotatory.1668. the two "diastereoisomeric" combinations thus formed then react at different rates.
the method might be particularly useful for demonstrating the resolvability of certain unstable or tertiary alcohols for which other methods are unsuitable. rend..A. it is probable that metabolic products are formed in the active condition through mechanisms essentially similar to those described in the preceding paragraphs. and Nakamura. Asymmetric Biochemical Reaction Biosynthesis appears to be controlled by asymmetric influences of a highly specific nature.96 Pasteur observed that. 615 (1858). Kobayashi. Nature. The method has not been studied sufficiently to assess its generality and usefulness. . Since chemical reactions are not involved. 56.92 apparently because both antipodes were strongly adsorbed.1339 (1935) [C. "Karagunis and Coumoulos. gave negative or doubtful results. A. 33. and the method would appear to have interesting possibilities for resolving alcohols and phenols if a suitable variety of adsorbents and solvents can be found. Japan. On the other hand it may be noted that the method is based upon the continuous countercurrent principle and is therefore capable of effecting substantially quantitative separation of both antipodes.. 162 (1938) [C. and cotton. such as wool. 1032 (1857). 45. 7165 (1939)]. adsorptive power. the dextro component was decomposed com98 Tsuchida. 7411 (1938). Since the fundamental constituents of living matter are almost always optically active.or Z-quartz 93>94 powder as adsorbents. silk. 142. Less complete separations of various racemic substances appear to have been made with certain other sugars and with d. Compt. Hydroxylic compounds are usually readily adsorbed. Biochemical Resolution (Pasteur's Third Method). Chem. The controlling agents are probably optically active enzymes or other asymmetric cell constituents which are able to exert a selective influence upon metabolites through differential reaction. 298 (1860).390 THE RESOLUTION OF ALCOHOLS process on the partially separated fractions finally gave both pure antipodes. 30. Two interesting methods of preparing optically active substances (including alcohols) are based on these phenomena. adsorption. Numerous earlier attempts to effect differential adsorption of optical antipodes on amorphous active adsorbents.. Soc. The success of crystalline adsorbents may be attributed 92 to the presence of active crystal surfaces having limited. 46. The principal defect. or catalysis. when salts of dZ-tartaric acid were introduced into cultures of yeast or of certain molds. 926 (1936)]. but sterically specific. is the necessity for handling large volumes of solvent and adsorbent in order to separate a small amount of material. "Pasteur. 32. even when the differential adsorption coefficient is fairly large. 61. J.
Soc. the excreted glycuronate contained an excess of the d-form. 32. [3] 7.BIOCHEMICAL RESOLUTION 391 pletely while the levo form largely remained and could be isolated. Chem.106 Though a considerable number of active alcohols have been prepared by these methods.. 86. Thus dJ-borneol when fed to rabbits or dogs was excreted as the glycuronate. Bull. incidentally. Sometimes both forms are largely destroyed or the more resistant form is still optically impure. [2] 33.. 33. soc. Bull. 96 . Z. the other usually must be sacrificed.6 propylene glycol.96> n and various other lower secondary alcohols 98> "• 10° were obtained.. 89. [3] 9. In order to obtain one antipode.. These results. 102 McKenzie.106 The feeding of cM-camphor to dogs gave a glycuronate from which impure f-campherol was obtained. Aba. Chem.. and especially phenols. Mm. chim.. Only one instance is recorded in which both forms were obtained by using two different agents. Arch. Compt. Chem. 41 (1902). 532 (1881). 81. rend. are the earliest recorded examples of the resolution of alcohols by any method.pt. Le Bel and others extended this procedure to various racemic substances and demonstrated its generality. rend. [2] 34. Cmn. 103 Magnus-Levy. (i) 326 (1910). 88 Le Bel. Vs Williams. 1252 (1899). 2. 297 (1910). Biochem. soc. 147 (1879). the organisms usually employed being Penicillium glaucum or various species of mildew. J. " Le Bel r Bull. Bull. 23.106.97 the natural antipode is usually the less resistant to all agents. there are many serious limitations and disadvantages. Thus the partially pure active forms" of s-butyl carbinol. 97 Kling. soc.. chim... chim. The facilities and technique for isolating pure cultures of micro•" Le Bel. 1409 (1902). 312 (1879). The form that is obtained is not always the one desired. 319 (1907). 129. It also was found by various workers that the active components of certain racemic substances were unequally affected when fed to or injected into animals.. J.101. 106 Mayer. Biochem. 1519 (1939). 1849 (1938). Many alcohols. 92. 552 (1892). when dJ-menthol was fed to rabbits. physiol. 98. cannot be used at all because they are toxic to the organism or are not affected by it.. 9. Z.. Aside from these inherent defects the fermentation method of resolution in particular is experimentally difficult since it requires large volumes of dilute solutions (1 to 5%) and periods of time ranging from 2 to 60 days. Physiol. 439 (1908).102 Similarly. refeeding this product gave a small yield of the pure d-form. . rend. 101 Neuberg and Wohlgemuth. Skand. 676 (1893). hydrolysis of this gave slightly levorotatory borneol.101-104 the more resistant component or one of its derivatives could then be isolated in partially pure form from the urine. 100 Combes and Le Bel. 104 Hamalainen. or because they are physically unsuitable. Compt. Soc. soc.. Biochem.. 36. 129 (1882). Z.
62. Biochem.. 2248 (1910).. 10. Z.. 227 (1927). 98. Biol. The introduction of benzaldehyde into a solution of sugar undergoing fermentation by yeast gave Z-phenylacetylcarbinol. 115 Levene and Walti. Org. 112. has the advantage that. 327 (1922). 313 (1920).. Z. Jacobsohn. . 11J Farber. Syntheses. 107 . The introduction of methyl ethyl ketone into fermenting sugar gave a moderate yield of dextrorotatory methylethylcarbinol. 84 (1930). 114 Levene and Walti.. 491 (1929). 188.. and Neuberg. 735 (1932). 109 Tanko. Z. 361 (1931).1U. 111 Neuberg and Nord. Thus when df-bornyl dihydrogen phosphate was gradually hydrolyzed in the presence of yeast phosphatase 107 the first half of the process gave nearly pure Z-borneol. Ber. within limits. Biochem. Various optically active alcohols have been prepared by processes employing purified enzyme preparations or well-defined enzyme systems developed by living tissues under controlled conditions. At present it appears that all the biochemical resolution methods for alcohols can be used profitably only in a few specially favorable instances or when other methods fail. Biochem.392 THE RESOLUTION OF ALCOHOLS : organisms and providing for their highly specialized nutritional and environmental requirements are usually not available to the chemist. Controlled Asymmetric Biosynthesis. 110 Neuberg and Nord. Nord.»»• u * and from 3-keto2-butanol66 and 3-keto-l-butanol. Fermentforechung. The method based upon animal feeding and subsequent isolation of products from the urine is perhaps less inconvenient and deserves further study. 92. Chem. 96 (1918). 94. The laboratory application. 91 (1940). Biol. Ber. 108 Neuberg and Ohle. Among the more interesting examples are the series of active glycols derived from ketones of the type RCOCHzOH(R = methyl to n-amyl) »2. 610 (1922). " • Leven© and Walti.1U and hydroxy aldehydes. 128. notably by Neuberg and Levene and their associates. however.. the latter half nearly pure (i-borneol.109 These results are presumably due to asymmetric acyloin syntheses controlled by enzymes."• M. and Wagner. Z..110 The effective agent in this instance was the sterically specific yeast reductase system. Z. Chem. Biochem. " • Neuberg and Kerb. and Abonyi.The yeast reduction method has been applied with considerable success.. / . to several simple ketones. 264. physM.108 similarly the perfusion of acetaldehyde through the liver or muscles of pigeons gave d-acetoin. 2237 (1919). Munk."«• 1U the products being active alcohols or glycols.lu Active glycols have been prepared Neuberg.*•• "• 6S .112.113. All these processes doubtless are fundamentally the same as natural asymmetric biosynthesis. 127. 10. the nature of the starting material and the type of reaction are under experimental control. 52. Chem.110 as well as to a few diketones U1> 108 and many hydroxy ketones " 2 . J.
PREPARATION OF ACID ESTERS 116 114 393 also from 3-hydroxybutanal. If it does. EXPERIMENTAL CONDITIONS IN RESOLUTIONS THROUGH SALTS OF ACID ESTERS Preparation of Acid Esters The hydrogen phthalates may be prepared from nearly all stable secondary alcohols by heating equimolar quantities of pure phthalic anhydride and the di-alcohol for twelve to fifteen hours in a flask in an oil bath at 110-115°. It is then taken up in cold sodium carbonate solution. Phthalic acid is the usual major impurity and may interfere with the crystallization of the ester. and purified as usual. rend. The hydrogen succinates are more soluble in the usual solvents than the corresponding phthalates and often do not crystallize readily.117 The solution finally is poured onto a mixture of ice and excess hydrochloric acid. except that succinic anhydride is used. When the alcohol or the phthalate is unstable the esterification may be completed simply by refluxing the reagents in a low-boiling solvent w such as chloroform or petroleum ether or by allowing the mixture to remain overnight or longer at the ordinary temperature. or if the ester is liquid. and the crude ester is extracted with chloroform or benzene. The hydrogen phthalates are usually solids that may be crystallized from petroleum ether. reprecipitated by acidification. 2-hydroxypentanal. or acetic acid. it is convenient to extract the crude product with chloroform or benzene..74 with or without a diluent such as benzene or xylene. The hydrogen succinatee are prepared by procedures closely similar to those followed for the phthalates.114 The method appears to be particularly suitable for the preparation of. Their alkaloid salts also >17 Duveen. It is important to use rather pure acid esters for the resolution step. and the method is subject to most of the disadvantages referred to above (p. benzene. in which phthalic acid is nearly insoluble. Primary alcohols usually require a shorter period of heating. and the solution is washed with water to remove succinic acid. 391). Compt. Distillation of the solvent from the dried extract usually leaves the ester pure enough to crystallize or to use directly. The yields usually do not exceed 50%. Heating for two to three hours in a steam bath is then usually sufficient. 1185 (1938).'0 The crude ester is best taken up at once in ether or benzene. 206. .glycols and certain alcohols that are not readily obtained by other methods. A milder and much more rapid procedure consists in heating the alcohol and phthalic anhydride in the presence of about two molecular equivalents of dry pyridine. and 2-hydroxyhexanal.
and Kenyon.394 THE RESOLUTION OF ALCOHOLS are usually more soluble than those of the phthalates. Solvents. It is suggested that these amines.. This may be an advantage when the alcohol is of high molecular weight or whenever the alkaloid salts of the phthalate are too sparingly soluble or too unstable "• 6S for convenient recrystallization. Resolving Agents. The salts of the acid esters with the alkaloid or other active base are usually formed by adding one equivalent of the base in.or Z-a-phenylethylamine. and induce crystallization by adding chloroform or some other less powerful solvent. Experimental difficulties are encountered principally in the problem of separating the two diastereoisomeric derivatives by fractional crystallization. This is then recrystallized from the same or another solvent. cinchonidine. This. is a special case of 118 Gough. strychnine. J. A few other alkaloids. such as ephedrine. pure or aqueous methanol or ethanol. morphine. and quinidine.61 Occasionally the desired salt is too sparingly soluble to be recrystallized conveniently. . Soc. 1926. as well as numerous other synthetic amines that have been introduced as potential resolving agents.74 Water is almost never suitable as a solvent since the salts are usually partially hydrolyzed. yohimbine. pseudoephedrine. of course. The active bases most frequently used are brucine.36'38> S9 might well be investigated further when alkaloids are unsuitable or unobtainable.powdered form or in a solvent to the acid ester dissolved in acetone. or ethyl acetate. cinchonine. Sometimes it is advantageous to form the salts in a small amount of an effective solvent. such as J-menthylamine 48 and d. and apomorphine have found some general use for resolving acids but rarely or never have been used for resolving acid esters. deposits the greater part of the less soluble salt.118 have found only occasional use. Warming usually results in the formation of a complete solution which on cooling. Chem. it may then be purified by repeated extraction of the more soluble salt with hot solvent. Formation and Separation of Salts Since specific conditions for obtaining appropriate diastereoisomeric salts of any particular acid ester are difficult to define. Hunter. Synthetic amines. quinine. 2052. the comments which follow refer to a general procedure and some of the more common variations for preparing and separating such compounds. Fractional Crystallization. cocaine. in about the order given. such as acetone or methanol. or on concentration and cooling.
'Should no satisfactory solvent be found. Findlay. Green & Co. (c) Much more frequently than is commonly realized the two isomers cannot be separated satisfactorily by crystallization. 120 119 . Z. 494 (1899). until a successful resolution is effected or until all available combinations of resolving agents and solvents have been tried. "The Phase Rule. New York. a change must be made to another system. The d-form of the phthalate formed the less Rooseboom. Pickard and Kenyon used brucine and acetone successfully for the initial resolution of the hydrogen phthalatea of a series of alcohols of the type CH3—CHOH—R. physik. 28. In general. The course of the separation is followed generally by determining the rotatory power of the various fractions and by observing the changes in solubility and crystalline appearance of the successive fractions.119*120 In practice three fairly distinct situations may be encountered: (a) The two diastereoisomers may have adequate crystallizing power and at the same time may differ considerably in crystalline character and/or in solubility in the available solvents. When a favorable result is not obtained with a given resolving agent and solvent. the original resolving agent may be replaced by another. A prolonged systematic fractionation is then required. 7th ed. Chem. 1931.. Moreover." Chapters XXV and XXVI. and not infrequently the more soluble as well as the less soluble can be obtained pure.. (6) The two diastereoisomers do not differ greatly in solubility. Longmans. Such isomers are readily separated by simple fractional crystallization.FRACTIONAL CRYSTALLIZATION 395 the general problem involved in dealing with a heterogeneous system of three components. No method for predicting the combination of resolving agent and solvent for any particular substance has been discovered. in the most unfavorable instances (which are far from uncommon) the two diastereoisomers may crystallize together as a stable double compound or as a series of solid solutions. mixed solvents are sometimes useful.60 in which R represents normal alkyl groups from ethyl to undecyl. This situation results when the substances are so low in crystallizing power or so similar in solubilities or so unstable chemically that separation is impracticable.' The resolution then necessarily fails.. Even minor structural differences such as exist between neighboring homologs may lead to the necessity of using different resolving agents and solvents. and so on. it is most convenient first to remove the original solvent and substitute another. and usually only the less soluble salt is obtained pure. if necessary.
through^the rather soluble cinchonidine salts prepared from' toe residual levorotatory phthalates. Purely synthetic amines. J. Purification of Both Active Forms. When the second form also is required. 56. This procedure may be applied to the original racemic substance. Am. which almost invariably have been used for resolving acid esters. 402. the usual procedure is to seek another combination of solvent and resolving agent such that the second active form now produces the less soluble of the two derivatives. Am. but this agent was not useful for initial resolution of the dlAorm. 124 Ingersoll and Little. 400. Ber. 47. The fact that the cM-amine itself must be resolved before the active forms are available has prevented extensive use of Marckwald's method.. Am.' 123>1W by which the dWorm of an amine sometimes may be used directly for completing a resolution. Soc.. Chem. 116g (1925).and t-a-phenylethylamine. Sae. 121 122 1SS Marokwald. In many otherwise satisfactory resolutions only the less soluble of the two diastereoisoraers can be purified. 50. more commonly it is applied to the partially resolved material recovered from the more soluble fractions of the original resolution. Up to R « hexyi the less soluble salt was that of the d-form. since this already oontains an excess of the desired form. Soc. 55. for the remainder of the series it was that of the Worm.396 THE KE8QUJTIQN OF XWQT&QIS soluble salt in most instances. Except when R was methyl or n-propyl. 411 (1933). but it may be noted that a procedure hag been described m> 38' ". pp. ' The phthalates of a similar series of the type (CH3)2CH—CHOH—R " were resolved with strychnine. The difficulty is that alkaloids. are rarely available in both forms. brucine formed only stable double salts in this series. this yields only one of the desired active forms. . and Burns. Babcook. / . Ingereoll.. 29. J. such as d. Chem. the enantiomorph of the less soluble salt in the initial resolution is then formed. which gave the cWorms. Other procedures for obtaining both active forms of alcohols are included in the examples and text. 2264 (1928). Chem. 43 (1896). are not subject to this limitation 118 and might well find increasing use for this reason. The phthalates of a series of the type CaHs—CHOH—R63 were resolved with strychnine. the Worms usually were purified from the residual material through the brucine salts. 397-308. Marekw&ld m has introduced a generally reliable method of obtaining the second form pure by the use of the enantiomorph of the original resolving agent. Ingersoll. 2123 (1934). Tartially resolved fractions rich in the d-form also were purified readily through the strychnine salts. with some difficulty. The Worms of most of this series were purified.
Kenyon. the active acid esters are set free from the salts merely by a"dding the salts. Either the 126 128 Kenyon. Chem.127 Should the alcohol be found to be optically impure at this stage it sometimes may be purified by recrystallization. and Phillips. 118. Otherwise the impure product (or any incompletely resolved fractions) may be recombined with the original or anothef resolving agent and the fractionation continued. Usually this procedure will show whether some of the racemic form is still present since this form probably will tend to accumulate at either. refiltered. Kuna. ground in a mortar with water. Soc. When the active form is pure or becomes so on recrystallization it is ready for hydrolysis. to warm water containing a moderate excess of hydrochloric acid. They are filtered. J. . Bid. and Phillips. both in the hydrolysis 82 and in the subsequent final purification. The crude active hydrogen phthalates separate sometimes as oils which solidify on cooling and standing. the crude ester may contain traces of the resolving agent and other impurities. 127 Bartlett.. No evidence of racemization has been observed with various types of saturated alcohols even on prolonged boiling with concentrated aqueous alkali. to test the purity of the crude active ester. Hydrolysis of Active Acid Esters The hydrolysis of the active alkyl phthalates is usually carried out by dissolving them in a 20-25% aqueous solution of sodium hydroxide containing 2. and. Certain alcohols of the allylic type m ' m or alcohols otherwise sensitive to alkali or to heating may require more cautious treatment.5 moles of alkali and distilling the mixture with steam. The fractionation of the'alkaloid salts may not have given optically pure products. 85. 513 (1937). Partridge.he melting points and rotatory powers of the various fractions. and Levene. When the active acid ester crystallizes well it may be examined by recrystallization and observation of J. Partridge. J. depending on whether it is less soluble or more soluble than the active form. 1936. Purification of Active Acid Esters It is usually advisable. and washed with dilute hydrochloric acid and water to remove any entrapped base. the head or the foot of the series. 1937.. 207. in any event. Soc. alone or dissolved in aoetone or ethanol. J. Chem.'Chem.HYDROLYSIS OF ACTIVE ACID ESTERS Isolation of Active Acid Esters 397 In general. after removing the resolving agent. Filtration or extraction " of the alcohol may be necessary when it is not volatile with steam.
2137 (1931). 52. Soc. Soc. J. 56. J. of water is then added.4 atoms) of sodium in thin slices or wire form. 133 Hiickel and Naab. 1733 (1916). (2. of course. 35. Chem. Higher temperatures or excessively prolonged heating are inadvisable since isomerization of the menthol may occur. (2. flask there is added 55 g. Soc. J. Org. U1 ° Leffler and Calkins. J. 64. fiuss. and the mixture is heated in a steam bath with frequent shaking for five to eight hours. Ber. 138 Wagner and Biykner. Am Chem..132-133> m The mixture is allowed to cool somewhat. Phys. 131a To a solution of 312 g. Frankland and O'Sullivan. 76. 74. 181 Holmes and Adams. Chem. 23. and 125. 1930. may be used for this purpose. 189 128 .. of sodiumdried toluene in a 5-1. showing various further modifications and helpful devices. may be found in references 53. Soc. 99. 1931. Chem.398 . The mixture finally is heated in a steam bath for twenty-four hours or longer. such as the benzoate or pnitrobenzoate. 128. A solution of 80 g. 134 Windaus. J. 49. is practicable only when the active and racemic forms are separable by crystallization. 55 (1943). 2375 (1911). 130. Preparation of Z-Menthoxyacetic Acid 129.. In addition to the preparations described in this chapter other instructive examples.THE RESOLUTION OF ALCOHOLS alcohol itself or a suitable solid derivative. 537 (1903). (Emulsions usually may be broken by passing the mixHoussa and Kenyon. (0. Soc. and the excess sodium is removed mechanically. (2) resolution by crystallization of brucine salts of acid phthalates which are readily separated. 2260. during this period it is protected by a soda-lime tube and is maintained in a fluid condition by the addition of more toluene and by frequent shaking. and (3) a similar resolution in which the separation of the diastereoisomeric salts is difficult.0 moles) of i-menthol in 750 cc. 180 Rule and Tod. and the mixture is shaken and separated in the usual way. 131. Syntheses. 2093 (1934). EXPERIMENTAL PROCEDURES Procedures are given for (1) resolution by the use of a simple ester. each layer being carefully washed with the other solvent. Ber. of dry toluene is then gradually added while the solution is stirred rapidly so that the precipitate of sodium chloride and sodium chloroacetate remains finely divided. Chem. 1932. _The flask is attached to an upright condenser provided with a soda-lime tube. The purification in this way. About 500 cc. 69.85 mole) of'anhydrous chloroacetic acid in 11.
the solution is dried by distilling a portion of the toluene and is used in the next run. the yield in the following procedure is assumed to be quantitative. and the i-menthoxyacetic acid is distilled under reduced pressure. and the solution is washed with dilute hydrochloric acid. based on the chloroacetic acid. VMost of the excess thionyl chloride is then distilled through the condenser at atmospheric pressure and the remainder is removed by warming the mixture for a short time under slightly reduced pressure (water pump).7 parts by weight of thionyl chloride in a flask connected by a ground-glass joint to an upright condenser (hood). dilute sodium hydroxide. the crude £-menthoxyacetic acid is extracted with a liberal amount of toluene. the extract is distilled to remove toluene and water. The residue is satisfactory for most purposes. ' d-Menthoxyacetic acid and its chloride may be prepared similarly by starting with d-menthol. is satisfactory for conversion to the chloride.p. b. The major part of the pyridine is then recovered by distillation. m. .. The mixture is warmed in a water bath at 50° for three hours.p. and water. The solvent is then distilled. The solid is then dissolved in the same solvent (including the extract). The pure acid has b. The yield is 70-78%^. and is used directly in the next step [ah . This may be recovered by distillatidn. 163-164°/10 mm.RESOLUTION o£ e«-MENTHOL 399 ture slowly through a suction filter. The principal fraction. and [a]g . of water. or. One part of the acid is mixed with 2. The crude dJ-menthyl-f-menthoxyacetate after filtering and drying amounts to 310-320 g. 132°/10 mm.. Z-Menthoxyacetyl chloride is conveniently prepared immediately before use. 160-170°/10 mm.5° (a = 2. The crystalline precipitate is filtered. of anhydrous pyridine. if desired. 1 mole) is added slowly to 157 g. The aqueous layer is acidified. and the residue is distilled with steam to remove unchanged menthol. 95% ethanol).91. and the filtrate is extracted with several portions of ether or benzene. and the mixture is left overnight. The active menthoxyacetyl chlorides have been employed in a useful method for resolving amino acids l s l as well as for the resolution of alcohols and phenols.50° to -55° (c = 2. (1 mole) of dt-menthol dissolved in 750 cc. Resolution of (//-Menthol26 l-Menthoxyacetyl chloride (233 g. when several runs are to be made. This may be slightly levorotatory. and the residue is poured into 2 1..p.p. b. chloroform).) The toluene layer contains more than half of the menthol originally taken. A little menthoxyacetic acid may be recovered by acidifying the sodium hydroxide washings. 52-54°. the chloride may be distilled.
Vol.2 mole equivalents of 5-10% ethanolic potassium hydroxide. and the remaining fractions are crystallized in order from the mother liquors of the preceding fraction. Pure ?-menthyl-Jmenthoxyacetate has [a]o — 109. p. Crude Z-menthol is.p.5° and [afo — 6. It may be purified by esterification with dmenthoxyacetyl chloride and crystallization of the resulting mixture of esters. Soc. In this process the successive crops obtained from the original solution are examined polarimetrically and are then rearranged for recrystallization in the order of increasing negative rotation. obtained similarly from the strongly levorotatory fractions of the ester.. Various other methods for purifying the partially active ^-menthol also may be used if desired. I. Chem. m.. Coll. Org. Fractions having high negative rotations are best combined. See references in Table III. 42°. The Z-alcohol-c£-acid ester is then readily purified since it is the less soluble and also the more abundant component. and [a]|>0 + 49. 2nd ed. higher temperatures produce a lower yield of dark product.. The menthol is conveniently extracted with benzene and purified by distillation under reduced pressure. Pure d-menthyl-I-menthoxyacetate is hydrolyzed by refluxing for an hour with 1. 2540 (1922). A mixture of 130 g. 408). for the later recovery of crude J-menthol.p. 91. Kenyon. closely similar fractions may be combined. 97-99°/10 mm. (1 mole) of resublimed phthalic anhydride is_heated for twelve to fifteen hours in a flask in an oil bath at 110115°.7°. 1941. (More vigorous hydrolysis is inadvisable since Z-menthol may thus be formed from the resolving agent by rupture of the ether linkage.) The mixture is almost neutralized to phenolphthalein with hydrochloric acid and is distilled with steam to remove first the ethanol and then the menthol. Fractions initially having specific rotations substantially lower than that of the dZ-alcohol-Z-acid ester usually yield pure d-menthyl4methoxyacetate after five or six crystallizations.5°(c = 2. The fraction of lowest negative rotation is recrystallized from fresh solvent. The yield in this step is 80-85%. This has m.. Syntheses. 121.p.6°(c = 2. 95% ethanol). - Resolution of d*-2-Octanol *»•136- m Preparation of eff-Octyl Hydrogen Phthalate. The 188 18<! Kenyon. J. . 418. 216-2167760 mm. chloroform). (1 mole) of cM-2-octanol and 148 g. without attempting complete purification. About 40% of the calculated amount of this ester can be obtained fairly readily.400 THE RESOLUTION OF ALCOHOLS The crude ester is resolved by semi-systematic crystallization from methanol. It has b.
The cooled mixture is poured into a solution of ISO g. (1 mole) of dlroetyl hydrogen phthalate in 600 cc. 60-90°). The crude product is recovered by distillation of the chloroform and recrystallized. (1. with a Httle additional chloroform. which contain principally the brucine salt of J-octyl hydrogen phthalate. A somewhat lower yield may be obtained by a shorter method. is poured upon 500 g. of dry pyridine is refluxed in a steam bath for three hours. and dried. filtered.DECOMPOSITION OP THE BRtJClNE SALTS 401 mixture is stirred occasionally during the heating to give a homogeneous liquid. the heating may be shortened to one hour. A warm solution of 278 g. 1. and the mixture is stirred without warming until the solid dissolves. and the initially oily precipitate of dJ-octyl hydrogen phthalate is allowed to harden. of acetone is treated with 394 g. The extracts. The product may be used directly for the next step if colorless and dry. A mixture of 130 g. On cooling. preferably from 90% acetic acid. crushed to a powder. Resolution with Brucine in Acetone. are united and used in the next step. The filtrates and washings. (1. and again filtered. the nearly pure brucine salt of d-octyl hydrogen phthalat© crystallizes and is filtered. preferably overnight in a cold room. of warm acetone. are used to dissolve the crude hydrogen phthalate. The salt is removed from the funnel.) The mixture. stirred with 250 cc. (If the mixture first is allowed to stand overnight. The yield is substantially quantitative when pure alcohol is used.p. of water. the aqueous portion is decanted from the oily or semi-solid hydrogen phthalate and extracted with three 50-ce. while still somewhat warm. When the ice has melted. The pure product melts at 55d. (1 mole) of dWJ-oeteool and 155 g. of hydrochloric acid (sp. The acetone filtrate is concentrated by distillation to about half its original volume and is stirred . Decomposition of the Brucine Salts. and the solution is warmed until clear. A wide-mouthed Erlenmeyer flask covered by a "cold finger" or Friedriehs condenser is convenient for this step. Otherwise it may be reerystallteed from about its own weight of 90% acetic acid or from petroleum ether (b. portions of chloroform. The yield by this method is 82-88%. gr. A slight excess of hydroehloric acid is then added. and the solution is freed from adhering water and pMhah'e acid by gentle suction filtration through a layer of powdered anhydrous sodium sulf ate. Unless* the solution is completely dear it is beat extracted with a little benaene (to remove unreacted alcohol and neutral phthalate ester) and passed through a wet filter to remove suspended benzene. (1 mole) of powdered anhydrous brueine.05 moles) of' resublimed phthalic anhydride in 150 co.4 moles) of sodium carbonate in about 8 1.18) has been added. of clean ice to which 175 cc.
and have [OJD ± 9. When this has solidified it is filtered. Thorough washing in this way is necessary to remove entrapped brucine hydrochloride.8° (c = 5. and distilled. The purpose of this step is to remove the small proportion of cM-octyl hydrogen phthalate that still is present in the crude active forms. Alternatively the alcohols may be taken up in about 5 volumes of pure benzene and dried by distilling the moist benzene. It may be noted that the purification of the crude active hydrogen phthalates by recrystallization m permits a considerable simplification of the original procedure. of concentrated hydrochloric acid (sp. Crude J-octyl hydrogen phthalate precipitates as an oil. The active alcohols boil at 86°/20 mm. gr. in which the racemic form is much more soluble than the active forms. The active forms are crystallized separately from about 2 parts by weight of 90% acetic acid. Each of the pure hydrogen phthalates is hydrolyzed by dissolving it in 2.402 THE RESOLUTION OF ALCOHOLS slowly while still warm into 1. Purification of the Crude Active Hydrogen Phthalates. and dried. before it became pure. after recovery from the mother liquors. washed. transferred to a mortar. of water to which 100 cc. This is first dissolved in the minimum amount of hot ethanol. .18) has been added. Recovery of the Active Alcohols. and ground to a powder in the presence of a little water. dried with potassium carbonate. The yield of the active f forms at this point is about 70%. A small additional amount of the phthalate may be obtained from the mother liquors and washings by extraction with benzene.49 In the original procedure the crystalline brucine salt of d-octyl hydrogen phthalate had to be recrystallized two or more times from acetone.5 moles of sodium hydroxide (in 20-25% solution) and distilling the mixture" with steam. The yield in this step is practically quantitative. 1. The crude active hydrogen phthalates obtained by removing the resolving agents were then hydrolyzed without further purification. It is then filtered. The alcohol layer of the distillate is separated. in which it is sparingly soluble.4° (c = 5. also the crude ?-octyl hydrogen phthalate. 95% ethanol). in which it is rather soluble. and this required six or more recrystallizations from acetone. The aqueous solutions containing brucine hydrochloride are retained for the recovery of brucine. The crude dMorm may be recovered from the acetic acid mother liquors and used in another run. and the solution is poured into the dilute acid. had to be converted to the cinchonidine salt. 95% ethanol).5 1. Two crystallizations are usually required to give products melting at 75° and having [O:]D =c 48. Crude d-octyl hydrogen phthalate is obtained similarly from the crystalline brucine salt. before it became pure.
The combined filtrate and washings are concentrated to about 11. fitted with a reflux condenser or distilling head as required. 138. J. Am. Soc. Pharmacol. the yield depends on how long the fractionation is continued and how the mother liquors are handled (see below). Chem. S3. 69..8° or less (c = 4. Working in this way it is possible to obtain fairly readily about 50-55% of the calculated amount of pure brucine d-s-butyl phthalate. The crystalline fractions are now systematically recrystallized from methanol. . Crop Ax is recrystallized from about 1. The solution is kept for several hours in a cold room or icebox. When pure. It is unnecessary to take rotation values until the crystalline appearance and solubility behavior of the head fraction become approximately constant. When large quantities of alcohol are to be resolved it is convenient to unite the material from several runs at this stage. The final mother liquor is united with that from the original solution. the head fraction is removed from the series and the recrystallization of the remaining crops is continued as long as it appears " profitable. 259. after which the first crop (A{) of crude brucine d-s-butyl phthalate is filtered and washed with about 300 cc. 139 A solution of 447 g. 1717 (1934). J. Biochem. may yield a small third crop (A3). The crystalline crops amount to 60-75% of the total salt. The filtrate on concentration may give additional small crops. Usually five to seven reerystallizations are necessary for purification. The final mother liquor is set aside. Sprung and Wallis. The head crop is recrystallized from about 600 cc. 189 Butler and Diokison. The recrystallization is continued.01 moles) of anhydrous brucine and the mixture is kept under reflux at about 40° for an hour. of this solvent. At each stage the volume of the solution is adjusted by addition or distillation of solvent so that from one-third to onehalf of the salt crystallizes. The solution is then heated to boiling and filtered hot. A series of large Erlenmeyer flasks. 137 138 Viditz. using fresh or recovered solvent. of cold acetone.5 1. 137. is convenient for the purpose. Z.. and a second crop (A2) is taken. 225 (1940). of acetone. (2 moles) of pure s-butyl hydrogen phthalate Bo in 2 1. 294 (1933). 56. and the remaining crops are crystallized in order from the successive mother liquors. (2. and crops A% and A3 are united and crystallized from the mother liquor. Further concentration to about 400 cc. until the head fraction has [a]f? — 2. The final mother liquor from each series is reserved. methanol). of warm acetone is treated with 790 g..RESOLUTION OF s-BUTYL ALCOHOL 403 Resolution of s-Butyl Alcohol 50.
393). phenols. Alternatively.5° (c = 4. b.p.83° (without solvent). saturated alcohols containing aryl groups. Table VII. The oily succinate is combined with one molecular proportion of cinchonidine in acetone. Table III. private communication.63 For this purpose the alcohol is recovered from the mother liquors of the brucine salt and converted to the hydrogen succinate by the general procedures previously outlined (p.404 THE RESOLUTION OF ALCOHOLS The d-s-butyl hydrogen phthalate and the corresponding pure alcohol may be obtained from the brucine salt by the general procedure previously described for the octyl hydrogen phthalates (p. Table VIII. acyclic unsaturated alcohols. may then yield more of the crude d-salt and then again the £-salt. alicyclic and terpenoid alcohols.. these are separated by filtration or decantation. alkylcycloalkylcarbinols. [a]v — 18.p. They are arranged in the order of increasing molecular weight and are classified as follows: acyclic saturated monoalcohols. [a]D . upon concentration. The alcohol is recovered from the pure salt in the usual way. The Z-alcohol also can be purified by fractionation of the cinchonidine salts of the hydrogen succinate. miscellaneous monoalcohols. Table II. The very soluble cinchonidine Z-s-butyl succinate is purified by five or six crystallizations and then has m. TABLES OF OPTICALLY ACTIVE ALCOHOLS AND PHENOLS In the tables which follow are listed the various alcohols and phenols which have been resolved or which have been obtained in optically active forms from natural sources by equivalent procedures. 95% ethanol). 140 Dickison. the process may be shortened considerably by treating the brucine salt directly with a small excess of dilute sodium hydroxide and distilling the alcohol with steam. Table IX. . Pure d-sbutyl hydrogen phthalate has [a]o + 38. Table VI. unsaturated alcohols containing aryl groups. The solution. The method is tedious but gives rather good yields. The i-form of the alcohol can be obtained in 86-90% purity from the combined acetone and final methanol mother liquors by a rather laborious process of fractional crystallization aided by mechanical separation. 54-55°.137' 140 Thus on long standing the acetone solution may deposit characteristic nodular aggregates of leaflets of nearly pure brucine £-«butyl phthalate. 98°/750 mm. Table V.0°.95% ethanol). Table I. Table IV. and distilled. dried.85° (c = 5.138 The alcohol is extracted or is salted out with potassium carbonate. [a]% + 10. 402). glycols'and polyalcohols. especially when large quantities of material may be worked up in a leisurely fashion.
137. 144 Quinidine phthalate f 144 Biochemical resolution t 96. 142 110 91 16 90 * Methods resulting in failure or unsatisfactory results t Partial resolution only . 72.99 41 Strychnine and morphine sulfates * 42 42 50. 141 50. 75 Cinchonidine succinate 50. 143 Strychnine phthalate 74 Asymmetric biosynthesis 110 Biochemical resolution f 98 Tartranilate 40 Strychnine and brucine phthalates 51 Brucine succinate 51 Brucine 3-nitrophthalate 82 Cinchonidine 3-nitrophthalate 82 Brucine. 139.TABLES OF OPTICALLY ACTIVE ALCOHOLS AND PHENOLS TABLE I ACYCLIC SATURATED MONOALCOHOLS 405 Alcohol Derivative Employed or Method of Resolution Brucine sulfate Brucine tetrachlorophthalate * Brucine phthalate Reference C4 Methylethylcarbinol CB Methyl-n-propylcarbinol Methylisopropylcarbinol s-Butylcarbinol C» Methyl-n-butylcarbinol Methylisobutylcarbinol Methyl-J-butylcarbinol Ethyl-n-propylcarbinol * Strychnine succinate Tartranilate Biochemical resolution t Asymmetric biosynthesis Decomposition. p-bromotartranilate t 40 Brucine and strychnine phthalates 50. 67 Cinchonidine succinate 50 Brucine and strychnine phthalates 55 Cinchonidine phthalate f 55 Brucine and strychnine phthalates 53. 143 Strychnine succinate 50. 139 40 99. cinchonidine and 82 Z-menthylamine phthalates * Tartranilate. strychnine.53Tartranilate 40 Biochemical resolution f 96. 53. 138. on active catalyst t Distillktion of esters t Partial esterification with tartaric acid * Brucine phthalate 50. 100 Distillation of esters f 16 42 Brucine sulfate * Brucine phthalate 50.
144 Strychnine and cinchonidine phthal53. 75 Strychnine phthalate Brucine and qumidme phthalates t 53. 67 Brucine phthalate 145 148 Strychnine phthalate Strychnine and brucine phthalates 50 149 Brucine phthalate t Distillation of ester f 16 50 Brucine phthalate Brucine and cinchonidine phthalates 50.75 Brucine phthalate 145.144.75 ates Strychnine phthalate Cinchonidine succinate t Strychnine phthalate Brucine phtbalate Strychnine phthalate Strychnine phthalate Cinchonidine succinate t Strychnine phthalate Brucine phthalate Asymmetric biosynthesis»t Strychnine phthalate 51 51 67 50 53 51 51 67 50. 54 99 Biochemical resolution f 53. 145 146 Brucine phthalate Brucine phthalate * 146 Strychnine and brucine phthalates 51 49. 50. 54.406 THE RESOLUTION OF ALCOHOLS TABLE I—Continued ACYCUC SATURATED MONOALCOHOLS Alcohol Derivative Employed or Method of Resolution Reference Ethylisopropylcarbinol c7 Methyl-n-amylcarbinol Ethyl-n-butylcarbinol Ethylisobutylcarbinol a-Ethyl-s-butylcarbinol i8-Ethyl-s-butylcarbinol n-Propylisopropylcarbinol Methyl-n-hexylcarbinol c8 Ethyl-?fc-amylcarbinol n-Propyl-w-butylcarbinol n-Propylisobutylcarbinol n-Propyl-s-butylcarbinol n-Propyl-<-butylcarbinol Isopropyl-w-butylcarbinol 2-Ethyl-l-hexanol Methyl-n-heptylcarbinol Ethyl-n-hexylcarbinol Isopropyl-re-amylcarbinol ra-Butylisobutylcarbinol Cio Methyl-n~octylcarbinol Et^yl-n-heptylcarbinol Isopropyl-n-hexylcarbinol Isobutyl-n-amylcarbinol 51 Strychnine phthalate Brucine phthalate t 51 Brucine and cinchonidine phthalates • 50. 54 110 53 ~ ~ Cu Methyl-rwionylcarbinol Ethyl-n-octylcarbinol * Methods resulting fn failure or unsatisfactory results f Partial resolution only . 50 Cinchonidine phthalate 40 Tartranilate 53 Strychnine phthalate Brucine phthalate f 53 Strychnine and brucine phthalates 68. 136. 147 49. 144 Strychnine phthalate 67 Brucine phthalate t 49. Brucine phthalate * 135.
Chem. 591 (l'927). 633. soc. 1120 (1938). 3332 (1930). . 52.. 60. Biol. Levene. Norris and Green. Chem. 26. 72.. Chem. J. Bull. Higbee. Am. Soc. J. Soc. Soc. 1926. Am. 148 Stevens. and Haller. / . "« Duveen and Kenyon. 293 (1901). / . Am. 146 Lowry. Soc. 2226 (1914). Chem. 147 Shriner and Young. Chem. 60. Ber.. 1939. J. Soc. 148 Kenyon and Platt. 1297 (1927). Pickard. 94 (1914). 148 TABLE II AliKTLCYCLOALKYLCARBINOLS Alcohol Derivative Employed or Method of Resolution Brucine and cinchonine phthalates Strychnine phthalate Strychnine phthalate Strychnine phthalate Strychnine phthalate Reference Methylcyclohexylcarbinol Ethylcyelohexylcarbinol n-Propylcyclohexylcarbinol w-Butyicyclohexylcarbinol 150. J. Chem. J.66 69 74. 105. Soc.. J. chim. [5] 5. Chem.TABLES OF OPTICALLY ACTIVE ALCOHOLS AND PHENOLS 4 0 7 TABLE I—Continued ACYCLIC SATURATED MONOALCOHOLS Alcohol Derivative Employed or Method of Resolution Brucine phthalate Strychnine phthalate Strychnine phthalate Brucine phthalate Strychnine phthalate Strychnine phthalate Strychnine phthalate Strychnine phthalate Strychnine phthalate Strychnine phthalate Reference C12 Methyl-n-decylcarbinol Ethyl-w-nonylcarbinol Isopropyl-n-octylcarbinol C13 Methyl-n-undecylcarbinol Ethyl-n-decyloarbinol Cw Ethyl-n-undecylcarbinol Isopropyl-n-decylcarbinol C15 Ethyl-n-dodecylcarbinol Cie Ethyl-n-tridecylcarbinol Ci8 Ethyl-n-pentadecylcarbinol 141 142 50 53 51 50 53 53 51 53 53 53 Kuhn and Albrecht. 106...69 69 69 "° Domleo and Kenyon. and Kenyon. and Armstrong. 144 Kenyon. 1841. Chem. Walti. 74. 2558 (1938).
154 Cinchonidine succinate f 83 Strychnine phthalate 155 (J-Camphor-10-sulfonate 25 d.408 THE RESOLUTION OF ALCOHOLS TABLE III ALICYCLIC AND TERPENOID ALCOHOLS Alcohol Derivative Employed or Method of Resolution Reference a-2-Methylcyclohexanol j9-2-Methylcyclohexanol ac-Tetrahydro-/3-naphthol cis-j9-Decalol Borneol Isoborneol Carvomenthol a-(?)-Fenchol Linalool Menthol Neomenthol Tsomenthol Neoisomenthol Pulegol Isopulegol 118 Strychnine phthalate Z-o-Phenylethylamine phthalate 118 Strychnine phthalate 118 J-Menthylurethane t 20 Cinchonine and brucine phfhalates " 52 87 Digitonide t Hydrogen d-camphorate * 22 Various alkaloid phthalates * 8 i-Menthylamine phthalate 48 d. 83 Quinine succinate 83 Cinchonidine and quinine phthalates f 83 Cinchonidine succinate f 83 <J-Camphor-10-sulfonate * 27 J-Menthoxyacetate * 27 Animal feeding f 105 d-Camphor-10-sulfonate * 33 J-Menthoxyacetate * 33 Fractionation of crystaUine esters 156 Strychnine phthalate 155 Strychnine phthalate 157 * Methods resulting in failure or unsatisfactory results.and Z-Bornoxyacetates 28 Enzymic hydrolysis of acid phosphate t 107 Animal feeding f 104 Z-Menthylamine and cinchonine phthal48 ates Cinchonidine succinate f 151 152.80 Strychnine phthalate f Digitonide * 87 Enzymic hydrolysis of pyrophosphate f 153 Strychnine phthalate 81 Cinchonine and brucine phthalates 83. t Partial resolution only. .and J-Menthoxyacetates 26 Tartranilate 40 Enzymic hydrolysis of acid phosphate f 107 Animal feeding f 105 Brucine phthalate .
(i) 82. Penfold. Hunter. and Pennington. Atti acad. J. *Paoli"ni. 45. 162. Z.. [5] 28. (ii) 134 (1919) [C. 14. Lincei. [5] 28. 186 (1932). Chem.. 1935. 87 Tartranilate * 40 Cinchonine and strychnine phthalates 159. / . . 117. 1M Kenyon and Pickard. 487 (1909). 160 Cinchonine and strychnine phthalates 160 Cinchonine and strychnine phthalates 160 Beckmann. 1M Huckel and Niggemeyer. 1M "Short and Read. 73f 76. Ber. Ber. 1672 (1920)]. 163. 1M Bradfield.166 * Methods resulting in failure or unsatisfactory results. Atti acad. 253. 78..80 Digitonide t. 42. Chem.. 163. 2173 (1920)]. Lewoock. Biockem.. Soc.. 16 1M TABLE IV SATURATED ALCOHOLS CONTAINING A R T L G R O U P S Alcohol Derivative Employed or Method of Resolution Brucine succinate Brucine phthalate Asymmetric biosynthesis t Asymmetric acylation f Hydrogen d-camphorate * Digitonide * Tartranilate * Brucine and strychnine phthalates Reference Cs Methylphenylcarbinol C» Methylbenzylcarbinol 50.. 1939. A. 1354 (1939). Chem.TABLES OF OPTICALLY ACTIVE ALCOHOLS AND PHENOLS TABLE III—Continued ALICTCLIC AND TERPENOID ALCOHOLS 409 Alcohol Derivative Employed or Method of Resolution Reference a-Santalol 0-Santalol a-Terpineol Thujol (Tanacetol) Isothujol Neothujol 161 Strychnine phthalate 81. and Simonsen. Ber... 167 Pickard. 158 Strychnine phthalate 81. 1040. 1248 (1920). 72.. 1293 (1912). 161. 128 110 164 22 87 40 55. Soc. t Partial resolution only. 309. J. A. Lincei. (ii) 190 (1919) [C. / . Soc. 165. 14. 45 (1915) N 165 PaoUni. Ochiai. 128. 158 Brucine and strychnine phthalates 79. 1M Tschugaeff and Fomin. Chem. 107. Soc.
Ber. Ann. 2644 (1914). 76 Quinidine and strychnine phthalates 168 Strychnine and brucine phthalates 73 Isopropylphenylcarbinol 3-Phenyl-l-butanol Strychnine 3-nitrophthalate 82. 1936. 127. Soc. la Downer and Kenyon. J.410 THE RESOLUTION OF ALCOHOLS TABLE IV— Continued SATURATED ALCOHOLS CONTAINING ARYL GROUPS Alcohol Derivative Employed or Method of Resolution Reference Brucine and cinchonidine succinates 50 Strychnine phthalate 73. 167 Coppock. 676. Soc. 687 (1913). J. Soc. and Pittman.71 Strychnine and cinchonidine phthal169 Cii Ethyl-/3-phenethylcarbinol ates ' n-Butylphenylcarbinol Cinchonidine phthalate 73. 2564. J. 498. 1156. Phillips. 128. Chem.74 Cu Methyl-a-naphthylcarbinol Methyl-/3-naphthylcarbinol Cinchonidine and strychnine phthal170 ates «-PropylT8-phenethylcarbinol Brucine phthalate 169 Cinchonidine phthalate Cu Cyclohexlylphenylcarbinol 74 Quinine phthalate 72 CM Phenylbenzylcarbinol Quinine and cinchonine phthalates 171 Brucine phthalate * 14 Phenyl-p-tolylcarbinol 169 Cu Phenyl-/3-phenethylcarbinol Brucine and strychnine phthalates Brucine phthalate • > 172 ClT n-Hexyl-a-naphthylcarbinol i Ethylphenylcarbinol * Methods resulting in failure or unsatisfactory results. 172 Kenyon and Piokard. 62 (1932).. Chem. Chem. Soc. 103. Soc.69 Brucine and strychnine phthalates 55. Soc.. 72 (1933). Chem. "'Hewitt and Kenyon. 105. Kenyon. 1072. J. 165 Kenyon and Pickard. 76 Hydrogen d-camphorate * 20 Dideuteroethylphenylcarbinol Fractionation of crystalline esters * 167 2-Phenyl-l-propanol Brucine and cinchonidine S-nitro. and Partridge. t Partial resolution only. Soc. 1928. 2262 (1914). " l McKenzie and Clough. 61. Chem. 506. Soc. 170 Collyer and Kenyon. Chem. 161 Ott. J. Chem. Chem. 1940. 164 Wegler. 1938. J. Soc. 188 Kenyon and Partridge. Soc. J. Chem. 1939. 171 Gerrard and Kenyon.71 phthalates Cinchonine and strychnine 3-nitro•82 phthalates f Brucine phthalate * 82 Brucine and cinchonidine phthaiates 55 CIO Methyl-jS-phenethylcarbinol Desoxycholic acid t 86 Ethylbenzylcarbinol Strychnine phthalate 77 n-Propylphenylcarbinol Strychnine phthalate 73. 1094 (1926). J. J. 69.. 2139 (1928). Chem. / .• 82. 1935. 166 Kenyon. 1069. . 105.
60 Brucine phthalate 61. 177 Ethylallylcarbinol Strychnine phthalate 56 n-Propylvinylcarbinol Strychnine and brucine phthalates 169. 117 125. 126.TABLES OF OPTICALLY ACTIVE ALCOHOLS AND PHENOLS TABLE V (JNSATXJRATBD ALCOHOLS CONTAINING ABTL GROUPS 411 Alcohol Derivative Employed or Method of Resolution Quinidine phthalate Quinidine phthalate Quinidine phthalate Cinchonidine phthalate f Brucine and strychnhie phthalates Reference Vinylphenylcarbinol o-Propenylphenylcarbinol. C4 Methylvinylcarbinol C6 Methylallylcarbinol Methyl-a-propenylcarbinol Ethylvinylcarbinol .76 Isobutylvinyl carbinol Brucine and strychnine phthalates * 127 Allyl-a-propenylcarbmol Brucine phthalate 182 Ephedrine phthalate * 182 Cinchonidine and quinidine phthal182 ates * * Methods resulting in failure or unsatisfactory results. 64. 173 Strychnine phthalate 169 Brucine phthalate 174 Ethylethynylcarbinol Brucine phthalate 175 C« l-Hexene-5-ol Brucine phthalate 58 2-Methyl-2-pentene-4-ol Brucine and strychnine phthalates 176. 126 77 77 TABLE VI ACYCLIC UNSATXJRATED ALCOHOLS Alcohol m Derivative Employed or Method of Resolution Reference Brucine phthalate 169 Brucine phthalate 59. t Partial resolution only. 65 Vinylallylcarbinol Brucine phthalate 63 C7 2-Methyl-2-hexene-5-ol Brucine phthalate 62 3-Heptene-5-ol Strychnine phthalate 178 TKPropylallylcarbinol Brucine phthalate 179 n-Propyl-a-propenylcarbinol Brucine phthalate 70 Strychnine phthalate 180 Isopropyl-a-propenylcarbinol Strychnine phthalate 181 n-Butylvinylcarbinol Strychnine and morphine phthalates 169. Methyl-a-styrylcarbinol Ethyl-a-styrylcarbinol 117 125.
660 (1933). 94. 1938. 178 Duveen and Kenyon. Chem. Chem. t Partial resolution only . 184 Kuna and Levene. Duveen.. Bull. 1936. Chem. Chem. 118. 460 (1931). Chem..B. Soc. and Kenyon. 178 Platt. J.S. Kuna..412 THE RESOLUTION OF ALCOHOLS TABLE VI—Continued ACYCLIC UNSATURATED ALCOHOLS Alcohol Derivative Employed or Method of Resolution Cinchonidine phthalate f Strychnine phthalate f Strychnine phthalate Brucine phthalate Reference Cs n-Butyl-ct-propenylcarbinol Isobutyl-a-propenylcarbinol C9 ra-Amylallylcarbinol C10 Cyclohexyl-a-propenylcarbinol 173 64 127 183 184 Hills. 315 (1937). 1912.B. J. 1941. J. Chem.. J. Soc. 593 (1931). J. and Levene. Soc. 2104. 118. Bwl. 1938. 1497 (1937). 1936. 1451. Soc. Gen. 182 Duveen and Kenyon. 180 Arous and Kenyon. 1. 316.. / . soc chim. 174 176 Kamai. 52.. Chem. 177 Kenyon and Young. Am. 576. McGrew and Adams. J. 1452.and M-(a-phenylethylamine) semicarbazide (2-Camphorsulfonate ester * Hydrolysis of active thioglycollic acid derivative * Reference Tetrahydrofurylcarbinol Methyl-a-furylcarbinol Methyl-a-tetrahydrofurylcarbinol (a-form) Phenylacetylcarbinol Benzoin Methylethylphenylcarbinol 185 186. 59. Soc. 704 (1938). Biol. J. J. [5] 5. 312. and Phillips. Chem. TABLE VII MISCELLANEOUS MONOALCOHOLS Alcohol Derivative Employed or Method of Resolution Brucine phthalate Quinidine and brucine phthalates Brucine phthalate Asymmetric biosynthesis Asymmetric biosynthesis f d. Chem.. 179 Consden. 181 Bartlett. 1938. J. Chemistry & Industry. 187 187 108 111 188 189 189 * Methods resulting in failure or unsatisfactory results. U. Bwl. Kenyon. 503 (1937). Sor. J. Chem. Chem. Soc. 183 Levene and Walti.
Chem. J. 186 Duveen and Kenyon.2-diol Pentane-l.. Soc. J. chim. 56 191 191 191 7 57. 113 116 111.3-diol Hexane-l... 97. 3 1 2 . 41.2-diol 96. Soc.. 180 Porter and Hirst.2-diol traws-Cy clopentane-1. J. 188 Hopper and Wilson. 53. TABLE VIII GLYCOLS AND POLTALCOHOLS Alcohol Derivative Employed or Method of Resolution Biochemical resolution f Strychnine disulfate f Asymmetric biosynthesis Asymmetric biosynthesis Asymmetric biosynthesis Asymmetric induction Asymmetric induction Asymmetric induction Spontaneous segregation t Asymmetric biosynthesis Asymmetric biosynthesis Asymmetric biosynthesis Asymmetric biosynthesis Strychnine disulfate Enzymic hydrolysis of d-glucbside H-Menthylurethane Strychnine disulfate Z-Menthoxyacetate > Reference Propane-l.2-diol Heptane-l. [5] 7. soc. Am. Chem. 621. 114 115 47 85 186 45 29 * Methods resulting in failure or unsatisfactory results t Partial resolution only.2-diol (propylene glycol) Butane-l. 187 Duveen and Kenyon. Bull.3-diol er2/<Aro-3-Bromo-2-butanol tAreo-3-Bromo-2-butanol Erythritol Pentane-l. 189 Wallis and Adams. 1941. 1264 (1919). 165 (1940). Hydrolysis of active thioglycollic acid derivative * Differential adsorption * 189 190 186 Balfe. Soc. 2483. a n d K e n y o n . Chem. 55 3838 (1933).TABLES OF OPTICALLY ACTIVE ALCOHOLS AND PHENOLS TABLE VII—Continued MISCELLANEOUS MONOALCOHOLS 413 Alcohol Derivative Employed or Method of Resolution i Reference Phenyldiphenylyl-a-naphthylcarbinol p-Azo-a-naphthol-diphenylmethylcarbinol . Am. . Soc.2-diol tra?w-Cyclohexane-l. 1928.3-diol frww-Butane-2. Chem. J. Soc. 2253 (1931). 99 104 112. Chem. I r w i n . 114 114 58. J.. 1936.
Am. 1919 [C. J. 31.4diol «s-l-Methylcyclohexane-3. <rans-Hydrindene-l. Thesis. Hdv. 1956 (1923)]. 13 192 Winstein and Lucas. 193 Karrer. 12. Soc. t Partial resolution only.4-diol v Isohydrobenzoin 46.47 47 47 Strychnine disulfate Spontaneous segregation from ether f 10. 32.2-diol trans-l-Methylcyclohexane-3. 1139 (1939). 520. Chem.4-dimethylpbenyl)-2. Fritzsohe.6-Di(2. 9. Van Loon. 2845 (1940). A.5-dibromohydroquinone ~ 7-Hydroxyflavanone Demethoxymateucinol Equilenin Isoequilenin a-Tocopherol Z-Menthylurethane i-Menthoxyacetate J-Menthoxyacetate I-Menthoxyacetate i-Menthoxyacetate dr. 1576.6-Di(3-bromo-2. 17.and I-Menthoxyacetates Z-Menthoxyaeetate * d-Camphor-10-sulfonate ester f 20 30 30 31 31 32 32 193 * Methods resulting in failure or unsatisfactory results. Ada. 12 11.6-trimethylphenyl)-2.. 820 (1938).4. Chim.5dibromohydroquinone cw-3.2-diol 191 192 Spontaneous segregation from ethyl acetate Z-Menthylurethane 14. . and Salomon. TABLE IX PHENOLS Alcohol . 14. 62.414 THE RESOLUTION OF ALCOHOLS TABLE VIII—Continued GLYCOLS AND POLYALCOHOLS Alcohol Derivative Employed or Method of Resolution Strychnine disulfate Strychnine disulfate Reference trans-Cycloheptane-1.. Delft. Eingier. 11. Derivative Employed or Method of Resolution Reference a-Phenyl-a-p-hydroxyphenylethane 3.
. BECHAMP. the arsinic acids are similarly derived by replacement of 415 .CHAPTER 10 THE PREPARATION OF AROMATIC ARSONIC AND ARSENIC ACIDS BY THE BART.a-Naphthylarsonic Acid Anthraquinone-1-Arsonic Acid 2-Arsonofluorene p-Nitrophenylarsonic Acid BECHAMP REACTION . • t 419 ' 423 423 423 424 425 425 420 426 427 428 Scope and Limitations of the Reaction Side Reactions Procedures Arsonation of ot-Naphthylamine ROSENMUND REACTION 428 430 430 431 431 Discussion Procedures • • • „• o-Carboxyphenylarsonic Acid TABLES OF COMPOUNDS PREPARED BY THE BART AND BECHAMP REACTIONS . . MORGAN University of Nebraska CONTENTS INTRODUCTION BART REACTION PAGE 415 417 Effect of Substituent Groups on Yields Procedures Phenylarsonic Acid o-Nitrophenylarsonic Acid o-Nitrodiphenylarsinic Acid Modified Scheller-Bart Reaction . AND ROSENMUND REACTIONS C L I F F S. 431 432 432 433 Table of Compounds Prepared by the Bart Reaction Table of Compounds Prepared by the Bechamp Reaction INTRODUCTION 434 449 Arsonic acids may be regarded as derived from orthoarsenic acid. . by replacement of one of the hydroxyl groups with an organic residue. HAMILTON AND JACK F. (HO)3As—»O.
. Ger.. I. 250. II. aromatic amines. 438 (1921). 0 T T RAs(OH)2 for arsonic acids and R2As—OH for arsinic acids. Ber. Zentr. BECHAMP. Compt.3 + K B r This method is of only limited application. is employed. For example. along with a Bart. 418) arsenic trichloride. rend.+ C6H6As(ONa)2 -> (CeEWjAsOuNa + NaCl + N2 Similarly. pat. Ger. diphenylarsinic acid is obtained from benzene'diazonium chloride and disodium phenylarsenite. s 3 1 . leads to triphenylarsine oxide. ' 4 Bart. Three methods for the preparation of asdmatic arsonic acids are described in this review.. The general* formulas for the two types are O . Bechamp.. (C6H5)2AsONa. Rosenmund. pat. Thus. rather than the alkali arsenite. as shown in the following equation. may be considered as derivatives in which all the hydroxyl groups have been replaced by organic residues.4 Arsinic acids are obtained also as by-products in the Bechamp synthesis. By far the most widely applicable of these is the Bart reaction.4'-diaminodiphenylarsinic acid. 1172 (1863).264 (1910) [Chem. Zentr. The neutral arsine oxides. C6H6N2+C1. which involves the interaction of a diazonium salt with an inorganic arsenic compound. H3ASO4 -» HO<f 9 MsO3H2 + H2O In the Rosenmund synthesis salts of arsonic acids are obtained by treatment of aryl halides with sodium or potassium arsenite. The next most useful process is that of Bechamp.345 (1910) [Chem. R3As—>O.. 54.. 4. C6H6N2tCl. In the original Bart process x and most of its modifications an alkali arsenite is used. (C6H5)3AsO. 254. 196 (1913)].416 BART. 882 (1912)1.2 which involves the direct arsonation of phenols. the reaction of benzenediazonium chloride with sodium diphenylarsenite.+ As(ONa)3 -» C6H6As03Na2 + NaCl -f N2 In the Scheller modification (p. 56. AND ROSENMUND REACTIONS two hydroxyl groups. Arsinic acids and arsine oxides may be prepared by extensions of the t Bart synthesis. and certain of their derivatives by heating with arsenic aeid.
tend to increase the yield. Ger. Sodium carbonate is often employed as a buffering agent in the ordinary Bart reaction.. the speed of reaction. Chem. 118. is formed when aniline is heated with arsenic acid.4'-diaminodiphenylarsinic acid. Zentr. sodium hydrosulfite. 34. guim. fis. Anales soc.BART REACTION 417 lesser amount of 2. The nature of the reducing agent is varied according to the hydrogen-ion concentration of the reaction mixture.9 Mouneyrat10 modified Bart's procedure by the simultaneous use of two catalysts... The yield from benzenediazonium chloride and sodium arsenite is greatly influenced by the concentration of the arsenite. like sodium carbonate. 448 (1939) [C. Soc.. 308 (1914)]. All compounds.092 (1910) [Chem.A. himself. 34. Ger. 115. For example... 10 Mouneyrat.. In this way phenylarsonic acid has been prepared in yields ranging from 50-60% 7 to as high as 86% 8 as compared with yields of 40-50% by the original process.A. and in these 6 Bart. pat.. as well as their salts is said to facilitate the removal of diazo nitrogen at low temperatures and to obviate the formation of by-products. 196 (1913)]. Though many have since observed that the coupling reaction is speeded by the use of the above catalysts. espaft. or cobalt. sodium hydrosulfite or sodium formaldehyde sulfoxylate can be used in neutral or alkaline solution. C6HBNH2 + H3As04 -> p-NH2C6H4AsO3H2 + H20 p-NHzCeHiAsOaHa + C6H6NH2 ->• (p-NH2C6H4)2As02H + H2O BART REACTION Since 1910 the method of Bart x has been modified by a number of investigators.. He found that coupling of aryldiazonium compounds with alkali arsenites is catalyzed by copper salts and by silver or copper powder. 142. no systematic study has been made to determine the effect of such catalysts on the final yield.. J.172 (1912) [Chem. and in alkaline solution. Soc. which play the role of buffer. 579i (1920)1. 1356 (1922). and especially by the pH of the solution (which should remain constant).. 264. pat. 107 (1940) [C. Am. sodium formaldehyde sulfoxylate. 213 (1914)]. Chem. This modification has been utilized in very few instances. . 254. Zentr. 8 Bias. 268. I. 8. one a salt of copper and the other a reducing agent. Ger. The reaction medium is either water or a water-alcohol solution. Bart.947 (1919) [/.. hypophosphorous acid may be employed in acid solution. pat. nickel. copper. 7 Palmer and Adams.924 (1910) [C. being the first to improve the reaction. I.A. or excess alkali arsenites are substances available as reducing agents.. 44. G&nie civil. 7286 (1940)]. 8 Bias.6 In a later patent 6 the use of metallic catalysts. 36. pat. 2342 (1940)]. 6 Bart. Brit.
U. the proportion of by-products.4-dinitroaniline. Ger. S. increases with higher alkalinity.537.026 (1925) [C. Ger. 3519 (1932)]. 21.075. 7.. 4046 (1913)]. 103 (1922). 13 Kalb. Whether the modification has certain advantages over the original method of Bart is uncertain. 3371 (1927)].14' 1B> 16 Though the modification of Sakellarios may be of relatively general application to weakly basic amines. Special conditions are required to effect the reaction in the case of 2.. especially the parent hydrocarbon (benzene in the illustration). Brit.4-dinitrobenzenediazoninm chloride. in the ortho and para positions (as in 2.. Ann. Scheller 17 modified the Bart reaction to such an extent that his method is often referred to as the "Scheller reaction. 159 (1920). 421. 429...A.724 (1929) [C. pats..075. Ann. 547. Sakellarios 12 improved the synthesis of o-nitrodiphenylarsinic acid by coupling o-nitrobenzenediazonium chloride with phenylarsenous oxide in a buffered acid solution (acetic acid-sodium acetate) without the aid of a-catalyst. Ann.A. In acid solution the yields are low unless the aromatic diazo compounds contain strongly negative substituents. 261. to 87%. Removal of the solvent followed by treatment with water and sodium hydrosulfite gives the expected arsonic acids. AND ROSENMUND REACTIONS cases no yields are available." Primary aromatic amines. for example). 55.. 1905 (1913)]. 1.. Zentr.538 [C. dissolved in methanol or glacial acetic acid. "Sakellarios. BECHAMP. 401 (1914)].944 (1911) [Chem. pat. II..A.. 423. 1514 (1924). 17 Scheller. 266. The best yields were obtained when the aryldiazonium chloride reacted with dipotassium arsenite in aqueous solution. " B e n d a . 24. o-nitrophenylarsonic acid was prepared in a yield of 86% as compared with a yield of only 60% by the original Bart process. pat. " B a r t . are diazotized in the presence of arsenic trichloride and a trace of cuprous chloride. 26. The reaction may be carried out in strong mineral acid solution or preferably by the procedure of Sakellarios. Schmidt. 39 (1921). this technique increased the yield from 54%. the method has been so little used that no statement as to its applicability can be made.. 57. pat. Schmidt u suggested that the coupling reaction be carried out in neutral solution and without a catalyst. Ber. 11 . 15 Sievers.667 (1912) [C. O S2+C1ri^SAs-OH t •f K2HAs03 -> L I \ + N2 + KCl % / OK By means of this method. pat... such as nitro groups. According to Schmidt.418 BART.1S by the original method of Bart.A. 8.. Brit. 1.
Starkey. J. the method has' failed to convert metanilic acid. and 2. J. Although m-aminobenzenesulfonamide cannot be converted to an arsonic acid by the usual methods.6-dimethylphenylarsonic acid is realized by the original Bart process. 828 (1942). Soc. Am. since a 30% yield of 2.5-xylidine. Oneto and Way. The modification appears to be particularly useful in the preparation of p-nitrophenylarsonic acid. Soc. particularly if a negative substituent is present in the meta position. 63. the reactions could be carried out at room temperature. furthermore. 167 (1940). 3068 (1941).. 2489 (1923)... When other diazonium borofluorides were used as starting materials the yields were sometimes lower than those reported by the usual Bart procedure.. 56. The most recent modification of Bart's reaction involves the use of aryldiazonium borofluorides in place of the customary diazonium chlorides. Soc. 2157 (19lb). Ber. Am. fluorene. Apparently the difficulty with 2. 62. 19 20 18 . Chem. m-carboxyphenylarsonic acid. Soc. This method has been used to prepare arsonic acids of the benzene. J.EFFECT OF SUBSTITUENT GEOUPS ON YIELDS 419 // HiO EN2+HSO4. but more often they were as good or slightly better. J.. Because of their increased stability the diazonium borofluorides were observed to have less tendency to decompose or to form byproducts when allowed to react with sodium arsenite. 64. 3-nitro-4methylphenylarsonic acid.6-xylidine is not due to sterio hindrance. 62. and p-sulfamidophenylarsonic acid.+ AsCls -» N2 + R—As^-Cl -> R—AsOsH2 \OSO3H In this manner Scheller has been able to convert p^nitroaniline and paminoacetophenone to the corresponding arsonic acids. Am.18 Oneto and Way.22 Effect of Substituent Groups on Yields In general. and anthraquinone series as well as of a number Doak. naphthalene.21 Scheller's reaction gives better yields than the original Bart synthesis in several instances. Oneto and Way. 3. nevertheless. The same procedure improves the synthesis of wwiitrophenylarsonic acid. and Hartung. Am.18 However. primary aromatic amines can be converted into the corresponding arsonic acids by the Bart reaction or by one of its modifications. Chem. ffl Ruddy.6-xylidine into the corresponding arsonic acids. Chem. a 58% yield is obtained in a modified Scheller reaction using ethanol as the solvent and cuprous bromide as catalyst. the yield being 79% as compared with 45% by the original method of Bart.19'20 and Foldi. Chem. The method of Scheller has been extended by Doak. !1 Foldi.
. o-Butylphenylarsonic acid is obtained by the Bart method in only a 12% yield. 1931. [4] 49. which proceeds in an average yield of 45-55%. all three toluidines give toluenearsonic acids in good yields (45-55%). The preparation of phenylarsonic acid.24 the yield of arsonic acid decreases as the length of the side chain is increased. Thesis. Soc. must of necessity serve as the basis for comparison of yields from substituted amines.and o-nitroanilines further illustrates the hampering effect of m-nitro groups and the strong beneficial influence of o-nitro groups. [4] 53.420 BART. examples from the benzene series only will be considered. As expected. University of Nebraska. J. M.28 The failure of the Bart reaction on this compound may be due to steric hindrance.26 " Nitro Groups. 1930. soc. S. 28 Gibson and Johnson. 26 McGrew. J. the few exceptions being noted. 330 (1933). 1935. M. Two examples are given below: YIELD. % jw-Nitrophenylarsonic acid 0-35 p-Nitrophenylarsonic acid 36-45 o-Nitrophenylarsonic acid 80-90 2. 1213 (1931). Nitroanilines are converted to the corresponding arsonic acids in the following yields: YIELD. Thesis. and p-aminobenzyl alcohols the corresponding arsonic acids result in yields of 12-20%. Alkyl Groups. 1930. 1910.. Chem.. Bull. 24 23 . BECHAMP. S. 3270. practically all the yields reported in this discussion are by either the original Bart process or by Schmidt's modification. 25 John. chim. dam. From the o-. A survey of Bart reactions on variously substituted m. The following discussion deals primarily with reactions taking place in neutral or alkaline solution. For a study of the effect of substituents on yields. Baranger. Soc. Chem. % p-Hydroxyphenylarsonic acid " 92 3-Nitro-4-hydroxyphenylarsonic acid u 38 jre-Hydroxyphenylarsonic acid 26 0 2-Nitro-5-hydroxyphenylarsonic acid " 37 An apparent exception to the favorable influence of an o-nitro group is found in 2-bromo-6-nitroaniline. soc. BtiH. AND ROSENMUND REACTIONS of heterocyclic types. m-.23 When the reaction is applied to 2-hydroxy-4-nitro-5-alkylanilines.4-Dinitrophenylarsonic acid 68-70 v A comparison of the yields of the meta and ortho isomers is significant. Fourneau and Lestrange. University of Nebraska. 27 Phillips.
5-. 48. Doak. 499 (1927). m-hydroxyphenylarsonic acid could not be prepared from wi^aminophenol. 28.A.29 The o-iodophenylarsonic acid first formed reacts with another molecule of sodium arsenite (Rosenmund reaction) to produce the diarsonic acid.and p-hydroxyphenylarsonic acids in satisfactory yields (35-90%). 9..31 and p-chloroaniline gives somewhat better yields (60-80%). Prom. 36 Bauer. Am. 38 Gough and King. and Benoit. 3721 (1934)]. 817. 1920. » Etzelmiller and Hamilton. Gen. 33 8583 (1939)] 34 Harrington. [4] 41.and m-|8-hy20 Barber. o-Chloroaniline andra-chloroanilineare converted to the corresponding arsonic acids in yields of 40-70%. 63.R. 2333. J. 317 [C. and 3. Chem. 1930. Although o. Am. Soc. Chem. together with a lesser amount of 0-iodophenylarsonic acid. 3085 (1931).. Soc. Chem. soc. o. 32 Izmailskii and Simonov.29 When o-iodoaniline is subjected to the Bart reaction two products result. U.4dichloroaniline to the corresponding arsonic acids takes place in yields of 60-70%. "• I4 the reaction fails with the meta isomer. Soc.S. / . Simple alkoxyl substituted phenylarsonic acids may be synthesized from the corresponding amines without difficulty. % 2-Hydroxy-4-nitrophenylarsonic acid 36t M 55-78 2-Hydroxy-3-nitrophenylarsonic acid 37 29 3-Hydroxy-5-nitrophenylarsonic acid w 8 4-Hydroxy-3-carboxyphenylarsonic acid S8 46 Alkoxyl Groups. Chem. J.30'32 Similarly. Thesis. Bull. 1933. 33 Fargher. 1929. 3S Braz and Tuturin. 30 .39 As previously mentioned. With m-iodoaniline as a starting material a 24% yield of the corresponding arsonic acid is obtained. J. M.S. Chem. and Eagle. Soc. Trefouel. / . Khim. S.33 Hydroxyl Groups. "Fourneau.4-. 1579 (1915). 99 (1941). and a nearly quantitative yield of p-ethoxyphenylarsonic acid is obtained from pphenetidine. Soc. 992 (1939) [C. oMethoxyphenylarsonic acid may be prepared in 58% yield. University of Nebraska. chim. M Hewitt and King.. o-phenylenediarsonic acid in 20% yield.. 2.. Soc. The conversion of 2.14 The favorable influence of a p-alkoxyl group is further illustrated by the preparation of 3-hydroxy-4-methoxyphenylarsonic acid in a 26% yield. 865. 29 ' 30 . Chem. Steinman. 53.ALKOXYL GROUPS 421 Halogen.. J. the presence of halogen in the nucleus does not interfere with Bart's method.and p-aminophenols have been converted into o. Chem.26 Several substituted hydroxyphenylarsonic acids have been prepared by the Bart reaction. Ber. Farm. the three monobromoanilines are converted into bromophenylarsonic acids in slightly lower yields.. In general. J. Following are a number of examples: YIELD. 669. 1935.A. 1926.
BECHAMP. Soc. Thesis. Chem. 60 Oneto and Way. 2105 (1939). and p-aminoacetophenones may be converted to the corresponding arsonic acids in yields of 75%. Chem. 4122 (1930). 2-Carboxy-4-nitrophenylarsonic acid has been prepared in a 76% yield.g.46 Arsono Groups. M. 46 Gibson and Levin. Chem. Soc. J. 60. Am. AND ROSENMUND REACTIONS droxyethylphenylarsonic acids result in yields of 10% and 53% respectively when the corresponding amines are used in the Bart reaction. m-. 1931.14. 425 (1923).50 although "a better yield (57%) is obtained by a modified Scheller reaction. 56. and 66% respectively. 46 Scott and Hamilton.46'46 That a nitro group in the ortho position to the amino group aids the reaction is shown by a 47% yield of 3-nitro-4-arsonobenzaldehyde.18'61 Although ra-sulfamidophenylarsonic acid is not available by the usual procedure it can be prepared in a 58% yield by the method of Scheller..13 and a 14% yield of p-phenylenediarsonic acid is recorded. / . 2117 (1921) 43 Lewis and Cheetham. metanilic acid and naphthionic acid will not yield the corresponding arsonic acids.. in p-/3diethylaminoethoxyaniline) decreases the yield and may even prevent the formation of an arsonic acid. J. J.. It has been shown that sulfanilic acid can be converted into p-sulfophenylarsonic acid (25^-45%). 61. Yields of 50-60% of o. Ber. Chem..45 Strangely enough. Morgan. S. Chem. a-chloro. "Oneto.42-43 and the meta isomer has been prepared but no yield was given. Soc. J. Am. Chem. 1716 (1937). 47 Lieb.18 Binkley and Hamilton.40'36 The presence of a basic group in the alkoxyl side chain (e. J. Am. 1940. J.and p-carboxyphenylarsonic acids have been reported. 52.46 From m. Sulfo and Sulfamido Groups.4t It is to be noted that the presence of the o-nitro group in 2-nitro-4-arsonoaniline increases the yield from 14% to 70-85%.Nebraska. Chem..422 BART.. Ber.... Ber.34-48 .49' 60 By the ordinary Bart reaction p-sulfamidophenylaTsonic acid (25%) may be prepared. Am. 48 Lieb and Wintersteiner.41 Carbonyl Groups. The three isomeric aminophenylarsonic acids can be converted into the corresponding phenylenediarsonic acids by means of the Bart reaction. Soc. Soc. M.. 59. 1058 (1915). 45%.1S Apparently. Am. 48. 41 40 . S. 42 Lewis and Cheetham. 2058 (1938). 1511 (1921). University of . The o-isomer gives a 44% yield of the diarsonic acid. 54. Am. 61 Weitkamp.44 Ketone and Aldehyde Groups. Thesis. The o-.and a-bromoacetophenone-p-arsonic acids could not be prepared by the Bart-Schmidt reaction on the corresponding amino compounds. 2388.and paminobenzaldehydes the arsonio acids are obtained in yields of 4% and 22% respectively. 510 (1923). With negative substituents in the ortho and para positions the reaction is usually improved. 1935. Soc. Soc. University of Nebraska. 43. 45. 44 Karrer.
the mixture is chilled to 10° and 62 Jacobs. (50%) and in many cases runs well over 1000 g. of 1 : 1 hydrochloric acid. of anhydrous sodium carbonate. C6H5As02. is employed. a 25-1. pale yellow solution results. of concentrated hydrochloric acid. (62%). of water. Stirring is continued for one hour after all the diazo solution has been added.o-NITROPHENYLARSONIC ACID 423 Procedures PHENYLARSONIC ACID 7 For the production of phenylarsonic acid on a large laboratory scale. is made and placed in a 4-1. 40. In the tank are placed 41. 1580 (1918). The phenylarsonic acid is now precipitated by the addition of more hydrochloric acid. of sodium nitrite.. Concentrated hydrochloric acid is added in small portions. The solid material does not entirely dissolve unless the solution is heated. and the walls of the tank are cooled by several streams of water. the product is filtered off and washed with a little distilled water. An excess must be avoided since it causes a certain amount of the phenylarsonic acid to go into solution. and sufficient ice to bring the total volume to 31. this is deep brown in color. 0-NlTROPHENYLABSONIC A d D 62 One hundred grams (0. of water. . The stirrer is started. During this addition. the temperature of the arsenite being maintained at 15°. foaming can be controlled by regulating the speed of stirring and also by adding about 10 cc. After recrystallization from water the product is practically white and softens at 158°. (2 moles) of aniline. provided with mechanical stirrer. cylindrical copper tank. The yield of white or cream-colored product averages more than 800 g. the addition of diazo solution is begun. and 45 g. 1 kg.725 mole) of o-nitroaniline is ground under 500 cc. passing into the infusible anhydride. 400 cc. Heidelberger. This mixture is diazotized in the usual manner with a concentrated aqueous solution of 140 g. A mixture of 186 g. Chem. The acid is added until after filtering a clear. As soon as the temperature of the arsenite solution falls to 15° (part of the sodium arsenite precipitates at this temperature). Three hours or more is required for running four of these ice-cold diazo solutions into the arsenite. When this neutralized mixture has cooled. Small quantities of phenylarsonic acid remaining in the filtrate may be precipitated as the ferric salt by adding ferric chloride. 2 kg. of crystallized copper sulfate. of benzene whenever excessive foaming threatens to occur. The mixture is now filtered and the filtrate concentrated to a volume of approximately 51. Florence flask. 1 1. It is convenient to prepare the diazo solution in four portions. of technical arsenious oxide (about 20% excess). Soc. and Rolf. and the tarry material which separates is filtered off. J~Am.
of concentrated hydrochloric acid. the temperature being kept below 0°. The solution should be stirred for thirty minutes after the addition.5 g. of 5 N sodium hydroxide as used in the above preparation. 0-NlTRODIPHENYLARSINIC A d D n o-Nitroaniline (138 g. during which time a slow but steady nitrogen evolution occurs. To the above solution is added (during forty-five minutes) a buffered phenylarsenous oxide solution containing 185 g. This hot solution is poured in a thin stream onto 16 kg.4 moles) in water (410 cc).. it weighs 334-400 g. 1. of phenylarsenous oxide * in 440 cc. Two to three hours is usually required for this reaction. which is readily available from phenylarsonic acid. 2 moles) is dissolved in concentrated hydrochloric acid (700 cc. pale yellow powder.) to the stirred suspension. into 550 cc. of potassium iodide is usually sufficient to complete the reduction). . the mixture is heated a few minutes to form the hydrochloride. and hydrochloric acid is added to the deep yellow filtrate until it is strongly acid to Congo red.. and then heated with 500 cc. and fractionally distilled at reduced pressure in a stream of carbon dioxide or nitrogen. After about half of the phenyl*The phenylarsenous oxide solution is most conveniently prepared from phenyldichloroarsine. When the hydrochloric acid solution becomes clear and the addition of more potassium iodide does not form a permanent cloudiness the reaction is complete.hour and a half to two hours. of technical sodium acetate in 5000 cc. The alkaline solution is then added to 135 g.5 g. of sodium arsenite dissolved in 1250 cc. depending on the purity of the original phenylarsonic acid. The yield is 110 grams (61%). 1 mole) is suspended in 800 cc. of boiling water to dissolve the hydrochloride.2-0. of water and the mixture heated to 60-70° for an . of sodium nitrite. After ten to fifteen minutes' stirring the solution is filtered from traces of undiesolved nitroaniline and poured slowly. After acidification with a slight excess of acetic acid the dark-colored solution is clarified with charcoal.) and treated with a stream of sulfur dioxide. of 5 N sodium hydroxide and 800 g. Overheating is particularly to be avoided. The solution described here represents 185 g. The oil is removed. The crude phenyldichloroarsine separates as a heavy oil. The solution may be filtered to remove any unchanged o-nitroaniline.. 4. Diazotization is accomplished by adding a solution of sodium nitrite (76 g. Phenyldichlbroarsine (245. On thorough chilling the nitrophenylarsonic acid crystallizes as a heavy. is collected. It will not matter if this solution remains slightly turbid. of phenylarsenous oxide in 440 cc.. From time to time a trace of potassium iodide solution is added (0.424 BART.1 moles) is placed in a dropping funnel and very cautiously added dropwise to a warm stirred solution of sodium hydroxide (176 g. of water. with shaking. of well-stirred crushed ice. The nearly colorless product boiling at 140-143°/40 mm. dried with calcium chloride. AND ROSENMUND REACTIONS diazotized with a solution of 55 g. (75-90%). BECHAMP.) is added to maintain a low temperature. During the addition more ice (5 kg. precipitating the hydrochloride as a fine suspension. of 25% sodium hydroxide solution. Crude phenylarsonic acid (404 g.
of anhydrous sodium arsenite in 2000 cc.57. of sulfuric acid and 28 g.a-NAPHTHYLARSONIC ACID 425 arsenous oxide solution is added. and the second figure to the modified one: p-sulfamido. The yield is 50 g. of water. the mixture is thoroughly stirred. and when it is complete the liquid is filtered from the brown by-product and then acidified with hydrochloric acid. (54%) of m-nitrophenylarsonic acid. the mixture is neutralized with 5 N sodium hydroxide (about 920 cc). 76.54. 40. and filtered. 0. 200 cc. and not before. J. m-sulfamido. 44. On acidifying the light yellow solution with concentrated hydrochloric acid. m-carboxy. 1 g. 58. Chem. The precipitate of crude a-naphthylarsonic acid is filtered off and purified by dissolving in a cold concentrated solution of sodium bicarbonate.. 28. . 1. 0. is diazotized with a saturated aqueous solution of the calculated amount of sodium nitrite (starch-iodide end point). of cuprous bromide is added. gr. The evolution of nitrogen occurs for several days. o-nitrodiphenylarsinic acid begins to precipitate. One mole of m-nitroaniline (138-g. 36. The best yield is obtained by allowing the diazonium compound to decompose slowly at room temperature.5. of concentrated hydrochloric acid. The yield is 265. a-NAPHTHYLARSONIC AciD 6 3 One mole of a-naphthylamine is dissolved in a mixture of 3000 cc. and then distilled with steam. 53 Hill and Bails. w-nitro. At the end of the addition. m-Nitrophenylarsonic Acid. of hydrochloric acid (sp. of absolute alcohol. with 10 g. Soc. After cooling to 0°. the insoluble residue is filtered out. The advantage of the modified Bart procedure in certain cases may be shown by the following percentage yield figures.) gives 133. MobiFiED SCHELLER-BART REACTION18 General Experimental Procedure. cooled to 0°. (87%).1 mole in 250 cc. (20%). o-nitrodiphenylarsinic acid separates as a crystalline powder.6. 3-nitro-4-methyl. heated for a time with charcoal. . 15. 2051 (1922). . after one recrystallization from water. Then. in the usual manner.5 g. The separated arsonic acid is recrystallized. warmed to 60° until no more nitrogen is evolved. of hot water and 100 cc.5 g.18) is added and the a-naphthylamine is diazotized. The diazo solution thus obtained is poured into a solution of 600 g. On recrystallization from water the product separates as white needles melting at 197°. A mixture of the amine. the first figure of each pair corresponding to the ordinary procedure. and naphthylarsonic acid is reprecipitated with hydrochloric acid. with one mole of sodium nitrite. 25. of arsenious chloride. Am.
The acid. treated with charcoal. AND ROSENMUND REACTIONS ANTHRAQUINONE-1-ARSONIC ACID M a-Aminoanthraquinone (22. and the solution acidified with hydrochloric acid.de of 2-aminofluorene. of ice and then allowed to stand for one-half hour. of water. 74 (1917). acid. slightly soluble in hot water. and heated to boiling. When all the diazo compound M 66 Benda. The resulting clear solution is cooled (40°) rapidly..426 BART. and the filtrate cooled to 20°. a saturated aqueous solution of 6 g. A vigorous evolution of nitrogen takes place. anthraquinone-a-arsonic acid separates as colorless needles. On recrystallization from 75% acetic acid. prakt.. of water. of sodium arsenite in 250 cc. of sulfuric acid (66° Be\). almost insoluble in methyl or ethyl alcohol. From the mother liquor of the sodium salt an additional 7 g. Cislak and Hamilton. chem. . of water and 250 cc. (46%). 2-ARSONOFLUORENE M Fifteen grams (0.083 mole) of 2-aminofluorene is mixed with 550 cc. of concentrated hydrochloric. J. [2] 95. While this mass is stirred. of sulfuric acid containing 47% nitrosylsulfuric acid and 60 cc. J. thereby causing the precipitation of the hydrochlori. the mixture of solid fiuorenediazonium chloride and its saturated solution is added to the arsenite at room temperature. treated with 20 cc. On the next day the precipitate is dissolved in 500 cc. This solution is stirred during the entire course of the arsonation. BECHAMP. Without heating. Am. 746 (1931). 53. The total yield is 15 g. Chem.solution is stirred with 600 g. of water. of sodium 'nitrite is added dropwise. 0. during which time the sodium salt of the desired arsonic acid usually separates in silver-gray flakes. of 2 N sodium carbonate. causing 1^ie precipitation of golden yellow needles of 2-fluorenediazonium chloride. Soc. The resulting brownish yellow solution is gradually heated to 60°. The colorless to light yellow crystalline precipitate is washed with water and dried to obtain 8 g. Thirteen grams of sodium metaarsenite and 1 g. of hot water. of the free arsonic acid is precipitated on acidification. In small portions. After washing with 250 cc. and the reddish crystals are filtered off.1 mole) is dissolved in-80 cc. filtered hot. filtered. At once a vigorous evolution of nitrogen occurs. Sufficient 6 N sodium hydroxide solution is added from time to time to make this arsenite solution just alkaline. of sulfuric acid (66° Be\) and diazotized at room temperature with a mixture of 70 g. of copper sulfate are dissolved in 300 cc.3 g. of pure product. the diazonium compound is dissolved in an arsenite solution containing 25 g. the reaction mixture is stirred for three to four hours.
100 cc. and the fluoborate should be stirred well on the filter with each washing. 40 (193B). 19. and then the mixture is allowed to stand overnight. beaker. of a sodium hydroxide solution (0. The next morning it is warmed at 65° for about thirty minutes and then filtered with suction through a Buchner funnel.25 mole) is gradually added to maintain the proper alkalinity. the solution is stirred for fifteen hours. The solid diazonium fluoborate is washed once with 25-30 cc. (Fluoboric acid is made by adding 184 g. (A sintered glass filter should be used for filtering. twice with 95 per cent alcohol.p-NITROPHENYLARSONIC ACID 427 has been added. the mixture is stirred for a few minutes and filtered by suction on a sintered glass filter. p-NlTROPHEljTYLARSONIC A d D 22 The preparation of p-nitrobenzenediazonium borofluoride is described in Organic Syntheses56 and is carried out as follows. the diazonium borofluoride (from a quarter-mole of p-nitroaniline) suspended in 300 cc.25 mole) of sodium nitrite in 34 cc. and the solution is stirred with an efficient stirrer.) The product weighs 56-59 g.4 mole) of sodium metaarsenite (NaAsC^) and 6 g. Org.25 mole) of p-nitroaniline is dissolved in 110 cc. any tar separating at this point is removed by filtration. filtered hot. separated by filtration. with vigorous stirring. and several times with ether. lead. of cold water. reprecipitated with hydrochloric acid. over a period of an hour. The foaming which accompanies the evolution of free nitrogen is controlled by the addition of small amounts of ether as needed. or silver-plated container placed in an ice bath. To this mixture is added.) The beaker is placed in an ice bath. A cold solution of' 17 g. of concentrated hydrochloric acid. of water at room temperature are added 52 g. (95-99% of the theoretical amount). Hydrochloric acid is added to the filtrate until it is acid to litmus.7%). This precipitate is washed with water. and dried. As the reaction proceeds.5 g. of fluoboric acid solution in a 400-cc. and the filtrate acidified with 10 cc. of cold fluoboric acid. . to 450 g. Syntheses. Stirring is continued for another hour. (0. dissolved in a dilute solution of sodium carbonate. Thirty-four grams (0. When the addition is complete. thereby precipitating 2-arsonofluorene. (0. Activated charcoal is added. The yield is 4. The diazonium fluoborate is stable and may be dried in a vacuum desiccator over phosphorus pentoxide. washed. with constant stirring. of water is added dropwise. After heating to 90° the solution is stirred for three-quarters of an hour. before suction is applied. and the solution is concentrated over a flame to approximately 66 Starkey. of cuprous chloride. To 600 cc. of boric acid slowly. (18. of hydrofluoric acid (48-52%) in a copper.
For example. involves the replacement of a nuclear hydrogen by the arsono group and that the compound produced is 4-aminophenylarsonic acid. phenols. Ber. apparently due to conflicting orientation. The total yield is 79% of the theoretical. J. o-toluidine gives only a 14% yield of 3-methyl-4-aminophenylarsonic acid 61 and from o-cresol there results an 8% yield of 3-methyl-4Ehriich a n d Bertheim. Ber. 1672 (1908). BECHAMP REACTION In 1863. the literature contains more than sixty articles dealing with this method. In all. / . and their derivatives. and their various derivatives. However. amines. Brown and Hamilton. Am. which might be expected to undergo arsonation in the alpha position. does not react with arsenic acid.. 60 Skiles and Hamilton. Even though the Bechamp reaction has been applied to numerous derivatives of benzene. M Hamilton and Major. Soc. Soc. AND ROSENMUND REACTIONS 200 cc. 151 (1934). 1128 (1925). Chem. 47. The reaction is somewhat analogous to sulfonation.60 . but it is less general in application because arsonation requires a more labile hydrogen atom than sulfonation. Scope and Limitations of the Reaction Arsonation of aromatic compounds by treatment with arsenic acid is. applicable only to the amines. Since its discovery the Bechamp reaction has been extended to include many phenols. l-amino-2-naphthalenearsonic acid. now known as the Bechamp reaction. Soc. Only one naphthalene derivative. Bechamp heated aniline arsenite with an excess of aniline at 190-200° and obtained a colorless solid which he thought was an acidic anilide. J. substituted phenyl ethers. 69.428 BART. The presence of methyl groups in the oriho position causes a marked decrease in yield. and the filtrate is made acid to Congo red with hydrochloric acid. 1006 (1937). 56. BECHAMP. 3292 (1907). On cooling the p-nitrophenylarsonic acid separates and a further small amount of product may be obtained by further concentration of the mother liquor. there is no evidence that it has been applied extensively to other aromatic nuclei. 41. Chem. The charcoal is removed by filtration. The compound is purified either by dissolving in ammonium hydroxide solution and reprecipitating with hydrochloric acid or by recrystallization from water. in 1907. Am. 68 69 67 2 . is reported as having been prepared by the Bechamp reaction. Benda and Kahn. Chem. Am. in general..68 |3-Naphthylamine.69 Dibenzofuran reacts with arsenic acid to give an 11% yield of 2-dibenzofurylarsonic acid. 4 0 . Ehrlich and Bertheim 67 clearly demonstrated that the reaction.
. 800 (1923). 23. Ind. 2.. 70 Beguin and Hamilton. 74 Lieb and Wintersteiner. 4-arsonodiphenylamine. Ber. 68 Pepe. 105 (1928) [C.70 2.74 Christiansen. 3619 (1909). J. 509 (1915). Soc.62 The effect of nuclear chloro and nitro groups. 66 Lucius and Bruning.SCOPE AND LIMITATIONS OF THE REACTION 429 hydroxyphenylarsonic acid.. I. 480 (1935)].4-dimethoxy-5-acetoxyphenylarsonic acid in only a 7% yield.4% of its isomers. x 73 Benda. If acetylated aminophenols are employed as starting materials. (London).62 Methyl groups in the meta position appear to exert little or no influence on the yield..36 The urethanes derived from aminophenols can be arsonated without difficulty. Am. Bull. Zentr. 243. 42. nac.4'-diarsonodiphenylamine. 5. farm. 7i Omer and-Hamilton.. Am. 48. 59.. 29. 180 (1935)]. pat. 25^6 (1912)].. Chem... and some arsinic acids were obtained in a combined yield of 18-20%. Chem. 2-methyl-4-hydroxyphenylars'onic acid is obtained in a 20% yield with only 0. the reaction proceeds ^in the expected manner with o. 3293 (1911). 44.36 and 4-carbethoxyamino-2-hydroxyphenylarsonic acid is produced from m-carbethoxyaminophenol in a 74% yield.A.68 Aminophenols 36 and polyhydroxyphenols. 107 (1928). respectively. La Plata.. Pt. pat. facultad dene. 71 Bauer. Ret. However.71 These two examples illustrate the highly favorable influence of the m-hydroxyl group. 61. Soc.417 (1934) [C. on the yields in the Bechamp reaction has not been studied.4Dihydroxyphenylarsonic acid is obtained from resorcinol in a 62% yield. As a result m-toluidine apparently can be arsonated readily.73 No N-alkyl or N-dialkyl anilines have been arsonated by the Bechamp method. Fr. Ber.. pat. Ber.71 From o-aminoanisole there was formed 3-methoxy-4-aminophenylarsonic acid in a low yield. 69 Sonn. 61. 64 Mameli... 68 62 . I. Soc. 66 Benda. from m-cresol. Brit. Soc. With diphenylamine as starting material. Strangely enough. J. J. 4. 29.196 (1911) [/. Gardner. as well as 2% of the ortho isomer. 996 (1914).693 (1910) {Chem. pat. guim Univ.67 but fails completely with o-nitrophenol.4-dimethoxyphenylarsonic acid (44%). chim.. 682 (1909) [Chem. cannot be arsonated by arsenic acid because of their susceptibility to oxidation. 762 (1912)]. Ber. Chem. 355 (1939). the mon\>. 642 (1937). alone.921 (1934) [C. 47.is-64 and p-nitroaniline 66 ' 66 and o-69 and p-chloroaniline. Am. 67 Benda.. 1704 (1919). 45.72 Although the arsonation of ethers of phenol has not been investigated. Ber. 3216 (1929)].69 and.A. 29. Ger. 1856 (1909)]. Zentr. II.69 except for resorcinol. Chem. 768. 48. 413.and di-methylethers of resorcinol can be arsonated to yield 2methoxy-4-hydroxyphenylarsonic acid (31%) and 2. hydrolysis and subsequent oxidation of the aminophenol prevent arsonation. 31.A. 5 2 .. Ber.4-dimethoxyacetophenone yields 2. Brit.
none of the meta isomer results.430 BART. of boiled arsenic acid. the most desirable reaction temperature varies with the relative reactivity of the substance being arsonated. 4. phenol. As the reaction temperature rises the proportion of arsinic acids increases until at 220-230° they are the principal products.. a large excess of the base is advisable to keep the mixture fluid. para orientation predominates. BECHAMP. If the para position is blocked.. J. the yields are often low with larger runs because of inefficient stirring. Chem.77 The reaction between phenol and arsenic acid is reversible. and many of their derivatives are best arsonated at temperatures of 150-160° for six to twelve hours. in the case of p-hydroxybenzenesulfonic acid no reaction occurs.4'-diaminodiphenylarsinic acid from aniline). By continuous removal of 75 76 '.76 As might be expected. 451 (1919). With the more reactive types such as resorcinol or m-carbethoxyaminophenol a temperature of 100° for two days is sufficient. Cheetham and Schmidt. it should be stirred efficiently. As would be expected. small amounts of arsinic acids are produced. Soc. When aniline is used.76 Procedures . of phenol. Am. AND ROSENMUND REACTIONS Side Reactions In the Bechamp reaction. together with some arsinic acids (e. / ^ . Soc. although email amounts of ortho isomers are formed. orthoy substitution prevails when a-naphthylamine is employed as the starting material. The best yields of l-amino-2naphthalene arsonic acid are obtained by heating a-naphthylamine with solid arsenic acid at 165-175° for fifteen minutes. no reaction takes place.68 Since the reaction mixture ordinarily consists of two phases. The phenol or amine and the arsenic acid are heated in the absence of a sojvent. 77 Barber. p-Hydroxyphenylarsonic acid is hydrolyzed in water to a marked degree even at 130°. 100 g. Chem. 828 (1920). however. 4. Am. Chem.g. when 200 g. J. 1930. 41.68 In addition to ortho isomers. A survey of procedures used in the Bechamp reaction reveals a few general rules of value in improving yields. 2047. Soc. the reaction usually yields the ortho isomer in a low yield. Experience has shown that aniline. of water are heated and stirred under sufficient pressure to maintain the mixture at 140-150°. 42. J. Kober and Davis. as by-products in the Bechamp reactions. At higher temperatures oxidation brings about a decrease in yield. and 20 cc.4'-Diaminodiphenylarsinic acid has been prepared in a 20-30% yield by the interaction of aniline with arsenic acid at 230°.
are published in Organic Syntheses.ROSENMUND REACTION 431 the water formed during the arsonation of phenol the yield of p-hydroxyphenylarsonic acid is considerably increased. 1439 (1883). Syntheses. and reprecipitating with hydrochloric acid. The extract is allowed to cool with occasional stirring until the tar has solidified. Soc. ™ Lewis a n d C h e e t h a m . maximum yield. 4 5 . 16. prepared phenylarsonic acid (in low yield) and o-carboxyphenylarsonic acid (44% yield) from tripotassium arsenite and bromobenzene and o-bromobenzoic acid.5 N sodium carbonate.. respectively. From two other aromatic bromides. 2 n d ed. 1 9 4 1 . of molten a-naphthylamine (previously heated to 150° for ten minutes and then allowed to cool to 75-90°).. 2nd ed. o-phenylenediarsonic acid. developed a very interesting and useful method of preparing aliphatic arsonic acids from alkyl halides and. Chem. RX + As(0Na)8 -> RAsO(ONa)8 + NaX It was not until thirty-eight years later that this method of synthesis was applied to the aromatic series. filtering through charcoal. and the filtrate is acidified to Congo red paper with 6 N hydrochloric acid.. Soc. 175-176° (dec). Coll.29-82 has been obtained in good yields by Rosenmund's method. Am. Rosenmund.6 g.5 N sodium hydroxide.p..8 in 1921. m. 1 9 4 1 . When dried in the oven at 110° the l-amino-2naphthalenearsonic acid turns slightly pink on the surface. Coll. Bet. 2188 (1923). poured into 250 cc. allowed to cool to about 100°. 70. trisodium arsenite. I. Vol. 58.. in 1883. Since that time only one other arsonic acid. 81 M e y e r . casserole suspended in an oil bath. Chem. average yield. 20%. or 30% based on arsenic acid used. J. Org. J. 81 * . 490. and heated to boiling. The white precipitate of the arsonic acid is purified by dissolving in 0. Am. 81 Hamilton and Ludeman.5. Org.78 Detailed procedures for the preparation of arsanilic acid and sodium p-hydroxyphenylarsonate. Syntheses.™-80 Arsonation of a-Naphthylamine M Ten grams of solid arsenic acid. respectively. by arsonation of aniline and phenol. it is then filtered through a thin layer of charcoal. 3284 (1930). The mixture is heated rapidly to 170° and then for fifteen minutes at 165-175° with constant stirring. dried for three hours at 110°. of 0. p-bromobenzoic acid arid 78 C h r i s t i a n s e n a n d N o r t o n . Vol. is slowly stirred into 50 g. 1. contained in a 250-cc. 80 Christiansen a n d N o r t o n .. ROSENMUND REACTION Discussion Meyer.
Chem. I. I. 41. It is somewhat surprising that ochloronitrobenzene. Certain minor modifications of this procedure have been employed.82 Copper powder. 63 cc.... J. and the residue is washed with ether to remove salicylic acid and unchanged o-bromo83 84 Albert and Sohulenberg. 40 cc. Zentr.4-dinitrochlorobenzene the corresponding phenol84-82 or phenetole88 is formed. BECHAMP. Rec. of concentrated hydrochloric acid. is sometimes employed as catalyst. o. 1986.1 mole) of o-bromobenzoic acid.A. but the value of either is uncertain. of ethyl alcohol. 1805 (1941)].432 BART. Ger. The resulting residue is extracted with absolute methanol.. as well as cuprous chloride.82 Refluxing o-bromonitrobenzene with an excess of 50% trisodium arsenite gives a small amount of arsonic acid. (0. made acid to Congo red paper with 20 cc. the Rosenmund reaction is carried out by heating one mole of trisodium or tripotassium arsenite with one mole of aromatic halide in boiling aqueous ethanol solution. Jap.. 36. but no 2. 88 '". The reaction mixture is filtered hot to remove copper. Zentr. of 50% tripotassium arsenite solution. _ Procedures In general.. but this alone does not insure a successful reaction.4-dinjtrophenylarsonic acid results. chim. trax. 87 Austrian pat. the methanol extract is evaporated to dryness.211 (1922) [Chem. no ethanol is necessary. pat..82 From 2. 569. and evaporated to dryness on a steam cone.and p-bromonitrobenzene.4'-dibromoazoxybenzene. of 10% potassium hydroxide solution. Nijk. 129. 20 cc. 1148R (1929)]. AND BOSENMUND REACTIONS p-bromoacetophenone. "•Tanaka.82'86 Reactions of bromobenzene and p-bromoacetophenone must be run in sealed tubes at temperatures of 150-200 0 . the corresponding arsonic acids have been produced in low yields.595 (1939) [C. 100. and even 2. pat. and a little freshly reduced copper is refluxed at 90-95° for twelve hours with constant stirring. If the aromatic halide contains an acidic group (e. 82 O-CARBOXYPHENYLABSONIC ACID 82 A mixture of 20 g. p-bromonitrobenzene yields traces of the arsonic acid together with a 45% yield of 4. 86 .. Balaban. o-bromophenylarsonic acid).84-29> 82 No reaction takes place when ochloronitrobenzene is used as the starting material.403 (1923) [Chem. 461 (1922).g. 357 (1927)].. 468. Soc.83-29> 82 Apparently a rather active halogen atom is required.4-dinitrochlorobenzene either" fail to undergo the Rosenmund reaction or yield only traces of arsonic acids.
6-. yield. The starting material is listed in parentheses under the product if its nature is not obvious. 10. The compounds in the table are grouped according to the number of carbon and hydrogen atoms present. 3-. or 8-position but are not included if the attachment occurs in the 2-. Nearly all the compounds were prepared by the method of Bart or Schmidt. or 4-position. this fact is noted. All known examples of the Bart and Bechamp reactions in which the product contains an arsonic or arsinic acid group attached directly io an aromatic carbocyclic ring structure have been included.% tion already have been briefly outlined. quinoline arsonic acids are included if the arsono group is linked to the 5-.COMPOUNDS PREPARED BY THE BART REACTION 433 benzoic acid. . No table for the Rosenmund reaction is presented because the few known examples of this reac.«l g. 7-. TABLES OF COMPOUNDS PREPARED BY THE BART AND BECHAMP REACTIONS In the following tables are listed the compounds which have been prepared by the Bart and Bechamp reactions. This method of arrangement is the same as that used by Chemical Abstracts. The ether-washed residue is twice recrystallized from hot water after decolonization with bone black. For example. When Scheller's modification was used. (41%) of ocarboxyphenylarsonic acid.
. 418). 60-75% 40% — 52% 45% — 60-85% 80% 55% Reference 17*' 29 28 10 88 89 90 91 90 10 91 33* 33* 33* 15 14 16 92 93 94 29 13 29 95 96 29 10 1 96 7 31 14 22 35 14 7 32 95 3-Chloro-4-nitrophenylarsonic acid 3-Nitro-4-chlorophenylarsonic acid 2-Nitro-5-chlorophenylarsonic acid 2. * Soheller's modification was used (see p. 451-454. AND ROSENMUND REACTIONS COMPOUNDS PREPARED BY THE BART REACTION C6 Formula CjHBAsBrNOs CoHsAsBrNOs CsH&AsBrNOs CeHsAsBrNOs CeHnAsClNOs ' CeHjAsClNOe CeHsAsClNOs C6H6AsClNO6 CBHSASCINOB Compound 2-Bromo-4-nitrophenyIarsonic 2-Bromo-5-nitrophenylarsonic 2-Bromo-4-nitrophenylarsonic 3-Nitro-4-bromophenylarsonic 2-Chloro-4-nitrophenylarsonic 2-Chloro-5-nitrophenylarsonic acid acid acid acid acid acid Yield 42%* 25% 42% — — 50% 33.4-Dichlorophenylareonic acid 2.4-Dichlorophenylarsonic acid 3. BECHAMP.5-Dichlorophenylarsonic acid 2.% 45% ' 32% — 64% 62%* 60%* 70%* 70% 68% — 56% — 70% 42% 37% 35% 55% 69% 55% ~ 97% .4-Dinitrophenylarsonic acid 3.434 BART.5-Dinitro-2-hydroxyphenylarsonic acid --p-Phenylenearsinic acid o-Bromophenylarsonic acid • m-Bromophenylarsonic acid p-Bromophenylarsonic acid CeHsAsCljOa C6H5ASO2O3 CeHsAsC^Os CeHjAsNsOv CeHjAsNaOg CeHjAsOa CeHjAsBrOa CeHeAsBrOs CeHsAsBrOs COHIIASCIOS o-Chlorophenylarsonic acid CeHsAsClOa CaHnAsClOg wi-Chlorophenylarsonic acid p-Chlorophenylarsonic acid - References 88-231 appear on pp.
4-Dinitroaniline) 2-Hydroxy-4-nitrophenyIarsonic acid Kfe 36 35 37 104 14 37 105 104 14 106 104 CoHeAsNOe 2-Nitro-4-hydroxyphenylarsonic acid C 6 HBASNO 6 2-Hydroxy-5-nitrophenylarsonic acid References 88-231 appear on pp 451-454.COMPOUNDS PREPARED BY THE BART REACTION^ COMPOUNDS PREPARED BY THE BART REACTION—Continued 435 Formula Compound Yield Reference 14 10 22 CsHeAsPOsS CeHeAsIOs C6H6AsIO3 CsHsAsNO* 3-Sulfonylfluoridiphenylarsonic acid p-Iodophenylarsonic acid m-Iodophenylarsonic acid o-Nitrophenylarsonic acid C6H6AsNO6 m-Nitrophenylarsonic acid C6H6AsNO6 p-Nitrophenylarsonic acid - 46% — 63% * 10% 24% 86% 84% 60% — 61% — 67% 54%* 36% 35% — 28% •— 47% 79% 45% 36% — » * — 78% 55% — s 62% 53% — 50-60% 50% 46% — — 97* 98 29 11 13 14 100 52 15 22 18* 26 • 101 61 14 52.11 22 22 14 52 100 102* 17* 1 C 6 HBASNO 6 CsHBAsNOe 2-Hydroxy-4-nitrophenylarsonie acid (2. . * Seheller's modification was used (see p 418).
BECHAMP. 451-454. 418).107 37 37 108 22 - 8 7 14 61 109 40-50% 45% 39-45% • C6H 7 As0 3 S CgHyAsOi 111 112 1 1 .4-Dihydroxyphenylarsonic acid w-Sulfophenylarsonic acid p-Sulfophenylarsonic acid Chloro-p-phenylenediarsonic acid (3-Chloro-4-aminophenylarsonic acid) 4-Nitro-TO-phenylenediarsonic acid (2-Amino-5-riiWophenylarsonic acid) 2-Nitro-p-phenylenediareonic acid w-Arsonobenzenesulfonamide 70% — 28% — 115 116 117 o%* 18*. AND ROSENMUND REACTIONS CoMPOtmDs PREPARED BT THE BART REACTION—Continued Formula Compound Yield Reference CgHoAsNOe CoHeAsNOe CcHeAsNOe " CHsAsNOe C«H6AsNO6 C6H7ASN2O5 CSHTASOS 2-Nitro-5-hydroxyphenylarsonic aqid 37% 38% — 27 14 3-Nitro-4-hydroxyphenylajrsonic acid 2-Hydroxy-^nitrophenylarsonic acid 3-Hydroxy-5-nitrophenylareonic acid 2-Hydroxy-6-nitrophenylarsonic acid 2-Nitro-4-aminophenylarsonic acid (2-Nitro-4-acetyl-p-phenylenediamine) Phenylarsonic acid 29% 50% 8% 15% — 58% 72-86% 50-62% 54% — 10 37 . .436 BART. 49 118 55% 85% "70% 118 119 48 18* 58%* References 88-231 appear on pp. p-ThioIphenylarsonic acid o-Hydroxyphenylarsonic acid w^-Hydroxyphenylarsonic acid p-Hydroxyphenylarsonic acid — — XI 113 10 C e H 7 As0 4 CeHyAsOi >90% 35% — 0% 92% — — 114 14 34 99 26 14 10 C 6 H 7 As0 6 C 6 H 7 As0 6 S C 6 H 7 As0 6 S CeH 7 As 2 C10 6 C 6 H 7 As 2 NO8 C 6 H 7 As2NO 8 CeHgAsNOeS 3. * Scheller's modification was used (see p.
COMPOUNDS PREPARED BY THE BART REACTION COMPOUNDS PREPARED BY THE BART REACTION—Continued 437 Formula Compound Yield Reference 18* 50 29 13 47 14 47 1 CHgAsNOsS CjHsAssOe CeH8As2O6 C6H8As2Oa CeHgAsjOe p-ArsonobenzenesulfonaWde o-Phenylenediarsonic acid o-Phenylenediarsonic acid (o-Arsanilic acid) m-Phenylenediarsonic acid (»&-Arsanilic acid) p-Phenylenediarsonic acid (p-Arsanilic acid) 4-Hydroxy-m-phenylenediarsonic acid (3-Amino-4-hydroxyphenylarsonic acid) 57%* 25% 20% 44% — 28% 20% ' CeHgAsaO? 1 120 CTHBASCINOS C 7 H 6 AsNO 3 S CrHeAsNOe C7H5ASN2O7 C7H6ASNO6 QHoAsNOs CrHeAsNOg C7H6AsNO7 CjHeAsO? CyHyAsNijOaS C7H7ASO3 C7H7ASO4 7-Chlorobenzoxazolone-5-arsonic acid p-Thiocyanophenylarsonic acid Nitro-p-aldehydophenylarsonic acid 6-Nitrobenzoxazolone-5-arsonic acid 6-Arsonobenzoxazolone Benzoxazolone-5-arsonic acid 3-Nitro-4-arsonoberu!aldehyde 2-Carboxy-4-nitrophenylarsonic acid 6-Nitro-3. 461-154.4-methylenedioxyphenylarsonic acid •6-Arsono-2-mercaptobenzimidazole o-Hydroxymethylphenylarsonic acid anhydride p-Arsonobenzaldehyde 50%* — 42% 47% 76% 37% or 74% " — 14% 22% * — — 4% 0% 50-60% 37. * Scheller's modification was used (see p. 40% 67% 121 122* 123 15 37 121 46 44 124 114 23 45 102* 125 123 46 45 42 14 22 C7H7ASO4 C7H7ASO6 m-Arsonobenzaldehyde p-Carboxyphenylarsonic acid References 88-231 appear on pp. 418). .
4-Methylenedioxyphenylarsonic acid 3-Carboxy-4-hydroxyphenylarsonic acid x 40% 37% 2-Methyl-4^chlorophenylarsonic acid 9% 2-Nitro-4-methylphenylarsonic acid 88% 69% 58% 3-Nitro-4-methylphenylarsonic acid 40%* 15% 2-Nitro-6-methylphenylarsonic acid 50% — 2-Methyl-4-nitrophenylarsonic acid 55% — 2-Methyl-5-nitrophenylarsonic acid 35% 2-Hydroxy-4-nitro-5-methylphenyl30% arsonic acid 2-Hydroxymethyl-4-nitrophenylarsonic 78% acid 3-Hydroxymethyl-4-nitrophenylarsonic 42% acid — 2-Nitro-4-hydroxymethylphenylarsonic 75% acid 2-Methoxy-4-nitrophenylarsonic acid 60% 3-Nitro-4-methoxyphenylansonic acid — 2-Nitro-4-/3-hydroxyethylphenylarsonic 43% acid — 2-Methoxy-6-nitrophenylarsonic acid o-Toluenearsonic acid 60-73% 49% 40% 19% 63% m-Toluenearsonic acid ' 49% 45% 54% 50-60% 44. BECHAMP. 418).438 BART. 56% 56% 65% 76%* 36% 42% 43 14 126 22 18* 14 124 107 38 127 128 129 52 18* 52 52 100 52 100 52 24 23 23 130 23 100 10 23 100 131 14 7 127 22 131 14 22 References 88-231 appear on pp. AND R08ENMUND REACTIONS COMPOUNDS PBEPAKED BY THE BART REACTION—Continued Formula Compound Yield Reference C7H7ASO5 o-Carboxyphenylarsonic acid C7H7ASO6 C7H7ASO5 C7H7ASO6 C. 451-464.H B AsC10 3 CTHJASNOS m-Carboxyphenylarsonic acid CTHSASNOS C7H8ASNOB C^HsAsNOs C7H8AsNO6 CyHsAsNOe * C 7 HgAsNO 6 C^HsAsNOe C 7 H 8 AsNO6 C 7 H 8 AsNO6 C7H 8 AsNO 6 C 7 H8AsNOe ' CjHgAsNOe C7H9ASO8 C7H9ASO3 3. * Scheller's modification was used (see p. .
COMPOUNDS PREPARED BY THE BART REACTION COMPOUNDS PREPARED BT THE BAET REACTION—Continued 439 Formula Compound Yield Reference 22 7 131 14 132 21 10 133* 134 134 23 135* 23 100 100 in CrHjAsOs p-Toluenearsonic acid 73% 50-65% 57% 54% 47% 20% 50%* — — 20% • CTHJASOSS C7H9ASO4 C7H9ASO4 C7H9ASO4 C7H9A13O4 C7H9ASO4 C7H9ASO4 p-Methylthiophenylarsonic acid 2-Hydroxy-3-methylphenylarsonic acid 2-Hydroxy-5-methylphenylarsonic acid p-Hydroxymethylphenylarsonic acid m-Hydroxymethylphenylarsonic acid o-Methoxyphenylaraonic acid p-Methoxyphenylarsonie acid 3-Hydroxy-4-methoxyphenylarsonicacid 3-Methoxy-4-hydroxyphenylarsonic acid 4-Methylsulfonylphenylarsonic acid 3-Aminomethyl-4-hydroxyphenyIarsonic acid Methyl-p-phenylenediarsonic acid (3-Methyl-4-aminophenylarsonic acid) 12% 58% — 26% 34% 36% — 17% CrHjAsOe C7H9ASOB C7H9ASO6S C7H10ASNO4 C7H10AS2O6 39 39 75 136 48 c8 CSHTASNSO? 7-Nitro-3-hydroxy-l . * Scheller's modification was used (see p.4-benzisoxazine6-arsonic acid 6-Arsonopiperonal 2.3-Dicarboxyphenylarsonic acid 2-Bromo-4-acetylphenylarsonic acid 2-Bromo-5-acetylphenylarsonic acid 2-Acetyl-4-bromophenylarsonic acid p-Cyanomethylphenylarsonic acid 3-Hydroxy-l. 418).3-triazole 15 C8HgAsBr04 CsHgAsNOs CsHsAsNOs CsHgAsNOs CgHgAsNOe References 89-231 appear on pp. .4-benzisoxazine-6-arsonic acid 7-Methylbenzoxazolone-5-arsonic acid 2-Nitro-4-acetylphenylarsonic acid l-(p-Arsonophenyl)-l.2. 451-454.
3-Acetylamino-4r-hydroxy-6-chlorophenylarsonic acid 2-Methylbenziminazole-5-arsonic acid 2-Nitro-4-acetamidophenylarsonic acid 2-Nitro-5-acetamidophenylargonic acid p-Acetylphenylareonio acid o-Arsonoacetophenone m-Arsonoacetophenone p-Arsonoacetophenone * Yield Reference CfeHgAsNsOs CgHgAsNOr CgHaAsClNOs C8H 9 AsN 2 O. . CgHgAsNsOs C8H9ASO4 CgHjAsC^ 60% — — 30% 47% 67% 70% 75% 25% 25-45% 67%* 66% 65% 35-40% * 35% — — 20% 35%* 31-14% 42% 20-25% 20-25% • 30% — 10% 30% 35% — — 42% 141 123 142 ~ 143 144 27 22 45 145 45 102 • 45 145 146 17 • C«HeAsO4 CgHjAsOe CsH9As06 CsHsAsOe C 8 H 9 As0 6 CsHsAsOs C8H10ASNO4 2-Hydroxy-6-acetylphenylarsonic acid 3-Hydro«y-4-acetylphenylarsonic acid 3-Acetyl-4-hydroxyphenylarsonic acid p-Arsonophenylacetic acid Saligeninmethylenether-5-arsonic acid p-Acetamidophenylarsonic acid 2-Acetamido-3-hydroxyphenylarsonic acid 3-Acetamido-2-hydroxyphenylarsonic acid 3-Acetamido-4-hydroxyphenylarsonic acid 3-Hydroxy-4-acetamidophenylarsonic acid (5-Aminoethenyl-o-aminophenol) 2. 418). AND ROSENMUND REACTIONS COMPOUNDS PREPARED BY ^HE BABT REACTION—Continued \ Formula Compound 2-Methyl-6-nitro-5-beniimidazolearsonic acid Nitrohydroxyacetophenonearsonic acid . C8HioAsN06 CgHtoAsNOs C»HioAsN05 CDHIOASN0 6 W9 149 149 142 104 149 52 C 8 H 1 OASNO B CgHioAsNOe CgHioAsNOe CsHioAsNOe 15 10 24 References 88-231 appear on pp. 451-454. * Soheller's modification was used (see p.5-Dimethyl-4-nitrophenylarsonic acid 2-Nitro-4-ethoxypheIiylarsonic acid 3-Nitro-4-ethoxyphenylarsonic acid 2-Hydroxy-4-nitro-6-ethylphenylarsonic acid ' 147 45 45 133 133 • ' 148 14 11 XI.440 BART. BECHAMP.
451-454.6-Dimethylphenylarsonic acid p-Ethylthiophenylarsonic acid p-Ethoxyphenylarsonic acid Yield Reference C 8 HnAs0 3 C 8 HnAs0 3 CsHnAsOa C 8 HnAs0 3 S CgHnAsO.Os C9H7AsBrNO3 C9H7AsClNO8 C9H7AsClNO3 C9H7AsClNO3 C9H7AsClNO3 C9H7AsClNO3 C9H7AsN2O6 C8HJASN2O6 CgHsAsNOs C9HsAsNO3 CgHgAsNOs C9HgAsNO3 CglisAsNOjjS C9H8AsNO4 C9HsAsNO4 5-Chlorc-6-nitroquinoline-8-arsonic acid 8-Bromoquinoline-5-arsonic acid 2-Chloroquinoline-5-arsonic acid 2-Chloroquinoline-6-arsonic acid 2-Chloroquinoline-8-arsonic acid 5-Chloroquinoline-8-arsonic acid 8-Chloroquinoline-5-arsonic acid 8-Nitroquinoline-7-arsonic acid 6-Nitro-5-hydroxyquinoline-8-arsonic acid Quinoline-5-arsonic acid Quinoline-6-arsonic acid Quinoline-8-arsonic acid Isoquinoline-?5-arsonic acid p-(4-Thiazolyl-)phenylarsonic acid 2-Hydroxyquinoline-5-arsonic acid 2-Hydroxyquinoline-6-arsonic acid 37% 49% 24% 18% 11% 57% 57% — 45% 15% 18% 33% 40-60% 23% 55% 153 153 154 154 154 153 153 155 153 156 156 156 156 157 154 156 158 References 88-231 appear on pp. .COMPOUNDS PREPARED BY THE BART REACTION COMPOUNDS PREPARED BY THE BART REACTION—Continued 441 Formula Compound 2. 418).5-Dimethylphenylarsonic acid 2. 55% 40% 30% 24%* >90% • 73% — — o%* 38 132 30 18* 122* 14 X\J 1A C8HnAs04 C 8 HuAs0 4 C 8 HnAs0 4 S CgHnAsOs CsHnAsOs CgHnAsOs C 8 H u As0 6 C8Hi2AsNt»3 C8H12AsNO4 \ o-/3-Hydroxyethylphenylarsonic acid p-j8-Hydroxyethylphenylarsonic acid p-18-Hydroxyethylthiophenylarsonic acid o-/S-Hydroxyethoxyphenylarsonic acid m-|8-Hydroxyethoxyphenylarsonic acid p-0-Hydroxyethoxyphenylarsonic acid 3.4-Dimethoxyphenylarsonic acid p-Dimethylaminophenylarsonic acid 3-Methyl-4-hydroxy-5-aminomethylphenylarsonic acid 48% 10% 53% — — 24% — 22 23 23 150 34 40 151 39 152 136 c9 C^eAsClN.4-Dimethylphenylarsonic acid 2. * Soheller's modification was used (see p.
* Soheller'g modification was used (see p. 451-454. 418).4-dimethoxybenzaldehyde 2-Methoxy-4-hydroxy-5-acetylphenylarsonic acid p-Arsonobenzylacetamide 3-Methoxy-4-acetamidophenylarsonic acid 3-Acetamido-4-hydroxy-5-methylphenylarsonic acid 3-Hydroxy-4-carbethoxyaminophenylarsonic acid 3-Carbethoxyamino-4-hydroxyphenylarsonic acid a-Methyl-/3-2-arsonophenoxyethanol 13% 4% 55%* 30%* — 57% — 75% — 46% 23% 2% 60% 60% 46% 58% 62% — — 20% — — 15% CioHsAsClOs . BECHAMP. ANP ROSENMUND REACTIONS COMPOUNDS PBBPARED BY THE BART REACTION—Continued Formula Compound Yield Reference 154 159 133* 133* 132 132 132 45 123 45 160 161 22 147 162 163 152 164 142 149 14 10 99 C 9 H8AsNO 4 C 9 H 9 AsN 2 O 3 C»H9AsN2O6S2 C 9 H 9 As0 B C9HioAsNOe C9HioAsN06 C9HioAsN06 C 9 H u As0 4 C 9 HuAs0 4 C 9 H n As0 4 C 9 HiiAs0 8 C 9 H u AsO 6 C 9 H u AsO s C 9 H n As0 6 C 9 HnAs0 6 CjHuAsOe C9Hi2AsNO4 C 9 H 1 2 AsNO 6 QH12ASNO5 C 9 H 1 2 AsNO 6 C9Hi2AsNO6 C 9 Hi 3 As0 6 2-Hydroxyquinoline-7-arsonic acid Glyoxaline-4-phenyl-p-arsonic' acid p-(Benzenesulfonamido-2-thiazole)arsonic acid p-Arsonocinnamic acid 2-Acetamido-3-carboxyphenylarsonic acid 3-Carboxy-4-acetamidophenylarsonic acid p-Arsonohippuric acid Propiophenone-o-arsonic acid Propiophenone-p-arsonic acid Propiophenone-m-arsonic acid /3-p-Arsonophenylpropionic acid TO-Arsonophenoxy acetone p-Carbethoxyphenylarsonic acid 2-Methoxy-5-acetylphenylarsonic acid 6-Arsono-3.CioHgAsN08 CioHsAsNOs CIOHSASNOS 2-Chloro-l-naphthalenearsonic acid 2-Nitro-l-naphthalenearsonic acid 4-Nitro-l-naphthalenearsonic acid l-Nitro-2-naphthalenearsonic acid 56% 63% 80% 40% 88%" 67% 165 166 167 166 167 166 References 88-231 appear on pp. .442 BART.
4-dimethyl-l. 418). .3triazole 2-Chloro-4-methylquinoline-7-arsonic CioHjAsClNOs acid CioH 9 As0 3 .— 36% 80% 77-80% 41% — 47% 50% — 75% 56% 59% — 30% 154 53 169 170* 171 51 172 156 173 154 155 155 114 159 174 175 132 164 177 178 179 133 72 98 164 180 C 10 Hi 2 AsNO7 CioHi 2 AsN 3 0 3 C10H13ASN2O5 2-Acetamido-4-arsonophenoxyacetic acid l-(p-Arsonophenyl)-3. 451-154.3-dihydrobenzimidazole-5-arsonic acid Ci 0 Hi 3 AsO s CioH 1 3 As0 6 • CioHi 4 AsN0 6 S2 CioH 1 4 AsN0 6 C10H16ASN2O4 References 88-231 appear on pp. * Sfeheller's modification was used (see p..5triazole 3.4)thiazan 3-Acetamido-4-/3-hydroxyethoxyphenylarsonic acid 2-Hydroxy-l.4thiazine Glyoxaline-4'-carboxy-p-aminophenylC10H10AsN3O4 arsonic acid Dimethyl 4-arsonophthalate C10H11ASO7 CioHgAsNOj CioHgAsNOs CioHgAsNsO? 47% 40% . * Naphthalene-1-arsonio acid CioH«AsOs Naphthalene-2-arsonic acid C10H9ASO4 4-Hydroxynaphthalene-l-arsonic acid 7-Methylcoumarin-6-arsonic acid CIOH 9 ASOB CioH 9 As0 6 S 4-Sulfonaphthalene-l-arsonic acid C10H10ASCIN2O3 l-(4'-Arsonophenyl)-3-methyl-5-chloropyrazole 2-Methylquinoline-3-arsonic acid CioHxoAsNOs doHioAsNOi 2-Hydroxy-4-methylquinoline-6-arsonic • acid > 2-Hydroxy-4-methylquinoline-7-arsonic C10H10ASNO4 acid CioHioAsN0 4 6-Methoxyquinoline-8-arsonic acid CioHioAsN0 4 8-Methoxyquinoline-6-arsonic acid CioH 10 AsN04S 6-Arsonobenzene-3-ketodihydro-l.4-Dimethoxy-5-acetylphenylarsonic acid N-(p-Arsonophenylsulfonyl)-(l.4-Diacetamidophenylarsonic acid 7-p-Arsonophenylbutyric aqid 2.2.— 168 167 140 7% 20% 26% 3%* — 0% — — 18% 31% — — .3-trimethyl-2.2.COMPOUNDS PREPARED BY THE BART REACTION COMPOUNDS PREPARED BT THE BABT REACTION—Continued i 443 Formula Compound Yield Reference 6-Nitro-2-naphthalenearsonic acid 8-Nitro-2-naphthalenearsonic acid l-(p-Arsonophenyl)-4.5-dicarboxy-l)2.
2-/)quinoIine-2arsonic acid 8-Nitro-3-dibenzofurylarsonic acid 2-Bromo-2'-nitrodiphenylarsinic acid (o-Nitroaniline) 4.7-Dimethylcoumarin-6-arsonic acid 2-Hydroxy-4.7-dimethylquinoline-6arsonic acid 6-Ethoxyquinoline-8-arsonic acid 2-Hydroxy-4. AND ROSENMUND REACTIONS COMPOUNDS PREPARED BT THE BAHT RBACTION—Continued Formula Compound Yield Reference 181 25 182 CioHuAsN206 2-Diethylamino-5-nitrophenylarsonic acid o-Butylphenylarsonic acid 2-Hydroxy-3-arsono-p-cymene Cn 17% 12% CnHioAsN306 CiiHioAsN306 CIIHIOASN 3 OB CIIHHASN2O6S CiiHnAsOs CiiH12AsNQ4 C11H12ASNO4 3-Nitro-4^(p-arsonophenylamino)-pyridine 2-(m-ArsonophenylaJnino)-5-nitropyridine 2.4-Dihydroxyphenylarsonic acid diethylcarbamate 183 183 183 133* 171 173 155 173.8-dimethylquinoKne-6arsonic acid Ethyl o-arsonocinnamate 2.444 BART.(p-Arsonophenylamino)-5-nitropyridine p-Arsono-N-2-pyridylbenzenesulfdnamide 4.4-Dimethoxy-5-propionylphenylarsomc acid 3. BECHAMP. 451-454 * Scheller's modification was used (see p 418). 184 • 72 117 Gi2H8AsNO6 CwHgAsNOe Ci 2 H 9 AsBrNO 4 CuHsAsNsiOe Ci 2 H 8 As04 3-Keto-3-pyrano(3. .4'-Dinitrodiphenylarsinic acid (p-Nitroaniline) 3-Dibenzofurylarsonic acid • 185 35% 51% — 12% 70% 6% 60 186 14 187 188 187 Cl2HgAs04 2-DibenzofuryIarsonic acid References 8&-231 appear on pp.
23% 96 189 187 190 190 190 190 187 97* 191 12 13 96 192 170* 193 194 14 170 14 20* 195 196 187 190 197 19 170 198 194 199 19* 19 p-8ulfodiphenylarsinic acid (p-Sulfanilic acid) 3-Nitro-4.4'-biphenyldiarsonic acid Ci 2 HnAsN 2 O4 2-Hydroxy-5-arsonoazobenzene Ci2HnAsN 2 O B 3-Nitro-4-aminobiphenyl-4'-arsonic acid (3-Nitrobenzidine) Ci 2 HiiAs0 2 DipEenylarsinic acid Biphenyl-4-arsonic acid CiaHuAsO3 2-Biphenylarsonic acid Ci 2 HnAs0 3 CuHiiAsOsS o-Arsonodiphenyl sulfide Ci 2 HnAs0 4 p-Arsonodiphenyl ether Ci 2 H u As04 o-Arsonodiphenyl ether C12H11ASO6S C12H11AS2NO8 Ci2Hi 2 AsC104 C14H12ASNO3 Ci 2 Hi2AsNO s Ci 2 Hi2AsNO 4 S C^HioAsBrOs 40% 20% — 25% 18% 18% 24% — 35%* 27% 87% 54% 51% — 34%* — 65% 50% 15% — 40%* 60% 12% 26% 32% — 17% 19% 12% 19% — 29-32% * 11.4'-biphenyldiarsonic acid (3-Nitrobenzidine) 2-Arsono-4-ohloro-4'-methyldiphenyl ether 4'-Aminobiphenyl-4-arsonic acid 4'-Aminobiphenyl-2-arsonic acid p-Sulfonamidodiphenylarsinic acid (p-Sulfanilamide) References 88-231 appear on pp 451-454 * Scheller's modification was used (see p.6.8-Trisulfocarbazole-l-arsonic acid Ci2HioAs2N2Oio 3.5'-Dinitro-4.COMPOUNDS PREPARED'BY THE BART REACTION COMPOUNDS PREPARED BY THE BART REACTION—Continued 445 Formula Compound Yield Reference p-Br-diphenylarsinic acid (p-Bromoaniline) CwHioAsBrO* 2-Arsono-4'-bromodiphenyl ether Ci 2 HioAsBr04 ~4-Arsono-4'-bromodiphenyl ether Ci 2 HioAsC10 4 2-Arsono-4-chlorodiphenyl ether 2-Arsono-2'-chIorodiphenyl ether C12H10ASCIO4 CuHioAsCKU 2-Arsono-3'-chlorodiphenyl ether CUH10ASCIO4 2-Arsono-4'-chlorodiphenyl ether 4-Arsono-4'-chlorodiphenyl ether CisHioAsC10 4 C12H10ASFO4S m-Sulfonylfluoridediphenylarsinic acid (ro-AminobenzeneBulfonylfluoride) C 12 HioAsNO s Carbazole-2-arsonic acid Ci 2 HioAsN0 4 o-Nitrodiphenylarsinic acid" (o-NitroaniHne) jn-Nitrodiphenylarsinic acid Ci 2 HioAsN0 4 (m-Nitroaniline) C12H10ASNO4 p-Nitrodiphenylarsinic acid (p-Nitroaniline) Ci2HioAsN06 4-Nitrobiphenyl-4'-arsonic acid C12HioAsNOi2S3 3. . 418).
AND ROSENMUND REACTIONS COMPOUNDS PREPARED BY THE BART REACTION—Continued Formula Compound Yield Reference CuHuAsNOsS Ci2Hi 2 As 2 0 6 CisjHuAssOs Ci 2 H 12 As 2 O 6 CuiHiiiAsaOs N-p-Arsonophenylbenzenesulfonamide o-Arsonodiphenylarsinic acid (o-Arsanilic acid) o-Arsonodiphenylarsinic acid (o-Aminodiphenylarsinic acid) 2.4'-Biphenyldiarsonic acid Biphenyl-4. * Soheller's modification was used (see p. BECHAMP.446 BART. .4'-diaxsonic acid (Benzidine) 3.2-a-Napbthopyrone-6-arsonic acid p-Thiocyanodiphenylarsinic acid (p-Thiocyanoaniline) Acridine-1-arsonic acid Aeridine-2-arsonic acid Acridine-3-arsonic acid 2-(4-Arsonophenyl)-benzothiazole 2-Phenyl-6-arsonobenzothiazole Acridone-2-arsonic acid 2-(2-HydrQ3cy-5-arsonophenyl)-benzothiazole — — 40% — 55% 22% — — — 16%* 30%* 38%* 18%* 26% 5% 38% 7% 185 185 185 202 126 203 55 204 185 171 122* 205* 205* 205* 206 206 158 207 CisHjAsOs CisH 9 As06 CisHioAsNOijS Ci3HioAsN03 C18HioAsN03 CisHioAsNOs CuH^sNOaS CwHioAsNOaS CuHioAsN04 C13H10ASNO4S References 88-231 appear on pp 451-454. 418).4-Dihydroxyphenylcarboxylic acid piperidide-1-arsonic acid p-0-Diethylaminoethoxyphenylarsonic acid 47% 26% — 55% — 3% — 2% 10 13 13 199 194 201 170 117 41 CwHieAsNOo Ci2H2oAsN04 CisH7AsBrNO7 Ci 8 HgAsNO 7 CisHgAsNOr CisHjAsOa Ci8H 9 As03 CisH B AsO 4 9-Keto-nitrobromoxanthenearsonic acid 9-KetO-8-nitro-l-xanthenearsonic acid 9-Keto-7-nitro-2-xanthenearsonic acid o-Carboxydiphenylarsinic acid anhydride (Anthranilic acid) o-Carboxydiphenylarsinic acid anhydride (Aniline) 2-Fluorenonearsonic acid 9-Keto-3-xanthenearsonic acid l.
4'-diareonic acid (4.COMPOUNDS PREPARED BY THE BART REACTION COMPOUNDS PREPARED BY THE BART REACTION—Continued 447 Formula Compound • Yield Reference Ci3HnAsBrNO4 2'-Bromo-2-nitro-4-methyldiphenylarsinic acid (3-Nitro-p-toluidine) Ci8HiiAsBrNO4 2'-Bromo-2-nitro-6-methyldiphenylarsinic acid (3-Nitro-o-toluidine) 2-Aminoacridine-S-arsonic acid CuHuAsNijOs 2-Fluorenearsonic acid CMHUASOS C13H11A8O4 CisHnAsO 4 CisHnAsOs 22% 208 29% 208 8%* 19% — 60% — — — 35% — — 42% 205* 55 204 202 123 125 o-Carboxydiphenylarsinic acid Benzophenone-p-arsonic acid 3~Hydroxybenzophenone-4'-arsonic acid 9-Methylcarbazole-3-arsonic acid Benzophenone-4.8-diarsonic acid 46% 53% 23% 70% 31% 64% 54 214 54 54 54 32 References 88-231 appear on pp.4'-Diaminodiphenylmethane) C14 CwHuAsNOs C13HwAs2O7 CMHISASO 2 Ci S HisAs02 CuHiaAsOs Ci3Hi3AsO3S Ci8Hi8AsO4 CisHi8AsO4 123 181 123 125 192 192 210 211 188 189 189 35% 27% — 20-40% 20-35% 3(M0% 0% CuHiaAsO4 Ci 3 Hi S As0 4 Ci 8 Hi8As0 4 C 18 Hi3As0 6 C13H14AS2O6 47% 11% 36% 189 95 189 212 213 C14H9ASOB C14H9ASO5 C14H9ASO6 Anthraquinone-1-arsonic acid V CuHioAsNOe C14H10AS2O10 Anthraquinone-2-arsonic acid 4-Hydroxyanthraquinone-l-arsonic acid 4-Aminoanthraquinone-l-arsonic acid (1. 451-154.4'-diarsonic acid p-Methyldiphenylarsinic acid (p-Toluidine) p-Methyldiphenylarsinic acid (Aniline) o-Arsonodiphenylmethane p-Benzylthiophenylareonic acid 2-Arsono-4'-methyldiphenyl ether 2-Arsono-2'-methyldiplienyl ether 2-Arsono-3'-methyldiphenyl ether 2-Arsono-5-methyldiphenyl ether 4-Arsono-4'-methyldiphenyl ether 2-Arsono~4'-methoxydiphenyl ether Diphenylmethane-4. * Soheller's modification was used (see p 418).4-Diaminoanthraquinone) Anthrarufin-4. .
5'-dimethyldiphenyl ether 2-Arsono-2'. BECHAMP.(3-Arsonophenyl)-6-dimethylaminobenzothiazole 2-(4-Arsonophenyl)-6-dimethylaminobenzothiazole C16 12.5'-Dimethylbiphenyl-4.l-6)pyridine-iaarsonic acid 2-Phenyl-4-carboxyquinoline-6-arsonio acid Beferenoes 88-231-uppear on pp.2-a-naphthopyrone-6-arsonic acid p-Arsonophenylbenzylketone N-Acetyldiphenylamine-4-arsonic acid 3-Arsono-6-hydroxy-N-benzoylbenzyla"mine 2-Arsono-2'.5'-dimethyldiphenyl ether 6-Nitro-5-piperidinoquinoline-8-arsonic acid 3.4'-diarsonic acid (o-Tolidine) 8-Piperidinoquinoline-5-arsonic acid — 47% — 13% 12-16% 12% 57% 44% 0% 171 _ 123 186 215 189 180 189 153 194 153 C16 C16H1BASN2O3S 2-p-Arsonophenyl-4-phenylthiazole N-Phthalimido-2-hydroxy-5-arsonobenzylamine 2-Acetamidofluorene-7-arsonic acid 4-Aoetamidobenzophenone-3'-arsonic acid 2-Benzamido-4-arsonophenoxyacetic acid 2-(2-Arsonophenyl)-6-dimethylaminobenzothiazole 2.4'-dimethyldiphenyl ether 2-Arsono-3'. 451-454.448 BART. 185 24% 218 . AND R08ENMUND REACTIONS COMPOUNDS PREPARED BY THB BABT REACTION—Continued Formula Compovmd Yield Reference CHHUABOS _ C14H13ABO4 C14H14A8NO4 C14H14ABNO5 Ci4H 16 As04 Ci 4 H 16 AsO4 Ci4Hi6A8O4 CI4HI»ABN3O6 Cl4Hl6A8 2 O6 C14H17ASN2O8 4-Methyl-l.Keto-12-xantheno(2.
oxy-2'-methyl-4'-qumolylaminophenylarsonic acid p-6'-Methoxy-2'-methyl-4'-quinolylaminophenylarsonic acid Tri-p-nitrophenylarsine oxide hydrate Triphenylarsine oxide Phenylene-l. CwHwAsNOe Ci6Hi6As04 w-Phthalimidoacetophenone-p-arsonic acid 3-Arsono-5-methyl-6-hydroxybenzyIphthalimide 4.63 224 References 88-231 appear on pp.3'-dimethylbiphenylarsonic acid 4'.2-diphenylarsinic acid (o^Aminodiphenylarsinic acid) 4'-(6"-Methoxy-2"-methyl-4"-quinolylamino)biphenyl-4-arsonic acid p-6-Methoxy-2-methyl-4-quinoIylaminodiphenylmethane-p'-arsonic acid 4'. .4'-Diacetyldiphenylarsinic acid (p-Aminoacetophenone) C17-C26 123 215 — 219 220 C17H17A8N2O4 C17H17ASN2O4 CISHUAS^OS CISHIBASO CigHwAsaOi C23H21ASN2O4 C24H28ASN2O4 C2SH2BASN2O4 CU^SABNSOS »n^6'-Meth.6"-Methoxy-2"-methyl-4"-quinolylamino-3.6"-Methoxy-2"-methyl-4"-quinolylamino-3.3'-dimethoxybiphenylarsonic acid 19% 221 221 — — 28% 48% — 45% 4 4 222 * 221 223 223 74% 223 COMPOUNDS PREPARED BY THE BECHAMP REACTION c6 C 6 H 6 AsNO 6 C 6 H 7 AsClNOs C 6 H 7 AsClNO 3 C 6 H 7 AsN2O6 C 6 H7AsN 2 O6 CeHjAsOt 3-Nitro-4-hydroxyphenylarsonic acid 2-Amino-5-chlorophenylarsonic acid 3-Chloro-4-aminophenylarsonic acid 2-Amino-5-nitrophenylarsonic acid 3-Nitro-4-aminophenylarsonie acid o-Hydroxyphenylarsonic acid (Phenol) 0% — — — 3% 68 67 59 65. 37 64.COMPOUNDS PREPARED BY THE BECHAMP REACTION COMPOUNDS PREPARED BY THE BAKT REACTION—Continued 449 Formula Compound Yield Reference Ci6Hi2AsNO(. 66. 451-154.
33% 62% 26% 11-14% 18-19% 30% — — 78 225 226 224 80 227 71 77.450 BART. BECHAMP. .4-Dihydroxyphenylarsonic acid p-Arsanilic acid 33% 33% 22% 23% 33%.5-dimethylphenylarsonic acid 2. 451-454. 111 79 209 228 110 76 CyHjAsC^ C7H9A8O4 C7H|)AsO4 C7H9ASO4 CTHJASOS C7H10ASNO3 C7H10ASNO3 2-Hydroxy-3-methylphenylarsonic acid 2-Hydroxy-6 (or 4)-methylphenylarsonic acid 2-Methyl-4-hydroxyphenylarsonic acid 3-Methyl-4-hydroxyphenylarsonic acid 2-Metho'xy-4-hydroxyphenylarsonic acid 2-Amino-5-methyIphenylarsonic acid 3-Methyl-4-aminophenylarsonic acid 1% — 20% 8% 31% — 14% 62 62 62 62 71 67 61 229 59 230 59 73 C7HioAsN03 C7H10ASNO4 2-Methyl-4-aminophenylarsonic acid 3-Methoxy-4-aminophenylarsonic acid CSHHASOB C8H12AsNO3 CsHuAsNOs CsH^AsNOe CioHioAsNOs 2.5-Dimethyl-4-aminophenylarsonic acid 2-Hydroxy-4-carbethoxyaminophenylarsonic acid l-Aminonaphthalene-2-arsonic acid 44% — — — — 20-30% — 71 67 59 70 35 58 229 231 References 88-231 appear on pp. AND ROSENMUND REACTIONS COMPOUNDS PREPARED BY THE BECHAMP^ REACTION—Continued Formula Compound Yield Reference C6H7ASO4 p-Hydroxyphenylarsonic acid • CSHTASOB CiHsAsNOa 2.4-Dimethoxyphenylarsonic acid • 2-Amino-3.
S. University of Nebraska. Soc. 91 Maclay and Hamilton.. / . Ber.A.4'-Dihydroxy-3.4-Dihydroxyacetophenone) 2. Soc.3'-Dimethyl-4.3'-dimethyldiphenylarsinic acid (o-Cresol) 3.COMPOUNDS PREPARED BY THE BECHAMP REACTION COMPOUNDS PREPARED BY THE BECHAMP REACTION—Continued 451 Formula Compound 2.4-Dimethoxy-5-acetylphenylarsonic acid (2. J... Am. 560 (1926).4'-Dihydroxydiphenylarsinic acid (Phenol) 4. 1927. 183. Chem. 54. J. Thesis. 1931. 809. 59. J.4-Dimethoxy-5-propionylphenylarsonic acid 2-Dibenzofurylarsonic acid 2'-Nitrodiphenylamine-4-arsonic acid 3'-Nitrodiphenylamine-4-arsonic acid 4'-Nitrodiphenylamine^4-arsonic acid 2.3'-Dimethyl-4. 629 (1924) [C.379 (1926) [Chem. J. 1938. 807 (1929)].. Brit. 1049. 279.4-dihydroxyphenyl)-benzothiazole 2. 3310 (1932). Soc. •» Keimatsu and Yokota. Pharm. 91 Balaban.. Chem.4'-Diaminodiphenylarsinic acid (Aniline) Diphenylamine-4. »» Hac. M. . Soc.4'-Dihydroxydiphenylarsinic acid (Phenol) Diphenylamine-p-arsonic acid (Diphenylamine) 4.. pat. Soc. 81 King. Japan... 510. 2481 (1925)] "Schmidt and Hoffmann.4'-dihydroxydiphenylarsinic acid '(o-Cresol) 3. ZerUr.4'-diarsonic acid (Diphenylamine) 2-(2-Hydroxy-5-arsonophenyl)-benzothiazole 2-(5-Arsono-2. I. 90 Balaban.4'-diaminodiphenylarsinic acid (o-Toluidine) Bisdiphenylaminearsinic acid (Diphenylamine) Yield Reference CioHuAsOe 7% 72 CnHisAsOe C12H9ASO4 C12HHASN2O5 11% 11% 8% 6-8% 8% — 3% 18% 20-30% — 3% — 19% 20% — 72 60 200 200 200 224 224 74 76 176 230 74 207 207 62 Ci 2 HuAsN 2 O 6 C12H11ASN2O6 Cii!H u AsO4 C12H11ASO4 CwH^AsNOs C12H1SASN2O2 Ci2Hi8As2NO6 Ci 3 HioAsN0 4 S CisHioAsNOsS Ci4H 16 As0 4 C14H15ASO4 — 62 Ci4Hi7AsN 2 Oj — — — 230 176 74 C24H21ASN2O2 88 Freres and Fourneau. 1930. 19. Chem. Chem.
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206-208 mechanism. 198 455 . 132. 393-398 rangement of. 290. rangement of. preparation of.j8-unsaturated. 204 o-Acetylaminob$nzaldehyde in Cannizrearrangement of. resolution of. 398-404 2-Allylphenol. 98 178-223 reduction by aluminum alkoxides. 198-204 223 limitations. 102 Alcohols. 187-191 Alginic acid. Vol. Claisen Acetone. test for. 182 355. 26 409. ment. 200. Claisen rearrangement of. 264. in Cannizzaro reacscope. 7 Aluminum alkoxides. Allyl 2. 1035 108 Allyl vinyl ethers in Claisen rearrangeheterocyclic. 22-23 Acetoacetic ester condensation. 178experimental conditions. 376-414 Allyl phenanthryl ethers. tion. 136. 102-103 selective reduction. 14-15 Aluminum ethoxide. Claisen rearexperimental conditions. 186 tables of. specificity. reduction with. 182-194 tion. 61 rearrangement of. Claisen rearrangement of. rearrangement of. 108-109 ct-keto. 25 experimental procedures. a-amino.4-dichlorophenyl ether.Allyl thiocyanate. 99. 25 tion of. 294. 356. preparation of. dismutation of. 362 Acid chlorides. 181. 98.INDEX Numbers in bold-face type refer to experimental procedures Allyl aryl ethers. 362 stereochemical course. 356. periodic acid oxida. 4-5 Allyl phenyl ether. 180 a.Allyl 2-nitrophenyl ether. 182. Claisen rearrangement of. 183-185 Aldol condensation. use in preparation of l-Allyl-2-allyloxynaphthalene. periodic acid oxidation of. 13 N-Allylaniline. 13 . in Cannizzaro reac. cleavage of. 178-223.412 Aldehydes. 300-323 resolution of. 139. 5 Allyl p-tolyl sulfide. 130-155 Allyl aryl ethers. periodic acid Allyl fluoride. 98-103 aromatic. 343-344. aliphatic. 387. 6 cyclic ketones. 56. 27 tables. 1-48 Aluminum isopropoxide. 357. 202 in Claisen rearrangement.6-dichlorophenyl ether.5-diallylsalicylic acid. reartertiary. 390. Claisen Acetyl fluoride. in Cannizzaro reaction. 404-414 Allyl N-phenylbenzimino ethers. 26 zaro reaction. 102 side reactions. 11 -.Allyl 4-nitrophenyl ether. 355. rearrangement of. 179. 369 reduction of diazonium salts by. 277. 386.Allyl 2-formyl-4-allyl-6-methoxyphenyl ether. 185 Alkyl fluorides. 145-147 12 Acrolein in Cannizzaro reaction. 194-198 experimental procedures. in Cannizzaro reaction. 105 Allyl 2. 73 Aluminum chloride. I O-Allyl-3. 4. 52 oxidation of. 12 N-Acetyl-D-glucosamine.
97 0-Benzylglutaric acid".Anisyl . 227230 scope and limitations. 62 oxidation of. 110. 61. 415-454 Arsonofiuorene. 112 »re-Bromobenzyl alcohol. 343-344.y .65 Arndt-Eistert synthesis. I dZ-2-Butanol. 454 Benzaldehyde. reaction with organic halides. 193 Bucherer reaction. 118 /3-Bromoallyl phenyl ether.2-difluoroethane. 415-454 effect of substituents on yields. 426 7-Arylbutyric acids. 416. resolution of. cyclization of. primary aromatic. 201 Benzyl benzoate. 4 a-Benzyl-S-phenylvaleric acid. derivatives of. 422 modifications of. Vol. oxidation to hydrocarbons. 101. 74 0-Benzyladipic acid. cyclization of. rearrangement of. 236 Arylpyridines. 428-429 side reactions. 231-235 direct substitution in. cyclization of. 97 «-Bromoisobutyraldehyde in Cannizzaro reaction. cyclization of. 241-242 /S-2-Biphenylpropionic acid. periodic acid oxidation of. 115177 a-substituted. I Arsinic acids. preparation of. cyclization of.methoxyphenylbutyric acid. preparation of. 287-288. 203 Benzotrifluoride. 116 Benzyl phenyl ethers. 425 tables of compounds prepared.3 . 415-454 procedures. I a-Amino alcohols. 62-64 Antimony trifluorodichloride. 415-454 Arsonic acids. cycliza_ tion of. aromatic. 449 Bechamp reaction. 384. 252-261 Biphenyl. 243-245 experimental procedures. 112 l-Bromo-2. reduction of. 11 Bromoanilines. 163 Arylhydrazines. 63. 418. 118 Benzyl alcohol. cyclization of. 94r-113 crossed. aromatic. 236 • Bart reaction. 271. 426 Antimony fluorides. 147 a r p . 230-237 side reactions. 109. 430 tables of compounds prepared. 369 4-Amino-7-chlorohydrindone-l. 423-427 Scheller modification. cyclization of. 295 Amino group. cyclization of. 117. 272. 103. 403 Cannizzaro reaction. 430-431 scope. Vol. replacement by hydrogen. 201 Benzohydrol. 99 a-Bromoketones in aluminum alkoxide reduction. 236 Arylthiophenes. 119 Biaryls. 262-340 l-Amino-2-naphthalenearsonic acid. 224-261 experimental conditions. 113 Amination of heterocyclic bases by alkali amides. -replacement of bromine by chlorine during diazotization. 165 a-Benzyl-j3-w-tolylpropionic acid. 99. 431 Anhydrides. 118 Benzylsuccinic acid. 203 419- 419. 66 5-Bromofurfural in Cannizzaro reaction. 339-340 preparation of. 164 «-Benzyl-T-phenylbutyric acid. 280 rra-Bromobenzoic acid. 417—419 procedures. deamination of. Vol. 237-238 tables of compounds prepared. cyclization of. 170 Anthraquinone-1-acsonic acid. 53-55. preparation of. 287 Arylnaphthalenes.456 INDEX Benzophenone. 245-252 mechanism of the reactions. reduction of. cyclization of. 434- 449- . 51-56. unsymmetrical.
132.5-Diaminotriptycene. 296 Chloromethylation of organic compounds. 224-261 . 6-8 orfTw-rearrangement. 23. 21 Cinnamaldehyde in Cannizzaro reaction. Claisen rearrangement of. 114-177 condensing agents. 2. 97-110 Carbohydrates. I Chromans. in Cannizzaro reaction. 69 3. 145-147 steric factors in. 8 para-rearrangement. Claisen rearrangement of. o-Chlorobiphenyl. 289 Crotonaldehyde. 29-47 Claisen's alkali. 28 Claisen rearrangement. by intramolecular acylation. 4-6 side reactions. Claisen rearrangement of.5-Diallyl-2. 102 reduction of. 289-290 experimental procedures. 297 Diazoacetates in preparation of biaryls. 25 Crotyl phenyl ether. 274-276. 200 457 Crotyl 2. experimental conditions.174177 influence of substituents.6-diallyloxynaphthalene. 111-113 mechanism. 16-17 of open-chain compounds. I Copper hydride. 238-239 hydrolytic cleavage of other functional groups from. 10. 1-48 abnormal. 226. 294-298 methods. 224-261 Diazohydroxides in preparation of biaryls. 224-261 reaction with quinones and phenols. Vol. 96-97 peroxide effect in. 288. 24. 12. 285. 17-20 bond structure and. 178-223 o-Carboxyphenylarsonic acid. 11-12 l. 8-9 related rearrangements. 16 application in synthesis. 283-284 Diazo reaction in preparation of biaryls. 290 Diazo oxides. formation of. 10. 299340 stabilized. 2 Cyclic ketones. 24 tables. 130-174 polycyclic nuclei in. 9. 97 scope. 286-287 preparation of arsenic compounds from. 110 experimental procedures. Vol. 262-340 applications.5-Diallyloxyanthracene. 5 7. 20. periodic acid oxidation of. 23-26 inversion of allyl group during.4-dichlorophenyl ether. 132 direction of ring closure. 274-276.INDEX Cannizzaro reaction. 9. 351-357. 28 Carbonyl compounds. Claisen rearrangement of. 3. 122-124 Cyclohexyl fluoride. 224-261 Diazonium salts. 365-368 Carbon-alkylation of phenolic compounds. 122 solvents. dry. 432 . 13 1. reduction of diazonium salts by. 17 mechanism of. 3 2-Cmnamylphenol. 28 Clemmensen reduction. deamination of. 248 reduction of. 239-241 reduction to hydrocarbons. 18. 13-14 displacement of substituents during. 290-294 comparison of methods. 283-284. 11-13 experimental conditions and procedures. reduction with aluminum alkoxides. 118-122 methods. 247 7-Chlorohydrindone-l. 270.5-Diallyl-4-allyloxybenzoic acid. 16. 415^54 preparation of biaryls from. 263-290 tables of compounds prepared. 124-129. 200 Crotyl alcohol. 20. Claisen rearrangement of. 114-177 Cyclization of acids and acid chlorides. 102 Cinnamyl 2-carbomethoxy-6-methylphenyl ether. 14-16 solvents. 24 2.
cleavage of. 28 Diels-Alder reaction. 65 2.2-tribromoethahe. reduction of diazonium salts by.7-Diphenylbutyric acid. 391. addition to unsaturated compounds.204 /3.4-Dinitrophenylhydrazine test reagent. 392. 289 Glycerol o-benzyl ether. 98 Glyoxylic acid in Cannizzaro reaction. resolution of. Vol. 69 .458 INDEX Fluorination of organic compounds. 342. 288.3-Dimethyldihydrobenzofuran. 297-298. 2^ /3-(3. rearrangement of. 7 Ethyl 1-cyclohexenylallylcyanoacetate. by alkali. deamination of. 384. 113 in reduction of diazonium salts. Dihydrobenzopyran. 72 Fluoride. 52.2-tetrafluoroethane.2. 290. 379. 157-162 reaction with" organic halides. 14 2-(a.1. periodic acid oxidation of. Vol. 201202 1. 23 Homogentisic acid. periodic acid oxidation of. 298 l.3. 97-103. 6 o-Ethylallyl 2-carbomethoxy-6-methylphenyl ether. 69-73 Fluorine compounds. 117 Elba reaction. 56. 334-335 Formybfluoride. 64 l. Claisen rearrangement of. 66-69 cyclization of acids by. aliphatic. reaction with organic compounds. 7 Ethyl O-cinnamylacetoacetate. 196-197. 200.2-Difluoropropane.2. 21 2. a.4-(and 2. 382. in presence of alkali. 65 Formaldehyde.3-Hexachloro-l. 110. 63 l. internal Cannizzaro reaction of. 107 Hydrogen fluoride. 111 Glucose in reduction of diazonium salts. Claisen rearrangement of. 131 Fries reaction. 130 2. 18 Hydrastinine.l. 413. 107 2.3-difluoropropane.2-Dibromofluoroethane. 289 .1. 76-93 l-Fluoro-l. 414 Glyoxal.-y-Dimethylallyl 4-carbomethoxyphenyl ether. I' Furfural in Cannizzaro reaction. 242 Hahn partial condenser. 104 l. 51 Friedel-Crafts cyclizations. 9-10 7-Ethylallyl vinyl ether. 282. 109.2-dibromoethane. 9 m. 66 Dichlorodifluoromethane. condensation with phenolic compounds. 15 4-Hexenylresorcinol.6-) Dinitrobenzaldehyde.2.2. 6973 apparatus for.2. 60-75 tables. Claisen rearrangement of. 288. 288 1. cyclization of. 3 r-Ethylallyl phenyl ether. 242 Dienes.1. 108. 62 Hydroquinone. 368-369 . 130-156 by-products of. 18 9.2-Dimethylchroman. 68 Ferrous hydroxide. cyclization of. 285.3-Dimethyl-4-amino-5-bromobenzene. 64 1. I Ethyl O-allylacetoacetate. 56. 363 a-Diketones.2. 63. 2. 298 2. 6-6 Ethyl fluoride.3. in Cannizzaro reaction. 63 Hexahydrodibenzofuran. reduction of diazonium salts by.3-Hexachloro-3-fluoropropane.2. 53. Claisen rearrangement of.3.3-Heptachloro-3-f luoropropane.3-Dimethyl-5-bromobenzene. 51.(and p-) Dimethylaminobenzaldehyde in Cannizzaro reaction. 49-93 methods of preparation. 60. 387. 65 Dicinnamylphenol.2-Dichloro-1.5-Dimethylphenyl)-isovaleric acid.2. periodic acid oxidation of. 21 Difluoro-2. 363 Glycols. 98 Grignard reaction.l. reaction of.10-Dihydroxystearic acid.7-Dimethylallyl)-phenol.
126. arsonation of. 369 o. 111 m-Hydroxybenzyl alcohol. deamination of. 294-297. cyclization of. Vol.(and p-) Hydroxybenzaldehyde in Cannizzaro reaction. 178-223 tables of. introduction into phenolic ring. 125 7-2-Naphthylbutyric acid. cyclization of. 69 Isovaleraldehyde. 98. 158 o-Ketols. 361 Methyl glycosides. cyclization of.2-benzanthracene. comparison with periodic acid oxidation. reduction of diazonium salts by.4-tetrahydrochrysene.3. 350-351. 138 Lead tetraacetate oxidation. 111 Isobutyl group. 125 /3-1-Naphthylpropionic acid.6.3. reduction of derivatives of. 297 4-Methylbiphenyl. 157. 111 m-Hydroxyhydrocinnamic acid. 247 2-Methyldihydrobenzofuran. 2 (3-Methylallyl phenyl ether. 112 7-(4-Methoxy-3-biphenyl)-butyric acid. 431 a-Naphthylarsonic acid. periodic acid oxidation of. 157 .4-tetrahydrophenanthrene.7. Claisen rearrangement of. 104-105 m-Hydroxybenzoic acid. 204 4-Keto-l. 119. cyclization of. resolution of. cyclization of. 368-389 Ketones. cyclization of.INDEX Hydroxyamino acids. 60 Mercury fluorides. cyclization of. 58 Mercurimethyldihydrobenzofurans. cyclization of. I Meerwein-Ponndorf-Verley reduction. cyclization of. reduction of. 123 o-(8-Methyl-2-naphthylmethyl)-benzoic acid.5. 111 a-Methyl-D-glucopyranoside. 119. 170 a-Hydroxyisobutyraldehyde in Cannizzaro reaction. 125 7-5-Methoxy-l-naphthylbutyric acid. periodic acid oxidation of. reduction with aluminum alkoxides. periodic acid oxidation of. 10 4-Methyl-4'-aminodiphenyl ether. 175 7-2-Methoxyphenylbutyric acid. 111 a-Hydroxybutyric acid. 342. 345346 459 Mannich reaction.8-hexahydro-l. reaction with formaldehyde and alkali. cyclization of. 178-223 «W-Menthol. 209-223 4-Keto-l. 352-355. 426 7-1-Naphthylbutyric acid. 7 Keto esters.3y4-tetrahydrochrysene. reduction of. Vol. 65 o-Methoxybenzyl alcohol. 125 o-Methylallylphenol. 191-192 8-Keto-3. 123 Methylpropiolaldehyde. 361 7-8-Methyl-2-naphthylbutyric acid. 99 4-Hydroxy-1. 204 Hypophosphorous acid. 136.2. 277-282. 398 Mercuric oxide. 122 2. 60. 171 7-m-Methoxyphenylbutyric acid. 99. 15. 27 4-Methyldiphenyl ether.4. periodic acid oxidation of. 19 Mercurous fluoride. 324-333 Isobutylene glycol. I Ketene diallylacetal. cyclization of. cleavage by alkali. 192-193 Hydroxypivalaldehyde in Cannizzaro reaction.2.(and 4-) Methoxy-4'-bromobiphenyl. 111 Hydroxyketones. 56-58. 399 ^Menthoxyacetic acid.2. 18. Claisen rear-_ rangement of. 18 Isobutyraldehyde in Cannizzaro reaction. 102 Jacobsen reaction. 246 TO-Methoxyhydrocinnamic acid. 297 2-Methyl-2-ethylpropane-l. 103 a-Naphthylamine. 381. 98 Isopropyl fluoride.3-diol. 290.
deamination of. 99 Polyhydroxy acids. 349-350. 227. 248 7-Phenylpimelic acid. use in preparation of cyclic ketones. 272. 20 Picramide.2. 347. 370-371 Porphyrin derivatives. 3*50. 107 Oppenauer oxidation. 111 Periodic acid. 382. 387. 363 . deamination of.460 INDEXPeriodic acid. 427 j8-o-Nitrophenylpropionyl chloride. 18 Phenylacetic acids. 423 7-Phenylbutyric acid. cyclization of.2. 383. oxidation by. 170-171 Phosphorus pentoxide.l. 170 Phytadiene. by nitrosyl chloride. 351 comparison with lead tetraacetate oxidation. 344-357 sodium periodate. 249 o-Nitrodiphenylarsinic acid. 386. 424 m-Nitrophenylarsonic acid. use in preparation of cyclic ketones. 112 o-Nitrobenzoic acid.2. 241 removal from isopropyl alcohol. cyclization of. 120. 121 Phenylpropargyl ethers. 357-361 experimental procedures. 358. analysis for. cyclization of. 248-251 Nitrosoacetylamines in preparation of biaryls. 227. 64 Pentaerythritol. cleavage by alkali. 358-359. Vol. 120 Nitrosation. /3-. cyclization of. 251-252 by nitrous fumes. and 7-Phenylpyridines. 63 Pentachloroethane. 249-251 (O-Octanol-2. cyclization of. 4 Phenylpropiolaldehyde. 425 o-Nitrophenylarsonic acid. 344. 133 a-. 125 3-Nitro-4-aminotoluene.3-difluoropropane. periodic acid oxidation of. substituted. cyclization of. 294 Nitrous fumes. 424 Phenylarsonic acid. 21 Phytyl bromide. 345-346 experimental conditions. 414 Phenoxyacetonitrile. 248 2-Phenyltetralone-l. 198 7-Phenanthrylbutyric acids. 273. 280 NitrobenzaJdehydes in Cannizzaro reaction. 361 oxidation by. 224-261 Nitrosyl chloride. solvents. 279. 341• 344 Perkin reaction and related reactions. 296 Pivalaldehyde in Cannizzaro reaction. preparation of. 112 3-Nitrobiphenyl. 127-129. 112 o-Nitroben«yl alcohol. 105.3-Pentachloro-2. 120. cyclization of. 176 /3-Phenanthrylpropionic acids. 359-360 table. 261 use of. 121 Phenylarsenous oxide. 184 ^-2-Naphthylpropionic acid. 145 a-Phenylvaleric acid. 423 p-Nitrophenylarsonic acid. 369-370 Polyhydroxy alcohols. 134 Phenyldichloroarsine.2. cyclization of. 341-375 l. fluorination of.3-Pentachloro-3. 103 /3-Phenylpropionic acid. 346.3-trifluoropro•pane. periodic acid oxidation of. preparation of. 294 Nitroanilines. decomposition of. 73 l. 346. 18 /S-Phenyladipic acid. 342-343 scope. 252 m-Nitrotoluraie. 361-364 mechanism. replacement of nitro group by chlorine during diazotization. 101-102. aromatic acyl. reduction with aluminum isopropoxide. resolution of. 6 Phenylacetaldehydes. I Peroxides. 127-129 Phenols. 280. resolution of. 341-375 analytical applications. 400 Opianic acid in Cannizzaro reaction. substituted.l.3. 364-375 types of compounds oxidized. 181 Oxidation by periodic acid. cyclization of. 117 Phosphorus oxychloride. use of. 424 a-Phenylnaphthalene.
cyclization of. periodic acid oxidation of. 6 2. 198 Starch. 262 Terphenyls and derivatives. reaction with acyl halides.61 . synthesis of. 336338 Stannic chloride.17.6. 196 Toluene from o-toluidine.6-Trinitroaniline. 171 Zinc fluoride. 21 Vitamin K. 103 Propionaldehyde. reaction with acyl halides. reaction with formaldehyde and alkali. 56 * Sodium hydrosulfite. 356. 62 Trifluoroacetic acid. 119 p-Tolyloxyacetone. 364 2-Propenylphenol.6-Triallylphenol.INDEX Potassium fluoride. 363 Steroids. 27 Propiolaldehyde. 51.21-tetrol-3-one. 360. reduction of diazonium salts by. 51-52 A4-Pregnene-ll. 130 «.8-Tetrahydro-2-naphthylbutyric acid. cleavage by alkali. 162-168 461 p-Terphenyl.4. 20-21 Williamson synthesis. 415-454 procedures.3-trifluoro-l-propene. 296 Triphenylacetaldehyde. 289 Sodium periodiate oxidation. cleavage by al' kali. 29$ 1. I Resolution of alcohols. 15 a-Thiophenealdehyde in Cannizzaro reaction. 169 Stannous chloride as reagent for removal of peroxides from organic liquids. 359. 357. 107 7-3-Pyrenylbutyric acid. Vol.5-Trimethoxyphenylacetaldehyde. cleavage by alkali.3. cyclization of. cyclization of. periodic acid oxidation of 348.3. 11 Trichlorofiuoromethane. 102. 363 Sodium stannite. 135 a-Pyridylaldehyde in Cannizzaro reaction. 295 o-Toluidine. 23 Zinc chloride. 239 Pseudoopianic acid.2-Trichloro-3.?. deamination of.4. cyclization of. reduction of diazonium salts by. 290. 376-414 Rosenmund reaction. 175 •y-6-Tetralylbutyric acid. 243 Vinyl fluorides. 235 7-5. use in preparation of cyclic ketones. 358-359. periodic acid oxidation of.5-Trinitrobenzene. 298. 136-144. 102 Pschorr synthesis. 53 Vitamin E. 296 7-m-Tolylbutyric acid. 19. 18 2. 348. cyclization of. 74 3. 349. 108 Reformatsky reaction.1. synthesis of. 64 1. 99 Triptycene. 288. 371-373 Sulfuric acid.4. 188. use in preparation of cyclic ketones. 125 /3-?rc-Tolylhydroeinnamic acid. 297 Ullmann reaction.<*.7. deamination of. 287.Y-Tetramethylallyl phenyl ether. 286. 108 Tishchenko reaction. use in preparation of cyclic ketones. 432 Silver fluoride. 280.20.
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