The Conversion of Carboxylic Acids to Ketones: A Repeated Discovery

Research: Science and Education

The Conversion of Carboxylic Acids to Ketones: A Repeated Discovery John W. Nicholson* School of Natural Science, University of Greenwich, Chatham, Kent ME4 4TB, United Kingdom; *[email protected] Alan D. Wilson Materials Technology Group, Laboratory of the Government Chemist (Retired), London, United Kingdom

The conversion of carboxylic acids to ketones is a useful chemical transformation and one that has a long history. It is curious, though, in that it has been reported by several authors who believed that they were the first to have “discovered” the reaction. The most widely studied reaction of this type is the Dakin–West reaction (1). This reaction was described in 1928 by the two biological chemists whose name it bears (2) and involves the conversion of α-amino acids to α-acetimido ketones using acetic anhydride in the presence of base. Reaction of the amine group to amide was not surprising when the reaction was discovered but the conversion of the acid functionality to ketone was thought, wrongly, to be completely novel. The overall reaction may be written:

The mechanism has been studied in detail by a number of chemists. From these studies, it is clear that N-acetylation is relatively straightforward and requires little further comment. Of greater interest are the steps leading to the elimination of CO2 to form the keto group. This has been shown to occur via a cyclic intermediate, 2, formed by reaction with acetic anhydride: O R

CH HN

C C

R

Ac2O

OH

B

R

CH

C

OH

Ph

2

3

O

Ph

Ac2O

+ H3C C O C CH3 CH3

NH2 O R

CH HN

C C

CH3 CH3

+ CO2 + H2O

C

O

R

C

C

O

N

C

Ph

Oⴚ

In fact, Dakin and West were by no means the first to convert carboxylic acids to ketones. This part of their reaction had been described on a number of occasions in the previous 70 years, including in considerable detail by the famous organic chemist W. H. Perkin, Sr. (3). In this article, we will begin by considering the Dakin– West reaction in depth and then trace the history of the discovery of this type of synthesis. This includes our own work in which we used this reaction to crosslink polymers. We conclude by describing how the reaction was used in one of the most famous pieces of organic synthesis of the 20th century, namely Woodward’s total synthesis of strychnine. The Dakin–West Reaction The reaction is usually carried out with primary amino acids, though secondary amino acids will also form acylamino–ketones (4). The essential requirement is that the reacting compound possesses an α-hydrogen atom. The base is usually pyridine, though other compounds, such as sodium acetate have also been found to be effective in promoting the reaction.

Journal of Chemical Education

CH3

O

O

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O N

N

Ph

O O

R

O

1 O

Oⴚ

O

H

•

O

ⴚ

AcO

C

R

CH3

O N 4

R

Ph

–Ac2O

CH3

CH3 C

O

C

5

AcOⴚ

O

O

O

C

C

N

C

ⴚ

O

Hⴙ

–CO2

O

C

R

CH

Ph

HN

C

ⴚ

O 6

Ph

O 7

The cyclic compound belongs to the class known as oxazolones. The role of the base is then to deprotonate this to form a reactive anion, 3, which undergoes condensation with acetic anhydride. The resulting oxazolone then undergoes ring opening by reaction with acetate anion, forming 5, which, under the reaction conditions, readily undergoes deacetylation and decarboxylation. Kinetic experiments are consistent with this mechanism (5) and intermediates of the type shown as 2 can be prepared and shown to give the same products as the acylamino acids under the same reaction conditions (6, 7).

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This reaction must be distinguished from the superficially similar behavior of α- and β-ketoacids that undergo either thermal or enzymic decarboxylation to yield ketones (8, 9). The keto group in these products is the same as the one in the starting material and the decarboxylation process actually results in the replacement of the carboxylic acid by a hydrogen atom. This is illustrated in the reaction of pyruvic acid, which is decarboxylated under the influence of the enzyme pyruvate decarboxylase during alcoholic fermentation:

H3C

O

O

C

C

O Oⴚ

Hⴙ

+

H3C

C

H

+ CO2

The article (3) by W. H. Perkin, Sr., was cited by Dakin and West in their classic article of 1928 (2), though they missed other articles on the subject that appeared around the same time. For example, they did not seem to be aware that Wilhelm Heintz had reported the preparation of stearone from stearic acid in the presence of magnesium oxide as early as 1855 (10), a reaction whose efficacy has been confirmed in the encyclopedic collection Organic Syntheses Collection (11). Heintz’s work is of interest in that he noted that the product, stearone, had what he described as two melting points, a report that seems to be one of the earliest of what is now known as liquid-crystal behavior. The omission of any mention of the work of Perkin might be considered particularly noteworthy, because Perkin was an important figure in organic chemistry. His historical importance lies in his work, carried out while still a young man, on synthetic dyestuffs (12). He discovered the first synthetic dyestuff, mauveine, in 1856 and set up a factory to manufacture it. This involved the solving of a number of problems of scaleup that would today fall under the heading of chemical engineering (13). As well as this, Perkin devised a route to synthetic alizarin, which was also an important dyestuff. The manufacture of alizarin represented a step of great significance in the development of the chemical industry (14). Despite these successes, Perkin was unable to secure the financial backing necessary for him to expand his business, and he retired from it in 1874. In his retirement, he maintained a private laboratory at his home in Sudbury, Middlesex (12), and there pursued original research, out of which came his article claiming the discovery of the conversion of carboxylic acids to ketones. Perkin’s work was carried out on simple compounds under straightforward conditions, and he found that by refluxing butyric anhydride in the presence of what he simply referred to as “a butyrate”, presumably of sodium, he obtained the appropriate ketone: O C

O H3C

C

O O

C

O CH3

H3C

C

CH3

+ CO2

In this reaction, he was more explicit about the nature of the basic catalyst, which was sodium acetate. The gaseous byproduct, CO2, was then known as carbonic anhydride, and is the name used by Perkin throughout his article (3). Early History

Previous Work

CH3CH2CH2

To effect the equivalent conversion of acetic anhydride, he found it necessary to seal the reactants in a glass tube, prior to heating them to 190–200 ⬚C. Failure to do so led to the acetic anhydride distilling unchanged. The reaction may be represented as:

O O

C

CH2CH2CH3

Studies by Perkin, Jr., and Thorpe

O CH3CH2CH2

C

Though Heintz and Perkin described the reaction in modern terms, there is a considerable history of the ketonization of salts of organic acids prior to the second half of the 19th century. The earliest of all references to the reaction seems to have been by Jean Beguin in Tyrocinium Chymicum, published in 1612 and cited by Robert Boyle in The Sceptical Chymist in 1661 (15). Beguin described the preparation of a volatile substance that he called burning “Spirit of Saturn” from minium (a reddish oxide of lead) and distilled spirits of vinegar. He assumed the product, which was inflammable, contained lead. However, it was almost certainly acetone, so his assumption was mistaken. Another early reference to the preparation of acetone involving heating is found in the late 18th century in France (16). At the time, the prefix “pyro” was used as a method of naming compounds obtained by heating organic substances, including acids. A neutral substance “pyro-acetic spirit” (acetone) was known to be obtained by heating calcium acetate, though few details are available. In 1808 the Derosne brothers, who were pharmacists in Paris, distilled copper acetate, obtaining a liquid that they named “éther-pyroacétique”, which was also acetone but named to emphasize its relationship to acetic acid and also to distinguish it from “étheracétique” (17). However, Chenevix (1809) objected to the name as being too specific for a substance of unknown chemical nature and suggested instead the term “pyro-acetic acid spirit” (17). Most chemists, though, preferred the name suggested by the Derosne brothers. In 1833 Bussey decided to break away from the vagueness of the terms “spirit” and “ether” applied to the products of dry distillation of salts of organic acids (18). He proposed that each product should have a name related to the parent acid, plus the common suffix “–one”. For the product of acetic acid, he proposed the name acetone, a name that survives to the present day. In an article published in 1845, Chancel referred to all similar substances as acetones (18). The general name “ketone” was first applied by Gmelin in the 4th (1848) edition of his textbook of chemistry (19), and taken up by Beilstein in his influential Handbuch der Organischen Chemie (20).

CH2CH2CH3

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•

+ CO2

W. H. Perkin, Sr., had three sons, all of whom became chemists. The oldest of them, W. H. Perkin, Jr., had prob-


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ably the most distinguished career, taking a Ph.D. at Wurtzberg in Germany in 1882, then holding successively chairs of chemistry at the Universities of Manchester and of Oxford (21). While still at Manchester, Perkin, Jr., published an article in collaboration with J. F. Thorpe (22) in which he described the conversion of the sodium salt of 4methylpentane-1,3,4-tricarboxylic acid to the keto acid 2,2dimethyl-3-oxocyclopentanecarboxylic acid by refluxing in acetic anhydride at 140 ⬚C.

CH2

C

OH O

C

O

C

CH

H3 C

O Ph

OH

H3C

Warner Institute for Therapeutic Research, New York, and Buchanan and McArdle (27) at Glasgow University each carried out controlled conversions of arylacetic acids to ketones, using pyridine as the catalyst. In a typical reaction (26), phenylacetic acid was refluxed for six hours with acetic anhydride and pyridine to yield phenylacetone and diphenylacetone:

C

O CH2CH2

C

Ph OH

OH

H3C

C

CH2

+ CO2

C H3C

CH C

CH3

+

Ph

CH2 O

OH

This article is remarkable for the fact that the authors failed to cite the original work by Perkin, Sr. Indeed a footnote suggests that they thought that they were the first to discover this transformation, for they remark, “If this curious reaction should prove to be a general one, it will afford a convenient means of synthesizing many important closed chain keto-acids and, for this reason, experiments are being carried out by one of us with the object of ascertaining the exact conditions under which the change takes place.” Which of the authors was continuing the investigation was not known, though the synthesis of ring compounds was much more a feature of Perkin’s work than of Thorpe’s (21). The reaction did, indeed, prove to have some generality, though perhaps not what they were looking for and, as far as we have been able to discover, neither Perkin, Jr., nor Thorpe ever referred to it in print again.

C

CH2

(56%)

O

O

C

CH2

O CH2

(24%)

A similar reaction was found to occur with phenylacetic anhydride as the starting material, though this yielded less phenylacetone (33%). The yield of diphenylacetone was almost unchanged, at 26% (26). King and McMillan went on to postulate a mechanism for the reaction in which two anhydride molecules condensed together under the influence of base, losing CO2 while forming a ketone and regenerating one molecule of anhydride. Aspects of this mechanism were refined by Buchanan and McArdle (27). They recognized that the essential step of the reaction was attack at the reactive methylene group by a molecule of anhydride. Hence they suggested initially that molecules such as phenylacetic ester or benzyl cyanide, which contain even more reactive methylene groups, ought to undergo the reaction readily. When they tried these compounds, though, they found no reaction. This led them to modify the reaction mechanism and to propose the occurrence of a rearrangement: O

Oⴚ

O

O

base

Ph

CH2

C

O

C

Other Studies

R

O

Ph

CH

C

ⴚ

O

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•

Ph

CH C

C

O

C

R

O

ⴙ

H

A few years later, in an article that seems to have been consistently overlooked, Bamberger (23) described an analogous reaction to that studied by Perkin, Sr., though using calcium acetate rather than the sodium salt as the catalyst. He was thereby able to repeat the earlier preparation of acetone from acetic acid. His article contains no references to the work of Perkin, Sr., and he seems to have had the idea that he was the discoverer of the reaction. Similarly, an article was published in the 1930s by Stoemer and Stroh (24) in which the conversion of phenylacetic acid to phenylacetone using sodium acetate as base was reported and this also contains no references to previous work. It does not even mention the important studies of Dakin and West. By contrast, Hurd and Thomas, who published an analogous study, but using potassium acetate as base, made a better job of identifying previous reports of this reaction (25) and their article carries no implicit claim to have discovered the reaction. Moving forward in time, we come to a series of studies carried out in the 1950s. King and McMillan (26) at the

Ph

Ph

CH2

C

R

+ CO2

O

R

These reactions were carried out under controlled conditions, and this contrasted with the studies of Nakai et al. (28), whose work concerned the pyrolysis of various carboxylate salts, including sodium phenylacetate. The reaction gave an untidy mixture of products, including carbon dioxide, carbon monoxide, methane, ethane, propane, and butane, as well as the appropriate ketone, all of which were detected by gas chromatography (28). There have been other studies of the ketonization of acetic acid to acetone at elevated temperatures. One reaction takes place over metal oxide catalysts and was reviewed many years ago (29). Among the oxides that have been found to be effective are TiO2 (30), Cr2O3 (31), and SnO (32). However, this review makes no mention of the reports of more controlled conversions carried out at lower temperatures and without metal oxides as catalysts.


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Polymer Crosslinking Ketonization has also been used to crosslink polymer films to render them insoluble in water (33). The reaction employed partially neutralized films of polymers such as polyacrylic acid that were heated to 250 ⬚C for ten minutes (33). Kinetic studies using reflectance infrared spectroscopy showed that there was an initial formation of anhydride groups, and this was followed by gradual loss of such groups as ketonization took place (34). The reaction thus proceeded: O 2R

C

O

– H 2O

R

OH

C

The total synthesis was described in detail by Woodward et al. in 1963 (38). They used the acid–keto transformation to form keto ring of the strychnine structure. Having prepared the N-acetyl acid, designated XXXIX in their scheme, they converted 200 mg to the enol–acetate (XL) by refluxing with 10 ml each of acetic anhydride and pyridine. The process had a yield of 27.5%.

NCOCH 3 H

O O

C

R

– CO2

R

C

COOH

N

O R

As with so many previous reports, this was an independent discovery (33). It was our work, and we remember the surprise when we found what was happening to the polymers. However, we soon discovered the truth about the history of the reaction when one of us (JWN) happened to be reading a historical account of the work of W. H. Perkin, Jr., in a recently-acquired secondhand book (21). This led us to search the literature more thoroughly, and in our later articles we acknowledge the contributions of others. In our experimental work, we found that the neutralizing species had to be carefully chosen: only alkali metal cations would catalyze the reaction (33). Ions of other metals, such as calcium, magnesium (34), copper, cobalt, or zinc would not; and lithium was considerably less effective than sodium (35). Although originally applied to polyacrylic acid, we found the reaction to be applicable to other carboxylated polymers, including polymaleic acid (36) and copolymers of butyl acrylate with acrylic acid (37). Original results implied that the resulting crosslinked polymer films might be promising as the basis for novel industrial waterborne coatings, given the growing concern about the release into the environment of organic solvents from paints. Unfortunately, this did not prove to be the case and the technology has not, so far, been exploited commercially. Total Synthesis of Strychnine

H

O XXXIX

NCOCH3 H CH3

N

OCOCH3

O XL

Woodward et al. imply that finding the means of carrying out this step was not straightforward, but their article does not discuss any of the alternatives that they considered. Instead, they describe the reaction as “…an exceptionally simple method which ultimately proved successful.” They cite the earlier work of Dakin and West (2), as well as of Stoemer and Stroh (24) and King and McMillan (26), so were clearly aware that the process was already known. Nonetheless exploitation of such an effective but little known reaction is further testimony to the brilliance of Woodward in the design and execution of extraordinary feats of total synthesis. Conclusions

Despite the fact that the conversion of carboxylic acids to ketones has not become widely known or used in organic synthesis, it did prove to be useful in one of the most important total syntheses of the 20th century, namely that of strychnine. Strychnine has the following structure: N

N O

O strychnine

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This article has shown that several chemists have claimed, explicitly or implicitly, to have discovered the conversion of carboxylic acids to ketones, yet in fact, the reaction has actually been known for centuries. Of the various processes described, only the Dakin–West reaction has attracted any widespread attention, but in general, the reaction has not become well known. However, it was successfully exploited by Woodward et al. in their famous total synthesis of strychnine, as reported in 1963. The successful deployment of such a relatively neglected reaction is a tribute to Woodward’s deep knowledge of synthetic organic chemistry and in no way contradicts the general conclusion that the process lacks widespread synthetic usefulness. This probably explains its enigmatic status as a reaction whose rediscovery has occurred several times throughout the history of chemistry.


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Acknowledgments We thank the reviewers of an earlier draft of this article for their helpful comments, in particular, for drawing our attention to the use of this reaction by Woodward et al. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13. 14.

15. 16.

Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91. Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 91. Perkin, W. H., Sr. J. Chem. Soc. 1886, 317. Cornforth, J. W. In Heterocyclic Compounds; Elderfield, R. C., Ed.; John Wiley & Sons, Inc.: New York, 1957; Vol. 5, p 345. Allinger, N. L.; Wang, G. L.; Dewhurst, B. B. J. Org. Chem. 1974, 39, 1730. Julian, P.; Dailey, E. E.; Printy, H. C.; Cohen, H. L. Hamashige, S. J. Am. Chem. Soc. 1956, 78, 3503. Iwakura, Y.; Toda, F.; Suzuki, H. J. Org. Chem. 1967, 32, 440. Morrison, R. T.; Boyd, R. N. Organic Chemistry, 3rd ed.; Allyn & Bacon: New York, 1973. Hanson, R. W. J. Chem. Educ. 1987, 64, 591. Heintz, W. Jahnsberger. Chem. 1855, 8, 515. Dobson, A. G.; Hatt, H. H. Org. Synth. Coll. Vol. IV 1963, 854. Travis, A. S. The Rainbow Makers: The Origins of the Synthetic Dyestuffs Industry in Western Europe; LeHigh University Press: Bethlehem, PA, 1993. Leaback, D. H. Chemistry in Britain 1988, 24, 787. Campbell, W. A. In Recent Developments in the History of Chemistry; Russell, C. A., Ed.; Royal Society of Chemistry: London, 1985; Chapter 11. Davidson, J. S. J. Chem. Educ. 1985, 62, 751. Crossland, M. P. Historic Studies in the Language of Chemistry; Heinemann Educational Books: London, 1962; p 292.

17. Crossland, M. P. Historic Studies in the Language of Chemistry; Heinemann Educational Books: London, 1962; p 294. 18. Crossland, M. P. Historic Studies in the Language of Chemistry; Heinemann Educational Books: London, 1962; p 300. 19. Gmelin, L. Handbuch der Anorganischen Chemie, 4th ed.; J. Springer: Heidelberg, Germany 1848; Vol 1. 20. Beilstein, F. C. Handbuch der Organischen Chemie, Hamburg & Leipzig: Berlin 1883. 21. Robinson, R. William Henry Perkin, Jr., 1860–1929. In British Chemists; Findlay, A., Mills, W. H., Eds.; Chemical Society: London, 1947. 22. Perkin, W. H., Jr.; Thorpe, J. F J. Chem. Soc. 1904, 85, 128. 23. Bamberger, E. Berichte 1910, 43, 3517. 24. Stoermer, R.; Stroh, H. Berichte 1935, 68, 2112. 25. Hurd, C. D.; Thomas, C. L. J. Am. Chem. Soc. 1936, 58, 1240. 26. King, J. A.; McMillan, F. H. J. Am. Chem. Soc. 1951, 73, 4911. King, J. A.; McMillan, F. H. J. Am. Chem. Soc. 1955, 77, 2814. 27. Buchanan, G. L.; McArdle, J. J. Chem. Soc. 1952, 2944. 28. Nakai, R.; Sugii, M.; Nakao, A. J. Am. Chem. Soc. 1959, 81, 1003. 29. Jewur, S. S.; Kuriacose, J. C. Indian Chem. Manufact. 1974, 12, 13. 30. Bischoff, F.; Adkins, H. J. Am. Chem. Soc. 1925, 47, 807. 31. Kuriacose, J. C.; Smaminathan, R. J. Catal. 1969, 14, 348. 32. Senderens, I. B. Annal. Chem. Phys. 1928, 28, 243. 33. Nicholson, J. W.; Wilson, A. D. Br. Polym. J. 1987, 19, 67. 34. Nicholson, J. W.; Wilson, A. D. Br. Polym. J. 1987, 19, 449. 35. Nicholson, J. W.; Wasson, E. A.; Wilson, A. D. Br. Polym. J. 1988, 20, 97. 36. Nicholson, J. W.; Wasson, E. A. Br. Polym. J. 1989, 21, 513. 37. Nicholson, J. W.; Scott, R. P.; Wilson, A. D. J. Oil & Col. Chemists’ Assoc. 1987, 70, 157. 38. Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeneker, H. U.; Schenker, K. Tetrahedron 1963, 19, 247.

The structure of strychnine discussed in this article is available in fully manipulable Chime format as a JCE Featured Molecule in JCE Online.

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The Conversion of Carboxylic Acids to Ketones: A Repeated Discovery

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