the conversion of carboxylic acids to ketones
TRANSCRIPT
Research: Science and Education
1362 Journal of Chemical Education • Vol. 81 No. 9 September 2004 • www.JCE.DivCHED.org
The conversion of carboxylic acids to ketones is a usefulchemical transformation and one that has a long history. Itis curious, though, in that it has been reported by several au-thors who believed that they were the first to have “discov-ered” the reaction. The most widely studied reaction of thistype is the Dakin–West reaction (1). This reaction was de-scribed in 1928 by the two biological chemists whose nameit bears (2) and involves the conversion of α-amino acids toα-acetimido ketones using acetic anhydride in the presenceof base. Reaction of the amine group to amide was not sur-prising when the reaction was discovered but the conversionof the acid functionality to ketone was thought, wrongly, tobe completely novel. The overall reaction may be written:
R CH
NH2
CO2 H O2
C
O
OH + H
++
3C C
O
O C
O
CH3
R
HN
CH C
O
CH3
C
O
CH3
In fact, Dakin and West were by no means the first to con-vert carboxylic acids to ketones. This part of their reactionhad been described on a number of occasions in the previ-ous 70 years, including in considerable detail by the famousorganic 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 dis-covery of this type of synthesis. This includes our own workin which we used this reaction to crosslink polymers. We con-clude by describing how the reaction was used in one of themost 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 aminoacids, though secondary amino acids will also form acyl-amino–ketones (4). The essential requirement is that the re-acting compound possesses an α-hydrogen atom. The baseis usually pyridine, though other compounds, such as sodiumacetate have also been found to be effective in promoting thereaction.
The mechanism has been studied in detail by a numberof chemists. From these studies, it is clear that N-acetylationis relatively straightforward and requires little further com-ment. Of greater interest are the steps leading to the elimi-nation of CO2 to form the keto group. This has been shownto occur via a cyclic intermediate, 2, formed by reaction withacetic anhydride:
3
R
HN
N
HN
CH C
O
C
O
Ac2O
–Ac2O
–CO2
AcO�
AcO�
H�
Ac2O
OH
Ph NO
HR
O
Ph
B
NO
RO�
Ph21
45
76
Ph
NO
R
O
R CH
C
C
O
O
CH3
Ph
R C
C
C
CH3
O�
OO
R C
C
C
CH3
C
O�
Ph
N C
O�
Ph
O C
CH3
OO
O C
O
CH3
The cyclic compound belongs to the class known asoxazolones. The role of the base is then to deprotonate thisto form a reactive anion, 3, which undergoes condensationwith acetic anhydride. The resulting oxazolone then under-goes ring opening by reaction with acetate anion, forming 5,which, under the reaction conditions, readily undergoesdeacetylation and decarboxylation. Kinetic experiments areconsistent with this mechanism (5) and intermediates of thetype shown as 2 can be prepared and shown to give the sameproducts as the acylamino acids under the same reaction con-ditions (6, 7).
The Conversion of Carboxylic Acids to Ketones:A Repeated DiscoveryJohn W. Nicholson*School of Natural Science, University of Greenwich, Chatham, Kent ME4 4TB, United Kingdom;*[email protected]
Alan D. WilsonMaterials Technology Group, Laboratory of the Government Chemist (Retired), London, United Kingdom
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www.JCE.DivCHED.org • Vol. 81 No. 9 September 2004 • Journal of Chemical Education 1363
This reaction must be distinguished from the superfi-cially similar behavior of α- and β-ketoacids that undergoeither thermal or enzymic decarboxylation to yield ketones(8, 9). The keto group in these products is the same as theone in the starting material and the decarboxylation processactually results in the replacement of the carboxylic acid bya hydrogen atom. This is illustrated in the reaction of pyru-vic acid, which is decarboxylated under the influence of theenzyme pyruvate decarboxylase during alcoholic fermenta-tion:
H�+H3C C
O
C
O
O� CO2+H3C C
O
H
Previous Work
The article (3) by W. H. Perkin, Sr., was cited by Dakinand West in their classic article of 1928 (2), though theymissed other articles on the subject that appeared around thesame time. For example, they did not seem to be aware thatWilhelm Heintz had reported the preparation of stearonefrom stearic acid in the presence of magnesium oxide as earlyas 1855 (10), a reaction whose efficacy has been confirmedin the encyclopedic collection Organic Syntheses Collection(11). Heintz’s work is of interest in that he noted that theproduct, stearone, had what he described as two meltingpoints, a report that seems to be one of the earliest of whatis now known as liquid-crystal behavior.
The omission of any mention of the work of Perkinmight be considered particularly noteworthy, because Perkinwas an important figure in organic chemistry. His historicalimportance lies in his work, carried out while still a youngman, on synthetic dyestuffs (12). He discovered the first syn-thetic dyestuff, mauveine, in 1856 and set up a factory tomanufacture it. This involved the solving of a number ofproblems of scaleup that would today fall under the headingof chemical engineering (13). As well as this, Perkin deviseda route to synthetic alizarin, which was also an importantdyestuff. The manufacture of alizarin represented a step ofgreat significance in the development of the chemical indus-try (14).
Despite these successes, Perkin was unable to secure thefinancial backing necessary for him to expand his business,and he retired from it in 1874. In his retirement, he main-tained a private laboratory at his home in Sudbury, Middlesex(12), and there pursued original research, out of which camehis article claiming the discovery of the conversion of car-boxylic acids to ketones. Perkin’s work was carried out onsimple compounds under straightforward conditions, and hefound that by refluxing butyric anhydride in the presence ofwhat he simply referred to as “a butyrate”, presumably of so-dium, he obtained the appropriate ketone:
C
O
O C
O
CH2CH2CH3CH3CH2CH2
CH3CH2CH2 C
O
CH2CH2CH3 CO2+
To effect the equivalent conversion of acetic anhydride, hefound it necessary to seal the reactants in a glass tube, priorto heating them to 190–200 �C. Failure to do so led to theacetic anhydride distilling unchanged. The reaction may berepresented as:
H3C C
O
O C
O
CH3 H3C C
O
CH3 CO2+
In this reaction, he was more explicit about the nature of thebasic catalyst, which was sodium acetate. The gaseous byprod-uct, CO2, was then known as carbonic anhydride, and is thename used by Perkin throughout his article (3).
Early History
Though Heintz and Perkin described the reaction inmodern terms, there is a considerable history of theketonization of salts of organic acids prior to the second halfof the 19th century. The earliest of all references to the reac-tion seems to have been by Jean Beguin in TyrociniumChymicum, published in 1612 and cited by Robert Boyle inThe Sceptical Chymist in 1661 (15). Beguin described thepreparation of a volatile substance that he called burning“Spirit of Saturn” from minium (a reddish oxide of lead) anddistilled spirits of vinegar. He assumed the product, whichwas inflammable, contained lead. However, it was almost cer-tainly acetone, so his assumption was mistaken.
Another early reference to the preparation of acetoneinvolving heating is found in the late 18th century in France(16). At the time, the prefix “pyro” was used as a method ofnaming compounds obtained by heating organic substances,including acids. A neutral substance “pyro-acetic spirit” (ac-etone) was known to be obtained by heating calcium acetate,though few details are available. In 1808 the Derosne broth-ers, 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 relation-ship to acetic acid and also to distinguish it from “éther-acétique” (17). However, Chenevix (1809) objected to thename as being too specific for a substance of unknown chemi-cal nature and suggested instead the term “pyro-acetic acidspirit” (17). Most chemists, though, preferred the name sug-gested by the Derosne brothers.
In 1833 Bussey decided to break away from the vague-ness of the terms “spirit” and “ether” applied to the productsof dry distillation of salts of organic acids (18). He proposedthat each product should have a name related to the parentacid, plus the common suffix “–one”. For the product of ace-tic acid, he proposed the name acetone, a name that survivesto the present day. In an article published in 1845, Chancelreferred to all similar substances as acetones (18). The generalname “ketone” was first applied by Gmelin in the 4th (1848)edition of his textbook of chemistry (19), and taken up by Beil-stein in his influential Handbuch der Organischen Chemie (20).
Studies by Perkin, Jr., and Thorpe
W. H. Perkin, Sr., had three sons, all of whom becamechemists. The oldest of them, W. H. Perkin, Jr., had prob-
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ably the most distinguished career, taking a Ph.D. atWurtzberg in Germany in 1882, then holding successivelychairs of chemistry at the Universities of Manchester and ofOxford (21). While still at Manchester, Perkin, Jr., publishedan article in collaboration with J. F. Thorpe (22) in whichhe described the conversion of the sodium salt of 4-methylpentane-1,3,4-tricarboxylic acid to the keto acid 2,2-dimethyl-3-oxocyclopentanecarboxylic acid by refluxing inacetic anhydride at 140 �C.
CCHH3C
H3C CH2
CH2
C
OH
C
O
C
O
OH
O
H3C C
C
H3C
CH
O
OH
C O
OH
CH2CH2
CO2+
This article is remarkable for the fact that the authorsfailed to cite the original work by Perkin, Sr. Indeed a foot-note suggests that they thought that they were the first todiscover this transformation, for they remark, “If this curi-ous reaction should prove to be a general one, it will afford aconvenient means of synthesizing many important closedchain keto-acids and, for this reason, experiments are beingcarried out by one of us with the object of ascertaining theexact conditions under which the change takes place.” Whichof the authors was continuing the investigation was notknown, though the synthesis of ring compounds was muchmore a feature of Perkin’s work than of Thorpe’s (21). Thereaction did, indeed, prove to have some generality, thoughperhaps not what they were looking for and, as far as we havebeen able to discover, neither Perkin, Jr., nor Thorpe everreferred to it in print again.
Other Studies
A few years later, in an article that seems to have beenconsistently overlooked, Bamberger (23) described an analo-gous reaction to that studied by Perkin, Sr., though usingcalcium acetate rather than the sodium salt as the catalyst.He was thereby able to repeat the earlier preparation of ac-etone from acetic acid. His article contains no references tothe work of Perkin, Sr., and he seems to have had the ideathat he was the discoverer of the reaction.
Similarly, an article was published in the 1930s byStoemer and Stroh (24) in which the conversion of phenyl-acetic acid to phenylacetone using sodium acetate as base wasreported and this also contains no references to previous work.It does not even mention the important studies of Dakin andWest. By contrast, Hurd and Thomas, who published ananalogous study, but using potassium acetate as base, madea better job of identifying previous reports of this reaction(25) and their article carries no implicit claim to have dis-covered the reaction.
Moving forward in time, we come to a series of studiescarried out in the 1950s. King and McMillan (26) at the
Warner Institute for Therapeutic Research, New York, andBuchanan and McArdle (27) at Glasgow University each car-ried out controlled conversions of arylacetic acids to ketones,using pyridine as the catalyst. In a typical reaction (26), phe-nylacetic acid was refluxed for six hours with acetic anhy-dride and pyridine to yield phenylacetone anddiphenylacetone:
O
C OHCH2
CH2
O
C
(24%)
Ph
O
C CH3
(56%)
CH2Ph
Ph
CH2 Ph+
A similar reaction was found to occur with phenylacetic an-hydride as the starting material, though this yielded lessphenylacetone (33%). The yield of diphenylacetone was al-most unchanged, at 26% (26). King and McMillan went onto postulate a mechanism for the reaction in which two an-hydride molecules condensed together under the influenceof base, losing CO2 while forming a ketone and regenerat-ing one molecule of anhydride.
Aspects of this mechanism were refined by Buchanan andMcArdle (27). They recognized that the essential step of thereaction was attack at the reactive methylene group by a mol-ecule of anhydride. Hence they suggested initially that mol-ecules such as phenylacetic ester or benzyl cyanide, whichcontain even more reactive methylene groups, ought to un-dergo the reaction readily. When they tried these compounds,though, they found no reaction. This led them to modifythe reaction mechanism and to propose the occurrence of arearrangement:
C
O
C
O
C
O
CH2Ph
CH2Ph
O R
O�
C O
O
R
R
C
OO�
C O RCHPh
CCHPh CO2
H�
base
+
These reactions were carried out under controlled con-ditions, and this contrasted with the studies of Nakai et al.(28), whose work concerned the pyrolysis of various carboxy-late salts, including sodium phenylacetate. The reaction gavean untidy mixture of products, including carbon dioxide, car-bon monoxide, methane, ethane, propane, and butane, as wellas the appropriate ketone, all of which were detected by gaschromatography (28).
There have been other studies of the ketonization of ace-tic acid to acetone at elevated temperatures. One reactiontakes place over metal oxide catalysts and was reviewed manyyears ago (29). Among the oxides that have been found tobe effective are TiO2 (30), Cr2O3 (31), and SnO (32). How-ever, this review makes no mention of the reports of morecontrolled conversions carried out at lower temperatures andwithout metal oxides as catalysts.
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Polymer Crosslinking
Ketonization has also been used to crosslink polymerfilms to render them insoluble in water (33). The reactionemployed partially neutralized films of polymers such as poly-acrylic acid that were heated to 250 �C for ten minutes (33).Kinetic studies using reflectance infrared spectroscopy showedthat there was an initial formation of anhydride groups, andthis was followed by gradual loss of such groups asketonization took place (34). The reaction thus proceeded:
O
CR2 OH
O
CR R
C
O
C
O
O RR–H2O
–CO2
As with so many previous reports, this was an indepen-dent discovery (33). It was our work, and we remember thesurprise when we found what was happening to the poly-mers. However, we soon discovered the truth about the his-tory of the reaction when one of us (JWN) happened to bereading a historical account of the work of W. H. Perkin, Jr.,in a recently-acquired secondhand book (21). This led us tosearch the literature more thoroughly, and in our later ar-ticles we acknowledge the contributions of others.
In our experimental work, we found that the neutraliz-ing species had to be carefully chosen: only alkali metal cat-ions would catalyze the reaction (33). Ions of other metals,such as calcium, magnesium (34), copper, cobalt, or zincwould not; and lithium was considerably less effective thansodium (35). Although originally applied to polyacrylic acid,we found the reaction to be applicable to other carboxylatedpolymers, including polymaleic acid (36) and copolymers ofbutyl acrylate with acrylic acid (37). Original results impliedthat the resulting crosslinked polymer films might be prom-ising as the basis for novel industrial waterborne coatings,given the growing concern about the release into the envi-ronment of organic solvents from paints. Unfortunately, thisdid not prove to be the case and the technology has not, sofar, been exploited commercially.
Total Synthesis of Strychnine
Despite the fact that the conversion of carboxylic acidsto ketones has not become widely known or used in organicsynthesis, it did prove to be useful in one of the most impor-tant total syntheses of the 20th century, namely that of strych-nine. Strychnine has the following structure:
N
N
O O
strychnine
The total synthesis was described in detail by Woodward etal. in 1963 (38). They used the acid–keto transformation toform keto ring of the strychnine structure. Having preparedthe N-acetyl acid, designated XXXIX in their scheme, theyconverted 200 mg to the enol–acetate (XL) by refluxing with10 ml each of acetic anhydride and pyridine. The processhad a yield of 27.5%.
N
N
COOH
O
H
XXXIX
XL
NCOCH 3H
O
NCOCH3H
CH3
3OCOCH
Woodward et al. imply that finding the means of carry-ing out this step was not straightforward, but their articledoes not discuss any of the alternatives that they considered.Instead, they describe the reaction as “�an exceptionallysimple method which ultimately proved successful.” They citethe earlier work of Dakin and West (2), as well as of Stoemerand Stroh (24) and King and McMillan (26), so were clearlyaware that the process was already known. Nonetheless ex-ploitation of such an effective but little known reaction isfurther testimony to the brilliance of Woodward in the de-sign and execution of extraordinary feats of total synthesis.
Conclusions
This article has shown that several chemists have claimed,explicitly or implicitly, to have discovered the conversion ofcarboxylic acids to ketones, yet in fact, the reaction has actu-ally been known for centuries. Of the various processes de-scribed, only the Dakin–West reaction has attracted anywidespread attention, but in general, the reaction has notbecome well known. However, it was successfully exploitedby Woodward et al. in their famous total synthesis of strych-nine, as reported in 1963. The successful deployment of sucha relatively neglected reaction is a tribute to Woodward’s deepknowledge of synthetic organic chemistry and in no way con-tradicts the general conclusion that the process lacks wide-spread synthetic usefulness. This probably explains itsenigmatic status as a reaction whose rediscovery has occurredseveral times throughout the history of chemistry.
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Acknowledgments
We thank the reviewers of an earlier draft of this articlefor their helpful comments, in particular, for drawing ourattention to the use of this reaction by Woodward et al.
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The structure of strychnine discussed in this article is available in fully manipulable Chime formatas a JCE Featured Molecule in JCE Online.
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