Dimethylacetoacetic acid

A third early mechanism for enzymic processes involves the formation of imines between the amino group of a lysine residue on an enzyme and the carbonyl group of a substrate, followed by standard imine chemistry. The first example concerned the decarboxylation of acetoacetic acid (Hamilton and Westheimer, 1959). The mechanism was based on the non-enzymic physical organic chemistry of Kai Pedersen (Pedersen, 1934). He postulated that the catalysis by aniline of the decarboxylation of dimethylacetoacetic acid proceeds by a mechanism parallel to that shown in Scheme 7 for acetoacetic acid itself (Pedersen, 1938). 

Pedersen350 showed that a,a-dimethylacetoacetic acid cannot enolize decarboxylates readily and thus concluded that the keto tautomers of /3-oxo acids are kinetically unstable. The enol intermediate formed in the decarboxylation of /3-oxo acids has been trapped by reaction with bromine3S1 and has also been detected spectrophotometrically in the decarboxylation of a,a-dimethyloxaloacetic acid,341 oxaloacetic acid352 and fluorooxaloacetic acid.342... 

The intimate details of the decarboxylation mechanism of the free acid are not completely clear. Westheimer and Jones studied the effect of changing solvent polarity on the rate of decarboxylation of a,a-dimethylacetoacetic acid (Table 44). 

THE EFFECT OF CHANGING SOLVENT POLARITY ON THE RATE OF DECARBOXYLATION OF a,a-DIMETHYLACETOACETIC ACID AT 25... 

It was shown that an enol intermediate was initially formed in the decarboxylation of l -ketoacids and presumably in the decarboxylation of malonic acids. It was found that the rate of decarboxylation of a,a-dimethylacetoacetic acid equalled the rate of disappearance of added bromine or iodine. Yet the reaction was zero order in the halogen . Qualitative rate studies in bicyclic systems support the need for orbital overlap in the transition state between the developing p-orbital on the carbon atom bearing the carboxyl group and the p-orbital on the i -carbonyl carbon atom . It was also demonstrated that the keto, not the enol form, of p ketoacids is responsible for decarboxylation of the free acids from the observa-tion that the rate of decarboxylation of a,a-dimethylacetoacetic acid k cid = 12.1 xlO sec ) is greater than that of acetoacetic acid (fcacw = 2.68x10 sec ) in water at 18 °C. Enolization is not possible for the former acid, but is permissible for the latter. Presumably this conclusion can be extended to malonic acids. 

ProMem 26.13 When dimethylacetoacetic acid is decarboxyiated in the presence of iodine or bromine, there is obtained an iododimethylacetone or a bromodimethyl-acetone (3-halo-3 methyl-2-butanone), although under these conditions neither iodine nor bromine reacts significantly with the dimethylacetone. What bearing docs this experiment have on the mechanism of decarboxylation ... 

Thence it can be concluded that such decarboxylations can occur in either of two ways neither of these two routes involves the enol form of the acid or its salt since dimethylacetoacetic acid behaves in the same way. The two terms in the rate equation thus correspond simply to the monomolecular decomposition of the oxo acid or its anion, respectively. Here too decomposition of the oxo acid27 must be assumed to proceed by way of a cyclic intermediate containing an intramolecular hydrogen bridge, as formulated in the introduction (page 1004) for a type 2 reaction. 

It should also be noted that decarboxylation of / -oxo acids is subject to specific catalysis by primary amines as well as to general catalysis. For example, the very smooth decarboxylation of 2,2-dimethylacetoacetic acid in water is uninfluenced by addition of a secondary or tertiary amine but its rate is increased by a factor of 10 on addition of aniline. The explanation lies in the fact that primary amines can react to form / -imino acids, whose imino-nitro-gen atom, being considerably more strongly basic than the ketonic oxygen atom, causes almost complete transfer of the proton from the carboxyl group, and it is this transfer that initiates the decomposition. A further example is the violent decomposition to acetone and carbon dioxide that occurs when a small amount of aniline is added to acetonedicarboxylic acid. 

The thermal decarboxylation of jS-keto acids resembles that of substituted malonic acids. The structure of 2,2-dimethylacetoacetic acid and the equation representing its decarboxylation were given in the text. The overall process involves the bonding changes shown. 

Explain why decarboxylation of a,a-dimethylacetoacetic acid, CH3COC(CH3)2CO2H, in the presence of bromine gives a-bromoisopropyl methyl ketone, CH3COC(CH3)2Br. 

Now, decarboxylation of a,a-dimethylacetoacetic acid by the same method (that is, concerted and cyclic) would lead to the enol form of isopropyl methyl ketone as shown ... 

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