Decarboxylation 3-ketocarboxylic acids

Other contributions to this discussion have been made by Harvey, Miller and Robson, and by Dewar and King, and important additional experimental evidence for the location of the. CHOH group at has been provided by Witkop, who explains the improvement in the yield of yohimbone, which occurs when the decarboxylation of yohimbic acid takes place under oxidising conditions, as due to the primary formation of a j8-ketocarboxylic acid, which is readily decarboxylated. This may be represented, using part of the yohimbine formula fXIV), as follows MeO. OC. CH. 1 CHOH. ->HO. OC. CH. CHOH. ... 

Thermal degradation prior to ionization can cause decarbonylation or decarboxylation of the analyte. Decarbonylation, for example, is observed from a-ketocarboxylic acids and a-ketocarboxylic acid esters, whereas decarboxylation is typical behavior of P-oxocarboxylic acids such as malonic acid and its derivatives and di-, tri-, or polycarboxylic acids. 

Gas-phase decarboxylation of /i-ketocarboxylic acids XCOCH2COOH (X = H, OH, and CH3) has also been the subject of theoretical studies.42 Ah initio calculations reveal that decarboxylation via a six-membered (rather than four-membered) ring transition state is favoured. Activation barriers of 23.8, 23.3 and 28.5 kcal mol-1 have been calculated for decarboxylation of 3-oxopropanoic acid, acetoacetic acid, and malonic acid, respectively. Only marginal effects of solvent on the energy barriers and on the geometries of the reactants and transition structures are predicted. The activation energy predicted for reaction of malonic acid agrees well with the experimental value and rate constants have been predicted for decarboxylation of 3-oxopropanoic acid and acetoacetic acid in the gas phase. 

The butylated /J-ketoester C of Figure 13.26 is not the final synthetic target of the acetoacetic ester synthesis of methyl ketones. In that context, the /J-ketoester C is converted into the corresponding /J-ketocarhoxylic acid via acid-catalyzed hydrolysis (Figure 13.27 for the mechanism, see Figure 6.22). This /i-ketocarboxylic acid is then heated either in the same pot or after isolation to effect decarboxylation. The /f-ketocarboxylic acid decarboxylates via a cyclic six-membered transition state in which three valence electron pairs are shifted at the same time. The reaction product is an enol, which isomerizes immediately to a ketone (to phenyl methyl ketone in the specific example shown). 

STRATEGY AND ANSWER H2Cr04 oxidizes a primary alcohol to a carboxylic acid, which is consistent with the formula provided for A. Because A is a j8-ketocarboxylic acid, it decarboxylates on heating to form B. 

The ready decarboxylation of P-ketocarboxylic acids is shown to occur in a similar manner (Scheme 6.19). 

Sol 1. (c) Geminal dicarboxylic acid (i.e., compounds in which the two carboxyl groups are on the same carbon atom) and p-ketocarboxylic acid obtained by the oxidation of diols II and IV, respectively, readily undergo decarboxylation on heating. 

Although outside the scope of this section, the concurrent development of the Pd-catalyzed allylation of /3-ketocarboxylic acids via the formation and decomposition of allyl /3-ketocarboxylates is noteworthy (Sects. V.2.1.1 and V.2.1.2). The mechanism shown in Scheme 4, which involves (i) oxidative addition of allyl /3-ketocarboxylates, (ii) decarboxylation, and (iii) intermolecular enolate allylation was proposed and experimentally supportedUnfortunately, a-allylation with y-disubstituted allyl derivatives, such as geranyl carboxylates, proceeds in low yields, and there are some indications that the reaction may lack some specificity features, for example, stereospecificity of the allylic moiety. 

Scheme 9.160. A Thorpe-Ziegler reaction of 2,6-dicyano-2-methylhexane. First, base treatment allows the dinitrile to undergo acyloin-type condensation (Scheme 9.145) to an imino-nitrile. Hydrolysis of the imine (Scheme 9.65) generates a P-ketonitrUe, which, on further hydrolysis (Scheme 9.46), produces a P-ketocarboxylic acid, which then undergoes decarboxylation (vide infra). Interestingly, the intermolecular version of this reaction is the Thorpe reaction, while the intramolecular version is the Thorpe-Ziegler reaction. See Baron, H. Remfry, F. G. P. Thorpe, J. F. /. Chem. Soc., 1904,85,1726, as well as Ziegler, K. Eberle, H. Ohlinger, H. Liebigs Ann. Chem., 1933,504, 94, and Ziegler, K. Chem. Ber., 1934,67,139.

The small molecules that assist in the catalytic processes enzymes promote and that are not themselves proteins are called coenzymes. Again, it will be recalled that these molecules are used to help consummate the reactions between substrates. So, for example, the coenzyme pyridoxal (vitamin Bg, Table 12.2) can (among other functions already discussed in Chapter 11) be utilized by a transaminase enzyme to help move a nitrogen from an amino acid (via initial reaction at an active-site lysine in the active site of the enzyme) to the a-carbonyl of an a-ketocarboxylic acid and vice versa (the process is called transamination). The pyridoxal (Table 12.2) has served as a catalytic nitrogen carrier. In some cases where pyridoxal (vitamin Bg) is used as a coenzyme, it is altered in the process. Thus, for example, in amino acid decarboxylation, pyridoxamine (HC=0 replaced by H2CNH2) can result and an additional step is required to reconvert it to pyridoxal. Indeed, such changes are common among coenzymes. 

Ketones from / -ketocarboxylic acids s. 28, 733 stereoselective decarboxylation, in refluxing dioxane cf. Y. Kishi et al., Tetrah. Let. 1971, 4657... 

Decarboxylation under mild conditions is a general property of both cyclic and acyclic (open chain) 3-ketocarboxylic acids (Scheme 3.2). The mechanism of decarboxylation involves a concerted process during which bond breaking and bond formation take place simultaneously without any intermediates being involved. Hence, activation energies are low and reaction takes place under mild conditions. This mechanism also proceeds through the formation of a stable six-membered transition state (Scheme 3.3). 

Decarboxylation of ketocarboxylic acids leads initially to the formation of an enol and CO2. The enol then tantomerizes to corresponding ketone. However, in cases where enol formation is nnfavonrable, the relevant ketocarboxylic acid will be resistant to decarboxylation. 

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