Electronic factors influencing the decarboxylation of beta-keto acids. A model enzyme study

A theoretical study of the mechanism of decarboxylation of P-keto acids is described. A cyclic transition structure was, found with essentially complete proton transfer from the carboxylic acid to the beta-carbonyl group, The activation barrier for decarboxylation of formylacetic acid is predicted to be 28.6 kcal/mol (MP4SDTQ/6-31G*//MP2/6-31G*) while loss of CO2 from its anion exhibits a barrier of only 20.6 kcal/mol (MP4SDTQ/6-31+G*//MP2/6-31+G*). Barrier heights of decarboxylation of malonic acid and alpha,alpha-dimethylacetoacetic acid are predicted to be 33.2 and 26.7 kcal/mol, respectively. Model enzyme studies using a thio methyl ester of malonate anion suggests that the Pole of malonyl-CoA is to afford a polarizable sulfur atom to stabilize the developing enolate anion in the transition structure for decarboxylation. Adjacent positively charged ammonium ions;are also observed to stabilize the loss of CO2 from a carboxylate anion by through-bond Coulombic stabilization of the transition structure.