Generation and stability of a simple thiol ester enolate in aqueous solution

Article abstract of DOI:10.1021/ja00052a028

The exchange for deuterium of the α-protons of ethyl thioacetate and of acetone in 3-quinuclidinone buffers in D₂O at 25 °C and pD = 7.7-9.3 was followed by ¹H NMR spectroscopy. The exchange reactions lead to the appearance of signals due to the α-CH₂D and α-CHD₂ species that are cleanly resolved from each other and from the signal due to the α-CH₃ species. Observed rate constants for the 3-quinuclidinone-catalyzed exchange were determined during exchange of 30-37% of the first α-proton of each methyl group of ethyl thioacetate or acetone. The rate constants for exchange correspond to those for deprotonation of ethyl thioacetate and acetone by 3-quinuclidinone to give the free enolates, with k_B = 2.2 × 10^-5 and 5.2 × 10^-4 M^-1 s^-1, respectively. These rate constants were combined with the known pK_a of acetone to estimate pK_a = 20.4-21.5 for ethyl thioacetate and k_BH = 1.7 × 10⁸ to 2 × 10⁹ M^-1 s^-1 for the reaction of the free thiol ester enolate with the 3-quinuclidinone cation. The lifetime of the buffer acid-enolate intimate ion pair BH⁺·^-CH₂COSEt with respect to proton transfer to give B-CH₃COSEt is estimated to be from 10^-9 to 10^-10 s. These results provide evidence against the suggestion that enzyme-catalyzed Claisen condensation and related reactions proceed by concerted mechanisms that are enforced by the insignificant lifetime of the thiol ester enolate in the presence of an acidic amino acid residue at the enzyme.