Density functional theory study of the thiolysis reaction in penicillins

The chemical behaviour of the penicillin nucleus towards nucleophilic attack by two thiols of disparate basicity such as 2-mercaptoethanol (1) and 2-mercaptoethylamine (2) was studied using density functional theory computations at the B3LYP/6-31+G∗ level. The crucial role of the intramolecular bond in the β-lactam nitrogen was examined. Based on the energy values obtained, the formation of the tetrahedral intermediate (T in Scheme 1) is the rate-determining step of the process. The energies of activation for the process suggest general acid catalysis in 2 as a result of the presence of an effective proton donor group in β in the starting thiolate. This reduces the energy of formation of the tetrahedral intermediate from 12.04 kcal/mol for 1 to 4.51 kcal/mol for 2 - which possesses a more acidic group. This disparate behaviour is consistent with the experimental rate constant for the degradation of benzyl-penicillin in the presence of 2 [k1(2) = 1.3 × 10−1 mol−1 dm3 s−1], which is roughly two orders of magnitude higher than for other thiols of similar basic strength.