Neutral and Alkaline Hydrolyses of Model β-Lactam Antibiotics. An ab Initio Study of Water Catalysis

Abstract

The effect of an ancillary water molecule on the neutral and alkaline hydrolysis mechanisms of a simple β-lactam molecule (N-methylazetidinone) has been studied at the Hartree−Fock and MP2 levels using the 6-31G* and 6-31+G* basis sets. The results have been compared with a nonassisted study carried out previously. Solvent effects have been also considered by means of a polarizable continuum model. In the neutral hydrolysis, the additional water molecule diminishes the free-energy barriers only when correlation energy is taken into account. Concerted and stepwise mechanisms have been described. The corresponding barriers are close, and the actual mechanism could be conditioned by the molecular environment, solution, protein, etc. Using the results of a molecular dynamics simulation of N-methylazetidinone in aqueous solution, it has been shown that the stepwise process is more likely to occur in such conditions. In the alkaline hydrolysis, the first reaction step consists of the formation of a tetrahedral ...