NEUTRAL AND ALKALINE HYDROLYZES OF MODEL BETA-LACTAM ANTIBIOTICS - A AB-INITIO STUDY OF WATER CATALYSIS

The effect of an ancillary water molecule on the neutral and alkaline hydrolysis mechanisms of a simple beta-lactam molecule (N-methylazetid inone) 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 no nassisted study carried out previously. Solvent effects have been also considered bq means of a polarizable continuum model. In the neutral hydrolysis, the additional water molecule diminishes the free-energy b arriers only when correlation energy is taken into account, Concerted and stepwise mechanisms have been described. The corresponding barrier s are close, and the actual mechanism could be conditioned by the mole cular environment, solution, protein, etc. Using the results of a mole cular 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 intermediate which requires a desolvation of the hydroxyl anion difficult to reproduce by calcula tion, Afterward, the hydrolysis reaction proceeds through either conce rted or stepwise mechanisms for ring opening and proton transfer. The concerted channel presents a very low energy barrier, and the species involved are dependent on the calculation level. The stepwise mechanis m is virtually the same as that previously reported for the nonassiste d hydrolysis, the relative energy of all the points along the path bei ng diminished and the energy barriers remaining essentially unaltered.