Theoretical Study of the Alkaline Hydrolysis of a Bicyclic Aza-β-lactam

Abstract

Various mechanisms for the alkaline hydrolysis of an aza-β-lactam in the gas phase were studied by ab initio calculations at the RHF/6-31+G*//RHF/6-31+G*, MP2/6-31+G*//MP2/6-31+G*, and B3LYP/6-31+G*//B3LYP/6-31+G* levels. Solvent effects were considered via IPCM (isodensity polarizable continuum model) calculations at the IPCM/6-31+G*//RHF/6-31+G* level. The alkaline hydrolysis of β-lactams begins with a nucleophilic attack of the hydroxyl ion on the carbonyl of the β-lactam ring. The tetrahedral intermediate thus formed undergoes cleavage of the C7−N4 bond to give the reaction end products. In addition to the typical cleavage reaction, the β-lactam studied can undergo opening at the C7−N6 bond (Scheme 1). Both processes have a similar activation energy that varies slightly depending on the particular computation method used. The most stable end products are those formed via the typical mechanism. In any case, both mechanisms yield products possessing a carbamate group, which suggests that the starting aza-β-lactam might be an effective inhibitor for β-lactamases.