Theoretical study of the alkaline hydrolysis of a bicyclic aza-beta-lactam

Various mechanisms for the alkaline hydrolysis of an aza-beta -lactam in th e 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 continuu m model) calculations at the IPCM/6-31+G*//RHF/6-31+G* level. The alkaline hydrolysis of beta -lactams begins with a nucleophilic attack of the hydrox yl ion on the carbonyl of the beta -lactam ring. The tetrahedral intermedia te thus formed undergoes cleavage of the C-7-N-4 bond to give the reaction end products. In addition to the typical cleavage reaction, the beta -lacta m studied can undergo opening at the C-7-N-6 bond (Scheme 1). Both processe s have a similar activation energy that varies slightly depending on the pa rticular computation method used. The most stable end products are those fo rmed via the typical mechanism. In any case, both mechanisms yield products possessing a carbamate group, which suggests that the starting aza-beta -l actam might be an effective inhibitor for beta -lactamases.