| Abstract
| - Various potential mechanisms for the alkaline hydrolysis of an oxo-β-lactam in the gas phase (Scheme )were examined in the light of ab initio data obtained at the RHF/6-31+G*//RHF/6-31+G* and MP2/6-31+G*//MP2/6-31+G* levels. The influence of the solvent was also examined from IPCM (isodensitypolarizable continuum model) computations at the RHF/6-31+G* level. In penicillins and cephalosporins,alkaline hydrolysis begins with a nucleophilic attack on the carbonyl group of the β-lactam ring, which isfollowed by cleavage of the C7−N4 bond. In the oxo-β-lactam studied, the process additionally involvescleavage of the C7−O6 bond in the ring. In fact, this cleavage is subject to a very small activation energy, aslittle as 0.21 kcal/mol versus the 14.15 kcal/mol for the typical cleavage energy (based on MP2/6-31+G*//MP2/6-31+G* calculations) for the C7−N4 bond. In addition, the hydrolysis end products are more stablethan those resulting from the typical cleavage. Consequently, the alkaline hydrolysis involving cleavage ofthe C7−O6 bonds is kinetically and thermodynamically more favorable than the classical hydrolysis mechanismfor penicillins and cephalosporins. This suggests that oxo-β-lactams might act as β-lactamase inhibitors.
|
