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Theoretical calculations of β-lactam antibiotics. V. AM1 calculations of hydrolysis of cephalothin in gaseous phase and influence of the solvent

✍ Scribed by J. Frau; J. Donoso; F. Muñoz; F. García Blanco

Publisher
John Wiley and Sons
Year
1993
Tongue
English
Weight
697 KB
Volume
14
Category
Article
ISSN
0192-8651

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✦ Synopsis

A comprehensive study on the gas-phase alkaline hydrolysis of cephalosporins by using the semiempirical AM1 method was carried out. Cephalothin was the model compound used on account of the presence of a good leaving group at C(3'). According to the results obtained, the hydrolysis process takes place via a twostep reaction mechanism that involves the formation of an intermediate with a fully open plactam ring that still preserves the acetate group. Likewise, the exo methylene end product is chiefly formed by nucleophilic attack on the plactam carbonyl group of cephalosporins containing a good leaving group at C(3'). On the other hand, the alternative mechanism involving hydrolysis of the ester function in the side chain at 3' and subsequent hydrolysis of the resulting plactam yields essentially the corresponding enamine. The presence of a first solvation layer consisting of five water molecules showed that, even though some potential barriers are slightly increased, the mechanism involved is identical to that of the gas-phase hydrolysis of this antibiotic.

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Semiempirical AM1, MINDO/3, and MNDO methods have been used in the study of the alkaline hydrolysis of P-lactam antibiotics through a base-catalyzed, acyl-cleavage, bimolecular mechanism. In this work, the hydroxyl ion has been chosen as nucleophilic agent and the azetidin-2-one ring like a model of