Theoretical calculations of β-lactam antibiotics. V. AM1 calculations of hydrolysis of cephalothin in gaseous phase and influence of the solvent |
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Authors: | J Frau J Donoso F Muoz F García Blanco |
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Institution: | J. Frau,J. Donoso,F. Muñoz,F. García Blanco |
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Abstract: | 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 β-lactam ring that still preserves the acetate group. Likewise, the exo methylene end product is chiefly formed by nucleophilic attack on the β-lactam 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 β-lactam yieds 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. © John Wiley & Sons, Inc. |
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