THEORETICAL CALCULATIONS OF BETA-LACTAM ANTIBIOTICS .5. AM1 CALCULATIONS OF HYDROLYSIS OF CEPHALOTHIN IN GASEOUS-PHASE AND INFLUENCE OF THESOLVENT

A comprehensive study on the gas-phase alkaline hydrolysis of cephalos porins by using the semiempirical AM1 method was carried out. Cephalot hin was the model compound used on account of the presence of a good l eaving group at C(3'). According to the results obtained, the hydrolys is process takes place via a two-step reaction mechanism that involves the formation of an intermediate with a fully open beta-lactam ring t hat still preserves the acetate group. Likewise, the exo methylene end product is chiefly formed by nucleophilic attack on the beta-lactam c arbonyl 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 hydrolysi s of the resulting beta-lactam yields essentially the corresponding en amine. The presence of a first solvation layer consisting of five wate r molecules showed that, even though some potential barriers are sligh tly increased, the mechanism involved is identical to that of the gas- phase hydrolysis of this antibiotic. (C) 1993 by John Wiley & Sons, In c.