J. Frau et al., THEORETICAL CALCULATIONS OF BETA-LACTAM ANTIBIOTICS .5. AM1 CALCULATIONS OF HYDROLYSIS OF CEPHALOTHIN IN GASEOUS-PHASE AND INFLUENCE OF THESOLVENT, Journal of computational chemistry, 14(12), 1993, pp. 1545-1552
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.