Kinetic Approach to the Development in β-Lactam Antibiotics. I. Comparative Stability of Semisynthetic Penicillins and 6-Aminopenicillanic Acid in Aqueous Solution
1974 Volume 22 Issue 5 Pages 1186-1197
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1974 Volume 22 Issue 5 Pages 1186-1197
The kinetics of the hydrolyses of carbenicillin, sulbenicillin, propicillin, cyclacillin, 6-(α-toluenesulfonamido)-penicillanic acid (TSPA), the substituted phenylpenicillins and 6-aminopenicillanic acid (6-APA) were studied over wide pH ranges at 35° and μ=0.5. For the hydrolysis of penicillins, the psuedo first-order rate constants, kpH at zero buffer concentration were formulated as the equation : kpH=(kH [H3O+]+k0)ƒHP+(k'0+k'OH [OH-])ƒp-, where ƒHP and ƒp- are the fractions of free-acid penicillin (HP) and ionized penicillin (P-), respectively. These catalytic rate constants were compared with those reported previously for other penicillins. The activation parameters were also determined for some penicillins. In acidic solution, penicillins except TSPA were confirmed to be hydrolyzed to the penicillenic acids via hydronium ion-catalyzed rearrangement of HP the (kH) and spontaneous rearrangement of HP (k0). The Hammett plots for kH and k0 of the substituted phenylpenicillin series gave excellent linear correlations with both ρ=-1.60. The magnitude and sign of the ρ values were consistent with the intramolecular catalyzed mechanism by the neighboring side-chain amido groups. The hydrolysis of 6-APA was found to follow first-order kinetics at low initial concentration in the range of 0.005-0.01M. From the log kpH-pH profile and the pertinent primary salt effects, the possible mechanisms for the acidic hydrolysis of 6-APA were discussed. The activation parameters were evaluated at each reaction region. At pH 5, 6-APA was found to be hydrolyzed 3-6 times faster than relatively acid-stable penicillins, which may be attributed to the inductive effect by the protonated 6-amino group. The k'0 and k'OH values were nearly the same in the hydrolyses of all penicillins and 6-APA. It can be concluded that the basic and neutral hydrolyses of these compounds are, respectively, simple hydroxide catalyzed and water catalyzed reactions.
