Llinas, Antonio, Vilanova, Bartolomé, Frau, Juan, Munoz, Francisco, Donoso, Josefa and Page, Michael I. (1998) Chemical Reactivity of Penicillins and Cephalosporins. Intramolecular Involvement of the Acyl-Amido Side Chain. The Journal of Organic Chemistry, 63 (24). pp. 9052-9060. ISSN 0022-3263
Abstract

The rate of degradation of 6-epi-ampicillin in acidic, neutral, and alkaline aqueous solutions was followed at 35 °C and an ionic strength of 0.5 mol dm-3 (KCl) by high-performance liquid chromatography (HPLC) and spectrophotometric assays. Pseudo-first-order rate constants were determined in a variety of buffer solutions, and the overall pH−rate profile was obtained by extrapolation to zero buffer concentration. The hydrolysis of 6-epi-ampicillin is subject to acid and hydroxide-ion catalysis and, for a penicillin, an unusual pH-independent reaction. Intramolecular general base-catalyzed hydrolysis by the side chain amido group is proposed to explain the enhanced rate of neutral hydrolysis of 6-epi-ampicillin and cephalosporins. The β-lactam of 6-epi-ampicillin also undergoes intramolecular aminolysis by nucleophilic attack of the 6-α side chain amino group to give a stable piperazine-2,5-dione derivative. The low effective molarity for intramolecular aminolysis of only 40 M is partly attributed to the unfavorable trans to cis isomerization about the 6-amide side chain required for ring closure. Theoretical calculations show that the intramolecular aminolysis of 6-epi-ampicillin nucleophilic attack occurs from the α-face of the β-lactam ring with an activation energy of 14.4 kcal/mol.

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