Chemical reactivity of penicillins and cephalosporins. Intramolecular involvement of the acyl-amido side chain

Antonio Llinás, Bartolomé Vilanova, Juan Frau, Francisco Muñoz, Josefa Donoso, Michael I. Page

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)9052-9060
Number of pages9
JournalJournal of Organic Chemistry
Volume63
Issue number24
Early online date3 Nov 1998
DOIs
Publication statusPublished - 27 Nov 1998

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Chemical reactivity
Cephalosporins
Ampicillin
Penicillins
Lactams
Hydrolysis
Buffers
High performance liquid chromatography
Isomerization
Ionic strength
Extrapolation
Amides
Catalysis
Rate constants
Assays
Activation energy
Derivatives
Degradation
Acids

Cite this

Llinás, Antonio ; Vilanova, Bartolomé ; Frau, Juan ; Muñoz, Francisco ; Donoso, Josefa ; Page, Michael I. / Chemical reactivity of penicillins and cephalosporins. Intramolecular involvement of the acyl-amido side chain. In: Journal of Organic Chemistry. 1998 ; Vol. 63, No. 24. pp. 9052-9060.
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Chemical reactivity of penicillins and cephalosporins. Intramolecular involvement of the acyl-amido side chain. / Llinás, Antonio; Vilanova, Bartolomé; Frau, Juan; Muñoz, Francisco; Donoso, Josefa; Page, Michael I.

In: Journal of Organic Chemistry, Vol. 63, No. 24, 27.11.1998, p. 9052-9060.

Research output: Contribution to journalArticle

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