title: Kinetics and mechanism of hydrolysis of N-acyloxymethyl derivatives of azetidin-2-one.
abstract: The pH-independent, acid-catalyzed and base-catalyzed hydrolyses of N-acyloxymethylazetidin-2-ones all occur at the ester function. The pH-independent hydrolysis involves rate-limiting alkyl C-O fission and formation of an exocyclic beta-lactam iminum ion. This iminium ion is then trapped by water at the exocyclic iminium carbon atom, rather than at the beta-lactam carbonyl carbon atom, to form the corresponding N-hydroxymethylazetidin-2-ones. Calculations carried out at the B3LYP/6-31+G(d) level of theory also support that nucleophilic attack by water takes place at the exocyclic carbon rather than at the beta-lactam carbonyl carbon of the iminium ion. The mechanism for the acid-catalyzed pathway involves a preequilibrium protonation, probably at the beta-lactam nitrogen, followed by rate-limiting alkyl C-O fission with formation of an exocyclic iminum ion. The base-catalyzed hydrolysis involves rate-limiting hydroxide attack at the ester carbonyl carbon. These results imply formation of a beta-lactam system containing a positively charged amide nitrogen atom that hydrolyzes via a pathway that preserves the beta-lactam structure in the product and provide further evidence that cleavage of the beta-lactam C-N bond is not as facile as is commonly imagined.
authors.affiliation: CECF, Faculdade de Farmácia, Universidade de Lisboa, Av. Forças Armadas, 1600-083 Lisboa, Portugal.
authors.forename: Emília
authors.initials: E
authors.lastname: Valente
authors.forename: José R B
authors.initials: JR
authors.lastname: Gomes
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Jim
authors.initials: J
authors.lastname: Iley
mesh_terms: D000143:Acids / Q000737:chemistry; D001384:Azetidines / Q000737:chemistry*; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007097:Imines / Q000737:chemistry; D007700:Kinetics; D007769:Lactams / Q000737:chemistry; D015394:Molecular Structure
chemical_list: C116379:2-azetidinone; D000143:Acids; D001384:Azetidines; D004791:Enzyme Inhibitors; D007097:Imines; D007769:Lactams