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Kinetics and mechanism of hydrolysis of N-acyloxymethyl derivatives of azetidin-2-one

Valente, Emilia; Gomes, J. Richard. B.; Moreira, Rui and Iley, Jim (2004). Kinetics and mechanism of hydrolysis of N-acyloxymethyl derivatives of azetidin-2-one. Journal of Organic Chemistry, 69 pp. 3359–3367.

DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1021/jo0358123
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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 â-lactam iminum ion. This iminium ion is then trapped by water at the exocyclic iminium carbon atom, rather than at the â-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 â-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 basecatalyzed hydrolysis involves rate-limiting hydroxide attack at the ester carbonyl carbon. These results imply formation of a â-lactam system containing a positively charged amide nitrogen atom that hydrolyzes via a pathway that preserves the â-lactam structure in the product and provide further evidence that cleavage of the â-lactam C-N bond is not as facile as is commonly imagined.

Item Type: Journal Article
ISSN: 0022-3263
Keywords: beta lactam; acyloxymethyl; prodrug; iminium ion
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Item ID: 4003
Depositing User: James Iley
Date Deposited: 04 Jul 2006
Last Modified: 02 Dec 2010 19:50
URI: http://oro.open.ac.uk/id/eprint/4003
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