Study of the Alkaline Hydrolysis of the Azetidin‐2‐one Ring by ab initio Methods: Influence of the solvent

A comprehensive study of the alkaline hydrolysis of the b-lactam ring of azetidin-2-one was carried out using ab tnitio molecular-orbital calculations at the RHF/6-31 + G* level. The influence of the solvent on this reaction was investigated by using the reaction field method (SCRF); the solvent was found to suppress the interference of some gas-phase reactions and allow the presence of a transition state to be detected as the nucleophile approaches the b-lactam ring. The transition state corresponds to a structure where the OH- group lies at a distance of 1.927 8, from the C=O group of the p-lactam ring and exhibits a potential barrier of 13.6 kcal/mol. Introduction. - Since their discovery in the 1920s, p-lactam antibiotics have played a prominent role in the fight against bacterial diseases. The early theoretical studies of Boyd (l), who related various structural parameters of p-lactam antibiotics to their chemical reactivity and antibacterial action, have been followed by much research on their structure and reactivity. Such research has substantially expanded available knowledge on the mechanisms of action of p-lactam antibiotics, which in turn has facilitated the determination of new structures with a similar chemical reactivity besides resistance to bacterial defense mechanisms. Ab initio calculations were recently used to determine structural parameters for various p-lactams (2-71. On the other hand, the chemical reactivity (basically alkaline hydrolysis) of /3-lactam antibiotics has been studied preferentially by using semi-empiri- cal methods (8-121, with the exception of early investigations of Petrongolo et al. (13) It should be noted that most of such studies have been carried out in the gas phase and were thus subject to interferences from substitution and elimination reactions (9) (15) Neither ab initio study of the alkaline hydrolysis of p-lactams using quality basis sets nor analysis of the influence of the solvent on the process has been reported to date. This paper presents a comprehensive theoretical study of the alkaline hydrolysis of the azetidin-2-one ring. To elucidate the influence of the solvent, ab initio calculations were also performed by using the reaction-field method, which allows the solvent to be considered as a continuum with a given dielectric constant that surrounds the molecule. All calculations were based on a 6-31 + G* basis set including polarized and diffuse function on heavy atoms. ~41.

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