Theoretical calculations of β‐lactam antibiotics. III. AM1, MNDO, and MINDO/3 calculations of hydrolysis of β‐lactam compound (azetidin‐2‐one ring)

Abstract

Semiempirical AM1, MINDO/3, and MNDO methods have been used in the study of the alkaline hydrolysis of P-lactam antibiotics through a base-catalyzed, acyl-cleavage, bimolecular mechanism. In this work, the hydroxyl ion has been chosen as nucleophilic agent and the azetidin-2-one ring like a model of 0-lactam antibiotic. The MIND0/3 method does not predict correctly the energies of small rings. This, together with the fact that, like MNDO, it cannot detect the occurrence of hydrogen bonds, gives rise to uncertain estimates of energy barriers. The AM1 method can be considered the most suitable for studying the hydrolysis of P-lactam compounds.

Alkaline and acidic hydrolysis of the β‐lactam ring

“…The energy barrier regarding this process is only 0.82 kcal mol −1 (practically negligible), probably due to the solvent absence. This behavior is likewise similar to that described in the studies on alkaline hydrolysis in the absence of solvent [10,11].…”

“…Previously elucidated semiempirical structures [10,30] were used as the starting points for the ab initio calculations in both reactions, which were done on the 6-31+G * and 6-31G * * basis sets. In the alkaline hydrolysis, a polarized and a diffuse basis for heavy atoms were included in order to ensure reliable results for small charge-localized anions [31].…”

“…Ab initio calculations were recently used to determine structural parameters for various β-lactam compounds [4][5][6][7][8]. On the other hand, the chemical reactivity (basically alkaline hydrolysis) of β-lactam antibiotics has been studied by using semi-empirical methods preferentially [9][10][11][12][13], with the exception of the early investigations of Petrongolo and coworkers [14,15] and more recent studies with a high-quality basis set [16].…”

The Mechanism of Formamide Hydrolysis in Water from Ab Initio Calculations and Simulations

“…A number of theoretical studies have been devoted to the acid- [11][12][13][14][15] or base-catalyzed [11,[15][16][17][18][19][20][21][22][23] hydrolysis of amides as well as to the enzyme-catalyzed hydrolysis of peptides. [24][25][26][27][28][29][30][31][32][33][34] The catalysis of b-lactam-ring hydrolysis has also been studied, [35,36] in particular by Donoso and co-workers (see refs. [34,[37][38][39] and references cited therein) because of its relevance to the understanding of bacteria resistance to antibiotics.…”

“…[24][25][26][27][28][29][30][31][32][33][34] The catalysis of b-lactam-ring hydrolysis has also been studied, [35,36] in particular by Donoso and co-workers (see refs. [34,[37][38][39] and references cited therein) because of its relevance to the understanding of bacteria resistance to antibiotics. Nevertheless, some authors have studied the neutral hydrolysis reaction by assuming that gas-phase processes operate.…”