NH3-assisted ammonolysis of beta-lactams: A theoretical study

The ring opening of 2-azetidinone via a neutral NH3-assisted ammonolysis pr ocess is studied using different quantum chemical methods (MP2/6-31G**, B3L YP/6-31G**, and GB(MPS,SVP) levels of theory) as a first step toward the un derstanding of the aminolysis reaction of beta-lactam antibiotics. The expl oration of the corresponding potential energy surfaces renders two differen t mechanistic routes for the ammonolysis process catalyzed by one ammonia m olecule: a concerted pathway and a stepwise one through a tetrahedral inter mediate. The gas-phase activation Gibbs energies (G2-(MP2,SVP) electronic e nergies and B3LYP/6-31G** thermal corrections) predict that the nonconcerte d route is the more favored one, presenting a Delta G for the ring opening of the tetrahedral intermediate of 51.9 kcal/mol with respect to the separa te reactants. This gas-phase Delta G value is 4.9 kcal/mol lower than that for the concerted process. When the MP2/6-31G** SCRF electrostatic solvatio n Gibbs energy is taken into account, the resultant Delta G value in soluti on for the stepwise rate-determining step is 55.8 kcal/mol (1.8 kcal/mol lo wer than the corresponding Delta G value for the concerted route). The cata lytic effect of the second ammonia molecule on the stepwise mechanism amoun ts to 2.4 and 0.8 kcal/mol in terms of Gibbs energies in the gas phase and in solution, respectively. The rate-determining transition state has struct ural characteristics in accordance with the experimental interpretation of Bronsted plots for the aminolysis reaction of benzylpenicillin in which the catalytic moiety resembles an ammonium cation. Interestingly, a comparativ e analysis of our theoretical results for the ammonia-assisted ammonolysis of azetidinones and those previously reported for the water-assisted hydrol ysis shows that the two reactions follow opposite trends regarding the ener getic and structural nature of their rate-determining transition structures . The Gibbs energy profiles reported in this work may be useful as a prelim inary study to understand the aminolysis reaction of beta-lactam antibiotic s.