NH(3)-Assisted Ammonolysis of beta-Lactams: A Theoretical Study.

Abstract

The ring opening of 2-azetidinone via a neutral NH(3)-assisted ammonolysis process is studied using different quantum chemical methods (MP2/6-31G, B3LYP/6-31G, and G2(MP2,SVP) levels of theory) as a first step toward the understanding of the aminolysis reaction of beta-lactam antibiotics. The exploration of the corresponding potential energy surfaces renders two different mechanistic routes for the ammonolysis process catalyzed by one ammonia molecule: a concerted pathway and a stepwise one through a tetrahedral intermediate. The gas-phase activation Gibbs energies (G2(MP2,SVP) electronic energies and B3LYP/6-31G thermal corrections) predict that the nonconcerted route is the more favored one, presenting a DeltaG for the ring opening of the tetrahedral intermediate of 51.9 kcal/mol with respect to the separate reactants. This gas-phase DeltaG value is 4.9 kcal/mol lower than that for the concerted process. When the MP2/6-31G SCRF electrostatic solvation Gibbs energy is taken into account, the resultant DeltaG value in solution for the stepwise rate-determining step is 55.8 kcal/mol (1.8 kcal/mol lower than the corresponding DeltaG value for the concerted route). The catalytic effect of the second ammonia molecule on the stepwise mechanism amounts 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 structural characteristics in accordance with the experimental interpretation of Brønsted plots for the aminolysis reaction of benzylpenicillin in which the catalytic moiety resembles an ammonium cation. Interestingly, a comparative analysis of our theoretical results for the ammonia-assisted ammonolysis of azetidinones and those previously reported for the water-assisted hydrolysis shows that the two reactions follow opposite trends regarding the energetic and structural nature of their rate-determining transition structures. The Gibbs energy profiles reported in this work may be useful as a preliminary study to understand the aminolysis reaction of beta-lactam antibiotics.