NH₃-Assisted Ammonolysis of β-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.

Importance of a Synperiplanar Stepwise Mechanism through Neutral Intermediates in the Aminolysis of Monocyclic β-Lactams: A Theoretical Analysis

“…The exploration of the PES for the reaction between 2-azetidinone and the methylamine dimer rendered three possible pathways for this process starting with prereactive complexes (see Scheme ). The concerted and the anti stepwise processes are readily comparable to those previously described for the NH 3 -assisted ammonolysis reaction . In addition, as mentioned in the Introduction, a new stepwise mechanism is now examined in this work.…”

“…For these thermal reactions, the most favored mechanism is a stepwise route involving a syn tetrahedral intermediate for both the ammonolysis and aminolysis processes. We have also investigated the ring opening of 2-azetidinone via a neutral NH 3 -assisted ammonolysis process, rendering again a concerted pathway and a stepwise one through a neutral tetrahedral intermediate . According to these calculations, the most favored mechanism is the stepwise one whose rate-determining step implies the cleavage of the intermediate with a simultaneous NH 3 -assisted H-transfer from a hydroxyl group to the forming amino group, with both groups having an antiperiplanar orientation.…”

“…As a further step in the investigation of the aminolysis of β-lactams, we report in this work a quantum chemical study of the methylamine-catalyzed reaction between methylamine and 2-azetidinone, which is the structural unit common to all the β-lactamic antibiotics. An additional stepwise mechanism is presented that is more favorable than the previously reported one . To gain some theoretical insight into the kinetic influence produced by substitution on amines, the effect of the methyl groups on the catalyst and the nucleophile will be thoroughly analyzed.…”

A Combined Theoretical and Experimental Research Project into the Aminolysis of β‐Lactam Antibiotics: The Importance of Bifunctional Catalysis

“…[9] Computation: Molecular geometry optimisations followed by analytical frequency calculations were performed at the B3LYP/6-31ϩG* level of theory [25,26] by use of the Gaussian 98 suite of programs. [27] In previous work on the aminolysis of 2-azetidinone, [15,17] it had been discovered that the B3LYP density function combined with double-ζ basis sets provides relative electronic energies (∆E elec ) quite close (Ϯ1, 2 kcal·mol Ϫ1 ) to those predicted by the G2(MP2,SVP) composite approach, [28] which takes account of the effect of larger basis sets and more refined N-electron treatments.…”

“…In fact, theoretical optimization of T ؎ structures in solution found them to be very unstable intermediate species with very short mean lifetimes before fragmentation into reactants even in strongly polar media. [17,18] Similarly, in a recent computer simulation of the model reaction NH 3 ϩ HCOOH Ǟ HCONH 2 ϩ H 2 O in aqueous solution, [19] it was discovered that although T ؎ -like structures are formed at the beginning of the ammonolysis path, their lifetimes vary from 1 picosecond to only a few femtoseconds. In this scenario, the transition states sketched in Scheme 2 should be considered the most important critical structures, their geometries and energetics determining the mechanism of the aminolysis reaction of penicillins regardless of the actual lifetimes of the previous T ؎ -like structures in solution.…”