| Abstract
| - The ring opening of 2-azetidinone via a neutral H2O-assisted aminolysis process is studied usingdifferent quantum chemical methods (MP2/6-31G**, B3LYP/6-31G**, and G2(MP2,SVP) levels of theory)as a further step to the theoretical investigation of the aminolysis reaction of β-lactam antibiotics (Díaz, N.;Suárez, D.; Sordo, T. L. Chem. Eur. J. 1999, 5, 1045−1054; Díaz, N.; Suárez, D.; Sordo, T. L. J. Org. Chem.1999, 64, 9144−9152). The calculated pathways are analogous to those previously described for the amine-assisted aminolysis reaction, a syn stepwise mechanism being the most favored one both in the gas phase andin solution with an energy barrier of around 39.7 kcal/mol (ΔGsolution). For this process the strong catalyticaction of one water molecule amounts to 23.0 (G2(MP2,SVP) electronic energy), 12.6 (ΔGgas-phase), and 9.1kcal/mol (ΔGsolution). The water-assisted reaction between methylamine and the 3α-carboxypenam anion wasalso studied at the B3LYP/6-31+G* level of theory to model the specific role of water in the aminolysis ofbicyclic β-lactam antibiotics. For this system the most favorable attack of CH3NH2 to the carbonylic group ina low polar media can occur through simultaneous H-transfer to the carboxylate group assisted by the ancillarywater molecule with a ΔGgasphase barrier of 31.0 kcal/mol with respect to separate reactants. A concerted routebecomes the most favored mechanism for the aminolysis of penicillins assisted by an ancillary water moleculein aqueous solution. The structure of the concerted transition state is in agreement with the experimentallyreported Brønsted β-values close to unity. Interestingly, according to the experimental structure of the Lys199active center of Human Serum Albumin, the mechanism for the aminolysis reaction of β-lactams in a proteinenvironment may be similar to the stepwise route found in the gas phase for 3α-carboxypenam.
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