Theoretical Study of Ammonolysis of Monobactams: Kinetic Role of theN-Sulfonate Group

Abstract

The ammonolysis reaction of 3-(formylamino)-4-methyl-2-oxoazetidine-1-sulfonate is investigated by quantum-chemical methods (B3LYP/6-31+G*) as a model system of the aminolysis reaction of monobactam antibiotics involved in the allergic reaction to these drugs. The influence of the N-sulfonate group on the β-lactam ring, reaction intermediates, and transition states is characterized in terms of the geometries and relative energies of the corresponding critical structures located on the B3LYP/6-31+G* potential-energy surface. It is shown that the N-sulfonate group, which has only a moderate impact on the structure and charge distribution of the β-lactam ring, reduces the rate-determining ΔG barrier by ca. 20 kcal/mol with respect to a purely uncatalyzed ammonolysis of the unsubstituted system, azetidin-2-one. This intramolecular catalytic effect occurs through a −NH−SO↔[−N−SO3H]− isomerization process, which is involved in the proton relay from the attacking ammonia molecule to the β-lactam N-atom. Our theoretical results predict that, in aqueous solution, monobactams will show an intrinsic reactivity against amine nucleophiles more important than that of penicillins.