The hydrolysis of azetidinyl amidinium salts. Part 1. The unimportance of strain release in the four-membered ring

Abstract

The alkaline hydrolysis of azetidin-2-ylideneammonium salts gives a mixture of β-lactams, by exocyclic C–N bond fission, and β-amino amides, by opening the four-membered ring. Despite the anticipated release of strain energy in opening the four-membered ring the β-lactam is usually the major product i.e. exocyclic C–N fission is favoured over endocyclic C–N fission. This occurs even when the basicities of the endo- and exo-cyclic nitrogens are similar. The apparent reluctance of the four-membered ring to open is also not the result of entropic or stereoelectronic factors. The kinetics of the reaction indicate the presence of a neutral tetrahedral intermediate because there are two changes in the rate dependence upon hydroxide ion with increasing base concentration. There is also a term in the rate law for the carbonate-catalysed reaction which is both first order in carbonate ion and first order in hydroxide ion. The neutral tetrahedral intermediate must be formed reversibly and undergo deprotonation of its hydroxy group at high pH. By assuming that this deprotonation by hydroxide ion is rate limiting and diffusion controlled, the equilibrium constants for the formation of the neutral tetrahedral intermediate can be calculated. These are reported together with the calculated microscopic rate constants for the formation and breakdown of the intermediate.