Factors Governing the Enhanced Reactivity of Five-Membered Cyclic Phosphate Esters

Abstract

Ab initio calculations and continuum dielectric methods have been employed to map out the lowest activation free-energy profiles for the alkaline hydrolysis of a five-membered cyclic phosphate, methyl ethylene phosphate (MEP), its acyclic analog, trimethyl phosphate (TMP), and its six-membered ring counterpart, methyl propylene phosphate (MPP). The rate-limiting step for the three reactions was found to be hydroxyl ion attack at the phosphorus atom of the triester. By performing constrained optimization along the reaction coordinate, defined as the phosphorus to incoming hydroxyl oxygen distance, and computing the solvation free energies of the resulting stationary points, the rate-limiting transition states have been relocated in solution. Dihedral ring constraints in the five-membered ring leading to a more solvent-exposed hydroxyl group and, thus, better solvation of the cyclic transition state compared to its acyclic counter-part was found to be the dominant factor governing the rate enhancement of cyclic MEP relative to acyclic TMP alkaline hydrolysis. However, both ground-state destabilization of MEP relative to MPP, due to ring strain, and transition-state stabilization of the five-membered cyclic phosphate transition state relative to its six-membered ring analog, due to the differential location of the transition states in solution, were found to contribute to the enhanced rates of alkaline hydrolysis of five-membered ring MEP compared to six-membered ring MPP.