Phosphate ester hydrolysis: calculation of gas-phase reaction paths and solvation effects

Abstract

Quantum-mechanical and solvation-effect calculations of the hydrolysis mechanism of dimethyl and ethylene phosphate, which are model compounds for the hydrolysis of DNA and RNA, respectively, are reported and used to explain the fact that in solution, five-membered-ring cyclic phosphates hydrolyse 10⁶–10⁸ times faster than acyclic esters. Ab initio energy profiles for the base-catalysed hydrolysis (i.e. attack by OH^–) of dimethyl and ethylene phosphate are determined at the Hartree–Fock level and with MP2 correlation corrections. The reaction proceeds through the formation of a pentacovalent phosphorane transition state with attack by the hydroxide ion as the rate-determining step; stable phosphorane intermediates are not observed in the gas phase. A detailed analysis is made of the ring strain in the cyclic phosphate reactant, which had been proposed as the origin of the observed rate effect and the results for the reactants are compared with those for the transition state. Although there is strain in the ground state of the cyclic reactant, it does not contribute to the rate acceleration because of dihedral angle constraints present in the cyclic transition state. An estimate of solvation effects indicates that most of the rate acceleration observed in solution arises from differential solvation of the transition states.