Modelling Complex Bimolecular Reactions in a Condensed Phase: The Case of Phosphodiester Hydrolysis

(1) Background: the theoretical modelling of reactions occurring in liquid phase is a research line of primary importance both in theoretical–computational chemistry and in the context of organic and biological chemistry. Here we present the modelling of the kinetics of the hydroxide-promoted hydrolysis of phosphoric diesters. (2) Method: the theoretical–computational procedure involves a hybrid quantum/classical approach based on the perturbed matrix method (PMM) in conjunction with molecular mechanics. (3) Results: the presented study reproduces the experimental data both in the rate constants and in the mechanistic aspects (C–O bond vs. O–P bond reactivity). The study suggests that the basic hydrolysis of phosphodiesters occurs through a concerted ANDN mechanism, with no formation of penta-coordinated species as reaction intermediates. (4) Conclusions: the presented approach, despite the approximations, is potentially applicable to a large number of bimolecular transformations in solution and therefore leads the way to a fast and general method to predict the rate constants and reactivities/selectivities in complex environments.