Understanding thio-effects in simple phosphoryl systems: role of solvent effects and nucleophile charge.

Alexandra T P Carvalho,David R W Hodgson,Shina C L Kamerlin,Annmarie C O'Donoghue

doi:10.1039/c5ob00309a

Abstract

Recent experimental work (J. Org. Chem., 2012, 77, 5829) demonstrated pronounced differences in measured thio-effects for the hydrolysis of (thio)phosphodichloridates by water and hydroxide nucleophiles. In the present work, we have performed detailed quantum chemical calculations of these reactions, with the aim of rationalizing the molecular bases for this discrimination. The calculations highlight the interplay between nucleophile charge and transition state solvation in SN2(P) mechanisms as the basis of these differences, rather than a change in mechanism.

Highlights

The hydrolyses of these compounds are mechanistically complex, as they can proceed through multiple pathways ranging from fully dissociative (DN + AN), concerted (ANDN) to fully associative processes (AN + DN), depending on whether the reactions are driven by bond formation to the nucleophile or bond cleavage from the leaving group
The monochloridate products 3 and 4 are not observed in the hydrolyses of 1 and 2, it can be assumed that the subsequent reaction of these species to inorganicphosphate is fast, and the first, rate-limiting hydrolysis step is the only necessary focus of the present work
We followed the intrinsic reaction coordinate (IRC)[20] from this transition state in both reactant and product directions, and performed unconstrained geometry optimizations on the endpoints of the IRC calculations to obtain the relevant reactant and product complexes

Summary

Introduction

Phosphoryl transfer reactions are crucial to biology, being involved in a range of processes from ATP synthesis to maintaining the integrity of our genetic material.[1,2] The hydrolyses of these compounds are mechanistically complex, as they can proceed through multiple pathways ranging from fully dissociative (DN + AN), concerted (ANDN) to fully associative processes (AN + DN), depending on whether the reactions are driven by bond formation to the nucleophile or bond cleavage from the leaving group. 1 and references cited therein), in which one of the oxygen atoms of a phosphate ester is substituted for a sulfur atom. This single atom perturbation can have quite a dramatic effect on charge distribution and bondlengths around the phosphorus center, altering solvent interactions and the overall rate constant of reaction. In a recent study,[6] we explored the hydrolyses of dichloridates 1 and 2

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Conclusion