Strain-Dependent Acceleration of a Paradigmatic SN2 Reaction Accurately Predicted by the Force Formalism

Abstract

Experiment and theory suggest that the effect of strain on the kinetics of SN2 reactions is predicted accurately within the force formalism using a single structural parameter, the difference of the nonbonding separation of two atoms bound to the electrophilic atom in the ground and transition states of the corresponding strain-free reaction. We show that the difference of the H3C···OMs distance in EtOMs (Ms: SO2Me) and that in the corresponding transition state of its hydrolysis, H2O···(Me)CH2···OMs, calculated at the B3LYP/6-311++G(3df,2pd) level with the SMD solvent model accurately predicts the measured lowering of the free energy of activation across a series of increasingly strained macrocyclic sulfonates. The equivalent distance H2C···S in EtSSEt also accurately predicts the previously reported kinetics of thiol/disulfide exchange in strained disulfides. The elongation of the scissile C−O or S−S bond yields qualitatively incorrect predictions. The results are consistent with the established structu...