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

Experiment and theory suggest that the effect of strain on the kinetics of S N 2 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 H 3 C···O Ms distance in EtOMs (Ms: SO 2 Me) and that in the corresponding transition state of its hydrolysis, H 2 O···(Me)CH 2 ···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 H 2 C···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 structural origin of the S N 2 activation barrier and enable predictions of the kinetics of S N 2 reactions in stretched polymers. Such an ability is critical to the development of a conceptual framework for controlling chemically driven multiscale dynamics through molecular design and of polymers with stress-responsive properties engineered at the monomer level.