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 the corresponding strain-free reaction. We show that the difference of the H3C center dot center dot center dot O-Ms distance in EtOMs (Ms: SO2Me) and that in the corresponding transition state of its hydrolysis, H2O center dot center dot center dot(Me)CH2 center dot center dot center dot 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 center dot center dot center dot 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 SN2 reactions in stretched polymers. Such an ability is critical to the development of conceptual framework for controlling chemically driven multiscale dynamics through molecular deign and of polymers with stress-responsive, properties engineered at the monomer level.