Exploring Secondary Electrostatic Interactions Using Molecular Rotors: Implications for S _N 2 Reactions

Benzylic and allylic electrophiles are well known to react faster in S_N2 reactions than aliphatic electrophiles, but the origins of this enhanced reactivity are still being debated. Galabov, Wu, and Allen recently proposed that electrostatic interactions in the transition state between the nucleophile (Nu) and the sp² carbon (C2) adjacent to the electrophilic carbon (C1) play a key role. To test this secondary electrostatic hypothesis, molecular rotors were designed that form similar through-space electrostatic interactions with C2 in their bond rotation transition states without forming bonds to C1. This largely eliminates the alternative explanation of stabilizing conjugation effects between C1 and C2 in the transition state. The rotor barriers were strongly correlated with the experimentally measured S_N2 free energy. Notably, rotors where C2 was sp² or sp-hybridized had barriers that were consistently 0.5-2.0 kcal mol^-1 lower than those for rotors where C2 was sp³-hybridized. Computational studies of atomic charges were consistent with the formation of stabilizing secondary electrostatic interactions. Further confirmation came from observing the benzylic effect in rotors where the first atom was varied, including oxygen, sulfur, nitrogen, and sp²-carbon. In summary, these studies provided strong experimental support for the role of secondary electrostatic interactions in the S_N2 reaction.