Nucleophilic substitution reactions of cyclic thiosulfinates are accelerated by hyperconjugative interactions

Cyclic thiosulfinates are a class of biocompatible molecules, currently expanding our in vivo toolkit. Agar and co-workers have shown that they are capable of efficient cross-linking reactions. While strain energy has been shown to promote the nucleophilic substitution reactions of cyclic disulfides, the reactivities of cyclic thiosulfinate nucleophilic substitution is unexplored. We used density functional theory calculations [M06-2X/6-311++G(d,p)] to determine the activation and reaction free energies for the reactions of 3-10-membered cyclic thiosulfinates and cyclic disulfides with methyl thiolate. The nucleophilic substitution reaction of cyclic thiosulfinates was found to be strain-promoted, similar to the strain-promoted nucleophilic substitution reactions of cyclic disulfides. The origin of the nearly 100-fold rate enhancement of cyclic thiosulfinates over cyclic disulfides was understood using the distortion/interaction model and natural bond order analysis. The cyclic thiosulfinates benefit from a hyperconjugative interaction between an oxygen lone pair and the orbital . This interaction generally lengthens the reactant S-1-S-2 bond, which pre-distorts cyclic thiosulfinates to resemble their corresponding transition structures. The inductive effect of the oxygen in cyclic thiosulfinates lowers the orbital energies relative to cyclic disulfides and results in more stabiliizing transition state frontier molecular orbital interactions with methyl thiolate.