The Role of Conformational Preorganization in the Reactivity of cis-1,2-Dimesylate-bis(benzyloxy)cyclooctane: An Activation Strain Perspective

A computational study was performed to elucidate the factors governing the reactivity of a cis-substituted cyclooctane dimesylate toward sodium azide. The calculated energy profile reveals a clear kinetic preference for formation of the monosubstituted intermediate, while the second SN2 substitution is associated with a significantly higher activation barrier. Activation Strain Model (ASM) analysis indicates that this increase arises primarily from a larger distortion energy and less favorable interaction energy. Consistent with these findings, Non–Covalent Interaction (NCI) analysis reveals diminished stabilizing interactions and enhanced steric repulsion in the higher-energy transition state. Further analysis of the cyclooctane conformations demonstrates that the two pathways differ in their torsional distortion patterns. The lower-energy transition state proceeds through a more preorganized geometry, whereas the higher-energy pathway requires additional conformational reorganization to achieve the reactive arrangement of the leaving group. Together, these results establish conformational preorganization as a key factor governing reactivity in this flexible ring system.