The Role of Conformational Preorganization in the Reactivity of <i>cis</i> ‐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 S N 2 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.