Stereoelectronic Control of Conformation and Reactivity in Substituted Disulfides

Disulfide bonds play central roles in chemical, biological, and materials sciences, yet the substituent effects governing their conformational preferences and reactivity remain incompletely understood. Here, a systematic computational investigation of HSSR disulfides (R = F, Cl, Br, CF 3 , Me, t Bu) was performed using DFT and NBO analyses to dissect the stereoelectronic, electrostatic, and steric contributions that shape the S–S torsional landscape. Across the series, the preferred orthogonal geometry consistently arises from dominant n S → σ* SX hyperconjugation, while steric and electrostatic effects modulate (but do not control) the rotational barriers. The nature of the substituent strongly alters the LUMO character, switching between σ* SX (halogens) and σ* SS (alkyl groups), which might strongly impact how these disulfides react with nucleophiles. Frontier molecular orbital energies and S–S bond dissociation thermodynamics further reveal enhanced electrophilicity and radical formation in halogenated disulfides, especially HSSBr. These insights provide a unified stereoelectronic framework for predicting the structure and reactivity of disulfides in synthesis and materials design. • n S → σ* SX hyperconjugation dominates the conformational preferences of substituted disulfides. • Substituents switch LUMO character between σ SX and σ SS , highlighting possible distinct reactivities. • Halogenated disulfides show enhanced reactivity, with HSSBr displaying the lowest S–S bond BDE.