Electrostatic Effects on the Stability of 2,4,6-Trifluoromethylidenecyclohexanes, Cyclohexanones, and Cyclohexanethiones: Beyond Nonconventional Hydrogen Bonding

Six-membered rings provide valuable frameworks for investigating intramolecular interactions, as their axial and equatorial bonds create distinct chemical environments governed by steric, electrostatic, and hyperconjugative effects. Fluorine is an especially suitable probe for such studies because the C─F bond is among the most polar in organic chemistry. In this context, 2,4,6-trifluoromethylidenecyclohexanes (1), cyclohexanones (2), and cyclohexanethiones (3) were investigated by quantum chemical calculations at the B3LYP/def2-TZVP level to evaluate the role of unconventional C─F···H─C hydrogen bonding and electrostatic effects on stereoisomer stability. For compounds 1 and 3, the eae stereoisomer is favored not only by unconventional hydrogen bonding but also by stabilizing electrostatic gauche interactions. Interestingly, the C─F···H─C interaction is weaker than in the monofluorinated counterparts because fluorination decreases the acidity of the α-hydrogens while simultaneously rendering the α-carbon atoms positively charged, thereby enhancing favorable F···C electrostatic interactions. Although this electrostatic effect is also present in compound 2, the eae stereoisomer is primarily stabilized by σ_C─H → π*_C═O hyperconjugation, since the equatorial α-fluorine atoms at C2 and C6 experience dipolar repulsion with the C═O bond, diminishing the electrostatic stabilization. These electrostatic interactions persist in a high-dielectric medium (water), where increased solvent polarity further stabilizes the more polar stereoisomers.