Effect of fluorination of cyclohexanes on electrostatic interactions and unconventional C–F···H–C hydrogen bonding

Fluorination strongly affects the stability and conformation of cyclohexanes through a balance of steric, electrostatic, and stereoelectronic effects. In this theoretical study, isodesmic reactions were investigated at the B3LYP/def2-TZVP level to evaluate the energetic impact of introducing fluorine atoms at axial and equatorial positions in cyclohexane, mono-, and difluorinated cyclohexanes. Monofluorination favors the equatorial conformer, consistent with steric expectations. However, further fluorination leads to nonintuitive stability trends governed by electrostatic interactions. Notably, the 1 a → 2 ae transformation is the most favorable pathway, driven by stabilizing intramolecular F···C and C–F···H–C contacts. Analysis of natural Coulomb electrostatic energies shows that these interactions can outweigh steric penalties and dictate conformational preferences. In trifluorinated systems, greater stabilization is achieved when a single axial fluorine interacts with multiple electropositive hydrogens. At higher fluorination levels, positive electrostatic contributions indicate that additional effects, such as hyperconjugation, also contribute to stability. These findings highlight the role of electrostatic interactions in fluorinated cyclohexanes and provide a basis for the rational design of organofluorine compounds.