Strong hyperconjugative interactions limit solvent and substituent influence on conformational equilibrium: the case of -2-halocyclohexylamines.

The presence of strong stereoelectronic interactions involving the substituents in -2-substituted cyclohexanes may lead to results different from those expected. In this work, we studied the conformational behavior of -2-fluoro- (), -2-chloro- (), -2-bromo- () and -2-iodocyclohexylamine () by dynamic NMR and theoretical calculations. The experimental data pointed to an equilibrium strongly shifted toward the conformer (equatorial amine group and axial halogen), with populations greater than 90% for , and in both dichloromethane- and methanol- . Theoretical calculations (M06-2X/6-311++G(2df,2p)) were in agreement with the experimental, with no influence of the solvent or the halogen on the equilibrium. A principal component analysis of natural bond orbital energies pointed to the σ* and σ orbitals and the halogen lone pairs (LP) as the most significant for the hyperconjugative interactions that influenced the equilibrium. The σ → σ* hyperconjugation and the interactions involving the LP counterbalance each other, explaining the non-influence of the halogen on the conformational equilibrium. These interactions are responsible for the strong preference for the conformer in -2-halocyclohexylamines, being strong enough to restrain the shift in the equilibrium due to other factors such as steric repulsion or solvent effects.