biostudies-literatureUnknown15Francisco CBThe presence of strong stereoelectronic interactions involving the substituents in <i>cis</i>-2-substituted cyclohexanes may lead to results different from those expected. In this work, we studied the conformational behavior of <i>cis</i>-2-fluoro- (<b>F</b>), <i>cis</i>-2-chloro- (<b>Cl</b>), <i>cis</i>-2-bromo- (<b>Br</b>) and <i>cis</i>-2-iodocyclohexylamine (<b>I</b>) by dynamic NMR and theoretical calculations. The experimental data pointed to an equilibrium strongly shifted toward the <b>ea</b> conformer (equatorial amine group and axial halogen), with populations greater than 90% for <b>F</b>, <b>Cl</b> and <b>Br</b> in both dichloromethane-<i>d</i> ₂ and methanol-<i>d</i> ₄. 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*_C-X and σ_C-H orbitals and the halogen lone pairs (LP_X) as the most significant for the hyperconjugative interactions that influenced the equilibrium. The σ_C-H → σ*_C-X hyperconjugation and the interactions involving the LP_X counterbalance each other, explaining the non-influence of the halogen on the conformational equilibrium. These interactions are responsible for the strong preference for the <b>ea</b> conformer in <i>cis</i>-2-halocyclohexylamines, being strong enough to restrain the shift in the equilibrium due to other factors such as steric repulsion or solvent effects.Beilstein journal of organic chemistry818-829https://www.ebi.ac.uk/biostudies/studies/S-EPMC6466766biostudies-literatureStrong hyperconjugative interactions limit solvent and substituent influence on conformational equilibrium: the case of <i>cis</i>-2-halocyclohexylamines.PMC6466766Basso EAFrancisco CBGauze GFFernandes CSde Melo UZRittner RfalseStrong hyperconjugative interactions limit solvent and substituent influence on conformational equilibrium: the case of <i>cis</i>-2-halocyclohexylamines.The presence of strong stereoelectronic interactions involving the substituents in <i>cis</i>-2-substituted cyclohexanes may lead to results different from those expected. In this work, we studied the conformational behavior of <i>cis</i>-2-fluoro- (<b>F</b>), <i>cis</i>-2-chloro- (<b>Cl</b>), <i>cis</i>-2-bromo- (<b>Br</b>) and <i>cis</i>-2-iodocyclohexylamine (<b>I</b>) by dynamic NMR and theoretical calculations. The experimental data pointed to an equilibrium strongly shifted toward the <b>ea</b> conformer (equatorial amine group and axial halogen), with populations greater than 90% for <b>F</b>, <b>Cl</b> and <b>Br</b> in both dichloromethane-<i>d</i> ₂ and methanol-<i>d</i> ₄. 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*_C-X and σ_C-H orbitals and the halogen lone pairs (LP_X) as the most significant for the hyperconjugative interactions that influenced the equilibrium. The σ_C-H → σ*_C-X hyperconjugation and the interactions involving the LP_X counterbalance each other, explaining the non-influence of the halogen on the conformational equilibrium. These interactions are responsible for the strong preference for the <b>ea</b> conformer in <i>cis</i>-2-halocyclohexylamines, being strong enough to restrain the shift in the equilibrium due to other factors such as steric repulsion or solvent effects.2019-01-01T00:00:00Z20192025-04-19T11:09:37.412Z2019-06-06T22:56:20ZS-EPMC64667663101957410.3762/bjoc.15.79