1,3-Diaxial steric effects and intramolecular hydrogen bonding in the conformational equilibria of new cis-1,3-disubstituted cyclohexanes using low temperature NMR spectra and theoretical calculations

Abstract

The conformational equilibria of 3-X-cyclohexanol [X = F ( 1), Cl ( 2), Br ( 3), I ( 4), Me ( 5), NMe 2 ( 6) and MeO ( 7)] and of 3-X-methoxycyclohexane [X = F ( 8), Cl ( 9), Br ( 10), I ( 11), Me ( 12), NMe 2 ( 13) and MeO ( 14)] cis isomers were determined from low temperature NMR spectra and PCMODEL calculated coupling constants. The energy differences between aa and ee conformers were obtained from these data ( Δ G J av and Δ G PC av , respectively) and also by the additivity principle from data for the monosubstituted cyclohexanes (Δ G Ad). H-1 and H-3 hydrogen vicinal coupling constants and Δ G J av values showed that the diequatorial conformer is predominant in the conformational equilibrium of the compounds studied at low temperature. However, Δ G PC av data show that compounds 6 and 7 constitute an exception, since they are almost equally populated by ee and aa at room temperature, due to stabilization of their aa conformer by an intramolecular hydrogen bond. Δ G Ad values, obtained according to the additivity principle, show a better agreement for compounds 2 and 3, since the 1,3-diaxial steric effect is counterbalanced by the formation of an intramolecular hydrogen bond (IAHB). For the remaining compounds, Δ G Ad values underestimate the energy differences, since the 1,3-diaxial steric effect, between X and OH or OCH 3, is absent in the monosubstituted compounds used as references. Moreover, the Δ G PC av , calculated from the coupling constants, obtained through the PCMODEL program, are rather smaller than the Δ G J av values, since the program does not have parameters for the effect, observed in this report, of a substituent at γ position on coupling constants values for the hydrogen under consideration.