Influence of OH⋯N and NH⋯O inter- and intramolecular hydrogen bonds in the conformational equilibrium of some 1,3-disubstituted cyclohexanes through NMR spectroscopy and theoretical calculations

Abstract

The analysis of concentration effects in the 1H NMR data of cis-3-aminocyclohexanol ( ACOL) showed that its diequatorial conformer changes from 60% at 0.01 mol L −1 to 70% at 0.40 mol L −1 in acetone-d 6. A similar increase was also observed for the diequatorial conformer of cis-3-N-methylaminocyclohexanol ( MCOL), from 32% (CDCl 3 0.01 mol L −1) to 55% (CDCl 3 0.40 mol L −1). The increase in solvent basicity leads to a large stabilization effect for the diequatorial conformer of both compounds too. For ACOL, it changes from 47% (Δ G eqeq– axax = 0.06 kcal mol −1) in CCl 4 to 93% (Δ G eqeq– axax = −1.53 kcal mol −1) in DMSO, while for MCOL it goes from 7% (Δ G eqeq– axax = 1.54 kcal mol −1) in CCl 4 to 82% (Δ G eqeq– axax = −0.88 kcal mol −1) in pyridine-d 6. These results indicate that the intr amolecular hydrogen bonds (IAHB) OH⋯N and NH⋯O stabilize the diaxial conformers of these compounds in a non-polar solvent. For cis-3-amino-1-methoxycyclohexane ( ACNE) and cis-3-N-methylamino-1-methoxy-cyclohexane ( MCNE) no changes were observed in equilibrium with the variation of solvent polarity. These results indicate for the first time that the IAHB NH⋯O is not strong enough to stabilize the diaxial conformer of these compounds and that the conformation equilibria of the cis isomers of compounds ACOL and MCOL are influenced only by the IAHB OH⋯N. Moreover, the presence of a secondary amino group (93% of diaxial conformer in CCl 4) leads to an IAHB OH⋯N stronger than in primary and tertiary amino-derivatives (53 and 54% of diaxial conformer, respectively) for 1,3-disubstituted cyclohexanes. Values obtained from the theoretical data through the B3LYP functional are in agreement with the experimental results and indicate that the IAHB strength that influences the conformational equilibrium of these compounds is the IAHB OH⋯N. Thus, the IAHB NH⋯O do not stabilize the diaxial conformer of the cis isomer of compounds ACNE and MCNE showing that the diequatorial conformer will always be more stable than the diaxial conformer, independent of concentration or solvent.