Atropisomerism about Aryl-C(sp(3)) Bonds: Conformational Behavior of Substituted Phenylcyclohexanes in Solution

A catalytic hydrogenation of cannabidiol derivatives known as phenylcyclohexenes was used to prepare epimeric (1R,1S) and/or rotameric (M,P) phenylcyclohexanes. The reaction is diastereoselective, in favor of the 1S epimer, when large groups are attached to the phenyl ring. For each epimer, variable-temperature NMR experiments, including EXSY spectroscopy and DFT calculations, were used to determine the activation energies of the conformational exchange arising from the restricted rotation about the aryl-C(sp(3)) bond that led to two unequally populated rotamers. The conformational preference arises essentially from steric interactions between substituents vicinal to the pivot bond. The conformers of epimers (1S)-2e,f show high rotational barriers of up to 92 kJ mol(-1), unlike those of (1R)-2e,f and with much lower barriers of ∼72 kJ mol(-1). The height of the barriers not only depends on the substituents at the axis of chirality but also is influenced by the position of a methyl group on the monoterpene ring. The feature most favorable to high rotational barriers is when the methyl at C1 lies equatorially. This additional substituent effect, highlighted for the first time, seems fundamental to allowing atropisomerism in hindered ortho-substituted phenylcyclohexanes.