Dynamic nuclear magnetic resonance and empirical force field studies of cannabidiol

Internal rotation of cannabidiol (1), its mono-(2) and dimethyl (3) derivatives has been studied by ¹H and ¹³C dynamic NMR spectroscopy. The free energy of activation for the rotation of C₃-C₂, bond that we have observed for cannabidiol of 14.7 kcal/mol at 22° in CDCl₃ is in contrast with values previously reported in the literature. Molecular mechanics simulation of the rotation of C₃-C₂, bond of a model structure (4) well reproduced the presently determined barrier height. Analysis of the calculated rotational transition state structure revealed severe nonbonded C₂H/O and C ₈/O interactions as the source of barrier. Calculations of other model structures indicate general occurrence of restricted rotation about the pivot bond of phenylcyclohexanes appropriately substituted at β-carbon of cyclohexane ring and at ortho position of phenyl ring. The fully substituted 2,6-dimethyl-1-(o,o'-dimethylphenyl) cyclohexane (10) is predicted to show atropisomerism.