Dimerization of dexanabinol by hydrogen bonding accounts for its hydrophobic character

Abstract

Dexanabinol, a dihydroxylated synthetic cannabinoid, is a member of . the nonpsychotropic q 3S, 4S enantiomeric series. Experimental evidence suggests that . dexanabinol might form aggregates e.g., dimers in which the two OH a phenol and an . allylic alcohol groups are involved in hydrogen bonding. The extremely low solubility of dexanabinol in water implies that this interaction may not involve solvent molecules. A theoretical study of this phenomenon in the framework of the PM3 molecular approximation is described. Simple molecular models phenol and 6-cyclohexene-1- . methanol were initially examined followed by extension of the calculations to dexanabinol. The results indicate that dimers of dexanabinol resulting from hydrogen bonding are more stable than the isolated molecules with the differences attributed to hydrogen bonding energies. It is suggested that the phenolic hydroxy group of one molecule forms a hydrogen bond with the allylic OH group of the second molecule and vice versa, resulting in dimers which contain two hydrogen bonds. The hydrogen bonds . are more stable 6.14 kcalrmol and the complex formed is more favored energetically when the phenol groups act as hydrogen bond donors and the allylic OH groups as acceptors. These interactions are also energetically more favored than those between . dexanabinol and water 3.70 kcalrmol . The dexanabinol dimer manifested a lower . dipole moment as compared to the monomer 1.211 vs. 2.221 debye as well as a much . larger log P 11.16 vs. 5.90 , indicating strong hydrophobic character. The optimized structure shows that the OH groups involved in hydrogen bonds are oriented to the interior of the dimers, while the lipophilic side chains are oriented toward the exterior. These properties of the dimer may explain the low water solubility of dexanabinol.