Structural and energetic effect of the intramolecular hydrogen bonding in 4,6-dihaloresorcinols: ab initio calculation, vibrational spectroscopy, and molecular docking studies

The intramolecular hydrogen bonding in the series of 4,6-dihaloresorcinols (with halogen atoms being F, Cl, Br, or I) is believed to play a noticeable role in determining the structural and electronic aspects. All theoretical levels employed in this work suggested that the intramolecular O–H…X-C bonding greatly stabilizes the anti (A) configuration that is at least 5 kcal/mol more stable than the syn (S) form, where such an interaction is absent. Vibrational spectroscopic examination of the OH stretching and bending modes suggested that the dibromo derivative encounters a relatively greater extent of intramolecular hydrogen bonding interaction compared to the corresponding molecules, which is in agreement with the ab initio MP4(SDQ) results. The A ↔ AS ↔ S interconversion barriers were predicted to be in the range of 5–10 kcal/mol, with the difluoro derivative corresponding to the smallest energy barriers in the series in the gas phase. The order of the frontier molecular orbitals and electrostatic potential maps showed a consistent correlation with the size and mass down the halogen group. The calculated infrared and Raman wavenumbers were compared with the experimentally observed ones to assist systematic assignments of the vibrational modes. Molecular docking analysis suggested that the difluoro derivative shall be a potent halo-substituted resorcinol candidate in the treatment of specific types of skin inflammation.