Theoretical Studies of the Solvent Effect on the Conformation of the HO–C–C–X (X = F, NH₂, NO₂) Moiety with Competing Intra- and Intermolecular Hydrogen Bonds

Theoretical calculations up to the ab initio IEF-PCM/CCSD­(T)/CBS//IEF-PCM/B3LYP/6-311++G** and IEF-PCM/B97D/aug-cc-pvtz levels have been performed for 2X-ethanol and 2X-phenol systems with X = F, NH₂, NO₂ in chloroform and aqueous solution. The calculated relative free energies by means of the IEF-PCM continuum dielectric method do not differ very much at the DFT and ab initio levels. Application of explicit solvent models and the FEP/MC method for determining relative solvation free energies causes, however, large deviations in the predicted equilibrium compositions, although the predominant conformation for the solute is generally in agreement with that from the corresponding IEF-PCM calculations. Existence of an intramolecular hydrogen bond (HB structure) for species with the HO–C–C–X moiety is preferred compared with a conformation when the hydrogen bond is disrupted (NoHB) for the considered F- and NO₂-substituted molecules both in chloroform and aqueous solution. For 2NH₂-ethanol, the HB structure is predominant in chloroform, whereas the 93:7 ratio for the OCCN trans/gauche species was obtained in aqueous solution. 2NH₂-phenol exhibits a subtle equilibrium of the HB and NoHB conformations in both solvents. Potential of mean force calculations predict about a 10% solute association for the trans 2NH₂-ethanol solute even in the fairly dilute 0.22 molar solution, whereas direct MC simulations do not support the maintenance of a doubly hydrogen-bonded dimer. Aqueous solution characteristics, as coordination numbers and numbers of strongly bound water molecules to the solute at <i>T</i> = 298 K and <i>p</i> = 1 atm, correspond reasonably to the derived molecular structures