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

Abstract

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, NH(2), NO(2) 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 NO(2)-substituted molecules both in chloroform and aqueous solution. For 2NH(2)-ethanol, the HB structure is predominant in chloroform, whereas the 93:7 ratio for the OCCN trans/gauche species was obtained in aqueous solution. 2NH(2)-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 2NH(2)-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 T = 298 K and p = 1 atm, correspond reasonably to the derived molecular structures.

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…Although the solute-solvent interactions are substantial, the effect of a non-polar or only slightly polar solvent (CCl 4 , CHCl 3 ) on the molecular geometry is generally small [104,105]. The geometric effect could be, however, large when a solute with an intramolecular H-bond in the gas phase dissolves in a protic solvent such as water or methanol, which has both proton donor and acceptor sites.…”

Theoretical Calculations on the Conformational/Tautomeric Equilibria for Small Molecules in Solution

“…Also one has to make a choice if the optimized solute geometry is being used as a rigid one in explicit solvent simulations. An attempt for resolving the problem was made by Nagy [19] who compared the IEF-PCM optimized geometries of the internally hydrogen-bonded 2-F-ethanol and its monohydrate in aqueous solution. In that lucky case, the characteristic HOCC and OCCF torsion angles did not change too much, thus the geometry of the optimized bare solute was accepted in further studies.…”

“…The proposed values for the "n" exponent are 3 and 2.2 [17,18] respectively. Using the aug-cc-pvqz basis set, X=4 [19].…”

“…If ab initio geometry optimization was chosen, upto very recently it generally has not exceeded the MP2 level with the 6-311++G** Pople basis [73] or the Dunning basis set aug-cc-pvtz [74][75][76]. Use of the latter basis set, however, requires long calculations and slow convergence for the in-solution geometry [19,49].…”

“…2-F-ethanol and 2-NO 2 -ethanol were studied by Nagy using the IEF-PCM method and calculating relative solvation free energies at the FEP/MC level [19]. Relative internal free energies were obtained at the ab initio IEF-PCM/CCSD(T)/CBS//IEF-PCM/B3LYP/6-311++G** and the IEF-PCM/B97D/aug-cc-pvtz levels, using geometries from optimizations in water and chloroform.…”