Thermodynamics of Water-octanol and Water-cyclohexane Partitioning of some Aromatic Compounds

Abstract

Abstract:The Gibbs free energy, enthalpy and entropy of partitioning of 45 simple aromatic compounds (phenols, benzoic acids and acetanilides) from water to octanol and from water to cyclohexane have been determined using the filter-probe method. This involved the measurement of partition coefficients over the temperature range 20-45 o C.The aim of the work was to explore the effects of intramolecular hydrogen bonding and steric factors on the partitioning process. It was found that the intramolecular hydrogen bond is intact in 2-nitrophenol and salicylic acid, and possibly in 2-hydroxybenzaldehyde, in all three solvents, but 2-chlorophenol is intramolecularly hydrogen bonded only in inert solution. The evidence indicates that 2-nitroresorcinol and 2,6-dihydroxybenzoic acid possess only one intramolecular hydrogen bond, although they are theoretically capable of possessing two. There is evidence of steric shielding in 2,6-dimethylphenol, whilst 2,6-dimethylbenzoic acid and ortho-substituted acetanilides show evidence of steric twisting of the carboxyl and acetamido groups respectively out of the plane of the aromatic ring. Unusual steric effects are displayed in the methyl-2-nitrophenols whereby, depending upon the position of the methyl group, the intramolecular hydrogen bond is either weakened or strengthened.

Towards an Understanding of the Molecular Mechanism of Solvation of Drug Molecules: A Thermodynamic Approach by Crystal Lattice Energy, Sublimation, and Solubility Exemplified by Hydroxybenzoic Acids

“…The scheme of the discussed transfer process of the investigated substances is presented in Scheme . A principally similar scheme was found when the molecules were actually distributed between phases of mutually saturated water and octanol in a partitioning experiment 24. It should be noted that the largest deviation from the present values are in 3‐OH‐BA.…”

Interactions of phenol with cationic micelles of hexadecyltrimethylammonium bromide studied by titration calorimetry, conductimetry, and 1H NMR in the range of low additive and surfactant concentrations

“…For example, the molar enthalpy of transfer from water to octanol was evaluated at −8.4 kJ mol −1 , whereas that of transfer from water to cyclohexane was found to be +15.3 kJ mol −1 (estimated from the van't Hoff equation based on the temperature dependence of the activity data [50]). In both cases, the entropy change upon transfer was positive (+17.7 J mol −1 K −1 and +52.5 J mol −1 K −1 , respectively), being interpreted as indicating the release of structured water (breaking of hydrogen bonds between water molecules) upon transfer from the aqueous phase to the nonaqueous solvent and a consequent increase in disorder of solvent molecules.…”

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

“…In the pharmaceutical context, hydrogen bonding influences solubility of drugs, both in water and in lipids, and the affinity with which they associate with their targets. Partition coefficients [388,389], especially when measured for the 1-octanol/water system, are widely used in drug discovery, and differences between values measured for a compound in different systems (e.g., cyclohexane/water) reflect the hydrogen-bonding characteristics of the compound [241,358,375,390,391,392,393]. Hydrogen bond (HB) strength can be quantified by the stability of the 1:1 complex between an HB donor and an HB acceptor in a nonpolar solvent such as tetrachloromethane or 1,1,1-trichloroethane [25,76,394,395].…”