Multiple hydrogen-bond accepting capacities of polybasic molecules:: The case of cotinine

The hydrogen-bond (HB) basicities of the carbonyl oxygen and pyridine nitrogen of the cotinine molecule, a long-lived metabolite of nicotine, have been measured in carbon tetrachloride and estimated in water. For the first time, the equilibrium constants of two coexisting 1:1 associations of a phenol on the basic centers of a bifunctional compound have been measured individually. The sum of these individual equilibrium constants closely corresponds to the global experimental constant obtained by the classical IR method based on the measurement of the free phenol OH absorption intensity. The solvation of the cotinine amide group has been examined in various mixed acetonitrile-water solutions revealing the presence of di- and tri-hydrogen-bonded carbonyl groups in pure water. Independently, the accepting strengths of the two sites of cotinine have been calculated from linear correlations between the pK(HB) scale and the electronic energy of the reaction of hydrogen fluoride complexation on substituted pyridines and carbonyl model compounds using density functional theory calculations at the B3LYP/6-31+G** level. The agreement between the calculated and the experimental individual equilibrium constants of cotinine is well inside the experimental error. The knowledge of the individual acceptor strengths of cotinine in carbon tetrachloride enables the calculation of the octanol-water partition coefficient, this estimation exactly fits the experimental data. Contrary to the order of basicity measured by the pK(a) scale, the HB basicity of the carbonyl group appears to be 1.6 pK units greater than the HB basicity of the pyridine moiety in water.