Hydrophobicity parameter of diazines IV: a new hydrogen-accepting parameter of monosubstituted (di)azines for the relationship of partition coefficients in different solvent systems.

We recently proposed a new hydrogen-accepting scale, S(HA), for each member of the substituted (di)azine series on the basis of the heat of formation calculated under various dielectric environments by the COSMO method. In this paper, the S(HA) scale was used to examine relationships between log P(CL) (P(CL): CHCl(3)/H(2)O partition coefficient) and log P(oct) (P(oct): 1-octanol/H(2)O partition coefficient) for each of the 2-substituted pyridine (I), monosubstituted pyrazine (II), and pyrimidine (III) series. This S(HA) parameter worked nicely, representing the hydrogen-accepting effect of the solute molecule. A correlation equation with excellent quality, such as log P(CL) = a log P(oct) + sS(HA) + constant, was obtained for each series. We further defined the parameter S(HA/PY), derived from S(HA) values for the heterocyclic series by shifting the reference points to unsubstituted pyridine, to unify separately derived correlation equations. Thus, the correlation between log P(CL) and log P(oct) for all combined data of three series was derived by using a single equation as log P(CL) = a log P(oct) + sS(HA/PY) + constant. The S(HA) parameters were reasonably considered as being free-energy related, and the rationale for the hydrogen-bond-acceptor scale was presented.