Hydrophobicity parameter of diazines. II: Analysis and prediction of partition coefficients of disubstituted pyrazines.

The partition coefficient in a 1-octanol-water system (log P) of a number of disubstituted pyrazines was measured. The increment produced by introduction of two substituents [pi(disubst)PR] was analyzed in terms of the pi value of substituents in monosubstituted pyrazine (pi 2PR) and other physicochemical substituent parameters, considering electronic and steric interactions operating bidirectionally between individual partners of substituents and aza-functions. When the substituents were nonamphiprotic and their steric interaction was not significant, the pi (disubst)PR value was approximately predicted by the summation of the pi 2PR values of corresponding substituents. For amphiprotic substituents, a correction for electronic interactions between the two substituents was needed but it was less important than that required in disubstituted benzenes. The results suggest that the difference in the pi values between disubstituted pyrazine and benzene systems was mostly governed by that between monosubstituted pyrazine and benzene systems with component substituents. In 2,6- and 2,3-disubstituted derivatives, bulky substituents had steric effects in such a way that the log P value was lowered.