Hydrophobicity Parameter of Diazines. II: Analysis and Prediction of Partition Coefficients of Disubstituted Pyrazines

Abstract

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 [π(disubst)PR] was analyzed in terms of the πvalue of substituents in monosubstituted pyrazine (π2PH) and other physicochemical substituent parameters, considering electronic and steric intractions operating bidirectionally between individual partners of substituents and aza-functions. When the substituents were nonamphiprotic and their steric interaction was not significant, the π (disubst)PR value was approximately predicted by the summation of the π2PR 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 π 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.