HYDROPHOBICITY PARAMETER OF DIAZINES .2. 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 intractions 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.