MODEL SOLVENT SYSTEMS FOR QSAR .4. THE HYDROGEN-BOND ACCEPTOR BEHAVIOR OF HETEROCYCLES

An LSER analysis based on the partitioning of 15 proton acceptor heter ocycles has succeeded in extracting Sigma beta values, but only at the cost of demonstrating solvent dependence for some of them, As noted b y Abraham, the division lies between protic and aprotic organic phases . His observation that pyridine and quinoline are less effective accep ters when surrounded by solvent than in 1:1 association was confirmed, and possible reasons for this are discussed, Two other such cases are N-methylimidazole and pyridazine, both of which give lower Sigma beta values in octanol than in PGDP. For both, Sigma beta in PGDP is what would be expected on the basis of log K-beta. The value for pyridazine in octanol suggests that, here, the 'alpha-effect' is no longer opera tive; it is possible that this result can be generalized to other such heterocycles. Elsewhere, the most remarkable finding is that, where t here are two proton acceptor sites in one heterocyclic ring, Sigma bet a is the simple unattenuated sum of the separate beta(f) values. If th is result is general, it leads to a very simple way of estimating Sigm a beta for heterocycles by calculation where data are unavailable, Evi dence was also found, in certain cases, for hydrogen bonding to the pi -donor heteroatom or the aromatic ring, The QSAR implications of these results are discussed.