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

An LSER analysis based on the partitioning of 15 proton acceptor heterocycles has succeeded in extracting Sigma beta values, but only at the cost of demonstrating solvent dependence for some of them, As noted by Abraham, the division lies between protic and aprotic organic phases. His observation that pyridine and quinoline are less effective accepters 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 operative; it is possible that this result can be generalized to other such heterocycles. Elsewhere, the most remarkable finding is that, where there are two proton acceptor sites in one heterocyclic ring, Sigma beta is the simple unattenuated sum of the separate beta(f) values. If this result is general, it leads to a very simple way of estimating Sigma beta for heterocycles by calculation where data are unavailable, Evidence 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.