Rationalisations among Heterocyclic Partition Coefficients. Part 3: π‐Excessive Heterocycles. Some Comments on the CLOGP Algorithm

The partition coefficients for 123 furans, thiophenes, pyrroles and their benzofused derivatives are listed and the results discussed in terms of Δπ, i.e. the difference in π‐value from that expected for benzene. The smaller internal bond angle of 5‐membered rings leads to characteristically larger π‐values for some bulky groups, notably tertiary amide, since these can approach planarity more closely than in benzene. By contrast, lone pair repulsion lowers π for some 2‐substituted furans. Otherwise, π is very slight in furans and thiophenes, demonstrating the absence of appreciable electronic interactions. Because pyrroles and indoles are proton donors, they superficially show electronic effects similar to anilines. Closer analysis, based partly on the existence of anomalous negative Δπ values, demonstrates complications which the CLOGP algorithm does not consider. The rationale of electronic interaction and its effect on log P is discussed in terms of the need to consider (a) separate proton donor and acceptor terms, (b) rises as well as falls in lone pair electron density. It is pointed out, inter alia , that π‐donor ring hetero‐atoms are not proton acceptors, and that aromatic ring hetero‐atoms in general do not behave like ring substituents. While no attempt is made to construct an alternative algorithm, various suggestions are made concerning the lines along which CLOGP might be modified.