Model solvent systems for QSAR. Part 3. An LSER analysis of the ‘critical quartet.’ New light on hydrogen bond strength and directionality

Abstract

An LSER analysis of log P for the ‘critical quartet’ of solvent systems has been carried out using, as initial variables, V_I for volume, µ² for dipolarity, and proton donor ∑α and proton acceptor β_f scales based on log K_α and log K_β respectively. A common data matrix and an unprecedented range of functionalities have been employed. By making the analysis stepwise, starting with the simplest solutes and adding more in order of increasing complexity, we have been able to identify hitherto unrecognised variables and ‘fine-tune’ established ones in such a way as to derive self-consistent proton donor and acceptor values applicable to the whole range of solvent systems. By this ‘LSER in reverse’ we have established, inter alia, the following new facts: (a)β_f possesses a constant effective zero whereas that for ∑α is solvent-sensitive; (b) a new term nβ_f is required for acceptor solutes with two or more available lone pairs; (c) when neither lone pair is available, the acceptor strength of carbonyl is sharply reduced; (d) a second term specific to NH₂ is required for ∑α in alkane and chloroform; (e) there is mutual shielding of XH and one lone pair in structures such as CO₂H and CONH₂; (f) ureas and other structures with parallel NH functions are proton donors of exceptional strength; (g) the acceptor ability of dipolar bases (PO and SO) varies with the solvent system.

Cooperativity in solute–solvent bonding exists but takes complex forms, and does not appear strong enough to account e.g. for the hydrogen bonding properties of bulk water and the alcohols, for which mass action appears a likelier explanation. We present evidence (see Appendix) that mass action will most probably explain certain well known anomalies in the apparent proton acceptor ability of water as revealed by partitioning studies.

The present results throw new light on previously anomalous octanol–water log P values and can predict f-values for other solvent systems. Most importantly, they provide new information not only on the strength of hydrogen bonding for more than 60 functional groups, but also on its directionality: we are able to predict, with reasonable certainty, which XH groups and lone pairs are actually available for bonding. This information is applicable to water, other solvents, and by implication to the biophase, so should find direct and immediate use in rationalising and quantifying drug–receptor interactions.