Issue 10, 1989

Hydrogen bonding. Part 9. Solute proton donor and proton acceptor scales for use in drug design


Hydrogen bonding equilibrium constants have been measured for a large and varied selection of proton donors against a common acceptor (N-methylpyrrolidinone) and of proton acceptors against a common donor (4-nitrophenol). Together these have been used to create the log Kα and log Kβ scales of proton donor and acceptor ability which are explicitly targeted to the needs of the medicinal chemist in the context of potential drug–receptor interactions. To this end they have been measured in 1,1,1-trichloroethane, a solvent never before used for hydrogen bonding studies but whose high dipolarity is considered a much better model for real biological membranes than the very non-polar solvents that have previously been employed. It is shown that this solvent imposes significant ranking changes on the solutes, since the charge transfer element in hydrogen bonding is reinforced at the expense of the purely electrostatic component. Nevertheless it is possible to scale previous data in such a way that over 80 functional group log Kα and log Kβ values become available to the medicinal chemist (Table 4). In addition, data are given for a large number of parent heterocycles, most of which have never before been studied. We note that heterocycles are uniquely able to ‘fine-tune’ these scales, so providing at least one justification for their special interest to the medicinal chemist.

In addition to equilibrium constants we have measured the spectroscopic quantities ΔνC[double bond, length half m-dash]O(for donors) and βsm(for acceptors). On various lines of evidence we suggest that these are enthalpy-related quantities and, following previous arguments, may function as alternative parameters suitable for use by the medicinal chemist under conditions of severe steric constraint.

Cross-comparisons of these data allow conclusions to be drawn which considerably illuminate the factors that influence hydrogen bond strength, and some of which have no precedent. A selection follows. Where a level comparison can be made, the donor order is OH > NH > CH and the acceptor order is N > O > S. However, within each category there are various sorts of family relationship. For example, phenols and alkanols lie on separate lines of log Kαvs. pKa, and a similar separation for log Kβ is shown by 5- and 6-membered ring heterocycles. By contrast, OH and NH donors show a single relation between log Kα and ΔνC[double bond, length half m-dash]O, negative deviations from which are satisfactorily accounted for in terms of steric and stereoelectronic factors. The most important of the latter is lone-pair repulsion: ‘α-effect’ heterocycles are anomalously strong acceptors, whereas certain classes of donor, notably sulphonamides and carboxylic acids, are much weaker than would be expected from their pKa values. More subtle anomalies attach, inter alia, to heterocycles as donors, CH donors generally, and amines and sulphonamides as acceptors; all however can be rationalised.

The extremes of both scales are charted. Alkyl thiols and amines are negligible as proton donors; correspondingly, π-donor hetero-atoms as e.g. in esters and amides are negligible acceptors. At the opposite extreme, heterocycles such as tetrazole and 4-quinolone figure prominently. Based on these results, some structural criteria are suggested that might lead to the synthesis of stronger proton acceptors than any so far known.

Article information

Article type

J. Chem. Soc., Perkin Trans. 2, 1989, 1355-1375

Hydrogen bonding. Part 9. Solute proton donor and proton acceptor scales for use in drug design

M. H. Abraham, P. P. Duce, D. V. Prior, D. G. Barratt, J. J. Morris and P. J. Taylor, J. Chem. Soc., Perkin Trans. 2, 1989, 1355 DOI: 10.1039/P29890001355

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