SK 70 4TG * These K z values are formally equivalent to equilibrium constants for the series of acids against a particular base with L, = 1 and D, = 0.

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 K, and log K, scales of proton donor and acceptor ability which are explicitly targeted t o the needs of the medicinal chemist in the context of potential drug-receptor interactions. To this end they have been measured in 1 ,I ,I -trichloroethane, a solvent never before used for hydrogen bonding studies but whose high dipolarity is considered a much better model for real bi.ological 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 K, and log K, 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 t o 'fine-tune' these scales, so providing at least one justification for their special interest t o the medicinal chemist.In addition t o equilibrium constants w e have measured the spectroscopic quantities Av,=, (for donors) and Psm (for acceptors). O n various lines of evidence w e suggest that these are enthalpy-related quantities and, following previous arguments, may function as alternative parameters suitable for use b y 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 n o precedent. A selection follows. Where a level comparison can be made, the donor order is O H > N H > CH and the acceptor order is N > 0 > S. However, within each category there are various sorts of family relationship. For example, phenols and alkanols lie on separate lines of log K, ws. pK,, and a similar separation for log K, is shown by 5-and 6-membered ring heterocycles. B y contrast, OH and N H donors show a single relation between log K, and Av,=,, 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: "-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 pK, values. More subtle anomalies attach, inter alia, to heterocycles as donors, CH donors generally, and amines and sulphonamides as acceptors; all however can be rat iona I ised.The extremes of both scales are charted. Alkyl thiols and amines are negligible as proton donors; correspondingly, 7c-donor hetero-a...

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Equilibrium constants and enthalpies of complexation are reported for 72 monomeric hydrogen-bond acids against the base N-methylpyrrolidinone in dilute solutions in 1 ,l , 1 -trichloroethane, using a discontinuous calorimetric titration method. Representative oxygen acids (carboxylic acids, phenols, alcohols and oximes) and representative nitrogen acids (anilides, amides, sulphonamides, aromatic amines and heterocyclic amines) are included : carbon acids seem too weak to measure by the present method. There is no general AHO us. AGO, nor a general AGO us. pK,, correlation, but families of acids (e.g. carboxylic acids, phenols and anilides) give rise to linear AH"/ AGO and AGo/pK, correlations. The slopes of the AHo us. AGO plots can be positive (substituted alcohols), nearly zero (3-and 4-substituted phenols) or even negative (carboxylic acids and anilides), and a theory invoking solvent participation is advanced to explain this behaviour. It is suggested that the AGO (or logK") values be used to construct a scale of monomeric solute hydrogen-bond acidity, rather than the AH" values.In the first part of this series' we described the determination of K" and AH" values for the hydrogen-bond complex formation of monomeric carboxylic acids with Nmethylpyrrolidinone (NMP) in solvent 1, 1,l-trichloroethane (TCE). We now report the experimental measurement of K" and AHo values for a wide range of hydrogen-bond acids, against the standard base system of NMP in TCE: