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

Abstract

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...

Structure−Activity Relationships for a Large Diverse Set of Natural, Synthetic, and Environmental Estrogens

“…It is important to point out that the H-bond donor ability of the phenolic OH is dependent on a number of factors, particularly the nature of ortho substituents that affect the OH accessibility. The H-bond donor ability for several ortho-substituented phenols follows this trend: (48), in which 2,6-di-tert-butylphenol is not a H-bond donor. This is consistent with the lack of binding activity observed for 4,4′-methylenebis(2,6-di-tert-butylphenol) ( Figure 4A).…”

The intriguing dual-directing effect of 2-cyanobenzyl ether for a highly stereospecific glycosylation reaction

“…Our rationale derived from the arming nature of the glycosyl donor: there is less destabilization with tetra-O-benzyl ethers on oxocarbenium ion II, thus allowing facile equilibrium shift between the three active species. Second, considering the nitrile group to be a weak H-acceptor, it is reasonable that sufficient H-bonding can only occur to stronger H-donors 42 . Incidentally, electron-poor alcohols not only increased donoring ability of the proton, but also decreased nucleophilicity on the oxygen atom 43 .…”

Interpretation of experimental hydrogen-bond enthalpies and entropies from COSMO polarisation charge densities

“…Most often the HBD and HBA strength parameters used as experimental basis are Abraham's ones. [2][3][4] Beyond more empirical increment schemes 11 quantum chemical descriptors have been used for a correlation of HB strength. Kenny 12 used the electrostatic potential as a quantum chemical descriptor for HBA strength of nitrogen bases.…”