A scale of solute hydrogen-bond basicity has been set up using log K values for the complexation of a series of bases ( i ) against a number of reference acids in dilute solution in tetrachloromethane, equation (i).Thirty-four such linear equations have been solved t o yield 1, and 0, values that characterise the acids, and log K$ values that characterise the base; all the thirty-four equations intersect at a point where log K = -1.1 with K on the molar scale. This primary set of log K z values involved 215 bases, and through a large number of secondary values we have been able to determine log K! for some 500 bases, that include nearly all the functional groups encountered in organic chemistry. By making use of the 'magic point,' we have transformed log K t into an entirely equivalent, but more convenient, scale through equation (ii). p ; = (log K,H + 1.1)/4.636 (ii) Since w e can take p? = 0 for all non-basic compounds such as alkanes and cycloalkanes, the new p ; hydrogen-bond solute basicity scale covers virtually all classes of base.We show that p$ is not generally related to measures of full proton-transfer basicity such as aqueous pK or gaseous proton affinity (€pa) values, although family dependence is observed, and w e stress that solute hydrogen-bond basicity must not be equated with full proton-transfer basicity. We also briefly investigate the solvent dependence of the pc values in terms of the Maria-Gal &value, and w e point out a number of exclusions t o the 'reasonably general' p ; scale.

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...

The interactions between a molecule and the aqueous environment underpin any process that occurs in solution, from simple chemical reactions to protein-ligand binding to protein aggregation. Fundamental measures of the interaction between molecule and aqueous phase, such as the transfer energy between gas phase and water or the energetic difference between two tautomers of a molecule in solution, remain nontrivial to predict accurately using current computational methods. SAMPL2 represents the third annual blind prediction of transfer energies, and the first time tautomer ratios were included in the challenge. Over 60 sets of predictions were submitted, and each participant also attempted to estimate the error in their predictions, a task that proved difficult for most. The results of this blind assessment of the state of the field for transfer energy and tautomer ratio prediction both indicate where the field is performing well and point out flaws in current methods.

BackgroundA significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms.Methods and ResultsSixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented.SignificanceThese data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk.

The enol imine a enaminone tautomerization constants, K T , and thermodynamic parameters, ∆H T and ∆S T , of 1-hydroxy-2-naphthaldehyde Schiff bases are determined by UV/vis spectroscopy. Polar solvents shift the equilibrium toward the quinone form (for the unsubstituted derivative 1c, K T ) 0.20 (cyclohexane) and K T ) 1.49 (ethanol)). Both donor (MeO, NMe 2 ) and acceptor (CN, NO 2 ) substituents lead to a decreased K T independent of solvent polarity. In apolar solvents, for all derivatives 1a-1e, the enol imine a enaminone equilibria are endergonic but exothermic. Linear solvation energy relationships allow extrapolation of ∆G T to the gas phase. Density functional theory calculations (B3LYP/6-311+G**) yield good agreement with these extrapolated ∆G T values. Solvent effects on 1c are also successfully reproduced by the calculations. Geometric (O‚‚‚N distance) and energetic criteria (conformer energy differences, homodesmotic reactions) establish the importance of intramolecular hydrogen bonding for the tautomerism of these compounds. The results obtained for 1a-1e are compared with tautomeric properties of the isomeric naphthaldehyde anils 2-4, the monocyclic analogues 5 and 6, the corresponding azo derivatives 7-9, and the N-alkyl derivative 10.

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