Philip P. Duce

Hydrogen bonding. Part 7. A scale of solute hydrogen-bond acidity based on log K values for complexation in tetrachloromethane

A scale of solute hydrogen-bond acidity has been constructed using equilibrium constants (as log K values) for complexation of series of acids (i) against a given base in dilute solution in tetrachloromethane, equation (A). Forty-five such equations have been solved to yield LB and DB, log Ki=LB log KAHI+DB(A) values characterising the base, and log KAH values that characterise the acid. In this analysis, use has been made of the novel observation that all the lines in equation (A) intersect at a given point where log K= log KAH=–1.1 with K on the molar scale. Some 190 log KAH values that constitute a reasonably general scale of solute hydrogen-bond acidity have been obtained. It is shown that there is no general connection between log KAH; and any proton-transfer quantities, although certain family dependences are obtained. A number of acid-base combinations are excluded from equation (A), and alternative log KAHE values have been determined for such cases. The general log KAH values may be transformed into α2H values suitable for use in multiple linear-regression analysis through the equation α2H=(log KAH+ 1.1)/4.636.

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 ΔνCO(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 ΔνCO, 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.

Solubilities of salts and kinetics of reaction between hydroxide ions and iron(II)–di-imine complexes in water–methanol mixtures. Derivation of single-ion transfer chemical potentials and their application to analysis of solvent effects on kinetic parameters

Kinetic data are reported for the reaction at 298 K and ambient pressure between two iron(II)–di-imine complex cations and hydroxide ions in water–methanol mixtures. Solubility data are reported for a range of inorganic salts containing simple and complex ions. Methods for calculating transfer chemical potentials of single ions are examined and, depending on the extrathermodynamic assumption, shown to predict different trends in the properties of ions in these aqueous mixtures. Further, calculated initial- and transition-state solvation effects on the kinetics are different: in some cases dramatically so. The solvation characteristics are compared for various ions in methanol–water mixtures as calculated using the tetraphenylphosphonium tetraphenylborate (TPTB) assumption, which sets the transfer chemical potential of tetraphenylphosphonium ions equal to that of tetraphenyl-boronate ions. Arguments are advanced for adopting single-ion transfer chemical potentials based on this assumption. Relationships are examined between the transfer parameters for H+, H3O+, ROH+2 and H9O+4 ions in binary aqueous mixtures, ROH + H2O.

Kinetic and spectroscopic intimations of intermediates in nucleophilic attack at diimine complexes of iron(II) and of molybdenum(O)

SummaryKinetics of nucleophilic substitution at a range of low-spin iron(II)diimine complexes have been examined in the presence of a variety of salts, to probe the role of hydroxide and cyanide as nucleophiles and of other ions in ion association equilibria. Equilibrium constants for interaction of hydroxide and of cyanide with many of these ligands, free or complexed with iron(II) or molybdenum(0), have been measured, in water and in binary aqueous solvent mixtures. Effects of solvent, temperature, and pressure on rate constants and on equilibrium constants have been monitored for selected systems. In the light of these results, and of ancillary qualitative observations, we discuss the role and nature of intermediates in nucleophilic substitution reactions of transition metaldiimine complexes.

Initial state and transition state contributions to reactivity in mercury(II)-catalysed aquation of thetrans-[Rh(en)2Cl2]+, [Cr(NH3)5Cl]2+, andcis-[Cr(NH3)4(OH2)Cl]2+ cations in binary aqueous solvent mixtures

SummaryRate constants are reported for mercury(II)-catalysed aquation of thetrans-[Rh(en)2Cl2]+, [Cr(NH3)5Cl]2+, andcis-[Cr(NH3)4(OH2)Cl]2+ cations in water and in methanol-, ethanol-, and acetonitrile-water solvent mixtures. In the case oftrans-[Rh(en)2Cl2]+, the dependence of rate constants on mercury(II) concentration indicates reaction through a binuclear (Rh-Cl-Hg bridged) intermediate. The dependence of the equilibrium constant for the formation of this intermediate and of its rate constant for dissociation (loss of HgCl+) on solvent composition have been established. With the aid of measured solubilities, published ancillary thermodynamic data, and suitable extrathermodynamic assumptions, the observed reactivity trends for these mercury(II)-catalysed aquations are dissected into initial state and transition state components. The reactivity patterns for these three complexes are compared with those for mercury(II)-catalysed aquation of other chloro-transition metal complexes, particularlycis-[Rh(en)2Cl2]+, [Co(NH3)5Cl]2+, and [ReCl6]2−.

Kinetics of reactions in microheterogeneous aqueous systems

Kinetics of reaction involving two low-spin iron(II) di-imine complexes, Fe(phen)2+3 and Fe(hxsbH)2+, are reported where the solvent media include three microemulsions and a range of aqueous 2-butoxyethanol mixtures. In certain systems containing Fe(hxsbH)2+ the rate of reaction follows zero-order kinetics for a considerable part of the reaction. The kinetics are accounted for using a reaction scheme in which the complex metal ion is adsorbed at an interphase between organic-rich and water-rich domains. The same model is used to account for the marked acceleration in the rate of reaction between Fe(phen)2+3 and hydroxide ions in these systems. The kinetics of a scheme in which reaction takes place in both domains are examined, the distribution of the substrate being at all times in equilibrium between the two microphases. In such cases a plot of In k(obs.) against 1/T can be S-shaped, where k(obs.) is the overall first-order rate constant. Effects of changes in acid, acid concentration and added surfactant on the rate of reaction in the microemulsions are reported.

Initial state and transition state solvation in substitution at the square-planar complexes, [PtCl4]2− and [Pd(Et4dien)Cl]+

SummaryRate constants have been determined for the reaction of [PtCl4]2− with cyanide in water and in 20% and 40% (v/v) methanol, and for the reaction of [Pd(Et4dien)Cl]+ with thiourea in water, in 50% methanol, and in 50% DMSO, in all cases at 298.2K. The solubility of K2PtCl4 has been determined in water and in 20% and 40% methanol; the solubility of [Pd(Et4dien)Cl]Cl has been determined in water, in 20%, 40%, 60%, and 80% methanol, and in 40% and 80% DMSO; again in all cases at 298.2K. From these solubilities, Gibbs free energies of transfer for the [PtCl4]2− and [Pd(Et4dien)Cl]+ ions have been estimated. From these transfer data, published transfer data for cyanide and thiourea, and these and earlier kinetic results, solvent effects on reactivity have been dissected into their initial state and transition state components for the following four reactions: [PtCl4]2− hydrolysis, [PtCl4]2− plus cyanide, [Pd(Et4dien)Cl]+ substitution, and [Pd(Et4-dien)Cl]+ plus thiourea. The patterns thus established are discussed, and compared with those previously obtained for some other reactions of transition metal complexes.

Hydrogen bonding. Part 1.—Equilibrium constants and enthalpies of complexation for monomeric carboxylic acids with N-methylpyrrolidinone in 1,1,1-trichloroethane

A novel calorimetric method has been derived for the simultaneous determination of equilibrium constants and enthalpies of complexation of monomeric carboxylic acids with bases in an inert solvent. The method requires a knowledge of the corresponding equilibrium constants and enthalpies for the monomer/dimer equilibrium in the same solvent. Both sets of K° and ΔH° values have been obtained for a number of carboxylic acids (and some other hydrogen-bond donors) in 1,1,1-trichloroethane at 298 K, using N-methylpyrrolidinone as a standard base. For the first time, it is possible to evaluate the relative hydrogen-bonding strength of monomeric carboxylic acids and other hydrogen-bonding species in an inert solvent. It is shown that unactivated carboxylic acids are no stronger than simple phenols: equilibrium constants for hydrogen bonding towards N-methylpyrrolidinone are acetic acid (109), benzoic acid (118) and phenol (137). It is further shown that the monomeric carboxylic acids are ca. 20 times as strong as the dimeric acids towards N-methylpyrrolidinone (NMP) in 1,1,1-trichloroethane, with respect to the formation of the species RCO2H·NMP in each case.

Solvation and reactivity of tris(diimine)–iron(II) complexes in aqueous ethane-1,2-diol, propane-1,2,3-triol and sucrose

The dependence of rate constants for base hydrolysis on solvent composition for several iron(II)–diimine complexes has been established for aqueous ethane-1,2-diol (ethylene glycol) and aqueous propane-1,2,3-triol (glycerol) mixtures, and for aqueous sucrose solutions. These dependences are compared with analogous reactivity trends for binary aqueous solvent mixtures containing monohydroxylic alcohols. Transfer chemical potentials for iron(II)–diimine complexes, and for simple cations and anions, have been estimated on the TATB assumption for transfer to aqueous ethane-1,2-diol and aqueous propane-1,2,3-triol. These transfer chemical potentials allow resolution of the observed reactivity trends into initial-state and transition-state contributions for the aqueous ethane-1,2-diol mixtures. Such information on the role of solvation in this type of reaction is complented by the determination of activation volumes for base hydrolysis for four iron(II)–diimine complexes in aqueous ethane-1,2-diol.

Initial state and transition state solvation effects in the cobaltitungstate oxidation of iodide in binary aqueous solvent mixtures

SummaryRate constants are reported for 12-tungstocobaltate(III) [CoW12O40]5− oxidation of iodide in water and in binary aqueous solvent mixtures containing up to 40% methanol, 40% acetonitrile, or 60% dimethyl sulphoxide. From these kinetic results, solubility measurements on potassium 12-tungstocobaltate(III), and published data on Gibbs free energies of transfer of appropriate ions, it has been deduced that the dominant factor in determining the marked decrease in rate observed on going from water into the binary aqueous solvent mixtures is destabilisation of the transition state for the electron-transfer reaction.