Albert J. Leo

Hydrogen bonding. Part 34. The factors that influence the solubility of gases and vapours in water at 298 K, and a new method for its determination

The solubility of 408 gaseous compounds in water at 298 K has been correlated through eqn. (i), where the solubility is expressed as the Ostwald solubility coefficient, Lw, and the solute explanatory variables are R2 an excess molar refraction, π2H the dipolarity/polarizability, Σα2H and Σβ2H the effective hydrogen-bond acidity and basicity, and Vx the McGowan characteristic volume. A similar equation using the log L16 parameter instead of Vx can also be used; L16 is the Ostwald solubility coefficient on hexadecane at 298 K. log Lw=–0.994 + 0.577R2+ 2.549 π2H+ 3.813Σα2H+ 4.841Σβ2H– 0.869 Vx(i), n= 408 ρ= 0.9976 sd = 0.151 F= 16810 The main factors leading to increased solubility are solute π2H, Σα2H and Σβ2H values; conversely, the corresponding properties of water are dipolarity/polarizability, hydrogen-bond basicity and hydrogen-bond acidity. Solute size plays a minor role, and slightly decreases solubility, contrary to observations on all non-aqueous solvents. It is shown that this peculiar behaviour of water is due to (a) a greater increase in the unfavourable cavity effect with increase in solute size, for solvent water, and (b) a smaller increase in the favourable general dispersion interaction with size, for solvent water.A new method for the determination of log Lw values is put forward, using the relationship Lw=L16/P where L16 is as above, and P is either the water–hexadecane partition coefficient or the water–alkane partition coefficient. For 14 solutes using the former P-value, agreement with values calculated through eqn. (i) is 0.08 log units on average and for 45 solutes using the latter P-value, the corresponding agreement is 0.15 log units, with log Lw values ranging up to 8 log units.

The expanding role of quantitative structure-activity relationships (QSAR) in toxicology

Quantitative structure-activity relationships (QSAR) have found wide use in correlating the bioactivity of all kinds of organic compounds with all kinds of biological entities. So many QSAR have been published that it is time for a new phase of study, that of comparative QSAR. From our current database of about 6000 QSAR illustrative examples are discussed.

TOWARD A QUANTITATIVE COMPARATIVE TOXICOLOGY OF ORGANIC COMPOUNDS

Correlation equations between logP (P = octanol water partition coefficient) and the biological activity of alcohols has been derived for 101 examples on all sorts of systems, from simple proteins to whole animals. This provides an overview of the toxic nature of hydrophobic compounds which can be used as a basis for comparison of more complex chemicals. About 100 examples of the hydrophobic effects of chemicals, other than alcohols, to various living systems or their parts are presented for comparison. It is clear that hydrophobic xenobiotics are toxic to almost every form of life, including humans (or parts there of).

On the Role of Polarizability in Chemical−Biological Interactions

This report considers the importance of electronic effects in their role in the QSAR of chemical-biological interactions. The problem of accounting for polarizability effects in ligand-substrate interactions is discussed in terms of molecular polarizability (MR) and NVE (number of valence electrons) using additive values for valence electrons. The two approaches give essentially the same result in examples of frog nerve toxicity and examples of nerve toxicity with rabbits and cockroaches. The point is made that no matter how one approaches QSAR, electronic interactions must be considered if we are to begin to develop a science of chemical-biological interactions.

Role of hydrophobic effects in mechanistic QSAR

To extend the successful application of Hammett equations, previously used to predict equilibrium and rates of physico-chemical reactions with electronic and steric parameters, to the realm of biology and biochemistry, a parameter that measures hydrophobicity is required. The partition coefficient of a solute between octanol and water, expressed in log terms to put it on the same free-energy basis as the classic Hammett parameters, has been shown to be widely applicable. It is directly involved in passive transport through membranes, in binding to proteins, and in specific binding at active sites in enzymes. Methods of calculating logP(octanol) that reflect the solvation forces involved, can be useful in elucidating unusual solute conformations that may be preferred in a non-polar environment.

The partition of compounds from water and from air into wet and dry ketones

Literature data on partitioning of compounds from the gas phase to ketones and from water to ketones has been collected and analyzed through the Abraham solvation equations. It is shown that for partition into both dry and wet ketones the main solvent factors that aid partitioning into the ketones are the polarizability/dipolarity, hydrogen-bond basicity and hydrophobicity (size) of the ketones. Reliable equations have been established for partitioning from the gas phase and from water to dry acetone, dry butanone, dry cyclohexanone and to wet methyl isobutyl ketone. It is further shown that partitioning into dry butanone and dry cyclohexanone leads to different equations than partitioning into the wet solvents, and that data on partitioning into the wet and dry ketones cannot be combined.

Partition of compounds from water and from air into the wet and dry monohalobenzenes

Values of the partition coefficient from the gas phase (Ks) and from water (Ps) to the monohalobenzene solvents have been collected for fluorobenzene (21 solutes), chlorobenzene (212 solutes), bromobenzene (126 solutes) and iodobenzene (65 solutes). It is shown that for the wide range of solutes studied, partitions into the dry and wet (water-saturated) solvents are essentially the same, and that equations can be constructed that include data on both dry and wet solvents. Using the Abraham equations, that contain a maximum of five descriptors, statistically satisfactory equations are obtained for log Ks and log Ps with estimated predictive standard deviations of around 0.20 log units. The coefficients in the Abraham equations for the four halobenzene solvents are surprisingly similar and except for the s-coefficient, which reflects the solvent dipolarity/polarisability, are also similar to the coefficients for partition into toluene.

Water–Solvent Partition Coefficients and Δ Log P Values as Predictors for Blood–Brain Distribution; Application of the Akaike Information Criterion

It is shown that log P values for water-alkane or water-cyclohexane partitions, and the corresponding Delta log P values when used as descriptors for blood-brain distribution, as log BB, yield equations with very poor correlation coefficients but very good standard deviations, S from 0.25 to 0.33 log units. Using quite large data sets, we have verified that similar S-values apply to predictions of log BB. A suggested model, based on log P for water-dodecane and water-hexadecane partition coefficients, has 109 data points and a fitted S = 0.254 log units. It is essential to include in the model an indicator variable for volatile compounds, and an indicator variable for drugs that contain the carboxylic group. A similar equation based on water-chloroform partition coefficients has 83 data points and a fitted S = 0.287 log units. We can find no causal connection between these log P values and log BB in terms of correlation or in terms of chemical similarity, but conclude that the log P descriptor will yield excellent predictions of log BB provided that predictions are within the chemical space of the compounds used to set up the model. We also show that model based on log P(octanol) and an Abraham descriptor provides a simple and easy method of predicting log BB with an error of no more than 0.31 log units. We have used the Akaike information criterion to investigate the most economic models for log BB.

Calculating the hydrophobicity of chlorinated hydrocarbon solutes

Abstract Due to the known bioaccumulation and potential toxicity of chlorinated aromatic compounds, a great deal of effort has been directed to the measurement of their partition coefficients in the octanol/water system. Only recently has a system been described which gives reproducible values of log P > 5.0. Using these values, which indicate an appreciable interaction of adjacent chlorine atoms on the same ring and an even greater interaction between those in the 2,2′,6,6′ positions of biphenyl, it is possible to introduce negative ‘ortho -correction factors’ in the CLOGP algorithm which now should give satisfactory hydrophobicity estimations for structures which have not yet been measured. It is surprising to find that the correction for the chlorine substituents between rings appears additive from one to four. Therefore, it appears that the correction is not directly related to the angle which these substituents force the two rings to attain.

Octanol/water partition coefficients of 4-substituted benzylidene τ-butylamine N-oxides

Abstract Experimental octanol/water partition coefficients are reported for five 4-substituted benzylidene τ-butylamine N-oxides at 25°C. The results of these measurements are used to calculate the aromatic fragment constants. π HC = N(O)C(CH 3 ) 3 and f HC = N(O) , for the group contribution methods of Mansch and Leo.