Hydrogen-bond Basicity Research Articles

Insights into the Solvation Characteristics of Zwitterionic Deep Eutectic Solvents Using Multiple Polarity Scales

Deep eutectic solvents (DESs) formed by mixing zwitterionic hydrogen bond acceptors (HBAs) with diol- and organic acid-based hydrogen bond donors (HBDs) are popular sustainable solvents. In addition to possessing an amphiphilic character, zwitterionic DESs offer unique solvation properties, unlike those composed of halide-containing HBAs. While all other popular classes of DESs have been investigated, no study has attempted to characterize the solvation characteristics of zwitterionic DESs. In this study, the solvation properties of betaine [Bet]-, sulfobetaine-, and l-carnitine [l-Car]-based DESs were thoroughly investigated for the first time using solvatochromic dye methods and inverse gas chromatography (IGC). The Nile red polarity scale revealed that DESs composed of organic acids were generally more polar than diol-based DESs. Kamlet–Taft solvent parameters revealed that glycerol-based DESs offered exceptionally high hydrogen bond donating ability compared to those composed of 1,4-butane diol and triethylene glycol. The Abraham solvation parameter model revealed hydrogen bond basicity to be the most dominant interaction, and it was generally higher for diol-based HBDs compared to organic acid-based HBDs. Additionally, sulfobetaine HBAs possessing longer alkyl chains generally offered higher dispersive-type interactions and hydrogen bond basicity compared to [Bet] and [l-Car] salts. This is the first study to combine and compare results from solvatochromic dye methods and IGC in an attempt to comprehensively explain and predict the solvation characteristics of zwitterionic DESs.

Supramolecular Tuning of Spin Crossover Properties in Isostructural Cocrystal Solvates

In order to improve strategies for the design of spin-crossover materials, it is necessary to develop and understand structure–property relationships, and this is best achieved by obtaining isostructural materials. In this work we synthesized a series of four isostructural cocrystal solvates using the [Fe(3-bpp)2][A]2 complex and the 2,2-dipyridyl disulfide coformer in methanol and ethanol (A = BF4– or PF6–). The spin-crossover properties of the materials were determined by variable temperature single-crystal X-ray diffraction. They show the same SCO behavior but with shifted spin-crossover temperatures, which has been related to the hydrogen bond basicity, pKBHX of the anions, and solvents present. This relationship between hydrogen bond basicity and the spin-crossover transition temperature offers a design strategy for the supramolecular tuning of spin-crossover properties in specific isostructural materials.

On donor-acceptor-bridging intramolecular hydrogen bonds in NIR-TADF molecules.

Following a report that highlights the importance of intramolecular hydrogen bonds for improved NIR-TADF efficiency in CAT-1 [Leng et al., J. Phys Chem. A, 2021, 125, 2905], an intramolecularly doubly hydrogen-bonded base design is investigated and compared to singly and non-bonded derivatives. It is found that the potential to form more intramolecular hydrogen bonds correlates with decreasing internal reorganization energies in most of the designed structures. In addition, our proposed base design facilitates the desired interlocking of charge transfer donor-, linker- and acceptor-planes through steric gauche-interactions to both linker-plane sides, allowing to trap also smaller heterocyclic linkers.

Organic-NaH2PO4-H2O aqueous biphasic system for extraction of paeonol from cortex moutan: Solvent selection and mechanism probing

Aqueous biphasic system (ABS) for extraction of active components attracted increasing attention due to advantages of high extraction efficiency and high product purity. However, solvent factors ruling extraction is still unclear. Four new ABSs with different organic solvent were designed for paeonol extraction, and the extraction conditions such as NaH2PO4 concentration, organic solvent fraction, extraction period and temperature were examined with single factor method. The paeonol extraction yield, partition coefficient and paeonol purity with ABSs at optimized conditions were in the order as follows: ABS-THF-EA (33.6 ± 1.5 mg/g) ≈ABS-Ac-EA (33.0 ± 1.3 mg/g) > ABS-EtOH-EA (31.6 ± 1.6 mg/g)≈70 % ethanol (v/v) (31.2 ± 1.4 mg/g) > ABS-THF (28.8 ± 1.0 mg/g) > ABS-Ac (27.6 ± 1.2 mg/g) > ABS-EtOH (25.2 ± 1.2 mg/g), suggesting that replacing fraction of acetone/THF with ethyl acetate (EA) in ABSs could improve paeonol yield. Compositions and solvatochromic parameters for top phase of 12 ABSs were detected. Using LSER model, paeonol yield was strongly correlated to the dipolarity/dipolarizability (π*), hydrogen bond acidity (α) and hydrogen bond basicity (β) of top-phase medium in ABS (r2 = 0.982, n = 12); and partition coefficient was reasonably correlated to π*, α and β (r2 = 0.942, n = 12). Hydrogen-bond interaction and hydrophobicity interaction between paeonol and top-phase medium were crucial for efficient extraction. Solvatochromic parameters can offer guidance to solvent selection in extraction with ABS.

The Solubility of Ethyl Candesartan in Mono Solvents and Investigation of Intermolecular Interactions

In this work, the experimental solubility of ethyl candesartan in the selected solvents within the temperature ranging from 278.15 to 318.15 K was studied. It can be easily found that the solubility of ethyl candesartan increases with the rising temperature in all solvents. The maximum solubility value was obtained in N,N-dimethylformamide (DMF, 7.91 × 10−2), followed by cyclohexanone (2.810 × 10−2), 1,4-dioxanone (2.69 × 10−2), acetone (7.04 × 10−3), ethyl acetate (4.20 × 10−3), n-propanol (3.69 × 10−3), isobutanol (3.38 × 10−3), methanol (3.17 × 10−3), n-butanol (3.03 × 10−3), ethanol (2.83 × 10−3), isopropanol (2.69 × 10−3), and acetonitrile (1.15 × 10−2) at the temperature of 318.15 K. Similar results of solubility sequence from large to small were also obtained in other temperatures. The X-ray diffraction analysis illustrates that the crystalline forms of all samples were consistent, and no crystalline transformation occurred during the dissolution process. In aprotic solvents, except for individual solvents, the solubility data decreases with the decreasing values of hydrogen bond basicity (β) and dipolarity/polarizability (π*). The largest average relative deviation (ARD) data in the modified Apelblat equation is 1.9% and observed in isopropanol; the maximum data in λh equation is 4.3% and found in n-butanol. The results of statistical analysis show that the modified Apelblat equation is the more suitable correlation of experimental data for ethyl candesartan in selected mono solvents at all investigated temperatures. In addition, different parameters were used to quantify the solute–solvent interactions that occurred in the dissolution process including Abraham solvation parameters (APi), Hansen solubility parameters (HPi), and Catalan parameters (CPi).

General Designs Reveal Distinct Codes in Protein-Coding and Non-Coding Human DNA.

This study seeks to investigate distinct signatures and codes within different genomic sequence locations of the human genome. The promoter and other non-coding regions contain sites for the binding of biological particles, for processes such as transcription regulation. The specific rules and sequence codes that govern this remain poorly understood. To derive these (codes), the general designs of sequence are investigated. Genomic signatures are a powerful tool for assessing the general designs of sequence, and cross-comparing different genomic regions for their distinct sequence properties. Through these genomic signatures, the relative non-random properties of sequences are also assessed. Furthermore, a binary components analysis is carried out making use of information theory ideas, to study the RY (purine/pyrimidine), WS (weak/strong) and KM (keto/amino) signatures in the sequences. From this comparison, it is possible to identify the relative importance of these properties within the various protein-coding and non-coding genomic locations. The results show that coding DNA has a strongly non-random WS signature, which reflects the genetic code, and the hydrogen-bond base pairing of codon-anti-codon interactions. In contrast, non-coding locations, such as the promoter, contain a distinct genomic signature. A prominent feature throughout non-coding DNA is a highly non-random RY signature, which is very different in nature to coding DNA, and suggests a structural-based RY code. This marks progress towards deciphering the unknown code(s) in non-protein-coding DNA, and a further understanding of the coding DNA. Additionally, it unravels how DNA carries information. These findings have implications for the most fundamental principles of biology, including knowledge of gene regulation, development and disease.

Estimating Equivalent Alkane Carbon Number Using Abraham Solute Parameters

The use of equivalent alkane carbon numbers (EACN) to characterize oils is important in surfactant-oil-water (SOW) systems. However, the measurement of EACN values is non-trivial and thus it becomes desirable to predict EACN values from structure. In this work, we present a simple linear model that can be used to estimate the EACN value of oils with known Abraham solute parameters. We used linear regression with leave-one-out cross validation on a dataset of N = 80 oils with known Abraham solute parameters to derive a general model that can reliably estimate EACN values based upon the Abraham solute parameters: E (the measured liquid or gas molar refraction at 20 °C minus that of a hypothetical alkane of identical volume), S (dipolarity/polarizability), A (hydrogen bond acidity), B (hydrogen bond basicity), and V (McGowan characteristic volume) with good accuracy within the chemical space studied (N = 80, R2 = 0.92, RMSE = 1.16, MAE = 0.90, p < 2.2 × 10−16). These parameters are consistent with those in other models found in the literature and are available for a wide range of compounds.

Study of solute-solvent intermolecular interactions and preferential solvation for mevastatin dissolution in pure and mixed binary solvents

The solute-solvent and solvent-solvent interactions between mevastatin and different solvents were studied. In pure solvent, the largest solubility was found in 2-butanone (2.592×10−2) and minimum in cyclohexane (5.068×10−5) at 318.15 K. The non-specific and hydrogen bonding interactions including the dipolarity/polarizability (π*), Hildebrand solubility parameter (δH), hydrogen bond acidity (α) and hydrogen bond basicity (β) were analyzed. In mixture of (ethyl acetate + ethanol), the maximum solubility (2.144×10−2) is observed in 80%: 20% w/w of ethyl acetate: ethanol. Almost the same interaction energy and equilibrium mixing energy between solute and solvent promote the occurrence of co-solvency phenomenon. Moreover, according to the preferential solvation results, it is conjecturable that in intermediate composition mixtures and ethyl acetate-rich mixtures, mevastatin molecules are acting mainly as Lewis acid and Lewis base, respectively. Meanwhile, two thermodynamic models including modified Apelblat equation and Jouyban-Acree model are suitable to evaluate the dissolution profile, and the maximum value of relative average deviation is no >5%. The apparent thermodynamic properties of dissolution process in all investigated solvents are calculated which suggest that dissolution process is an endothermic process.

Hirshfeld surface and electrostatic potential surface analysis of clozapine and its solubility and molecular interactions in aqueous blends

Solubility and relevant thermodynamic properties as well as molecular interactions of clozapine in aqueous systems of protic cosolvent, e.g. isopropanol, and aprotic cosolvents such as acetonitrile, dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidinone (NMP) are focus of this paper. The intermolecular interactions and overall charge distribution of clozapine were respectively investigated by using Hirshfeld surface analysis and molecular electrostatic potential surface. All experimentations were executed using a shake-flask approach under p = 101.2 kPa (local pressure) from 278.15 (293.15) to 323.15 (333.15) K. The minimum solubility data of clozapine appeared in neat water for each aqueous system at 278.15 K; and the maximum one, in neat cosolvent at 328.15 K. Correlation of the solubility data (mole fraction) through Jouyban–Acree and MRS models acquired acceptable results with relative average deviations (RAD) of no>9.15 %. The solvent descriptors of hydrogen-bonding basicity, solubility parameter and dipolarity-polarizability predominantly controlled the clozapine solubility variation through the quantitative analysis of linear solvation energy relationships in terms of the solubility data at 298.15 K. The extended Hildebrand solubility approach was also employed here to correlate the solubility and study the solvation behavior of solutions. Quantitatively analysis of preferential solvation of clozapine by solvent species in solutions was conducted by the method of inverse Kirkwood–Buff integrals. In the solutions with middle and cosolvent-rich compositions, the parameters of preferential solvation for DMSO, NMP, acetonitrile or isopropanol were positive, which specified that preferential solvation of clozapine was made by co-solvent. In addition, the thermodynamic properties of dissolution of clozapine along with enthalpy–entropy compensation were derived and deeply discussed.

A Density Functional Theory and Information-Theoretic Approach Study of Interaction Energy and Polarizability for Base Pairs and Peptides.

Using density functional theory (DFT) and the information-theoretic approach (ITA) quantities to appreciate the energetics and properties of biopolymers is still an unaccomplished and ongoing task. To this end, we studied the building blocks of nucleic acid base pairs and small peptides. For base pairs, we have dissected the relative importance of energetic components by using two energy partition schemes in DFT. Our results convincingly show that the exchange-correlation effect predominantly governs the molecular stability of base pairs while the electrostatic potential plays a minor but indispensable role, and the steric effect is trivial. Furthermore, we have revealed that simple density-based ITA functions are in good relationships with molecular polarizabilities for a series of 30 hydrogen-bonded base pairs and all 20 natural α-amino acids, 400 dipeptides, and 8000 tripeptides. Based on these lines, one can easily predict the molecular polarizabilities of larger peptides, even proteins as long as the total molecular wavefunction is available, rather than solving the computationally demanding coupled-perturbed Hartree–Fock (CPHF) equation or its DFT counterpart coupled-perturbed Kohn–Sham (CPKS) equation.

Solubility measurement, correlation and mixing properties of thioacetamide in fifteen pure solvents

The solubility of thioacetamide in fifteen pure solvents (methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol, ethyl acetate, 2-butanone, 2-pentanone, acetone, acetonitrile, ethyl formate and methyl acetate) was determined by a gravimetric method from 272.85 K to 323.95 K under ambient pressure. Four thermodynamic models, including the modified Apelblat equation, Buchowski-Ksiazaczak λh equation, non-random two-liquid (NRTL) model and the Wilson model were used to correlate the solubility data. And the NRTL model provides the best data fitting results among the four models. To elucidate the dissolution behavior of thioacetamide, the KAT-LSER model was introduced to analyze the solvent effect. The results revealed that hydrogen bond basicity and bipolarity/polarizability had a similar and significant favorable effect to the dissolution of thioacetamide. The mixing thermodynamic properties such as enthalpy, entropy and Gibbs free energy were calculated and the results indicated that the dissolution process of thioacetamide was spontaneous and favorable.

A Study of the Abraham Effective Solute Hydrogen Bond Basicity Parameter Using Computationally Derived Molecular Properties

A Study of the Abraham Effective Solute Hydrogen Bond Basicity Parameter Using Computationally Derived Molecular Properties

The pKBHX Hydrogen-Bond Basicity Scale: From Molecules to Anions

The pKBHX (logarithm of complexation constant K of 4-fluorophenol with bases) hydrogen-bond basicity scale of neutral hydrogen-bond acceptors (HBAs) is extended to anionic HBAs. The scale is constructed for 26 anions through (i) the infrared measurement of K on NBu4+X- ion pairs in CCl4, (ii) the estimation of K from linear free energy relationships between measured K values and literature K values for various phenols in polar solvents, and (iii) the computation of K at the density functional theory level in CCl4. The scale extends on a 9.4 pK unit range from fluoride to tetraphenylborate. Considering a number of anions as organic functions substituted with unipolar substituents, their pKBHX values can be related to the Hammett-Taft substituent constants σ. Unipolar substituents (O- and S-) obey the same pKBHX versus σ relationships as dipolar ionic (N-N+R3) and dipolar (OH, CF3, NR2, or OR) ones for the nitrile, carbonyl, nitroso, nitro, sulfonyl, and phosphoryl functions. Like dipolar substituents, unipolar substituents at carbon and nitrogen operate by field-inductive and resonance effects, whereas substituents at sulfur and phosphorus operate only by the field-inductive effect.

Solute–Solvent Interactions in Hydrophilic Interaction Liquid Chromatography: Characterization of the Retention in a Silica Column by the Abraham Linear Free Energy Relationship Model

The Abraham linear free energy relationship model has been used to characterize a hydrophilic interaction liquid chromatography (HILIC) silica column with acetonitrile/water and methanol/water mobile phases. Analysis by the model for acetonitrile/water mobile phases points to solute volume and hydrogen bond basicity as the main properties affecting retention, whereas solute hydrogen bond acidity, dipolarity and polarizability practically do not affect it. Formation of a cavity is easier in acetonitrile-rich mobile phases than in the aqueous stationary phase, and hence increase of solute volume decreases retention. Conversely, hydrogen bond acidity is stronger in the aqueous stationary phase than in the acetonitrile-rich mobile phase and thus an increase of solute hydrogen bond basicity increases retention. Results are similar for methanol/water mobile phases with the difference that solute hydrogen bond acidity is significant too. Increase in hydrogen bond acidity of the solute decreases retention showing that methanol mobile phases must be better hydrogen bond acceptors than acetonitrile ones, and even than water-rich stationary phases. The results are like the ones obtained in zwitterionic HILIC columns bonded to silica or polymer supports for acetonitrile/water mobile phases, but different for solute hydrogen bond acidity for a polymer bonded zwitterionic column with methanol/water mobile phases, indicating that bonding support plays an important role in HILIC retention. Comparison to RPLC characterized systems confirms the complementarity of HILIC systems to RPLC ones because the main properties affecting retention are the same but with reversed coefficients. The least retained solutes in RPLC are the most retained in HILIC.

Investigation on Hansen solubility parameter, solvent effect and thermodynamic properties of 3-methylflavone-8-carboxylic acid dissolved in different solvents

In this work, the dissolution behavior of a novel pharmacological factor, 3-methylflavone-8-carboxylic acid (MFCA) in different solvents was studied. Firstly, the solubility of MFCA in ten mono-solvents (acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, methyl acetate, ethyl acetate, butyl acetate, methanol, ethanol and isobutanol) and three binary solvents (N,N-dimethylformamide + acetonitrile, tetrahydrofuran + acetonitrile, methyl acetate + acetonitrile) at different temperatures (273.15–323.15 K) was determined by static equilibrium-high performance liquid chromatography. The experimental results showed that the solubility of MFCA increased with increasing temperature in tested solvents, and the solubility of MFCA in N,N-dimethylformamide was maximal. The Hansen solubility parameter was used to research the dissolution behavior of MFCA. Meanwhile, the solvent effect was discussed by KAT-LSER model in ten mono-solvents, and it was found that the hydrogen bond basicity and nonspecific dipolarity/polarizability were favorable to the dissolution of MFCA. In addition, modified Apelblat model, λh model, CNIBS/R-K model and Jouyban-Acree model were used to analyze the correlation and evaluate the applicability for the experimental solubility data of MFCA. The calculated data showed that modified Apelblat model and CNIBS/R-K model are the best models for mono and binary solvents, respectively. Finally, the dissolution thermodynamic properties of MFCA were studied by van't Hoff analysis, indicating that the dissolution of MFCA was an endothermic and entropic driven process. To sum up, these experimental results could provide pretty reference for purification and crystallization optimization of MFCA, and realize the industrial large-scale production of various drugs such as diuretic.

Enzymes in nearly anhydrous deep eutectic solvents: Insight into the biocompatibility and thermal stability

With the development of green chemistry, the demand for environmentally friendly and biocompatible solvents for non-aqueous enzymatic catalysis is increasingly urgent. Deep eutectic solvents (DESs) are viewed as the most promising alternatives to traditional organic solvents in non-aqueous biocatalysis. To expand the types of DESs and provide guidance for DESs design for non-aqueous enzymatic catalysis, the enzyme performance in aqueous buffer after incubation in nearly anhydrous DESs was associated with the properties and component structures of DESs. Almond β- Glucosidase (β-GC) and Candida antarctica lipase B (CALB) were selected as model enzymes. Physico-chemical properties of DESs (as inferred by their solvatochromic parameters) were applied to explore the influences of DESs properties on enzyme activity. For DESs with the same HBD, the biocompability of DESs and thermal stability of enzymes in DESs were negatively associated with the polarity and hydrogen bond acidity of DESs, and were positively associated with hydrogen bond basicity of DESs. Whereas an opposite trend was observed in DESs with the same HBA. Analyzing from the DESs components, the biocompatibility of hydrophobic DESs for enzyme was much lower than that of hydrophilic DESs. Generally, the amount of hydroxyl group and the length of carbon chain represent advantageous ingredients for maintaining natural structure of enzyme molecule. The presence of carboxyl group in hydrophilic DESs and carbon-carbon double bond may impair enzyme structure and activity. This work is hoped to be helpful in expanding the applications of DESs in non-aqueous biocatalysis.

Study of system properties in reversed-phase liquid chromatography for binary and ternary solvent mobile phase compositions using the solvation parameter model

System maps for the individual system constant of the solvation parameter model and five binary solvent containing 20–70% (v/v) acetonitrile, acetone, methanol, 2-propanol, and tetrahydrofuran on a single octadecylsiloxane-bonded silica column (Luna C18) are used to provide insight into the variation of system properties with mobile phase composition and solvent type. Selectivity differences are dominated by variation in solute size and hydrogen-bond basicity with solvent-dependent variation in dipole-type and hydrogen-bond acid interactions. Interactions involving lone pair electrons are important only in the case of the alcohols and to a lesser extent tetrahydrofuran. Selectivity differences are also dependent on solvent strength. To expand the selectivity space four ternary solvent systems (acetonitrile-methanol-water, acetonitrile-2-propanol-water, methanol-tetrahydrofuran-water, and tetrahydrofuran-2-propanol-water) 1:1:2% (v/v) containing 50% (v/v) total organic solvent are compared with the binary solvent systems at the same organic solvent composition. There is no simple model that links the system properties of the ternary solvents to the binary solvent systems, but it is demonstrated that the ternary solvent systems expand the selectivity space available for reversed-phase separations. The solvation properties of the bulk organic solvents provide insufficient information to predict selectivity in RPLC because of the dominant contribution of water and effects related to the selective solvation of the stationary phase and possible changes in the solvent-dependent microstructure of the mobile phase.

Retention properties of acetone-water mobile phases on a biphenylsiloxane-bonded silica stationary phase in reversed-phase liquid chromatography.

The solvation parameter model system constants and retention factors were used to interpret retention properties of 39 calibration compounds on a biphenylsiloxane-bonded stationary phase (Kinetex biphenyl) for acetone-water binary mobile phase systems containing 30-70% v/v. Variation in system constants, phase ratios, and retention factors of acetone-water binary mobile phases systems were compared with more commonly used acetonitrile and methanol mobile phase systems. Retention properties of acetone mobile phases on a Kinetex biphenyl column were more similar to that of acetonitrile than methanol mobile phases except with respect to selectivity equivalency. Importantly, selectivity differences arising between acetone and acetonitrile systems (the lower hydrogen-bond basicity of acetone-water mobile phases and differences in hydrogen-bond acidity, cavity formation and dispersion interactions) could be exploited in reversed-phase liquid chromatography method development on a Kinetex biphenyl stationary phase.

Investigating the effect of systematically modifying the molar ratio of hydrogen bond donor and acceptor on solvation characteristics of deep eutectic solvents formed using choline chloride salt and polyalcohols

Choline chloride-based deep eutectic solvents (DESs) are immensely popular in organic synthesis, catalysis, electrochemistry, and separation science. A popular choice of hydrogen bond donor (HBD) among these DESs consists of both straight-chain and branched polyols that can incorporate additional functional groups, such as ether linkages. Previous studies have shown that the extraction efficiency is significantly altered when the molar ratio of HBD in choline chloride-based DES systems is varied, but no study has been able to relate it to their solvation characteristics. This is largely due to the limited sensitivity of existing solvatochromic dye techniques to detect minor changes in solvation interactions when the DES composition is varied. In this study, inverse gas chromatography was employed for the first time to investigate the variation in solvation properties for DESs comprised of choline salts as hydrogen bond acceptors (HBAs) and polyols as HBDs when their HBA/HBD ratio is systematically altered. Unlike many organic solvents, DES systems investigated in this work possessed a significant hydrogen bond character. It was observed that the hydrogen bond basicity generally plateaued at higher molar ratios of HBD while the hydrogen bond acidity was observed to be the highest at HBA/HBD ratios of 1:10 in all DESs. Amongst all solvents, neat HBDs (triethylene glycol and 1,8-octane diol) possessed the weakest hydrogen bond basicity since they lack the chloride anion that acts as the primary hydrogen bond acceptor. Results from this study demonstrate that the solvation characteristics of DESs are largely different from their starting materials while the HBA/HBD ratio further influences their solvation interactions that can in turn impact important parameters such as extraction yields.

Abraham Model Descriptors for Melatonin; Prediction of Solution, Biological and Thermodynamic Properties

Literature solubilities have been used to obtain properties or descriptors of melatonin. These indicate the chemical nature of melatonin: it is dipolar and has moderate hydrogen bond acidity and hydrogen bond basicity. The descriptors can be combined with equations that we have previously constructed to estimate water–solvent partition coefficients and solubilities in a huge number of organic solvents. In the same way, a range of biological properties can be estimated. These include blood–tissue partitions, water–skin partition and permeability through skin.