pKa prediction from an ab initio bond length: part 3--benzoic acids and anilines

The prediction of pK(a) from a single ab initio bond length has been extended to provide equations for benzoic acids and anilines. The HF/6-31G(d) level of theory is used for all geometry optimisations. Similarly to phenols (Part 2 of this series of publications), the meta-/para-substituted benzoic acids can be predicted from a single model constructed from one bond length. This model had an impressive RMSEP of 0.13 pK(a) units. The prediction of ortho-substituted benzoic acids required the identification of high-correlation subsets, where the compounds in the same subset have at least one of the same (e.g. halogens, hydroxy) ortho substituent. Two pK(a) equations are provided for o-halogen benzoic acids and o-hydroxybenzoic acids, where the RMSEP values are 0.19 and 0.15 pK(a) units, respectively. Interestingly, the bond length that provided the best model differed between these two high-correlation subsets. This demonstrates the importance of investigating the most predictive bond length, which is not necessarily the bond involving the acid hydrogen. Three high-correlation subsets were identified for the ortho-substituted anilines. These were o-halogen, o-nitro and o-alkyl-substituted aniline high-correlation subsets, where the RMSEP ranged from 0.23 to 0.44 pK(a) units. The RMSEP for the meta-/para-substituted aniline model was 0.54 pK(a) units. This value exceeded our threshold of 0.50 pK(a) units and was higher than both the m-/p-benzoic acids in this work and the m-/p-phenols (RMSEP = 0.43) of Part 2. Constructing two separate models for the meta- and para- substituted anilines, where RMSEP values of 0.63 and 0.33 pK(a) units were obtained respectively, revealed it was the meta-substituted anilines that caused the large RMSEP value. For unknown reasons the RMSEP value increased with the addition of a further twenty meta-substituted anilines to this model. The C-N bond always produced the best correlations with pK(a) for all the high-correlation subsets. A higher level of theory and an ammonia probe improved the statistics only marginally for the hydroxybenzoic acid high-correlation subsets.     

Prediction of the dissociation constant pKa of organic acids from local molecular parameters of their electronic ground state

A quantum chemical method has been developed to estimate the dissociation constant pK(a) of organic acids from their neutral molecular structures by employing electronic structure properties. The data set covers 219 phenols (including 29 phenols with intramolecular H-bonding), 150 aromatic carboxylic acids, 190 aliphatic carboxylic acids, and 138 alcohols, with pK(a) varying by 16 units (0.38-16.80). Optimized ground-state geometries employing the semiempirical AM1 Hamiltonian have been used to quantify the site-specific molecular readiness to donate or accept electron charge in terms of both charge-associated energies and energy-associated charges, augmented by an ortho substitution indicator for aromatic compounds. The resultant regression models yield squared correlation coefficients (r(2)) from 0.82 to 0.90 and root-mean-square errors (rms) from 0.39 to 0.70 pK(a) units, corresponding to an overall (subset-weighted) r(2) of 0.86. Simulated external validation, leave-10%-out cross-validation and target value scrambling demonstrate the statistical robustness and prediction power of the derived model suite. The low intercorrelation with prediction errors from the commercial ACD package provides opportunity for a consensus model approach, offering a pragmatic way for further increasing the confidence in prediction significantly. Interestingly, inclusion of calculated free energies of aqueous solvation does not improve the prediction performance, probably because of the limited precision provided by available continuum-solvation models.     

Accurate prediction of basicity in aqueous solution with COSMO-RS

The COSMO-RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for realistic solvation simulations, has been used for the prediction of base pK(a) constants. For a variety of 43 organic bases the directly calculated values of the free energies of dissociation in water showed a very good correlation with experimental base pK(a) values (r2 = 0.98), corresponding to a standard deviation of 0.56 pK(a) units. Thus, we have an a priori prediction method for base pK(a) with the regression constant and the slope as only adjusted parameters. In accord with recent findings for pK(a) acidity predictions, the slope of pK(a) vs. DeltaG(diss) was significantly smaller than the theoretically expected value of 1/RTln(10). The predictivity of the presented method is general and not restricted to certain compound classes, but systematic corrections of 1 and 2 pKa units for secondary and tertiary aliphatic amines are required, respectively. The pK(a) prediction method was validated on a set of 58 complex multifunctional drug-like compounds, yielding an RMS accuracy of 0.66 pK(a) units.     

Extension of the self-consistent spectrophotometric basicity scale in acetonitrile to a full span of 28 pKa units: unification of different basicity scales

The earlier compiled self-consistent spectrophotometric basicity scale in acetonitrile (AN) was expanded to range from 3.8 to 32.0 pK(a) units, that is 28 orders of magnitude. Altogether 54 new relative basicity measurements (DeltapK(a) measurements) were carried out and 37 new compounds were introduced to the scale (it now includes altogether 89 bases). The relative basicity of any two bases in the scale can be obtained by combining at least two independent sets of measurements. Multiple overlapping measurements make the results more reliable. The overall consistency (as defined earlier) of the measurements is s = 0.03 pK(a) units. Thorough analysis of all of our experimental data (DeltapK(a) values of this and earlier works) and experimental pK(a) data in AN available in the literature (works from the groups of Coetzee and Padmanabhan, Kolthoff and Chantooni, Jr., the Schwesinger group, Bren' et al. and some others, altogether 19 papers) was carried out. On the basis of this analysis the anchor point of the scale-pyridine-was shifted upward by 0.20 pK(a) units thereby also revising the absolute pK(a) values of all the bases on the scale. This way very good agreement between our relative data and the absolute pK(a) values of the abovementioned authors was obtained. The revised basicity scale was interconnected with the earlier published self-consistent acidity scale by DeltapK(a) measurements between acids and bases. The rms deviation between the directly measured DeltapK(a) values and the absolute pK(a) values of the compounds was 0.10 pK(a) units.     

Thermodynamic dissociation constants of N-phenylbenzohydroxamic acids and benzohydroxamic acid

Thermodynamic association constants of benzohydroxamic acid and several ortho-substituted N-phenylbenzohydroxamic acids have been determined by pH titration in aqueous dioxan media at 25 degrees and 35 degrees . Empirical pH corrections for mixed aqueous media have been applied. The pK(a) values do not vary linearly with the reciprocal of dielectric constant of the medium, but a plot of pK(a) vs. the mole fraction of dioxan is linear at a given temperature. Values of DeltaG degrees , DeltaH degrees and DeltaS degrees are tabulated.     

Determination of the chromatographic hydrophobicity index for ionisable solutes

A model that relates the chromatographic hydrophobicity index (CHI) to the pH of the mobile phase has been tested in two of the most common high-performance liquid chromatography (HPLC) solvents: methanol and acetonitrile. A set of eight monoprotic acids and nine monoprotic bases of different chemical nature (phenols, benzoic acids, anilines, and pyridine) have been selected for the validation. The variation of CHI values with the pH of the mobile phase shows a good fit to the model for almost all compounds, regardless of their nature, and similar CHI values of the neutral form of the substances are obtained in both organic modifiers. On the contrary, higher differences are observed for the ionic form of the test solutes. The values of the other parameters obtained with the model (s, pK(a)) are discussed according to the nature of the compounds, and the variation of solvent pH and compounds pK(a) along the gradient elution.     

Concerted electron-proton transfer (EPT) in the oxidation of tryptophan with hydroxide as a base

Tryptophan is unique among the redox-active amino acids owing to its weakly acidic indolic proton (pK(a) ≈ 16) compared to the -O-H proton of tyrosine (pK(a) = 10.1) or the -S-H proton of cysteine (pK(a) = 8.2). Stopped-flow and electrochemical measurements have been used to explore the roles of proton-coupled electron transfer and concerted electron-proton transfer (EPT) in tryptophan oxidation. The results of these studies have revealed a role for OH(-) as a proton acceptor base in EPT oxidation of N-acetyl-tryptophan but not for other common bases. The reorganizational barrier for (N-acetyl-tryptophan)(+/?) self-exchange is also estimated.     

Capillary zone electrophoresis of basic analytes in methanol as non-aqueous solvent mobility and ionisation constant

The electrophoretically relevant properties of monoacidic 21 bases (including common drugs) containing aliphatic or aromatic amino groups were determined in methanol as solvent. These properties are the actual mobilities (that of the fully ionised weak bases), and their pKa values. Actual mobilities were measured in acidic methanolic solutions containing perchloric acid. The ionisation constants of the amines were derived from the dependence of the ionic mobilities on the pH of the background electrolyte solution. The pH scale in methanol was established from acids with known conventional pK*a values in this solvent used as buffers, avoiding thus further adjustment with a pH sensitive electrode that might bias the scale. Actual mobilities in methanol were found larger than in water, and do not correlate well with the solvent's viscosity. The pK*a values of the cation acids, HB-, the corresponding form of the base, B, are higher in methanol, whereas a less pronounced shift was found than for neutral acids of type HA. The mean increase (compared to pure aqueous solution) for aliphatic ammonium type analytes is 1.8, for substituted anilinium 1.1, and for aromatic ammonium from pyridinium type 0.5 units. The interpretation of this shift was undertaken with the concept of the medium effect on the particles involved in the acid-base equilibrium: the proton, the molecular base, B, and the cation HB+.     

Polymer-supported (2,6-dichloro- 4-alkoxyphenyl)(2,4-dichlorophenyl)methanol: a new linker for solid-phase organic synthesis

An acid and base stable hydroxytetrachlorodiphenylmethyl (HTPM) linker is developed for polymer-supported organic synthesis. The linkers reported here are utilized for loading carboxylic acids, amines, alcohols, and phenols, and are stable to Br?nsted and Lewis acids, Br?nsted bases, and a wide variety of nucleophiles. However, the HTPM linkers can conveniently be cleaved by the solvolytic displacement reactions with 20% TFA. [structure: see text]     

Protonation studies of modified adenine and adenine nucleotides by theoretical calculations and (15)N NMR

The acid/base character of nucleobases affects phenomena such as self-association, interaction with metal ions, molecular recognition by proteins, and nucleic acid base-pairing. Therefore, the investigation of proton-transfer equilibria of natural and synthetic nucleos(t)ides is of great importance to obtain a deeper understanding of these phenomena. For this purpose, a set of ATP prototypes was investigated using (15)N NMR spectroscopy, and the corresponding adenine bases were investigated by theoretical calculations. (15)N NMR measurements provided not only acidity constants but also information on the protonation site(s) on the adenine ring and regarding the ratio of the singly protonated species in equilibrium. Substituents of different nature and position on the adenine ring did not change the preferred protonation site, which remained N1. However, for 2-thioether-ATP derivatives a mixed population of N1 and N7 singly protonated species was observed. Reduction of basicity of 0.4-1 pK(a) units relative to ATP was also observed for all evaluated ATP derivatives, except for 2-Cl-ATP, for which K(a) was ca. 10,000-fold lower. To explain the substitution-dependent variations in the experimental pK(a) values of the ATP analogues, gas-phase proton affinities (PA), Delta Delta G(hyd), and pK(a) values of the corresponding adenine bases were calculated using quantum mechanical methods. The computed PA and Delta Delta G(hyd) values successfully explained the experimental pK(a) values. A computational procedure for the prediction of accurate pK(a) values was developed using density functional theory and polarizable continuum model calculations. In this procedure, we developed a set of parameters for the polarizable continuum model that was fitted to reproduce experimental pK(a) values of nitrogen heterocycles. This method is proposed for the prediction of pK(a) values and protonation site(s) of purine analogues that have not been synthesized or analyzed.     

Gas chromatographic and spectral properties of pentafluorobenzyl derivatives of 2,4-dichlorophenoxyacetic acid and phenolic pesticides and metabolites

Eleven phenols and 2,4-dichlorophenoxyacetic acid, compounds that may be found in body fluids of humans exposed to pesticides, are derivatized with pentafluorobenzyl bromide and characterized by gas chromatography with electron capture detection. These derivatives are further characterized by positive and negative chemical ionization mass spectrometry, nuclear magnetic resonance spectroscopy, and gas chromatography-Fourier transform infrared spectroscopy. Negative chemical ionization mass spectra of all derivatives have an anionic base peak derived from the parent analyte. In the positive mode the nonchlorinated derivatives have base peaks indicative of the analyte, while chlorinated derivatives are cleaved to give the pentafluorobenzyl cation as base peak. The possibility is explored that ortho-substituted phenols might be formed as byproducts in these derivatizations.     

The coulometric titration of acids and bases in dimethylsulfoxide media

The coulometric titration of 20–200 μeq of acids and bases in DMSO media is described. In the titration of bases, the electro-oxidation of hydrogen at a platinized platinum electrode is used as the source of protons. The conditions for 100 % current efficiency at this electrode are low current density to avoid passivity and regular treatment of the electrode with potassium dichromate—sulfuric acid to remove a poisoning sulfide layer. The accuracy of the titrations is better than ±1 %. Very weak acids like phenols (pK_a (DMSO) ≈16) can be titrated successfully. Tris(hydroxymethyl)aminomethane is the weakest base titrated.     

Potentiometric determination of pK(A) of organic bases in acetone by the application of coulometry

A coulometric-potentiometric method for the determination of pK(A) values of organic bases in anhydrous acetone is described. The bases were titrated with protons obtained by anodic oxidation of hydrogen dissolved in palladium, in the presence of sodium perchlorate as the supporting electrolyte. A pair of glass electrodes was used for measuring directly the difference between the half-neutralization potentials of the standard and the base being studied. The pK(A) values obtained were close to those reported in the literature. The effect of the supporting electrolyte concentration on the pK(A) values of some of the bases was also studied.     

A fast high throughput method for the determination of acidity constants by capillary electrophoresis. 3. Basic internal standards

A set of 25 monoprotic bases is proposed as internal standards for pK(a) determination by capillary electrophoresis. The pK(a) of the bases is determined and compared with available literature data. The capillary electrophoresis internal standard method offers numerous advantages over other typical methods for pK(a) determination, especially of analysis time and buffer preparation. However, it requires disposing of appropriate standards with reference pK(a) value. The set of bases established in this work together with the set of acids previously established provide a reference set of compounds with well-determined acidity constants that facilitate the process of selecting appropriate internal standards for fast pK(a) determination by capillary electrophoresis in high throughput screening of pharmaceutical drugs. In addition, the performance of the method when acidic internal standards are used for the determination of acidity constants of basic internal standards has also been tested. Although higher errors may be expected in this case, good agreement is observed between determined and literature values. These results indicate that in most cases structural similarity between the analyte and the internal standard might not be an essential requirement in the internal standard method.