Determination of weak (2.0–2.5) dissociation constants of non-UV absorbing solutes by capillary electrophoresis

Summary Capillary electrophoresis (CE) has proved to be a fast and convenient method for the determination of the dissociation constants of non-UV absorbing solutes in the acidic pK _A range (2.0–2.5). The electroosmotic flow was reversed by washing the capillary with 0.2% polybren aqueous solution. A series of background electrolytes was prepared with phenylphosphonic acid (pK _A=1.29) and β-alanine (pK _A=3.55) with the same ionic strength and a high buffer capacity in order to improve the repeatability (0.1–0.2 %) of the electrophoretic mobility and to determine the values of pK _A accurately. This procedure was applied to the determination of the dissociation constants of several alkyl-alkylphosphonic acids whose pK _A values have not yet been published in the literature. In this work, their dissociation constants have been found to vary between 1.91 and 2.34 for alkyl-methylphosphonic acids and between 2.10 and 2.38 for alkyl-ethylphosphonic acids.     

Determination of thermodynamic pKa values of pharmaceuticals from five different groups using capillary electrophoresis

A determination of the thermodynamic acid dissociation constants (pK_a) of 22 frequently used pharmaceuticals using capillary electrophoresis in aqueous media is presented in this work. The investigated pharmaceuticals belong to different pharmacological groups: macrolides, fluoroquinolones, sulfonamides, β‐lactams, tetracyclines, and other miscellaneous pharmaceuticals. The electrophoretic mobilities of the investigated analytes were monitored in a pH range from 2.00 to 10.82. The data were fitted with an appropriate mathematical model using a nonlinear regression analysis to obtain pK_a values. Experimentally obtained data were well described by the mathematical model chosen for each analyte that was confirmed by r² values higher than 0.99 for most of the investigated analytes. Extrapolations to zero ionic strength were used to determine the thermodynamic pK_a values. Experimentally obtained acid dissociation constants were interpreted using structural formulae of investigated analytes and the moieties corresponding to specific pK_a were identified.     

Stability of 2-Carboxyphenylhydrazoethylacetoacetate Complexes of Rare-Earth Elements in Dioxan-Water Solution

The results of pH-metric titration have been used to determine the acid dissociation constants of 2-carboxy-pheylhydrazo-ethylacetoacetate abbrivated (2-CPHEA) and the overall stability constant (log β=K_ML, K_ML2) of twelve rare earth element complexes in 75% dioxan were calculated.     

Dissociation constants of carboxymethyloxysuccinic acid

The dissociation constants of carboxymethyloxysuccinic acid (CMOS) have been measured at 25° and an ionic strength of 0·1M in sodium perchlorate. The values found were: pK₁ = 2·52, pK₂ = 3·77 and pK₃ = 5·00. CMOS is thus seen to be rather stronger than its isomer citric acid.     

Quantum-chemical DFT study of acid properties of thiols RSH and ligand power of their anions RS<Superscript>−</Superscript>

The DFT calculations of electronic and geometry structure, dissociation energies of S-H and S-C bonds, and acid dissociation constants (pK _a) for ten RSH thiols were fulfilled. Calibration corrections to the calculated pK _a^DFT values, which allowed obtaining a good correspondence with experimental data were introduced. Donor power of thiolate anions RS- was estimated for the prediction of stability of their compounds with ions of d-elements.     

Acidity of Several Anilinium Derivatives in Pure Tetrahydrofuran

The acidity constant (pK _a) of eleven substituted anilinium ions and the dissociation constants of their perchlorate salts (pK _salt) were determined in pure tetrahydrofuran by potentiometry and conductometry. The pK _a values of the studied aniliniums extend downward the range of previously determined pK _a values. The resolution of acid strength for cationic acids in tetrahydrofuran was compared with those obtained in other amphiprotic and aprotic solvents. It is shown that the resolution in tetrahydrofuran is higher than the ones in water and methanol, similar to those in acetone, dimethyl sulfoxide and isobutylmethylketone, but lower than those in acetonitrile and nitromethane.     

Determination of aqueous acid‐dissociation constants of aspartic acid using PCM/DFT method

Determination of acid‐dissociation constants, pK_a, of aspartic acid in aqueous solution, using density functional theory calculations combined with the conductor‐like polarizable continuum model (CPCM) and with integral‐equation‐formalism polarizable continuum model (IEFPCM) based on the UAKS and UAHF radii, was carried out. The computed pK_a values derived from the CPCM and IEFPCM with UAKS cavity model of bare structures of the B3LYP/6‐31+G(d,p)‐optimized tetrahydrated structures of aspartic acid species are mostly close to the experimental pK_a values. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

1H NMR spectroscopic identification of protonable sites in cryptolepines with C‐11 substituents containing two amino functionalities

Knowledge of protonable sites and acid dissociation constants of cryptolepine derivatives having C‐11 substituents containing two amino functionalities is of great importance to the understanding of the mechanism of their antimalarial action, which may contribute to their further development as drug candidates. In this work, we applied ¹H NMR titration to investigate the acid–base characteristics of these polyprotic compounds in the pH range 3–13. We identified three acid–base equilibria with most acid dissociation constants (pK_a*) being greater than 10.5, which prevented us from using the potentiometric method. Overall, ¹H NMR titration was sensitive and suitable for the determination of pK_a values for these drug leads. Copyright © 2012 John Wiley & Sons, Ltd.     

Influence of pH and organic modifiers on the dissociation constants of selected drugs using reversed‐phase thin‐layer chromatography: Comparison with other techniques and computational tools

Knowledge of the acid–base dissociation constants of drugs is the key to understanding their biopharmaceutical characteristics. In the present work, the effect of pH and organic modifiers (acetonitrile and methanol) was investigated in the determination of dissociation constants (pK_a) of nine representative drugs (atenolol, betahistine, clarithromycin, deferiprone, diclofenac, ibuprofen, metoprolol, naproxen and propranolol) using reversed‐phase thin‐layer chromatography. Mobile phase consisting of various buffers and methanol–acetonitrile (10, 20, 30, 40, 50 and 60%, v/v) was used to evaluate the retention pattern on reversed‐phase plates. Compared with methanol, acetonitrile gave better results for the experimentally determined pK_a values by extrapolation to zero organic modifier volume fractions. To assess the effectiveness of the developed method the results were correlated using principal component analysis and hierarchical cluster analysis. The calculated values of the aqueous dissociation constant were compared with those reported previously using potentiometry and capillary electrophoresis and also with different computational platforms like ACD/Lab, ChemAxon and Jchem calculator. The results obtained by the RPTLC method were in good agreement with potentiometric methods for pK_a determination.     

The Stabilities of the o-Carboxyphenylhydrazo-Ethylacetoacetate OF Cu,Ni, Co,Zn, Mn and Cd Chelate Compounds in Different Solvents

The dissociation constants for o-carboxyphenylhydrazoethylacetoacetate (o-CPHEA) ligand, as well as the stability constants for the divalent metal complexes of Cu, (II), Ni (II), Co (II), Zn (II)and Cd (II) ions, have been calculated pH-meterically in different solvents. The dissociation constans pK₁=4.10 and pK₂=10.55 of the insoluble organic ligand are calculated in aqueous medium. The effect of solvents, the relation between stabilities and both electronegativities and ionization potential are studied.     

Manganese Complexes with Octaphenyltetraazaporphine: Acid–Base Interactions and Kinetic Stability in Proton-Donor Solvents

Complexes of manganese(III) and manganese(V) with octaphenyltetraazaporphine (H₂OPTAP) were synthesized. Acid–base interactions of these complexes in the CH₂Cl₂–CF₃COOH system and kinetics of their dissociation in concentrated sulfuric acid, as well as kinetics of octaphenyltetraazaporphine destruction in sulfuric acid solutions were studied by spectrophotometric methods. Acid–base interactions in CH₂Cl₂–CF₃COOH were shown to involve two macrocyclic meso-nitrogen atoms in succession. Concentration stability constants of the acid forms obtained pK ₁ = 0.29 ± 0.01 and pK ₂ = –0.62 ± 0.08 for (chlorine)manganese(III)octaphenyltetraazaporphine ((Cl)MnOPTAP); pK ₁ = 0.99 ± 0.02 and pK ₂ = – 0.70 ± 0.03 for (nitrido)manganese(V)octaphenyltetraazaporphine ((N)MnOPTAP). The rate of dissociation of the complexes in 94–98% H₂SO₄ does not depend on the acid concentration. The manganese(V) complex is three times as stable as the manganese(III) complex.     

Acid–base characterization of 5-hydroxypyrazine-2-carboxylic acid and the role of ionic equilibria in the optimization of some process conditions for its biocatalytic production

This paper describes the use of potentiometric titration to determine the relevant acid–base properties of 5-hydroxypyrazine-2-carboxylic acid (5OH-PYCA), an important intermediate in the production of tuberculostatics. The data obtained were used for calculation of the dissociation constants of 5OH-PYCA. It was found that 5OH-PYCA dissociates in two steps, with the corresponding dissociation constants pK _a1=3.42 and pK _a2=7.96, designating 5OH-PYCA as a medium weak acid (1st step). The distribution diagram of dissociated species and the buffer-strength diagram of 5OH-PYCA provide useful information about its behaviour at different pH. The ionic equilibria data obtained can be used for selection of the optimum pH for biotransformation of pyrazine-2-carboxylic acid (PYCA) and for prediction of pH changes during the biotransformation. These data can also be used for selection of the optimum pH for precipitating 5OH-PYCA in downstream processing. All computations have been optimized by mathematical modelling using Solver.     

Studies on the Physical Chemistry of (2,4-Dichlorophenoxy)acetic Acid in Two-phase Systems: Organic Solvent-Water

The dissociation constants (p _s K _a ) of 2,4-D acid were determined in methanol-water mixtures of 10.9 to 38.9 wt.% methanol content. The Yasuda-Shedlovsky procedure was used to obtain the pK _a value in zero-% methanol. The distribution of 2,4-D acid in twelve two-phase organic solvent + water systems and its dimerization in the organic phase were investigated. Values of the distribution coefficient (D _HR), distribution constant (K _D ), and dimerization constant (K _dim) of 2,4-D were obtained. The influence of the structure and polarity of the investigated organic solvents, as well as that of pH of the aqueous phase, on the physical chemistry of 2,4-D in the two-phase systems are described.     

Thermodynamic dissociation constants of risedronate using spectrophotometric and potentiometric pH-titration

Risedronate inhibits bone resorption in diseases like osteoporosis, Paget’s disease, tumor bone diseases or the malfunction of phosphocalcium metabolism. The acid-base properties of risedronate in an aqueous solution have been studied in a pH range from 2 to 12 and can be described in terms of four dissociation steps: pK _a,2, pK _a,4, pK _a,5 (related to the dissociation of POH groups) and pK _a,3 related to the dissociation of protonated amino group NH₃ ⁺. The mixed dissociation constants were determined at different ionic strengths I = 0.02 to 0.20 mol dm⁻³ KCl and of 25°C and 37°C using pH-spectrophotometric and pH-potentiometric titration methods. Determination of group parameters L ₀, H _T might lead to false estimates of common parameters p K _a;therefore, the computational strategy employed is important. A comparison between the two programs ESAB and HYPERQUAD demonstrated that the ESAB program provides a better fit of potentiometric titration curve. The thermodynamic dissociation constants pK _a^T were estimated by a nonlinear regression of (pK _a, I) data and a Debye-Hückel equation at 25°C and 37°C, pK _a,2^T = 2.37(1) and 2.44(1), pK _a,3^T = 6.29(3) and 6.26(1), pK _a,4^T = 7.48(1) and 7.46(2) and pK _a,5^T = 9.31(7) and 8.70(3) at 25°C and 37°C using pH-spectroscopic data and pK _a,2^T = 2.48(3) and 2.43(1), pK _a,3^T= 6.12(2) and 6.10(2), pK _a,4^T = 7.25(2) and 7.23(1) and pK _a,5^T = 12.04(5) and 11.81(2) at 25°C and 37°C. The ascertained estimates of three dissociation constants pK _a,3, pK _a,4, pK _a,5 are in agreement with the predicted values obtained using PALLAS      

EFFECT OF THE BROMINE ATOM UPON THE DISSOCIATION CONSTANTS OF BROMOPYRIDINES,BROMOQUINOLINES AND 4-BROMOISOQUINOLINE IN THEIR LOWEST EXCITED SINGLET AND TRIPLET STATES*

Abstract— The lowest excited singlet-state dissociation constants (pK^S_a) of bromosubstituted pyridines, quinolines, and isoquinolines were determined from the pH-dependent shifts in their electronic absorption spectra. The lowest excited triplet-state dissociation constants (pK^T_a) of bromosubstituted quinolines and 4-bromoisoquinoline were obtained from the shifts of the 0–0 phosphorescence bands measured in rigid aqueous solution at 77 K. The pK^S_a values indicate that the basicity of these brominated nitrogen heterocycles is increased in the lowest excited singlet state by 2 to 10 orders of magnitude as compared with the ground state. The pK^T_a values are found to be significantly different from the corresponding ground-state pK_a values, indicating that the basicity of bromoquinolines is increased in the lowest excited triplet state by 1.7 to 3.0 pK units. The enhancement of the excited singlet-and triplet-state basicity of brominated nitrogen heterocycle derivatives as compared with the unsuhstituted parent compounds is attributed to the increased electron-donor conjugative interactions of the bromine atom pπ orbitals with π orbitals in the lowest excited singlet and triplet state.     

UV and MO study on the deprotonation of some 2-aryl-Δ2-1,3,4-oxadiazoline-5-thiones

Substituent effects on the deprotonation processes of a series of 2-aryl-Δ²-1,3,4-oxadiazoline-5-thione (1) derivatives have been studied experimentally as well as theoretically. The acid dissociation constants pK_a have been determined spectrophotometrically in ethanol-water solutions (7.5-92.5%) and vary between 3.76 and 5.80. Semiempirical molecular orbital (MO) calculations (AM1 and PM3) were used for the investigation of the existence of possible tautomeric thione and thiol forms of the studied compounds. Strong correlation between the pK_a values and the deprotonation enthalpies were evaluated.     

Acid-base and complexing properties of 10-carboxymethyl-9-acridone

Acid-base and complexing properties of 10-carboxymethyl-9-acridone in a multicomponent solvent H₂O-methanol-acetonitrile-dioxane were studied at 22°C, ionic strength I = 0.1 (NaClO₄), and different water-organic component ratios. The concentration protonation constants (logK _HL = 3.11), dissociation constants (pK _HL = 4.14), and stability constants of complexes (logK _MgL = 2.18, logK _CaL = 2.09, and logK _SrL = 1.96) were determined by extrapolation to zero content of organic solvent.     

The influence of cations on the dissociation behaviour of copolymers of propene and maleic acid and their modified products with taurine in salt-free solution

Potentiometric and conductometric titrations were used to study the dissociation behaviour of poly(propene-co-maleic acid) and poly(propene-co-maleic acid) modified with various contents of taurine (2-aminoethanesulfonic acid) in salt-free solution. Copolymers of propene and maleic acid with different molecular weights were titrated with LiOH, NaOH, and KOH. The influence of molecular weight on pK_a is ascertainable in both the first and second dissociation step. Of the various alkali metal cations studied, lithium had the most significant effect on the dissociation behaviour. The acidic strength decreased in the order lithium > sodium ≥ potassium. After insertion of sulfonic acid groups into poly(propene-co-maleic acid), the influence of strong acidic groups on the dissociation behaviour of carboxylic groups was studied. The contents of taurine were 10, 25, and 50 mol%. The second dissociation step was analyzed in this case. The pK_a values increased with increasing content of taurine for titrations with LiOH and KOH, but not NaOH. When NaOH was used, the pK_a decreases if the polymer was modified with 10% taurine. Higher taurine contents had no influence on the magnitude of pK_a. The results demonstrate the strong influence of short-range electrostatic interactions on the dissociation behaviour of weak polyacids. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1949–1955, 1999     

Oil-Water Partitioning of a Synthetic Tetracarboxylic Acid as a Function of pH

The oil-water partitioning of a synthetic tetraacid acting as a model compound for indigenous C₈₀-C₈₂ ARN acids has been studied as a function of pH, ionic strength and type of monovalent counterion. Experimental data obtained with ultraviolet-visible and HPLC/UV analyses have been fitted to thermodynamic models based on one, two or four dissociation steps to obtain o/w partition coefficients (K _wo ) of the fully protonated acid between chloroform and aqueous solutions, and its apparent acidity constant(s), pK _a. As the study is conducted above the CMC of the tetraacid, in general high apparent acidity constants were obtained in the range from 6 to 8 resulting from micellization equilibria. K _wo values were obtained in the range from 10^?3 to 10^?4, and decreasing with increasing salinity. At 50 mM K⁺, no conclusions could be made regarding the number of distinguishable dissociation steps, while at higher ionic strength (184 mM and 452 mM K⁺) and at 184 mM Na⁺ a model with two dissociation steps provided good fits to the experimental data. The first step was found to be given by a pK _a ≈ 6.6–6.8 and the second dissociation step at pK _a values ≈ 7.8–8.3. The two-step mechanism supports previous results obtained by potentiometric titrations. No significant difference in the o/w behavior was observed when changing the counterion from potassium to sodium. The main partitioning of the tetraacid in the aqueous phase occurred above pH 8, where the fully deprotonated acid was formed.     

Laws of complex formation in a series of azo-substituted pyrocatechol derivatives and their tin(II) complexes

Physicochemical properties of new reagents, azo-substituted pyrocatechol derivatives and their tin(II) complexes, are studied. The acid-base properties of the hydroxy groups (pK′_i, pK″_i), parameters of complex formation reactions (pH, temperature, time), and instability constants of the complexes formed (pK _i) are determined. Quantitative correlations between the dissociation constants (pK′_a) of the functional analytical group, and the electronic Hammett constant σ for a substituent (pK′_a-pH₅₀ of the complex formation reaction), as well as between pK′_a and instability constants of the complexes (pK _a), are established. The quantitative correlations established allow the prediction of the physicochemical properties of the reagents and tin(II) complexes with new reagents of this class with the same functional analytical group (FAG) but other substituents.