Studies on halogen derivatives of phenylazochromotropic acid: I. The acid-base properties

The acid-base properties of six halogen derivatives of phenylazochromotropic acid have been studied in an attempt to apply them as metallochromic or chromophoric indicators. The absorption spectra are studied in buffer solutions of varying pH values. The variation of spectra with pH indicates the presence of two equilibria between H₂D^2?, HD^3? and D^4? species. The pK values of the naphthlenic OH groups are determined spectrophotometrically and are discussed in relation to molecular structure while those of the sulfonic acid groups are determined potentiometrically.     

Potentiometric acid-base properties of the chloroazoxine S dyes

The pK_a of the sulfonic group in the Azoxine S dye o-, m-, and p-chloro derivatives and the parent 7-phenylazo-8-hydroxyquinoline-5-sulfonic acid was determined potentiometrically. The indicators were prepared, obtained in the acid form by percolation through a cation exchange resin, and titrated with NaOH. The pK_a amounts to 3.69, 4.25, 3.65, and 3.71, respectively. Interpretation of the pK_a values is given.     

Investigations on the dissociation behavior of hydrolyzed alternating copolymers of maleic anhydride and alkenes: 13C-NMR spectra and potentiometric titrations

The pK_a values of the succinic acid moieties of hydrolyzed alternating ethene- and isobutene-maleic anhydride copolymers were determined in D₂O. The pD-dependence on the ¹³C chemical shift of selected signals was analyzed for these copolymers. Four different pK_as were determined for the copolymer with ethene due to the existence of both the erythro- and threo-configuration of the succinic acid moiety: pK_01,erythro = 4.2, pK_0.1,threo = 4.1, pK_02,erythro = 6.1, pK_02,threo = 6.8. The isobutene-maleic anhydride copolymer contains only threo-units. Therefore, only two dissociation steps with pK₀₁ = 3.0 and pK₀₂ = 8.7 were observed for the hydrolyzed form. © 1996 John Wiley & Sons, Inc.     

SAMPL6: calculation of macroscopic p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> values from ab initio quantum mechanical free energies

Macroscopic pK_a values were calculated for all compounds in the SAMPL6 blind prediction challenge, based on quantum chemical calculations with a continuum solvation model and a linear correction derived from a small training set. Microscopic pK_a values were derived from the gas-phase free energy difference between protonated and deprotonated forms together with the Conductor-like Polarizable Continuum Solvation Model and the experimental solvation free energy of the proton. pH-dependent microstate free energies were obtained from the microscopic pK_as with a maximum likelihood estimator and appropriately summed to yield macroscopic pK_a values or microstate populations as function of pH. We assessed the accuracy of three approaches to calculate the microscopic pK_as: direct use of the quantum mechanical free energy differences and correction of the direct values for short-comings in the QM solvation model with two different linear models that we independently derived from a small training set of 38 compounds with known pK_a. The predictions that were corrected with the linear models had much better accuracy [root-mean-square error (RMSE) 2.04 and 1.95 pK_a units] than the direct calculation (RMSE 3.74). Statistical measures indicate that some systematic errors remain, likely due to differences in the SAMPL6 data set and the small training set with respect to their interactions with water. Overall, the current approach provides a viable physics-based route to estimate macroscopic pK_a values for novel compounds with reasonable accuracy.     

Acidity of several polyprotic acids, amiodarone and quetiapine hemifumarate in pure methanol

Methanol is the organic solvent closest to water and able to dissolve a huge amount of organic compounds. Therefore, it is a good candidate for pK_a determination of drugs sparingly soluble in water or a basic drug presented as a salt which pK_a is close to that of its counter-acid. In this work, the acidic dissociation constants in pure methanol of the most common acids used in pharmaceutical preparations (lactic, tartaric, fumaric, maleic and citric) were determined. In addition, the pK_a values of the antipsychotic quetiapine presented as hemifumarate (Seroquel) and the very insoluble antiarrhythmic amiodarone were also determined by potentiometry. From these values, the aqueous pK_a of these drugs were estimated by means of previously established equations. Estimated values are consistent with those from literature and show the interest of methanol for drug discovery pK_a measurements.     

Infrared spectrometric study of the interaction between 2-dimethylamino-3,3-dimethyl-1 azirine and some phenol derivatives

The H-bonded complexes between 2-dimethylamino-3,3-dimethyl-1-azirine (TMAAZ) and some phenol derivatives have been studied by IR spectrometry in carbon tetrachloride. The equilibrium constants at 300, 315 and 328 K and the ? ΔH°, ? Δν_OH and Δν_CN values have been determined. The comparison with previously studied OH … N complexes shows that TMAAZ forms stronger complexes than would be expected from the pK_a value. These facts are discussed in terms of steric, hybridization, solvation and charge transfer effects. From a pK_a of 8, the IR spectrum shows the appearance of ion pairs N⁺-H …^?O. A predominance of protonated species can be calculated for a pK_a of 6. This can explain why 1,2-ring cleavage whose first step is probably the formation of an azirinium cation, occurs for acids characterized by pK_a values lower than 5 but not for enolizable ketones having pK_a values higher than 9.     

Determination of pK a of benzoic acid- and p-aminobenzoic acid-modified platinum surfaces by electrochemical and contact angle measurements

Acidity constant values of benzoic acid (BA)-modified platinum electrode (Pt-BA) and p-aminobenzoic acid (pABA)-modified platinum electrode (Pt-NHBA) surfaces were determined using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and contact angle measurements (CAM). Diazonium tetrafluoroborate salt reduction and pABA oxidation reactions were used to prepare (Pt-BA) and (Pt-NHBA) surfaces, respectively. Both surfaces exhibited pH dependence with [Fe(CN)₆]^3?/4? redox probe solutions at different pH; this allowed us to estimate the surface pK _a values. Acidity constants for Pt-BA surface were found to be pK _a (3.09 ± 0.25), (4.89 ± 0.11), and (3.91 ± 0.54) by CV, EIS, and CAM techniques, respectively, while the values for Pt-NHBA surface were pK _a (3.16 ± 0.45), (4.24 ± 0.40), and (5.64 ± 0.12). The Pt-BA surface pK _a values were lower in CV and CAM measurements relative to the bulk solution of BA, while a higher value was observed in EIS for Pt-BA surface. The pK _a values determined for Pt-NHBA surface via both CV and EIS were lower than the bulk value; however, the result obtained from CAM was one unit higher than pK _a of bulk pABA.     

Comparative studies of 1-hydroxy-2-pyridinethione and its methyl derivatives as analytical reagents for metal ions

Comparative analytical studies on sodium salt of 1-hydroxy-2-pyridinethione (HPT) and some of its methyl derivatives are made using them for selective determination of certain metal ions. Data on elemental analysis, melting point, color, and solubilities of precipitates, pK_a of reagents and their metal derivatives, absorption spectra are tabulated. It is found that methyl derivatives of (HPT) are more selective than the reagent itself in acidic and alkaline medium and have a higher sensitivity, of about 10–12%, more than HPT for the spectrophotometric determination of Fe(III) and Cu(II). Methyl substitutions of (HPT) are less acid and have lower solubilities in water than HPT. Further work on the introduction of a larger substituent in (HPT) ring is desirable. The 1:1 Ag-HPT complex, which is not light sensitive, can be used for gravimetric determination of Ag⁺ in the presence of chloride.     

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.     

Determination of pKa values of some hydroxylated benzoic acids in methanol-water binary mixtures by LC methodology and potentiometry

An accurate estimation of pK_a values in methanol-water binary mixtures is very important for several separation techniques such as liquid chromatography and capillary electrophoresis that use these solvent mixtures. In this study, the pK_a values of 11 polyphenolic acids have been determined in methanol-water binary mixtures (10%, 20% and 30% (v/v)) by potentiometry, liquid chromatography (LC) and LC-DAD methodology.The results show a similar trend for the pK_a values of all the studied compounds, as they increase with increasing concentration of organic modifier, which allows a linear relationship between pK_a values and mole fraction of methanol to be obtained. The pK_a values obtained in aqueous medium have been compared with those given in the literature, and also with the values predicted by the SPARC on-line pK_a calculator. The data obtained have been used to test the feasibility of an estimation of dissociation constants in a methanol-water medium from the relationship between pK_a values and the organic cosolvent fraction in the mixtures.     

Influence of Solute–Solvent Interaction on Acid Strength of Some Substituted Phenols in Ethanol–Water Media

The solute–solvent interactions of some phenol derivatives were investigated potentiometrically in 0–60 % (v/v) ethanol–water mixtures. The acidity constants values were correlated with either macroscopic parameters such as molar fraction, permittivity and the solvating ability or microscopic parameters, such as the Kamlet–Taft solvatochromic parameters. Moreover, it is demonstrated that the pK _a values in any ethanol–water mixtures are linearly related to the pK _a values of the phenols in pure water. The slope and intercept parameters of the linear correlations are related with the mole fraction of ethanol. These equations permit accurate calculation of the pK _a values of the studied phenols at any ethanol–water composition.     

Relative pKa of some anilinium derivatives in methanol,acetonitrile, and tetrahydrofurane solvents

In this study, the relative pK_a values of nine anilinium derivatives in methanol (MeOH), acetonitrile (AN), and tetrahydrofurane (THF) solutions were successfully calculated with mean absolute deviations of 0.63, 0.68, and 0.75 pK_a units, respectively. To this aim, their gas‐phase basicities were computed using the CBS‐QB3 composite method. Also, conductor‐like polarizable continuum model (CPCM) with UAHF, UAKS and UA0 cavities and SM8 solvation models at HF/6‐31+G(d) level of theory were applied for the calculation of the solvation Gibbs free energies. The obtained results indicate that there is reliable correlation between the experimental and computed pK_a values in the studied solutions. Therefore, to extend the pK_a database for anilines, correlation equations were used to predict the pK_a values in the investigated solvents.     

Correlations of 95Mo NMR chemical shifts with ligand basicity in substituted pyridine pentacarbonylmolybdenum(O) complexes

Molybdenum-95 NMR chemical shifts are reported for a series of Mo(O) compounds of the type Mo(CO)₅L (L = pyridine derivatives). A good correlation is found between the δ(⁹⁵Mo) values and the Hammett sigma constant of the pyridine substituent or the pK_a of the substituted pyridine. The chemical shift values, which range from −1366 ppm (3-CN, σ = 0.62, pK_a = 1.35) to −1433 ppm (4-NMe₂, σ = −0.83, pK_a = 9.61), directly reflect the electronic properties of the pyridine derivatives even though the substituent is four or five bonds away from the molybdenum atom.     

Cyclobutadieneiron tricarbonyl carboxylic acids: Synthesis and acidity

Two carboxylic acid derivatives of the cyclobutadieneiron tricarbonyl (I) system have been synthesized and their pK_a values determined. It appears that I tends to be electron withdrawing by induction and electron releasing by resonance.     

What are the pKa values of organophosphorus compounds?

A first-principle theoretical protocol was developed, which could successfully predict the pK_a values of a number of amines and thiols in DMSO with a precision of about 1.1 pK_a unit. Using this protocol we calculated the pK_a values of diverse types of organophosphorus compounds in DMSO. The accuracy of these predicted values was estimated to be about 1.1 pK_a because phosphorus is in the same group as nitrogen and in the same period as sulfur. The theoretical predictions were also consistent with all the available experimental data. Thus, a scale of reliable pK_a values was constructed for the first time for organophosphorus. These pK_a values would be helpful to synthetic chemists who need to design the experimental conditions for handling deprotonated organophosphorus. On the basis of these pK_a values we also studied, for the first time, some interesting topics such as the substituent effects on the pK_a values of various types of organophosphorus, and the differences between the pK_a values of organophosphorus and organic amines.     

Determination of the ionization constants of natural cyclodextrins by high-resolution 1H-NMR and photon correlation spectroscopy

The purpose of this investigation has been to establish reference pK _a values in D₂O for the three natural CDs by high-resolution ¹H-NMR, according to the recent guidelines provided by the IUPAC for the determination of extreme pK _a values. The most alkaline conditions achieved in this study than in previous pH potentiometric assays have made possible to deduce the pK _a for the three acidic groups of each CD. In addition, we have studied the effects of the ionization of ??-CD on the aggregation properties of this macrocycle in H₂O by dynamic light scattering (DLS) as a function of pH. This procedure provides an indirect way of measuring the pK _a of ??-CD either by tracking the percentage of scattered light or the hydrodynamic radii of the species involved and reveals that the aggregates of ??-CD break and reduce their size progressively upon ionization of the OH^? groups in positions 2 and 3.     

Potentiometric and ab initio studies of acid-base interactions of substituted 4-halo(Cl, Br)pyridine N-oxide systems

By using the potentiometric method, acidity constants have been determined in systems of tri- and tetra-substituted pyridine N-oxides. The potentiometric measurements in systems of four 4-chloropyridine N-oxide derivatives containing the chlorine atom at position 4 to the NO₂ group and four bromine counterparts were carried out in polar non-aqueous solvents, viz. amphiprotic methanol (MeOH) and aprotic protophilic dimethyl sulfoxide (DMSO). It was found that in all the systems studied the pK_a values were readily determinable (as indicated by small standard deviations) in MeOH, whereas in DMSO large standard deviations were obtained making the pK_a values either hardly determinable or indeterminable from potentiometric measurements. Furthermore, it was demonstrated that the acidity constants of protonated N-oxides studied in MeOH changed according to the sequence of their acidity constants in water. It was also found that in the polar solvents studied, i.e. in the amphiprotic methanol and the highly basic aprotic dimethyl sulfoxide, the cationic homo-conjugation equlibrium constants could not be determined using potentiometric method. Also, by using ab initio methods at the RHF and MP2 levels and the PCM model, utilizing the Gaussian 6-31++G^∗∗ basis set, energies and Gibbs free energies of the protonation reactions of the N-oxides have been determined. The energy parameters have been compared with acidity constants of the protonated N-oxides determined by potentiometric titration in methanol to establish a correlation between these approaches.     

Theoretical Study of Firefly Luciferin pKa Values—Relative Absorption Intensity in Aqueous Solutions

Ground‐state vibrational analyses of firefly luciferin and its conjugate acids and bases are performed. The Gibbs free energies obtained from these analyses are used to estimate pK_a values for phenolic hydroxy and carboxy groups and the N–H⁺ bond in the N‐protonated thiazoline or benzothiazole ring of firefly luciferin. The theoretical pK_a values are corrected using the experimental values. The concentrations of these chemical species in solutions with different pH values are estimated from their corrected pK_a values, and the pH dependence of their relative absorption intensities is elucidated. With the results obtained we assign the experimental spectra unequivocally. Especially, the small peak near 400 nm at pH 1–2 in experimental absorption spectra is clarified to be due to the excitation of carboxylate anion with N‐protonated thiazoline ring of firefly luciferin. Our results show that the pK_a values of chemical species, which are contained in the aqueous solutions, are effective to assign experimental absorption spectra.     

Development of negligible depletion hollow fiber membrane-protected liquid-phase microextraction for simultaneous determination of partitioning coefficients and acid dissociation constants

A new method based on negligible depletion hollow fiber-protected liquid-phase microextraction coupled with high-performance liquid chromatography (HPLC) was developed for the simultaneous determination of partitioning coefficients (K_OW) and acid dissociation constants (pK_a), by using phenol, 4-chlorophenol and 2,4-dichlorophenol as model compounds. A 37-mm length polypropylene hollow fiber membranes (600 μm inner diameter, 200 μm wall-thickness, 0.2 μm pore size, ∼70% porosity) with two-end sealed were filled with 1-octanol by ultrasonic agitation to prepare the extraction device. The extraction device was deployed in sample solutions, prepared by spiking target analytes in 1-octanol saturated aqueous solutions (500 mL), for negligible depletion extraction. After equilibrium was reached (∼5 h), the 1-octanol in the lumen of the hollow fiber membrane was collected for HPLC determination of the target analytes. As the depletion of the analytes in aqueous samples was negligible, the distribution coefficient (D_OW) could be calculated based on the measured equilibrium concentration in 1-octanol (C_O) and the initial concentration (C_W) in the aqueous sample of the target analyte (D_OW = C_O/C_W). The D_OW values measured at various pH values were nonlinearly regressed with pH to obtain the K_OW and pK_a values of a compound. Results showed that the measured values of the K_OW and pK_a of these model compounds agreed well with literature data.