Keto-Enol tautomerization of quercetin in solutions of a cationic surfactant,miramistin

Tautomeric transformations of quercetin in solutions of a cationic surfactant, miramistin, have been spectrophotometrically studied. It has been established that, at pH ≥ 6, monoanions of enol-form quercetin are irreversibly transformed into keto-form monoanions, with the rate of this process depending on surfactant concentration and solution pH. It has been shown that the enol tautomer of quercetin is more stable in aqueous solutions, while the ketone form is stabilized in miramistin-containing media. The apparent dissociation constants have been determined for the enol (pK _a ^a= 6.60) and ketone = 5.64) tautomeric forms of quercetin in micellar solutions of miramistin.     

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.     

Thermodynamics and kinetics of protonated merocyanine photoacids in water

Metastable-state photoacids (mPAHs) are chemical species whose photo-activated state is long-lived enough to allow for proton diffusion. Liao''s photoacid (1) represents the archetype of mPAHs, and is being widely used on account of its unique capability to change the acidity of aqueous solutions reversibly. The behavior of 1 in water, however, still remains poorly understood. Herein, we provide in-depth insights on the thermodynamics and kinetics of 1 in water through a series of comparative ¹H NMR and UV-Vis studies and relative modelling. Under dark conditions, we quantified a three-component equilibrium system where the dissociation (K_a) of the open protonated form (MCH) is followed by isomerization (K_c) of the open deprotonated form (MC) to the closed spiropyran form (SP) – i.e., in the absence of light, the ground state acidity can be expressed as K^GS_a = K_a(1 + K_c). On the other hand, under powerful and continuous light irradiation we were able to assess, for the first time experimentally, the dissociation constant (K^MS_a) of the protonated metastable state (cis-MCH). In addition, we found that thermal ring-opening of SP is always rate-determining regardless of pH, whereas hydrolysis is reminiscent of what is found for Schiff bases. The proposed methodology is general, and it was applied to two other compounds bearing a shorter (ethyl, 2) and a longer (butyl, 3) alkyl-1-sulfonate bridge. We found that the pK_a remains constant, whereas both pK_c and pK^MS_a linearly increase with the length of the alkyl bridge. Importantly, all results are consistent with a four-component model cycle, which describes perfectly the full dynamics of proton release/uptake of 1–3 in water. The superior hydrolytic stability and water solubility of compound 3, together with its relatively high pK^GS_a (low K_c), allowed us to achieve fully reversible jumps of 2.5 pH units over 18 consecutive cycles (6 hours).

We rationalize the behaviour of protonated merocyanines in water through cross-validation of ¹H NMR, UV-Vis and pH measurements, and show their capability to act as reversible photoacids along light/dark cycles can be described by a four-state model.     

Kinetics and mechanism of the oxidation of a heterocyclic thioamide by silver(II)-cyclam

The kinetics of the oxidation of 4,6-dimethyl-2-mercaptopyrimidine (DMP) by Ag(cyclam)²⁺ were studied in buffer solutions from pH 5.8 to 7.2 at constant ionic strength of 0.10?M?(NaClO₄). The reaction is observed to be first-order with respect to [Ag(cyclam)²⁺] and to [DMP]. However, the reaction rate is affected by the pH of the solution owing to the acid–base equilibrium of the thiol. The mechanism postulated to account for the kinetics includes an acid–base equilibrium and oxidation of thiol (RSH) and thiolate ion (RS^?) by Ag(cyclam)²⁺ to RS^· radicals which undergo rapid dimerization to form disulfide (RSSR). From the postulated mechanism and the observed kinetics a rate expression was derived, and second-order rate constants and activation parameters were calculated. The pK _a values of the acid dissociation reaction of DMP were also determined at four temperatures using spectrophotometric methods, and thermodynamic parameters calculated from the K _a values.     

Absorption and emission behaviour of trans-p-coumaric acid in aqueous solutions and some organic solvents

The absorption and fluorescence behaviour of trans-p-coumaric acid (trans-4-hydroxycinnamic acid) is investigated in buffered aqueous solution over a wide range from pH 1 to pH 12, in un-buffered water, and in some organic solvents. Absorption cross-section spectra, fluorescence quantum distributions, fluorescence quantum yields, and degrees of fluorescence polarisation are measured. p-Coumaric acid exists in different ionic forms in aqueous solution depending on the pH. There is an equilibrium between the neutral form (p-CAH₂) and the single anionic form (p-CAH⁻) at low pH (pK_na ≈ 4.9), and between the single anionic and the double anionic form (p-CA²⁻) at high pH (pK_aa ≈ 9.35). In the organic solvents studied trans-p-coumaric acid is dissolved in its neutral form. The fluorescence quantum yield of trans-p-coumaric acid in aqueous solution is ?_F ≈ 1.4 × 10⁻⁴ for the neutral and the single anionic form, while it is ?_F ≈ 1.3 × 10⁻³ for the double anionic form. For trans-p-coumaric acid in organic solvents fluorescence quantum yields in the range from 4.8 × 10⁻⁵ (acetonitrile) to 1.5 × 10⁻⁴ (glycerol) were measured. The fluorescence spectra are 7700–10,000 cm⁻¹ Stokes shifted in aqueous solution, and 5400–8200 cm⁻¹ Stokes shifted in the studied organic solvents. Decay paths responsible for the low fluorescence quantum yields are discussed (photo-isomerisation and internal conversion for p-CA²⁻, solvent-assisted intra-molecular charge-transfer or ππ^∗ to nπ^∗ transfer and internal conversion for p-CAH₂ and p-CAH⁻). The solvent dependence of the first ππ^∗ electronic transition frequency and of the fluorescence Stokes shift of p-CAH₂ is discussed in terms of polar solute–solvent interaction effects. Thereby the ground-state and excite-state molecular dipole moments are extracted.     

H/P NMR pH indicator series to eliminate the glass electrode in NMR spectroscopic pKa determinations

NMR titration is an efficient method to determine pK_a values of multiprotic acids in aqueous solution. While modern 1D/2D NMR techniques yield chemical shifts with increasing precision, the glass electrode-based pH measurement becomes the limiting factor to affect the precision of the resulting dissociation constants. The pH in the NMR tube can also be deduced from the actual chemical shift of an appropriate monoprotic indicator molecule. In the present work, the in situ NMR pH measurement has been extended for the entire pH range 0-12 using indicators with overlapping ranges of dissociation. In the first, calibrating ¹H/³¹P NMR titration, limiting chemical shifts and pK were determined for each indicator. An analysis of error propagation showed that the accuracy and precision of glass electrodes can be achieved at 1.8 < pH < 12 and even exceeded at pH extremes by NMR indicators, respectively. The assembled set of indicators was applied for in situ pH monitoring in the following “electrodeless” ¹H/³¹P NMR titration of a newly synthesized aminophosphinophosphonic acid. Multivariate nonlinear parameter estimation was used to calculate the pK values that were confirmed by potentiometric titrations.     

Synthesis of some fluorine-containing pyridinealdoximes of potential use for the treatment of organophosphorus nerve-agent poisoning

Fluoroheterocyclic aldoximes were screened as therapeutic agents for the treatment of anticholinesterase poisoning. 2-Fluoropyridine-3- and -6-aldoxime, and 3-fluoropyridine-2- and -4-aldoxime, were synthesised. Attempts to obtain 3,5,6-trifluoropyridine-2,4-bis(aldoxime) and -2-aldoxime, however, proved unsuccessful. Pentafluorobenzaldoxime was prepared by oximation of pentafluorobenzaldehyde. Acid dissociation constants (pK_a) and second-order rate constants (k_ox−) of the fluorinated pyridinealdoximes towards sarin were measured. 2,3,5,6-Tetrafluoropyridine-4-aldoxime had the best profile: its k_ox− approached that of the therapeutic oxime P2S (310 vs. 120 l mol⁻¹ min⁻¹), but its higher pK_a (9.1 vs. 7.8) fell short of the target figure of 8 required for reactivation of inhibited acetylcholinesterase in vivo. N-alkylation of the fluorinated pyridine-aldoximes may reduce their pK_a nearer to 8 and enhance their therapeutic potential.     

The Effect of a Cationic Gemini Surfactant,Ethonium, on the Physicochemical Properties of Quercetin in Solutions and on the Surface of Highly Dispersed Silica

The formation of supramolecular complexes with ethonium, a cationic gemini surfactant having a broad-spectrum antimicrobial activity, is shown to significantly alter the physicochemical properties (spectral, protolytic, and adsorption properties and solubility) of a natural f lavonol, quercetin. The constant of binding between quercetin and ethonium is calculated. Apparent dissociation constants pK _a1 ^a of quercetin in solutions of this cationic surfactant are for the first time determined within a broad concentration range. A shift in the pH dependence of quercetin adsorption by 0.5 units to the alkaline region upon the transition from a premicellar ethonium solution to a micellar one correlates with an increase in pK _a1 ^a under these conditions. The value of quercetin adsorption from aqueous ethonium solutions depends on the concentration of the cationic surfactant, pH of a solution, and the pK _a1 ^a value of the f lavonol bound into the supramolecular complex.     

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.     

Hydrogen bond interactions at the TiO2 surface: Their contribution to the pH dependent photo-catalytic degradation of p-nitrophenol

We have obtained pK_a values of p-nitrophenol–TiO₂ by measuring the adsorption equilibrium constants of p-nitrophenol (PNP) on the TiO₂ surface at different pH values. These values have been obtained from Langmuir isotherms and from a plot of 1/rate vs. 1/[PNP]_o obtained during TiO₂ catalyzed solar light photo-degradation of PNP. Two limit equilibrium constants are readily obtained depending on the solution pH: at pH 5 at which the TiO₂ surface is mainly positively charged and at pH 8 when it is negatively charged. With these and other adsorption equilibrium constants and the PNP pK_a value in solution, thermodynamic cycles are established in order to obtain the PNP pK_a when it is adsorbed on positively charged, neutral and negatively charged TiO₂ surfaces. From these pK_a values useful information on the PNP–TiO₂ interaction is readily obtained. For instance, the PNP nitro group interacts with the TiO₂ surface via a hydrogen bond, arising from the complex of water molecules with the Ti⁴⁺ ions on its surface. The weaker the hydrogen bond donor, the stronger the oxygen nitro group basicity. Therefore, pK_a changes on the phenolic hydroxyl group result from these interactions. Linear free energy correlations, maximum PNP adsorption capacity values (Q_L) and FTIR ATR, spectrum support this proposal. A k_obs vs. pH degradation profile of p-nitrophenol is also provided.     

Prediction of the separation of phenols by capillary zone electrophoresis

The effect of pH and ionic strength on the migration of neutral acids in capillary zone electrophoresis (CZE) has been studied for several phenols. The mobilities of the phenols and the efficiency of the capillary have been related to the studied factors. The mobility can be related to the pH of the running buffer through the mobility of the phenolate ion, and the conditional acidity pK value of the phenol at the working ionic strength. This allows prediction of the migration of the phenol, solely from its pK_a^′ value (literature pK_a corrected for the ionic strength of the solution) and mobility of the anion, which can be easily calculated from the mobility at a basic pH value and the pK_a^′ value. Combination of the predicted mobility with the efficiency allows estimation of the resolution of the consecutive peaks obtained for a mixture of phenols. This method has been tested for two groups of phenols of environmental interest.     

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.     

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.     

Some new aromatic hydroxylamines as spectrophotometric reagents for vanadium

A comparative study is described of the use of N-benzoyi-o-tolyl-, N-benzoyl-m-tolyl, N-benzoyl-p-tolyl-, N-benzoyl-p-chlorophenyl- and N-phenylacetylphenyl-hydroxylamines, as spectrophotometric reagents for the determination of vanadium, after extraction with chloroform. All the reagents form 1:2 (metal:reagent) complexes in hydrochloric acid media or at pH 4.8–6.0; the dissociation constants of the complexes are of the order of 10^-9 and 10^-8, respectively, except those of N-benzoyl-p-chloro-phenylhydroxylamine which are of the order of 10^-8 in both media. The reactions in hydrochloric acid media are more selective and sensitive than those at pH 4.8–6.0. In presence of alcohol, the wavelengths of maximum absorption decrease. The pK_a values of the hydroxylamines were determined in water and in alcohol-water (1:1) solutions.     

Experimental evaluation of adsorption and electrode field effect on the constants of weak acid dissociation near the mercury electrode surface

Two methods are described for the experimental evaluation of the weak acid dissociation constants in the near electrode surface. One of them, based on the dependence of differential capacity of pH of the solution at constant potentials, gives the pK_A^s values for adsorbed acids; the second one uses the ψ₁-value dependence on pH in the presence of the cationic acids (as pyridinium ions) and comparison of the pH of the buffer solution of the weak acid under investigation with pK_A^s of the cationic acid and gives the pK_A values in the volume just near the electrode.     

Kinetics and mechanisms of the reactions of S-methyl chlorothioformate with pyridines and secondary alicyclic amines

The pyridinolysis of S-methyl chlorothioformate shows a biphasic Brønsted-type plot, in agreement with a stepwise mechanism and a change in the rate-limiting step, from formation of a zwitterionic tetrahedral intermediate (T^±) at high pK_a to its breakdown at low pK_a. The reaction of the same substrate with secondary alicyclic amines shows a linear Brønsted-type plot of slope 0.23, which is in accordance with a stepwise mechanism where formation of T^± is the rate-determining step for the whole pK_a range examined.     

A study of some problems in determining the stoicheiometric proton dissociation constants of complexes by potentiometric titrations using a glass electrode

Possible errors in the measurement of acid dissociation constants by potentiometric titration techniques have been considered, with particular references to nitrilotriacetic acid (NTA) and ethylenediaminetetraacetic acid (EDTA). Unknown junction potentials can arise when pH measurements are carried out using a glass electrode with saturated calomel reference electrode which have been previously calibrated with a standard buffer solution. The magnitude of the influence of these unknown potentials has been demonstrated and an experimental procedure recommended which gives meaningful results.The precision of calculated acid dissociation constants will also be influenced by the presence of cationic species (e.g. H₄L⁴), the total acid strength, the absolute values of the constants and the value accepted for the auto-dissociation constant of water (K_w). All these factors have been considered quantitatively and their effect on metal complex formation constants, calculated from these acid dissociation constants, noted. The proton dissociation constant of the cationic species of NTA (i.e. H₄L⁺) has been found to have the value of pK₀=0.80 at 20° and μ=0.10 M.     

Cadmium Malonate Complexation in Aqueous Sodium Trifluoromethanesulfonate Media to 75°C; Including Dissociation Quotients of Malonic Acid

The molal formation quotients for cadmium–malonate complexes were measured potentiometrically from 5 to 75°C, at ionic strengths of 0.1, 0.3, 0.6 and 1.0 molal in aqueous sodium trifluoromethanesulfonate (NaTr) media. In addition, the stepwise dissociation quotients for malonic acid were measured in the same medium from 5 to 100°C, at ionic strengths of 0.1, 0.3, 0.6, and 1.0 molal by the same method. The dissociation quotients for malonic acid were modeled as a function of temperature and ionic strength with empirical equations formulated such that the equilibrium constants at infinite dilution were consistent, within the error estimates, with the malonic acid dissociation constants obtained in NaCl media. The equilibrium constants calculated for the dissociation of malonic acid at 25°C and infinite dilution are log K _1a=-2.86 ± 0.01 and log K _2a=-5.71 ± 0.01. A single Cd–malonate species, CdCH₂C₂O₄, was identified from the complexation study and the formation quotients for this species were also modeled as a function of temperature and ionic strength. Thermodynamic parameters obtained by differentiating the equation with respect to temperature for the formation of CdCH₂C₂O₄ at 25°C and infinite dilution are: K = 3.45 ± 0.09, S° = 7 ± 6 kJ-mol^-1, S° = 91 ± 22 J-K^--mol^-1, and C _p ^o =400±300 J­K^-1­mol^-1.     

Acid dissociation constants of uridine-5′-diphosphate compounds determined by phosphorus nuclear magnetic resonance spectroscopy and internal pH referencing

The acid dissociation constant (pK_a) of small, biological molecules is an important physical property used for investigating enzyme mechanisms and inhibitor design. For phosphorus-containing molecules, the ³¹P nuclear magnetic resonance (NMR) chemical shift is sensitive to the local chemical environment, particularly to changes in the electronic state of the molecule. Taking advantage of this property, we present a ³¹P NMR approach that uses inorganic phosphate buffer as an internal pH reference to determine the pK_a values of the imide and second diphosphate of uridine-5′-diphosphate compounds, including the first reported values for UDP-GlcNAc and UDP-S-GlcNAc. New methods for using inorganic phosphate buffer as an internal pH reference, involving mathematical correction factors and careful control of the chemical shift reference sample, are illustrated. A comparison of the newly determined imide and diphosphate pK_a values of UDP, UDP-GlcNAc, and UDP-S-GlcNAc with other nucleotide phosphate and thio-analogs reveals the significance of the monosaccharide and sulfur position on the pK_a values.     

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.