Acid-base Dissociation Constants Research Articles

Modeling the Impact of pH- and Oxygen-Coupled Stimuli on Osmotic Pressure and Electrical Potential Responses of Hemoglobin-Loaded Polyampholyte Hydrogel.

A unique character of (bio) responsive materials is their capability to convert specific environmental biochemical cues into an electromechanical response. Thereby, this paper describes the impact of pH- and oxygen-coupled stimuli on osmotic pressure and electrical potential responses of hemoglobin-loaded polyampholyte hydrogel. Herein, a multiphysics model is developed for elucidating the multiphysical interaction between immobile functional components bounded onto polymeric network chains of the hydrogel and hydrogen ion-oxygen-enriched environmental solution. Two constitutive relationships are incorporated into the model to capture: (1) ionization of fixed charge group as a function of its ionization strength coupled with hydrogen ion concentration and (2) bioactivity of hemoglobin as a function of both its ionization and saturation states. The multiphysics model is verified by comparing with experimental observations in open-literature, capturing the oxygen-induced hemoglobin saturation and the pH-actuated deformation of polyampholyte hydrogel. The numerical finding demonstrates that the pH-activated osmotic pressure response of the present hemoglobin-loaded polymeric system is independent of ambient oxygen O2, whereas its electrical potential response is insensitive of ambient oxygen O2 level at pH neutral conditions. Furthermore, the pH-induced swelling deformation of initially balanced polyampholyte hydrogel changes from a "V-" to a "bowl"-shaped like pattern with increase in fixed acidic and basic group ionization strength, whereas the initially unbalanced polyampholyte hydrogel achieves a collapse state at environmental pH coinciding with acid-base dissociation constant of dominant immobile charge group, if the initial dominant immobile charge group density is twice that of its counter one.

Urease catalytic behaviors induced by both urea and salt concentrations in ion-exchange hydrogels as dialysis membranes

This paper provides an insight into the urease catalytic responsive behaviors in ion-exchange hydrogels, subjected to variation of environmental concentrations of urea and sodium chloride with different urease enzymatic properties, including catalytic and Michaelis constants. Herein, a multiphysics model is formulated to quantify the catalytic activity of the immobilized urease, accounting for the multiphysics interaction between the environmental solution and the functional components of the urease-loaded charged hydrogel, including the immobilized urease, fixed charge group, the polymeric network chains. The effects of both the urease inactivation and denaturation are also incorporated into the model to capture the pH- coupled with temperature-induced urease catalytic behaviors. It is found that the urease catalytic activity patterns differ in anionic and cationic urease-loaded hydrogels, when subjected to the increase in environmental concentration of sodium chloride at a relatively higher environmental concentration of urea. It is also observed that the urease catalytic activity remains almost unchanged, when the environmental pH increases above the acid-base dissociation constant pK of the present charged hydrogel. Consequently, these findings would facilitate the development of a high-performance hydrogel-based dialysis membrane for highly efficient removal of the toxic urea and separation of the ionic metabolites in an wearable artificial kidney system.

3-Hydroxynaphthalene-2-carboxanilides and their antitrypanosomal activity

Series of ring-substituted 3-hydroxynaphthalene-2-carboxanilides were screened for their in vitro activity against wild-type S427 (bloodstream form) of Trypanosoma brucei brucei. 3-Hydroxy-N-(3-trifluoromethylphenyl)- and 3-hydroxy-N-(4-trifluoromethylphenyl)naphthalene-2-carboxamides showed the highest biological activity (MIC = 1.56 and 2.08 µmol/dm3, respectively). Antitrypanosomal activity was correlated with the experimentally determined lipophilicity and acid–base dissociation constants of the compounds as well as with the calculated electronic properties of individual anilide substituents expressed as Hammett’s σ parameters. The substitution in the meta- or para-position of anilide of derivatives with higher lipophilicity by an electron-withdrawing moiety is favourable for higher activity. The optimum thermodynamic pK a T value was found to be ca. 7.5. The structure–activity relationships of all compounds are discussed.

Comparative analysis of oxidative mechanisms of phloroglucinol and dieckol by electrochemical, spectroscopic, cellular and computational methods.

Numerous studies have been carried out on the redox activities of phenolic compounds from terrestrial plants, however, the redox pathway of phlorotannins, a type of marine algae-derived polyphenol, is far from clear. In the present study, the redox mechanisms of two phlorotannins, phloroglucinol (PL) and dieckol (DL), were comparatively scrutinized. Differential pulse voltammetry was conducted in the pH range 2.0–12.0 to determine the acid–base dissociation constant (pKa) and the number of electrons and protons involved in the redox reactions of two phlorotannins. Cyclic voltammetry was applied to obtain the heterogeneous electron transfer rate constant (k0). By means of computational calculation, UV-vis spectroscopy, and electrochemical analysis, it is proposed that PL oxidation in the whole pH range undergoes two steps which are dominated by proton-coupled electron transfer (PCET) (pH ≤ 9) and sequential proton-loss electron transfer (SPLET) mechanisms (pH > 9), respectively. In contrast, the multiple steps taking place in the DL oxidation process rely on PCET (pH ≤ 5), mixed SPLET/PCET (5 < pH ≤ 10), and electron transfer (pH > 10) mechanisms, respectively. Also, the lower proton affinity and ionization potential values of DL, which are attributed to its conjugated Cπ–O–Cπ moieties, lead to relatively higher redox activity as compared to PL in various chemical and cellular models. These findings may provide useful insights into the oxidative conversion of phlorotannins in their biological and chemical processes.

Study of 3-amino phenylboronic acid interactions with selected sugars by optical methods

ABSTRACT The interactions of 3-amino phenylboronic acid with six saccharides (glucose, galactose, fructose, maltose, sucrose and lactose) were studied by absorbance, steady-state fluorescence and time-resolved fluorescence measurements. 3-Amino phenylboronic acid fluorescence is quenched by formation of esters with saccharides. Results of the steady-state fluorescence measurements fulfil the Stern-Volmer equation and quenching constants increase with a growing pH. The greatest quenching constant was observed for fructose. From the dependence of absorbance and fluorescence on pH the exponents of acid-base dissociation constants pK a were calculated giving similar values for both methods. The esterification of the boronic group shifted the acid-base equilibrium towards lower pH. This shift is growing with increasing bonding strength between sugar and boronic group. At acidic and neutral pH the decay of 3-amino phenylboronic acid fluorescence is monoexponential. The lifetime is about 8.3 ns and is independent of pH as well as sugar type and concentration. In alkaline environments the decays become biexponential with a shorter component about 1 ns or less. The contribution of this component is growing with increasing pH and affinity of sugar towards boronic group. This shorter component can be attributed to the anionic form of 3-amino phenylboronic acid or its ester. The results of absorbance and fluorescence measurements indicate that the studied sugars can be ordered by their affinity to 3-amino phenylboronic acid as follows: fructose>galactose>glucose>maltose≈lactose>sucrose.

Determination of pKa and Hydration Constants for a Series of α-Keto-Carboxylic Acids Using Nuclear Magnetic Resonance Spectrometry

The determination of the acid-base dissociation constants, and thus the pKa values, of α-keto acids such as pyruvic acid is complex because of the existence of these acids in their hydrated and nonhydrated or oxo state. Equilibria involved in the hydration and dehydration of the α-keto group of pyruvic acid and three other α-keto acids, 3-methyl-2-oxobutanoic acid, 4-methyl-2-oxopentanoic acid, and 2-oxo-2-phenylacetic acid, were investigated by proton and carbon nuclear magnetic resonance spectrometry, at constant ionic strength, 0.15, and 25°C. Dissociation constants for the oxo (pKaoxo) and hydrated (pKahyd) acids of each compound were estimated from the change in the degree of hydration with changes in pH and directly from the changes in chemical shifts of various hydrogen and carbons nuclei with pH. α-Keto acids showed greater hydration in their acidic forms than their carboxylate forms. The degree of hydration was sensitive to steric and electronic/resonance factors. As expected, the oxo forms of the acids were stronger acids compared with their hydrated analogs, and their dissociation constants were also sensitive to steric and electronic factors.

Redox Mechanism, Antioxidant Activity and Computational Studies of Triazole and Phenol Containing Schiff Bases

Electrochemical behavior of three biologically important triazole and phenol containing Schiff bases (E)-3-((4H-1,2,4 triazol-4-ylimino) methyl)benzene-1,2-diol (TMB), (E)-3-((4H-1,2,4 triazol-4-ylimino) methyl)para-phenol (p-TMP) and (E)-3-((4H-1,2,4 triazol-4-ylimino) methyl)ortho-phenol (o-TMP) were investigated by electrochemical, spectroscopic and computational methods. The peak potential of all the three compounds showed a linear dependence on pH under acidic conditions, but under alkaline conditions, electron transfer was not coupled to proton transfer. The acid-base dissociation constant (pKa) values of the compounds were evaluated both by electrochemical and UV-Vis spectroscopic techniques. On the basis of experimental and theoretical findings, redox mechanisms of the compounds were proposed and certain important kinetic and thermodynamic parameters were determined from their temperature and pH responsive redox response. Our studies showed a) low cytotoxicity for all three triazoles and b) antioxidant properties of these triazoles. TMB was found as the most promising antioxidant, which makes this compound interesting as a basis for further development as food supplement.

PH and Temperature Responsive Electrooxidation of Thiazole Derivatives and Preliminary Screening of Their Antioxidant Activity

Thiazole and its derivatives have extensive pharmacological, industrial and biological applications. In the present work an attempt has been made to evaluate important physico-chemical parameters of two thiazole derivatives, 2-amino-5-nitrothiazole (ANT) and 2-amino-3-thioxothiazolidin-4-one (ATO) for proposing their redox mechanism using cyclic, square wave and differential pulse voltammetric techniques. Differential pulse voltammetry was conducted in media of different pH for the determination of acid base dissociation constant (pKa) and number of electrons and protons involved in proton coupled electron transfer processes. Cyclic voltammetry was employed for getting general voltammetric portrait of the compounds and evaluation of kinetic parameters like diffusion coefficient and heterogeneous electron transfer rate constant. Square wave voltammetry was performed for ensuring the reversible or irreversible nature of the redox reactions of the analytes. The feasibility of the redox reactions were estimated by computing the thermodynamic parameters by observing the effect of temperature on the anodic response of the compounds. Computational studies were carried out and the theoretical findings were found in line with the experimental results. Moreover, the compounds were screened for cytotoxicity and antioxidant activity.

PH- and temperature-responsive redox behavior of hydroxyanthracenediones

The redox response of three anthracenediones; 4,8-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-1-yl acetate (HACAD), 1,4,5-trihydroxyanthracene-9,10-dione (HAD) and 1,4,5-trihydroxy-2-methyl-3-(3-oxobutyl)anthracene-9,10-dione (HOAD) was probed at the surface of a glassy carbon electrode (GCE) over a wide pH range from pH 3 to pH 12 using voltammetric techniques. Cyclic voltammetry (CV) allowed us to evaluate the redox processes in general. Temperature-dependent sweep rate experiments allowed us to obtain kinetic parameters like the diffusion coefficient and the electron transfer rate constant, which were further used to evaluate the thermodynamics of the processes. Differential pulse voltammetry (DPV) allowed the determination of the number of electrons and protons involved in the Faradaic processes. In addition, square-wave voltammetry (SWV) allowed us to assess the reversible/irreversible nature of the electrode processes and allowed the determination of analytical parameters, such as the limit of detection and the limit of quantification. A thorough UV–vis spectroscopy, in a wide pH range, allowed the determination of the acid-base dissociation constant, p K a , and of the molar extinction coefficient. The p K a values determined by different methods were found to be in very good agreement.

Benefit of Retraining pKa Models Studied Using Internally Measured Data.

The ionization state of drugs influences many pharmaceutical properties such as their solubility, permeability, and biological activity. It is therefore important to understand the structure property relationship for the acid-base dissociation constant pKa during the lead optimization process to make better-informed design decisions. Computational approaches, such as implemented in MoKa, can help with this; however, they often predict with too large error especially for proprietary compounds. In this contribution, we look at how retraining helps to greatly improve prediction error. Using a longitudinal study with data measured over 15 years in a drug discovery environment, we assess the impact of model training on prediction accuracy and look at model degradation over time. Using the MoKa software, we will demonstrate that regular retraining is required to address changes in chemical space leading to model degradation over six to nine months.

Synthesis, Spectroscopic Characterization, pH Dependent Electrochemistry and Computational Studies of Piperazinic Compounds

This work presents the synthesis, redox behavior and spectroscopic characterization of two novel compounds Sodium 4-(3-methoxyphenyl) piperazine-1-carbodithioate and sodium 4-(4-nitrophenyl) piperazine-1-carbodithioate. Pulse voltammetric techniques were utilized to determine the number of electrons involved in the oxidation and/or the reduction step and to ensure the nature of the redox processes. The pH dependent redox mechanistic pathways of the compounds were proposed on the basis of electrochemical and computational results. Different thermodynamic parameters like ΔG# and ΔH# revealed that electrode processes are non-spontaneous and endergonic in nature. Increase in ΔS# values at higher temperature indicated the randomness of the electrode reactions at higher temperatures. Limits of detection and quantification were determined by square wave voltammetry due to its high sensitivity and fast speed. Ionization energy, electron affinity, dipole moment and charge distribution on atoms were computationally determined. Acid-base dissociation constant (pKa) values of the compounds evaluated by voltammetry and electronic spectroscopy were found comparable.

Is the Isodesmic Reaction Approach a Better Model for Accurate Calculation of pK a of Organic Superbases? A Computational Study

The acid-base dissociation constant (p<i>K</i> _a) can be related to the solubility and binding of drugs. However, measuring accurate p<i>K</i> _a values is a challenging task. In this study, we have examined the p<i>K</i> _a of various organic superbases: naphthalenes, cyclic guanidines, vinamidines, and acyclic guanidines computationally. We have calculated the p<i>K</i> _a of such superbases by employing two methods: a conventional thermodynamic cycle and a second method based on an isodesmic reaction. The thermodynamic cycle involves computation of solvation free energy by using gas-phase free energy and the difference in solvation free energies (∆G_solv) between products and reactants. Calculations performed with the isodesmic reaction approach do not use the free energy of solvation; hence, the accuracy of the approach is less sensitive to solvent molecules and global charges of the calculated species. The root-mean-square errors (RMSE) predict that the p<i>K</i> _a of the studied organic superbases are more accurate when calculated with the isodesmic reaction approach.

Synthesis of new (arylcarbonyloxy)aminopropanol derivatives and the determination of their physico-chemical properties

Abstract Eight hydrochlorides of 3-{2-[(2/4-fluorophenoxy)-ethylamino]}-2-hydroxypropyl-4-alkoxybenzoates and four hydrochlorides of 3-tert-butylamino-2-hydroxypropyl-4-butoxybenzoates were prepared as potential antagonists of the β1-adrenergic receptor (beta-blockers). A multistep synthesis of these compounds is described as well as their detailed analytical characterization. The pharmacokinetic properties of these weak base compounds are significantly influenced by their acid-base dissociation constant, pK a. The knowledge of this value is crucial for new drug development. This paper is aimed at developing a methodology that utilizes pH-dependent 1H NMR spectroscopy for its routine analysis. The selected predicted physico-chemical parameters of the new (arylcarbonyloxy)aminopropanols (i.e., aryloxyaminopropanol derivatives) were compared with the model drugs esmolol and flestolol.

Determination of acid–base dissociation constants of very weak zwitterionic heterocyclic bases by capillary zone electrophoresis

Thermodynamic acid–base dissociation (ionization) constants (p K a) of seven zwitterionic heterocyclic bases, first representatives of new heterocyclic family (2,3,5,7,8,9-hexahydro-1 H-diimidazo[1,2- c:2′,1′-f][1,3,2]diazaphosphinin-4-ium-5-olate 5-oxides), originally designed as chiral Lewis base catalysts for enantioselective reactions, were determined by capillary zone electrophoresis (CZE). The p K a values of the above very weak zwitterionic bases were determined from the dependence of their effective electrophoretic mobility on pH in strongly acidic background electrolytes (pH 0.85–2.80). Prior to p K a calculation by non-linear regression analysis, the CZE measured effective mobilities were corrected to reference temperature, 25 °C, and constant ionic strength, 25 mM. Thermodynamic p K a values of the analyzed zwitterionic heterocyclic bases were found to be particularly low, in the range 0.04–0.32. Moreover, from the pH dependence of effective mobility of the bases, some other relevant characteristics, such as actual and absolute ionic mobilities and hydrodynamic radii of the acidic cationic forms of the bases were determined.

Hydrogen bond models and theories: The dual hydrogen bond model and its consequences

The H-bond can be reinterpreted starting from the dual H-bond model, for which any D–H···:A bond is not a bond donated by D–H to :A but rather consists of two bonds formed by the central proton with two adjacent acceptors. Analogously, the H-bond energy, E HB, is not the D–H···:A dissociation energy but the smaller of two bond-dissociation energies, D 0(D–H) and D 0(H–A), by which −D: and :A are competitively bound to the proton. If one is stronger, the other is weaker, and weak the overall H-bond will be. Strong bonds occur when Δ D 0 = D 0(D–H) − D 0(H–A) = 0 or, in terms of affinity for the proton ( pa), when Δ pa = pa(D −) − pa(A) = 0. H-bond properties are then function of two variables, pa(D −) and pa(A), or better of their linear combinations, Σ pa = pa(D −) + pa(A) and Δ pa = pa(D −) − pa(A), having respective meanings of mean donor/acceptor electronegativity and of energy difference, Δ rE , between tautomeric D–H···:A and −D:···H–A + forms. Two cases are studied. The case: ‘Σ pa variable for Δ pa = 0’ leads to quantitative relationships between D/A electronegativity and maximum energy, E HB,MAX, achievable for each D/A electronegativity class, EC(D,A). The case: ‘Δ pa variable for Σ pa = constant’ leads to formulate three different but inter-consistent H-bond theories which are separately discussed. The last one, which is called ‘p K a equalization principle’ and where Δ pa values are empirically estimated from the acid–base dissociation constants in water as Δp K a = p K AH(D–H) − p K BH+(A–H +), is shown to be a powerful method of large applicability for predicting the H-bond strengths from thermodynamic parameters.

Novel long alkyl side chain benzo[ a]phenoxazinium chlorides: synthesis, photophysical behaviour and DNA interaction

Several fluorescent benzo[ a]phenoxazinium chlorides possessing a propyl-, octyl-, decyl-, dodecyl- or tetradecylamino at the 5-position of the heterocyclic moiety were efficiently synthesised. The absorption and emission maxima of all compounds lie in the range 627–638 nm and 654–678 nm, respectively, with good fluorescence quantum yields. Studies of their photophysical properties in ethanol allowed for the estimation of the acid–base dissociation constant, K a, revealing an enhancement with the increase in the alkyl side-chain length. It is in the aqueous medium only that the acid form is observed as coexisting with H-aggregates. The solubility markedly decreased when the chain length increased. The residual ethanol (0.2% v/v) used to facilitate the solubilisation of the benzo[ a]phenoxazinium dyes allow for the existence of the basic form in an aqueous solution, possibly through preferential solvation. Photophysical studies in the presence of DNA revealed that the compounds with an alkyl side chain of up to eight carbon atoms could intercalate between DNA nucleotides. Moreover, other forms of DNA binding were found to be operative, involving also the basic form of benzo[ a]phenoxazinium dyes.

PH modelling in aquatic systems with time-variable acid-base dissociation constants applied to the turbid, tidal Scheldt estuary

Abstract. A new pH modelling approach is presented that explicitly quantifies the influence of biogeochemical processes on proton cycling and pH in an aquatic ecosystem, and which accounts for time variable acid-base dissociation constants. As a case study, the method is applied to investigate proton cycling and long-term pH trends in the Scheldt estuary (SW Netherlands, N Belgium). This analysis identifies the dominant biogeochemical processes involved in proton cycling in this heterotrophic, turbid estuary. Furthermore, information on the factors controlling the longitudinal pH profile along the estuary as well as long-term pH changes are obtained. Proton production by nitrification is identified as the principal biological process governing the pH. Its acidifying effect is mainly counteracted by proton consumption due to CO2 degassing. Overall, CO2 degassing generates the largest proton turnover in the whole estuary on a yearly basis. The main driver of long-term changes in the mean estuarine pH over the period 2001 to 2004 is the decreasing freshwater flow, which influences the pH directly via a decreasing supply of dissolved inorganic carbon and alkalinity, and also indirectly, via decreasing ammonia loadings and lower nitrification rates.

NMR determination of pKa values of indoloquinoline alkaloids

Malaria is one of the most serious global health problems. Isolating new therapeutic agents with potential antimalarial activity from natural sources or preparing such agents either semisynthetically or synthetically is one strategy for solving the problem of resistance constantly evolving to the drugs currently in use. For alkaloids, the acid-base dissociation constant, pK(a), is an important characteristic, thought to be associated with biological activity. In this contribution, pK(a) values for several indoloquinoline alkaloids were determined by using (1)H NMR spectroscopy in a mixture of solvents. The data were recalculated for water solutions using the correction factors reported previously. The structural dependence of the pK(a) values for cryptolepine and its isomers neocryptolepine, isocryptolepine and isoneocryptolepine as well as some substituted neocryptolepine derivatives is discussed.

X-Ray Crystal Structure, Acid - Base Properties and Complexation Characteristics of a Methylenephosphonate Derivative of 1,4,7,10-Tetraazacyclododecane

The X-ray crystal structures of 1,4,7-tris(methylenephosphonate)-1,4,7,10-tetraazacyclododecane (DO3P·3.5H2O) and 1,7-bis(methylenephosphonate)-1,4,7,10-tetraazacyclododecane dihydrochloride trihydrate (DO2P·2HCl·3H2O) reveal that two nitrogen atoms in the trans-annular positions are protonated. The macrocyclic ring adopts a (3,3,3,3)-B conformation stabilized by intramolecular hydrogen bonding involving oxygen atoms from the phosphonate groups and the protonated amines. The acid–base dissociation constants of DO3P and metal complex formation constants (for Ca2+, Mg2+, Zn2+, Fe3+) were determined using potentiometric measurements. The first two protonations of DO3P occur at quite high pH and, consequently, were determined by NMR measurements. The stability constants indicate that DO3P forms more stable complexes with the transition metal ions Zn2+ and Fe3+ (log K [ML] = 21.23(4) and 22.74(5) respectively) than with the alkaline earth metal ions Ca2+ and Mg2+ (log K [ML] = 10.96(6) and 8.72(6) respectively). For Fe3+, Ca2+ and Mg2+, the data support the formation of dinuclear species, presumably through the coordination of an additional metal ion to the phosphonate groups.

Control of DNA incorporation into nanoparticles with poly(L-lysine) multilayers

Nanoparticles coated with DNA and poly(L-lysine) (PLL) were prepared using a layer-by-layer assembly technique under various solution conditions. Both the level of DNA loading into the materials, the rate and the extent of DNA released from films upon degradation were controlled by varying the pH of polyelectrolyte assembly solutions. To determine optimal conditions for DNA loading, analogous films assembled on flat surfaces were prepared under various pH conditions. Using UV–vis spectroscopy and thin-film ellipsometry, it was found that the extent of DNA incorporation could be varied by more than a factor of two, and that the highest loading was obtained for films built using a combination of DNA and poly(L-lysine) solutions of pH = 4 and pH = 7, respectively. The layers coated onto the silica nanoparticles permitted the surface charge to be characterized by zeta potential electrophoresis. Furthermore, the acid–base dissociation constant measured for PLL on the outermost layer of the DNA/PLL film showed that the pKaof PLL can be shifted by more than three units. Film degradability was investigated via the exposure of films assembled under different pH conditions to α-chymotrypsin. The fraction of DNA released from degraded films can also be increased by a factor of three when films are built under conditions of pH = 4 for the DNA solution. The resultant effect on the transfection ability of pEGFP-N1/PLL coated particles was then measured, and results suggest that the control achieved over the bulk film properties also extends to a strong influence on cell uptake and transfection.Key words: polyelectrolyte multilayer, DNA incorporation, enzymatic degradation, nanoparticles, gene therapy.