The relationship among pKa, pH, and binding constants in the interactions between boronic acids and diols—it is not as simple as it appears

In our continuing efforts into designing boronic acid-based sensors that recognize cell-surface carbohydrates, it has been necessary to examine various factors that affect the binding affinity between a boronic acid moiety and a diol. The current prevailing view is that the strongest boronic acid/diol complexes are generated by a combination of high solution pH and a low boronic acid pK_a. However, there has never been a systematic examination of the relationship among the binding constants, boronic acid pK_a, and the pH of the solution. Herein we report our findings with a series of 25 arylboronic acids with various substituents and their binding affinities with diols. We have found that (1) the relationship between the pK_a of monosubstituted phenylboronic acid and its substituents can be described using a Hammet plot; (2) the optimal pH for binding is not always above the pK_a of the boronic acid, and is affected by the pK_a values of the boronic acid and the diol, and other unknown factors; and (3) the general belief that boronic acids with lower pK_a values show greater binding affinities for diols is not always true.     

Calculation of amino acid pKaS in a protein from a continuum electrostatic model: Method and sensitivity analysis

We used continuum electrostatic theory to calculate pK_as of amino acids in protein. A Green's function formalism, based on a finite-difference solution to the Poisson–Boltzmann equation for a unit point charge, yields electrostatic potentials that allow calculation of amino acid pK_as to an estimated accuracy of tenths of a pK_a unit. Improvements over previous methods include the ability to focus the finite difference grid to arbitrarily small grid spacing, an analytical representation of the molecular surface, and a novel procedure to calculate the reaction field potential. Using this method, we performed a sensitivity analysis of calculated pK_as in the photosynthetic reaction center. Calculated pK_as are most sensitive for residues that are not well-exposed to solvent. Variations in the parameters of the continuum electrostatic model cause pK_a shifts that are larger than the accuracy of the numerical method, but probably not large enough to account for some of the discrepancies between calculated and experimentally measured pK_as that have been reported for the reaction center. © 1996 by John Wiley & Sons, Inc.     

Validation of pH-Metric Technique for Measurement of pKa and log Pow of Ionizable Herbicides

Abstract

Knowing the values of pK_a and partition coefficients between 1-octanol and water (P_ow) of ionizable herbicides helps us to understand the movement of these compounds in plants and soil. However, shake-flask and high-pressure liquid chromatography (HPLC) techniques. though valuable for measurement of log P_ow of herbicide molecules that do not ionize in aqueous solution, are difficult to use for ionizable molecules; this is especially so for molecules that form ion pairs having appreciable log P_ow values, those with multiple ionizations and for bases with high pK_a values. Our aim in this study was to validate the use of the pH-metric technique (based on potentiometric titration) for measurements of pK_a and log P_ow of ionizable standard substances and herbicides. The values obtained show good correlation with results from other techniques, including shake-flask and HPLC. The OECD Guideline for Testing of Chemicals 117, adopted 30th March 1989, describes the use of HPLC for the measurement of log P_ow. It is hoped that these studies and further testing of this technique will permit it to be included in these OECD guidelines.     

Multiwavelength Spectrophotometric Determination of Acid Dissociation Constants. Deconvolution of Binary Mixtures of Ionizable Compounds

ABSTRACT

A spectral deconvolution method based on target factor analysis has been developed to determine pK_a values of binary mixtures of monoprotic and/or diprotic ionizable compounds. The technique makes use of the approach of Frans and Harris, which has been implemented previously for mixtures of monoprotic compounds (Anal. Chem. 1985, 57, 1718-1721), to extract the unknown pK_a values. The method has been illustrated by using the multiwavelength spectrophotometrictitation data of binary mixtures of: I. benzoic acid and phenol, 2. benzoic acid and nicotinic acid, 3. p-aminosalicylic acid and phthalic acid. It was demonstrated that the pK_a values as determined in this study are in good agreement with the literature.     

In pursuit of key features for constructing electrochemical biosensors – electrochemical and acid-base characteristic of self-assembled monolayers on gold

ABSTRACT

Electrochemical biosensors are a well-known group of tools used widely in a variety of industries. Due to interactions between analytes and a surface, a measurable signal occurs which can then be processed to quantitative and/or qualitative data. The knowledge of surfaces’ electrochemical properties as well as their pK_a is of great importance when it comes to the construction of biosensors based on an electrochemical signal. In our work, we focused on determining electrochemical properties as well as pK_a of thiol-based SAMs – commonly used linker layers in biosensors. By applying cyclic voltammetry and electrochemical spectroscopy we were able to describe the overall resistive behaviour of SAMs synthesised with both alkanethiols and thiols with carboxyl and amine groups. Coherent use of contact angle measurements let us also describe the overall polarity of the investigated surfaces. The obtained data of pK_a values differed from the ones described for bulk solutions of modifying agents, which yields important information for further modification of the surface.     

Modification of molecular properties of some dyes in sodium dodecyl sulphate (SDS) micellar aqueous solution

The influence of SDS upon the molecular properties of proflavine (3,6-diaminoacridine), acridine yellow (2,7-dimethyl-3,6-diaminoacridine) and methylene blue (3,7-bis-dimethylamino-phenothiazine) was studied comparatively to their properties in that of aqueous media. The absorption and emission spectra of the three dyes in SDS aqueous solution (1–100 mmol/l) were recorded. The spectroscopic data also allowed the evaluation of the critical micellization concentration (CMC), acidity constants in fundamental (pk_a) and excited (pK^*_a) states, and lifetimes of excited singlet states.     

Spectrophotometric determination of the acid dissociation constants for cacodylic acid and p-Nitrophenol at elevated temperatures

Using 2.5-dinitrophenol as an optical indicator, the pK_a of cacodylic acid were spectrophotometrically determined at elevated temperatures under saturation vapor pressures. The result is pK_a = -26.41 + 1296/T + 4.973 InT whereT is in Kelvin. In a similar way, the pK_a ofp-nitrophenol were obtained up to 200‡C giving pK_a = -24.82 + 2135/T + 4.353 InT From these results, several thermodynamic functions of cacodylic acid andp- nitrophenol were calculated.     

The Limit of Detection of a Weak Acid,in the Presence of Another,by Potentiometric Acid-Base Titrimetry and Deviation-Pattern Recognition

Abstract

When a solution containing a single monobasic weak acid is titrated potentiometrically with a strong base, non-linear regression analysis of the data yields a random scatter of the residuals around the best fit to the appropriate equation. If the same equation is used when a second weak acid is also present, systematic errors arise and yield a deviation plot having a characteristic shape. If the amplitude of that plot is substantially larger than the random error of measurement, the presence of the second acid can be detected, and its concentration can then be evaluated by non-linear regression onto the equation that takes its presence into account. The amplitude increases as the relative concentration of the second acid increases, and as the difference between the values of pK_a for the two acids increases. Examination of these dependences shows, for example, that it should be possible to detect 1 per cent of an impurity for which pK_a differs by 0.57 unit from that of the major component.     

Simple methods for the estimation of ionization constants of substituted pyridine N-oxides in polar aprotic solvents and water

A direct method for the determination of the pK _a values of acids conjugated to substituted pyridine N-oxides has been proposed which is based on the pH measurement of the solution of the basic salt. It has been experimentally shown that the method is reliable when applied to N-oxides of not too low basicity (pK _a >5). Correlation has been performed between the pK _a values in aqueous and aprotic media solutions which shows the great influence of the solvation effect on the acid-base equilibria. The good correlation between the pK _a values in aqueous and non-aqueous solutions enables the pK _a values in water to be estimated with sufficient accuracy, even in the cases when the experimental limitations make the determination impossible which is shown on the basis of selected examples.     

Quantum-chemical investigation of the dependence of pK a on the calculated energy of proton removal for certain derivatives of indole and phenol

The total energies of derivatives of N-hydroxyindole, indole, and phenol, and of their corresponding anions have been estimated with the aid of ab initio calculations on the 3-21G basis. The energies of proton removal were calculated from the difference in total energies of the appropriate anions and molecules. By comparing the calculated energies of proton removal with experimental values of pK_a (acidity characteristic) a practically linear dependence was shown for the acidity characteristic on the energy of proton removal for the series of compounds investigated. An empirical formula has been proposed expressing the dependence of pK_a on the energy of proton removal, which makes it possible to predict pK_a in this series by carrying out calculations of the energy of proton removal (transfer). __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 47–50, January, 2006.     

Calculations of pKa values of carboxylic acids in aqueous solution using Möller-Plesset perturbation theory

The acidity constants of some carboxylic acids in aqueous solution have been calculated. The calculations were carried out using Möller-Plesset (MP) perturbation theory. The Polarizable Continuum Model (PCM) is used to describe the solvent. This model furnishes pK_a values that agree more closely with experimental data than those obtained at the level of Hartree-Fock (HF) and Density Functional Theory (DFT-B3LYP). The root-mean-square of errors of the calculated pK_a values are less than 1.0 for the studied acids. The molecules analyzed consist of acids with pK_a values in the range of 1.30 to 5.05, and have been partitioned into three classes. Class I includes acids with pK_a values higher than 4.00. Class II includes strong acids with pK_a values between 3.00 to 4.00. Class III includes very strong acids with pK_a values less than 3.00. The calculated pK_a values for the acids in Class I and Class II agree more closely with experimental values. The root-mean-square of errors for the Class I and Class II compounds are 0.70 and 0.78 pK_a units, respectively.     

Calculation of acidic dissociation constants in water: solvation free energy terms. Their accuracy and impact

Three polarizable continuum models, DPCM, CPCM, and IEFPCM, have been applied to calculate free energy differences for nine neutral compounds and their anions. On the basis of solvation free energies, the pK_a values were obtained for the compounds in question by using three thermodynamic cycles: one, involving the combined experimental and calculated data, as well as two other cycles solely with calculated data. This paper deals with the influence of factors such as the SCRF model applied, choice of a particular thermodynamic cycle, atomic radii used to build a cavity in the solvent (water), optimization of geometry in water, inclusion of electron correlation, and the dimension of the basis set on the solvation free energies and on the calculated pK_a values. Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

Determination de pKa d'acides conjugues de carbanions dans le DMSO anhydre. Reexamen des correlations entre cés pKa et les potentiels d'oxydation Eox determines dans le mĕme solvant

The pK_a values of several pseudo-acids of general formula

in anhydrous DMSO have been determined.The pK_a values have been correlated with the oxidation potential E_ox of their conjugated carbanions (enolate anions). The variation of E_ox of these enolate anions (and even those of cyclopentadienyl, indenyl, fluorenyl and triphenylmethyl carbanions) as a function of the pK_a of their acidic form is consistent with a correlation line whose slope is ?0.067 V/unity pK_a.In DMSO, all the β-carbonylated nitriles are in their enolic form, except the 2-cyano-esters which are entirely in the carbonyl form. In spite of this, their acidity is intermediate between that of the methylketones (Z = CH₃) and the aldehydes (Z = H). Thus, in DMSO medium, for β-carbonylated nitriles it appears that the acidity is not dependent on the enolization tendency.     

DFT/TDDFT investigation of the stepwise deprotonation in tetracycline: pK<Subscript>a</Subscript> assignment and UV–vis spectroscopy

Tetracyclines are a class of derivatives of polycyclic naphthacene carboxamide, which have attracted wide interest in the pharmaceutical field for their use as antibiotics. These molecules are characterized by a substantial conformational flexibility and by the presence of different binding sites which endow tetracycline with a noticeable capability in binding biological targets. A salient property of tetracyclines is the presence of multiple acidic groups: four equilibrium constants have been measured for the fully protonated tetracycline (TCH₃ ⁺) but so far no clear information concerning the pK_as of the various sites has been reported. We present here a computational investigation on the correlation between the acid–base and the spectroscopic properties of this important class of compounds. Starting from the TCH₃ ⁺ species, the pK_a of all the possible deprotonation sites has been computed by DFT calculations. The computed pK_as nicely compare with the experimental data, within 1 pK_a unit, allowing us to individuate the products of the first deprotonation. This procedure has been iteratively repeated using as starting species the products singled out from the previous deprotonation, thus individuating the stepwise products of each deprotonation step. Then, the optical absorption spectra have been computed for all the species involved in the protonation/deprotonation equilibria, comparing the results with the experimental data. The good agreement between theory and experiment has allowed us to rationalize the correlation between the solution pH and the absorption spectra.     

Correlation Eox de carbanions/pKa de leurs acides conjugues,domaine d'existence stable des carbanions en solution aprotique ou partiellement p

pK_a values of 44 enolizable compounds have been determined and collated with the half-wave oxidation potentials of the corresponding anions. A correlation between the half-wave oxidation potential of an enolate anion and the pK_a of his conjugated acid was established. Generalization of this correlation allows to define a stability range of the carbanions in solution, as much with regard to oxidation-reduction as to their acidity.     

The connection between the ionization constants of alkaloids and their basicities

Summary 1. The pK_a values of a number of indole alkaloids ofVinca erecta in aqueous ethanolic solution and in chloroform have been determined.2. It has been shown that the pK_a value of an alkaloid in water or in chloroform is not connected with the pH of the transition from chloroform into a buffer solution.3. It is impossible to estimate the basicity of an alkaloid from its pK_a value.Institute of the Chemistry of Plant Substances, Academy of Sciences of the Uzbek SSR. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 57–59, January–February, 1973.     

Application of the pKa rule to synthesize salts of bezafibrate

ABSTRACT

Co-crystallization frequently employs forces such as hydrogen bonds, halogen bonds, and π-π stacking to assemble molecules in a multi-component crystal. In an effort to increase the strength of the intermolecular interaction between the anti-cholesterol drug bezafibrate (BEZA), a wastewater contaminant, and hydrogen-bond-acceptor molecules, we modified the pK_a values of the acceptors. Here, we describe the first series of salts incorporating BEZA and achieve a variety of supramolecular architectures including discrete assemblies, 1D chains, tapes, and 2D sheets. We discuss exceptions to the pK_a rule, and demonstrate that the presence of hydrogen-bond-donor atoms on the acceptor molecule supports salt formation.     

On the synthesis of hypericin by oxidative trimethylemodin anthrone and emodin anthrone dimerization: Isohypericin

Summary The base catalyzed oxidative dimerization of emodin anthrone exclusively yields hypericin. However, on oxidative dimerization of trimethylemodinanthrone a mixture of hexamethylhypericin and hexamethylisohypericin was obtained. Chromatographic separation of the hexabenzoyl derivatives was achieved, and by saponification about equal amounts of hypericin and isohypericrin were produced. Isohypericin could be characterized for the first time by its spectroscopic data and its protonation and deprotonationpK _a andpK _a ^* values.

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Zur Synthese von Hypericin durch oxidative Dimerisierung von Trimethylemodinanthron und Emodinanthron: Isohypericin

Zusammenfassung Die basenkatalysierte oxidative Dimerisierung von Emodinanthron liefert ausschließlich Hypericin. Oxidative Dimerisierung von Trimethylemodinanthron ergibt jedoch ein Gemisch von Hexamethylhypericin und Hexamethylisohypericin. Die Hexabenzoylderivate wurden chromatographisch getrennt, und Hypericin und Isohypericin konnten aus diesen Derivaten durch Verseifung freigesetzt werden. Isohypercin konnte erstmals durch seine spektroskopischen Daten und seine Protonierungs- und Deprotonierungs-pK _aundpK _a ^* -Werte charakterisiert werden.

     

Gradient reversed-phase high-performance chromatography of ionogenic analytes

This review highlights the basis of gradient reversed-phase high-performance liquid chromatography (RP-HPLC) of ionogenic analytes.We describe pH-gradient RP-HPLC in strict theoretical terms, with examples of experiments to provide improvements in analyte separations and peak shapes, and an original method of pK_a determination.Finally, we present the concept of the combined pH/organic-modifier gradient mode of RP-HPLC and illustrate it with applications. It allows optimization of separation of ionogenic analytes, along with a method for determining their biorelevant physico-chemical parameters [e.g., hydrophobicity (log k_w) and acidity (pK_a)]. The method is applicable to drugs and other xenobiotic mixtures, including individual analytes of interest assayed in biological fluids.     

Acidity Constants of Supported Salts of Heteropoly Acids Using a Methodology Related to the Potentiometric Mass Titration Technique

Using a potentiometric mass titrationmethod, the pK_a values of 12-molybdophosphoric acid (MPA) and 12-tungstophosphoric acid (TPA) were determined in aqueous solution and as a solid suspension in acetonitrile. The results were compared with the earlier reported values obtained using other methods like calorimetry and adsorption (Cal-ad). The acidity values in terms of pK_a and the number of acid sites were determined for the ammonium salts of MPA and TPA, and ammonium salts incorporated with vanadium and ammonium salts impregnated on a ZrO₂ support. The effect of the amount of the salt or acid in the suspension of acetonitrile on the potentiometric titration behavior was also studied and it was found that 0.1 g of the substance gives a good neutralization jump in the titration curve.