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.     

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.     

Computational Estimation of the Acidities of Pyrimidines and Related Compounds

Pyrimidines are key components in the genetic code of living organisms and the pyrimidine scaffold is also found in many bioactive and medicinal compounds. The acidities of these compounds, as represented by their pK_as, are of special interest since they determine the species that will prevail under different pH conditions. Here, a quantum chemical quantitative structure–activity relationship (QSAR) approach was employed to estimate these acidities. Density-functional theory calculations at the B3LYP/6-31+G(d,p) level and the SM8 aqueous solvent model were employed, and the energy difference ∆E_H2O between the parent compound and its dissociation product was used as a variation parameter. Excellent estimates for both the cation → neutral (pK_a1, R² = 0.965) and neutral → anion (pK_a2, R² = 0.962) dissociations were obtained. A commercial package from Advanced Chemical Design also yielded excellent results for these acidities.     

The acid/base profile of agrochemicals

Drug-likeness has long been studied in the pursuit of finding new medicines. Similarly, in the agrochemical field there is value in exploring the properties of the chemicals involved. Patterns that emerge can potentially influence future discovery campaigns to improve the probability of commercial success. In this study we investigate the acid/base properties and physicochemical characteristics of three classes of compounds: fungicides, herbicides and insecticides. In comparison with FDA-approved drugs, it was noted that the pesticides were generally smaller, possessed a neutral charge state and were more lipophilic. The results are discussed in the light of their intended targets.     

Determination of pKa of dyes by electrical impedance spectroscopy

In this work, we analyze the electrical response of aqueous solutions of dyes as a function of pH. When the acid-base equilibrium is reached, it is possible to detect structural transitions related with changes in molecular conformation. To this, it is necessary the introduction of parallel plates into the solution and from analysis of Nyquist diagrams of samples, it is possible to determine the values of pK_a. The advantage is the absence of redox markers in solution, thus avoiding charge transfer stimulated by the diffusion processes. The effects measured on the electrical response are function of the dye molecular aggregation state, which is structurally dependent on the solution protonation conditions. The detection of aggregated molecules such as dimers, trimers, and oligomers defines Electrical Impedance Spectroscopy (EIS) as a fundamental tool for the analysis of pK_a of dyes.     

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.     

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.     

A fast high throughput method for the determination of acidity constants by capillary electrophoresis. 3. Basic internal standards

A set of 25 monoprotic bases is proposed as internal standards for pK(a) determination by capillary electrophoresis. The pK(a) of the bases is determined and compared with available literature data. The capillary electrophoresis internal standard method offers numerous advantages over other typical methods for pK(a) determination, especially of analysis time and buffer preparation. However, it requires disposing of appropriate standards with reference pK(a) value. The set of bases established in this work together with the set of acids previously established provide a reference set of compounds with well-determined acidity constants that facilitate the process of selecting appropriate internal standards for fast pK(a) determination by capillary electrophoresis in high throughput screening of pharmaceutical drugs. In addition, the performance of the method when acidic internal standards are used for the determination of acidity constants of basic internal standards has also been tested. Although higher errors may be expected in this case, good agreement is observed between determined and literature values. These results indicate that in most cases structural similarity between the analyte and the internal standard might not be an essential requirement in the internal standard method.     

Acid Dissociation Constants of the Benzimidazole Unit in the Polybenzimidazole Chain: Configuration Effects

The acid dissociation constant of three benzimidazoles, namely 2,2′-bibenzo[d]imidazole, 2,5′-bibenzo[d]imidazole, and 5,5′-bibenzo[d]imidazole, have been investigated by means of density functional theory calculations in gas phase and in aqueous solution. The theoretical approach was validated by the comparing of predicted and experimentally determined pK_a values in imidazole, benzimidazole, and 2-phenylbenzimidazole. From the studied compounds, 2,2′-bibenzo[d]imidazole was found to be the most acidic, which made it a valuable candidate as a material for polymer electrolyte membrane fuel cells.     

Kinetics of the Protonation of Macrocyclic Amines in the Presence of Monovalent Cations in Aqueous Solution

Abstract

For macrocyclic bases such as: 1-aza-15-crown-5 (N15C5),1,4,10-trioxa-7,13-diazacyclopentadecan (21), 1,7,10,16-tetraoxa-4,13-diazacyclooctadecan (22) and 1, 4, 7, 13, 16-pentaoxa-10, 19-diazacycloheneicosane (23), the kinetics of deprotonation and protonation reactions in the presence of monovalent cations was studied using the temperature jump technique. For the sake of comparison, the measurements were also performed for 1,4-diazabicyclo[2,2,2]octane (DABCO) base, which does not form complexes with monovalent cations. The monovalent cations affect the temperature dependence of the kinetic parameters of deprotonation. They also affect the activation parameters, which is shown by a distribution of ΔH≠ and ΔS≠ values, but do not influence the value of ΔG≠.     

Evaluating hydrogen-bond propensity,hydrogen-bond coordination and hydrogen-bond energy as tools for predicting the outcome of attempted co-crystallisations

ABSTRACT

Two different structure-informatics based methods and one approach based on hydrogen-bond interaction energies were evaluated for their abilities to predict the experimental outcomes of attempted co-crystallisations between two known drug molecules, Nevirapine and Diclofenac, and a series of potential co-formers. The hydrogen-bond propensity (HBP) tool gave the correct result in 26 out of 30 cases, whereas a hydrogen-bond coordination (HBC) method predicted the correct outcome in 22 out of 30 cases. Finally, calculated hydrogen-bond energies (HBE) using a simple electrostatic model, gave the correct result in 23 out of 30 experiments. In those cases, where the crystal structure of a co-crystal of either Nevirapine or Diclofenac was known, we also examined how well the three methods predicted which primary hydrogen-bond interactions were present in the crystal structure. HBP correctly predicted 6 out of 6 cases, HBC could not predict any of the synthon formations correctly, and HBE successfully predicted 1 out of 6 cases.     

The speed of sound in mixtures of the major sea salts. A test of Young's rule for adiabatic PVT properties

The relative sound speed of mixtures of aqueous solutions of NaCl–MgSO₄ and MgCl₂–Na₂SO₄ at I=0.1 and 0.5m have been determined at 5, 15, and 25°C and pressures to 1000 bars. The resulting sound speeds, adiabatic and apparent molal compressibilities have been compared to results estimated from binary solutions using an additivity principle — Young's rule. The estimated sound speeds agree with the measured values for the NaCl–MgSO₄ system to ±0.15 m-sec^–1 and for the Na₂SO₄–MgCL₂ system to ±0.20 m-sec^–1. The deviations increase with increasing ionic strength (±0.08 m-sec^–1 at I=0.1 and ±0.25 m-sec^–1 at I=0.5 m).The sound speed of seawater have also been estimated from 0 to 40°C, 0.1 to 0.7 ionic strength and 0 to 1000 bars. The estimates were found to be in good agreement (±0.4 m-sec^–1) with the measured values.These results indicate that reasonable estimates of the adiabatic PVT properties of dilute mixtures of electrolyte solutions can be made using the additivity principle, without excess mixing terms.     

Inclusion compounds of thiourea and peralkylated ammonium salts. Part II. Hydrogen-bonded host lattices built of thiourea and cyclic dimeric bicarbonate moieties

New inclusion complexes R₄N⁺HCO ₃ ^– ·x(NH₂)₂CS·yH₂O (1, R=C₂H₅,x=1,y=1;2, R=n–C₃H₇,x=2,y=0;3, R=n–C₄H₉,x=3,y=0) have been prepared and characterized by X-ray crystallography. Crystal data, MoK radiation:1, space groupPbca,Z=8,a=8.839(2),b=14.930(3),c=24.852(5) Å, andR _F=0.063 for 1419 observed data;2, space groupC222₁,Z=8,a=8.521(3),b=16.941(4),c=32.022(7) Å,R _F=0.054 for 1689 observed data;3, space group ,Z=2,a=9.553(2),b=12.313(3),c=14.228(4) Å, =90.44(2),=103.11(2), =110.12(2)°,R _F=0.044 for 3925 observed data. In the crystal structure of1, the thiourea molecules form hydrogen-bonded zigzag ribbons running parallel to thea axis, and the cyclic dimeric bicarbonate moieties (HCO ₃ ^– )₂ together with water molecules behave likewise. A puckered layer is formed by further lateral hydrogen bonding between these two types of ribbons, and the (C₂H₅)₄N⁺ cations occupy the space between adjacent layers. In the crystal structure of2, the thiourea ribbons are cross-linked orthogonally by (HCO ₃ ^– )₂ unitsvia N–H...O hydrogen bonds to form a composite double layer. Half of the cations are enclosed within and the other half sandwiched between these double layers. In the crystal structure of3, the thiourea molecules form puckered double ribbons running in the [110] direction. The host framework is constructed by cross-linking the double ribbons with bridging bicarbonate dimers, yielding two channel systems aligned parallel to [100] and [111] that accommodate the cationic guests. The structural relationship between the present complexes and the classical thiourea channel adducts is discussed. Supplementary Data relating to this article have been deposited with the British Library as Supplementary Publication No. SUP 82178 (44 pages).     

Deuterium Isotope Effects on Acid-Base Equilibrium of Organic Compounds

Deuterium isotope effects on acid–base equilibrium have been investigated using a combined path integral and free-energy perturbation simulation method. To understand the origin of the linear free-energy relationship of ΔpKa=pKaD2O−pKaH2O versus pKaH2O, we examined two theoretical models for computing the deuterium isotope effects. In Model 1, only the intrinsic isotope exchange effect of the acid itself in water was included by replacing the titratable protons with deuterons. Here, the dominant contribution is due to the difference in zero-point energy between the two isotopologues. In Model 2, the medium isotope effects are considered, in which the free energy change as a result of replacing H₂O by D₂O in solute–solvent hydrogen-bonding complexes is determined. Although the average ΔpKa change from Model 1 was found to be in reasonable agreement with the experimental average result, the pKaH2O dependence of the solvent isotope effects is absent. A linear free-energy relationship is obtained by including the medium effect in Model 2, and the main factor is due to solvent isotope effects in the anion–water complexes. The present study highlights the significant roles of both the intrinsic isotope exchange effect and the medium solvent isotope effect.     

Potentiometric and spectrophotometric pKa determination of water-insoluble compounds: validation study in a new cosolvent system

In this paper the validation of pK_a determination in MDM-water mixtures is presented. The MDM-water mixture is a new multicomponent cosolvent mixture (consisting of equal volumes of methanol, dioxane and acetonitrile, as organic solvents) that dissolves a wide range of poorly water-soluble compounds. The cosolvent dissociation constants (p_sK_a) of 50 chemically diverse compounds (acids, bases and ampholytes) were measured in 15-56 wt% MDM-water mixtures by potentiometric or spectrophotometric titration and the aqueous pK_a values obtained by extrapolation. Three different extrapolation procedures were compared in order to choose the best extrapolation in MDM-water mixture using a sub-set of 30 water-soluble compounds. The extrapolated results are in good agreement with pK_a values measured in aqueous medium. No significant difference was found among these extrapolation procedures thus the widely used Yasuda-Shedlovsky plot was proposed for MDM cosolvent also. Further we also present that the single point estimation based on measurement in 20%/v MDM-mixture using a general calibration equation may be suitable for rapid pK_a determination in the early phase of drug research.     

Effect of salts on the excited state of pyranine as determined by steady-state fluorescence

Pyranine is a pH-sensitive fluorescent probe useful in the pH range of 4.5–8, and it has been extensively employed to determine pH inside cells, membranes and membrane models. The fluorescent properties of pyranine are a consequence of the excited states ROH^* and RO^−*. The prototropic equilibrium of these excited species has a much lower than that of the ground state. In this paper we determined the (1.42 ± 0.06) and the relative quantum yield of pyranine in the pH range of 1–8 by analyzing the component peaks of the steady-state of the dye's emission spectrum. As pyranine is very sensitive to the medium we studied the influence of salts formed by mono-, di-, and trivalent ions on the apparent . In all cases, the presence of salts reduced the apparent to varying degrees depending on the valence of the cations. The strategy used to obtain this information was a dual emission ratiometric method at 441 and 511 nm after excitation at 350 nm. The results obtained demonstrate that pyranine is suitable to determine the pH of aqueous solutions in the range of 1–3.5.     

Continuous screening of analytical parameters facilitates efficient development of HPLC methods required for impurity profiling

Developing a robust analytical HPLC–UV method to characterize a drug candidate during an early stage of development is a major challenge when not all impurity standards are available. Here, we report our efforts to devise an efficient strategy for HPLC method development using continuous screening of analytical parameters without impurity standards. This strategy uses small incremental changes in the mobile phase pH and column temperature to trace each impurity on an overlay chromatogram. We tested this method using benzocaine as the active pharmaceutical ingredient (API), and compounds with similar structures to represent unknown impurities. Despite the coelution of peaks, results identified the number of impurities and indicated the starting point and parameter variables of the ensuing optimization step. Further, we demonstrated that the retention time of each peak as a function of mobile phase pH accounts for the apparent pK_a of known and unknown compounds in the presence of an organic solvent. This information is critically important to the selection of a robust pH range for HPLC methods.