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.     

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.     

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.     

Beiträge zur Chemie der Pyrrolpigmente, 65. Mitt.

The title compound1 is found to be protonated corresponding topK _a 's of 2.5 and 0.5, thereby being two orders of magnitude less basic than bilatrienes-abc. Its deprotonation (pK _a =17.1) is found to be less easy than in case of the bilatrienes.1 is shown to exhibit a very pronounced reactivity for nucleophiles at the methine positions 10 and 15—a thiole adduct and the 10,15-dihydroderivative of1 are isolated and characterised. In contrast to the bilatrienes the adduct formation is irreversible. Accordingly, no diastereomers at exocyclic double bonds could be produced photochemically. Complexation of the lactam oxygens is achieved in case ofLewis acids (eg. AlCl₃), chelation after addition of a proton acceptor is observed in a few cases only (Zn⁺⁺, Hg⁺⁺, In⁺⁺⁺).

Herrn Prof. Dr.K. Kratzl zum 70. Geburtstag gewidmet.     

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.     

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.     

A Novel QSAR Approach for Estimating Toxicity of Phenols

Abstract

Toxicity values (log IGC^?1 ₅₀) for 60 phenols tested in the 2-d static population growth inhibition assay with the ciliate Tetrahymena pyriformis were tabulated. Each chemical was selected so the series formed uniform coverage of the hydrophobicity/ionization surface. A high quality hydrophobicity-dependent (log K _ow) structure-toxicity relationship (log IGC^?1 ₅₀ = 0.741 (log K_ow) ?1.433; n = 17; r² = 0.970; s = 0.134; F = 486.55; Pr > F = 0.0001) was developed for phenols with pK_a values > 9.8. Similarly, separate hydrophobicity-dependent relationships were developed for phenols with pK_a values of 4.0, 5.1, 6.3, 7.5, and 8.7. Comparisons of intercepts and slopes, respectively, revealed phenols with pK_a values of 6.3 to be the most toxic and the least influenced by hydrophobicity. These relationships were reversed for the more acidic and basic phenols. Plots of toxicity versus pK_a for nitro-substituted phenols and phenols with log K_ow values of either 1.75 or 2.50 further demonstrated bilinearity between toxicity and ionization. In an effort to more accurately model the relationship between toxicity and ionization, the absolute value function |6.3-pK_a| was used to model ionization affects for derivatives with pK_a values between 0 and 9.8. For derivatives with pK_a value > 9.8, a value of 3.50 was used to quantitate ionization effects. The use of log K_ow in conjunction with this modified pK_a (ΔpK_a) resulted in the structure-toxicity relationship (log IGC^?1 ₅₀ = 0.567 (log K_ow)-0.226 (ΔpK_a-0.079; n = 54; r² = 0.926; s = 0.215; F = 321.06; Pr > F = 0.0001). Derivatives with a nitro group in the 4-position typically did not model well with the above equation.     

Reaktivität der Pyrrolpigmente, 2. Mitt.: Deprotonierung von 3-Pyrrolin-2-onen

Deprotonation of 3,4-dimethyl-3-pyrrolin-2-on (1) int-butyl alcohol/potassiumt-butoxide solutions takes place on the N atom, as shown by¹H/²H exchange andpK _a determinations of1 (pK=17.1), 1,3,4-trimethyl-3-pyrrolin-2-one (pK _a =17.6), and 3,4-dimethyl-5-methoxy-2_H-pyrrole (pK _a =16.7). The SCF-MO approximation MINDO/3 indicates, however, that in the gas phase deprotonation of1 should occur at the C atom.

1.Mitt.:Ribó, J. M., Trull, F., Mh. Chem.110, 201 (1979).     

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.

     

The deprotonation and protonation equilibria of a hypericin derivative in aqueous solution

Summary A hypericin derivative ,'-appended at the methyl groups with two polyethylene glycol moieties (about 23 units long) and capped with acetyl groups was synthesized starting from emodin. This derivative proved to be soluble in water and was investigated by means of spectrophotometric titrations and electrophoresis experiments. Deprotonation at thebay-region hydroxyl group was observed atpK _a=1.6. This was followed by a second deprotonation step of aperi-hydroxyl group at apK _a value of 9.4. This derivative could be protonated at the carbonyl group characterized by apK _a value of –5.7. FrompK _a determinations in water-ethanol mixtures the correspondingpK _a values of hypericin itself determined in such mixtures were extrapolated to the aqueous phase. This resulted in estimatedpK _a values of 1.8, 9.2, and –6.

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Deprotonierungs- und Protonierungsgleichgewichte eines Hypericinderivates in wäßriger Lösung

Zusammenfassung Ein an den Methylgruppen von Hypericin mit endständig acetylierten Polyethylenglykolketten (ungefähr 23 Einheiten lang) ,'-disubstituiertes Derivat wurde ausgehend von Emodin synthetisiert. Dieses Derivat ist wasserlöslich, und es wurde mit Hilfe von spektrophotometrischen Titrationen und Elektrophorese untersucht. Die Deprotonierung derbay-Hydroxylgruppe erfolgt beipK _a=1.6. Diese wird von einem zweiten Deprotonierungsschritt an einerperi-Hydroxylgruppe bei einempK _a-Wert von 9.4 gefolgt. Dieses Derivat konnte an der Carbonylgruppe protoniert werden, was durch einenpK _a-Wert von –5.7 charakterisiert ist. Ausgehend vonpK _a-Messungen in Wasser-Ethanol-Mischungen wurden die entsprechendenpK _a-Werte auch für das Hypericin selbst in wäßriger Phase extrapoliert. Dies führte zu geschätztenpK _a-Werten von 1.8, 9.2 und –6.

     

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.     

Theoretische Untersuchungen zur Basizität substituierter Pyridine

The applicability of the MINDO/3 method for the interpretation of the basicity of a series of substituted pyridines is critically discussed. Special attention is paid to the difference in thepK _a -values of the two isomeric 4,6-diamino-2-methoxy-(2) and 2,4-diamino-6-methoxy-3-pyridine-carbonitrile (3) (2=2.01,3=4.17). Based on the concept of charge- and orbital-controlled reactions this difference can be explained readily.

     

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.     

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.     

Reversed Phase High Performance Liquid Chromatography Using Carboxylic Acids in the Mobile Phase

Abstract

This report describes the use of different carboxylic acids as mobile phase modifiers. The effect on retention of acid chain length, pH, and eluent composition for a series of phenylalkanols, phenol, and the amines aniline, N-methylaniline, and benzylamine is discussed. The retention of both neutral and positively charged compounds is influenced by the dissociation equilibrium of the carboxylic acid in the mobile phase. By using l-pentanol to coat excess exposed silanol groups on the reversed phase column used, the inflection in the retention of both neutral and charged solutes as pH is changed occurs at the pK_a of the acid in the mobile phase. In addition, by using an acid and amine with the same or similar pK_a values, selective ion-pairing of this pair over others with dissimilar pK_a values can be promoted. Application of this technique to the selective retention of amino acids and peptides was unsuccessful.     

Multimode Retention Behavior of Azaarenes in Size Exclusion Chromatography with Poly(Divinylbenzene)

Abstract

The size exclusion retention behavior of azaarenes on poly(divinylbenzene) is described. With dichloromethane as the mobile phase a strong nonsize effect was evident and retention was found to be governed by the pK_a of the eluate. By changing the mobile phase to N-methylpyrrolidinone, retention became independent of pK_a and components eluted in order of decreasing molecular weight. Some degree of nonsize behavior was still evident and separation proceeded through a multimode mechanism. LogMW for both the azaarenes and PAH. However, in the case of the azaarenes, a less than ideal correlation coefficient (-.705) suggests that retention is not purely size-dependent.     

Supramolecular architecture built of Co(II) and a tripodal ligand containing 1-D water tapes with (H2O)16 cluster units

The reaction of Co(NO₃)₂?·?6H₂O with a tripodal ligand leads to a new complex {[Co(L)]?·?2NO₃?·?8H₂O} (1) confirmed by single-crystal X-ray diffraction, infrared spectroscopy, and elemental analysis. The particular interest of 1 is in the formation of a 1-D water tape consisting of (H₂O)₁₆ cluster units, the neighboring water tapes are connected by free nitrate anions via hydrogen bonds into a 2-D guest layer. These guest layers are alternately packed face-to-face with the 2-D host layers along the a-axis to form a 3-D supramolecular architecture. There exist C–H?···?N and C–H?···?O weak hydrogen bonds between the guest layer and host layer. These weak hydrogen bonds and water–nitrate, water–water hydrogen bonds are important for the stability of the overall structure.     

On the bromination of hypericin: The gymnochrome chromophores

Summary Stepwise electrophilic bromination of hypericin in pyridine as the solvent yields regioselectively 2,5-dibromohypericin, 2,5,9-tribromohypericin, and 2,5,9,12-tetrabromohypericin. The compounds were characterized by means of NMR-, UV-Vis-, and fluorescence-spectra, andpK _a andpK* _a measurements. These properties were compared with those of hypericin on the one hand and of the recently isolated gymnochromes on the other hand.

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Zur Bromierung des Hypericins: Die Gymnochrom-Chromophore

Zusammenfassung Schrittweise elektrophile Bromierung von Hypericin in Pyridin als Lösungsmittel liefert regioselektiv 2,5-Dibromhypericin, 2,5,9-Tribromhypericin und 2,5,9,12-Tetrabromhypericin. Diese Verbindungen wurden durch NMR-, UV-Vis- und Fluoreszenz-Spektrometrie sowie durchpK _a - undpk* _a -Messungen charakterisiert. Diese Eigenschaften wurden mit jenen des Hypericins und der kürzlich isolierten Gymnochrome verglichen.

     

Thermodynamic dissociation constants of silychristin, silybin, silydianin and mycophenolate by the regression analysis of spectrophotometric data

Mixed dissociation constants of four drug acids, i.e. silychristin, silybinin, silydianin and mycophenolate at various ionic strengths I of range 0.01 and 0.30 and at temperatures of 25 and 37 °C were determined using the SQUAD(84) regression analysis program applied to pH-spectrophotometric titration data. The proposed strategy of an efficient experimentation in a protonation constants determination, followed by a computational strategy for the chemical model with a protonation constants determination, is presented on the protonation equilibria of silychristin. The thermodynamic dissociation constant pK_a^T was estimated by non-linear regression of {pK_a, I} data at 25 and 37 °C: for silychristin pK_a,1^T=6.52(16) and 6.62(1), pK_a,2^T=7.22(13) and 7.41(5), pK_a,3^T=8.96(9) and 8.94(9), pK_a,4^T=10.17(7) and 10.03(8), pK_a,5^T=11.89(4) and 11.63(7); for silybin pK_a,1^T=7.00(4) and 6.86(5), pK_a,2^T=8.77(11) and 8.77(3), pK_a,3^T=9.57(8) and 9.62(1), pK_a,4^T=11.66(3) and 11.38(1); for silydianin pK_a,1^T=6.64(7) and 7.10(6), pK_a,2^T=7.78(5) and 8.93(1), pK_a,3^T=9.66(9) and 10.06(11), pK_a,4^T=10.71(7) and 10.77(7), pK_a,5^T=12.26(5) and 12.14(5); for mycophenolate pK_a^T=8.32(1) and 8.14(1). Goodness-of-fit tests for various regression diagnostics enabled the reliability of parameter estimates to be found.     

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.