What are the pKa values of organophosphorus compounds?

A first-principle theoretical protocol was developed, which could successfully predict the pK_a values of a number of amines and thiols in DMSO with a precision of about 1.1 pK_a unit. Using this protocol we calculated the pK_a values of diverse types of organophosphorus compounds in DMSO. The accuracy of these predicted values was estimated to be about 1.1 pK_a because phosphorus is in the same group as nitrogen and in the same period as sulfur. The theoretical predictions were also consistent with all the available experimental data. Thus, a scale of reliable pK_a values was constructed for the first time for organophosphorus. These pK_a values would be helpful to synthetic chemists who need to design the experimental conditions for handling deprotonated organophosphorus. On the basis of these pK_a values we also studied, for the first time, some interesting topics such as the substituent effects on the pK_a values of various types of organophosphorus, and the differences between the pK_a values of organophosphorus and organic amines.     

Calculations of pKa values of carboxylic acids in aqueous solution using density functional theory

With the specific aim of calculating the acidity equilibrium constant (K_a) of carboxylic acids in aqueous solution we investigated the solute-solvent interactions of these acids and their corresponding anions. The pK_a (−lg K_a) values have been calculated using density functional theory (DFT). The polarized continuum model (PCM) is used to describe the solvent. Using these methods, we successfully predicted the pK_as of 66 carboxylic acids in aqueous with the average error of 0.5 in pK_a units. Two different thermodynamic cycles have been studied. The theoretical values are in better agreement with the experimental results for those acids with moderate strength of acidity with the pK_a value higher than 3.     

Acidity of several polyprotic acids, amiodarone and quetiapine hemifumarate in pure methanol

Methanol is the organic solvent closest to water and able to dissolve a huge amount of organic compounds. Therefore, it is a good candidate for pK_a determination of drugs sparingly soluble in water or a basic drug presented as a salt which pK_a is close to that of its counter-acid. In this work, the acidic dissociation constants in pure methanol of the most common acids used in pharmaceutical preparations (lactic, tartaric, fumaric, maleic and citric) were determined. In addition, the pK_a values of the antipsychotic quetiapine presented as hemifumarate (Seroquel) and the very insoluble antiarrhythmic amiodarone were also determined by potentiometry. From these values, the aqueous pK_a of these drugs were estimated by means of previously established equations. Estimated values are consistent with those from literature and show the interest of methanol for drug discovery pK_a measurements.     

Charge equilibria and pK values of 5-carboxypyranomalvidin-3-glucoside (vitisin A) by electrophoresis and absorption spectroscopy

Apparent pK values of the wine pigment, 5-carboxypyranomalvidin-3-glucoside (vitisin A), were determined using UV-vis spectroscopy, viz. pK_a1=0.98 (±0.10), pK_H1=4.51 (±0.03) and pK_H2=7.57 (±0.02). An additional ionisation constant at high pH (pK_a4=8.84±0.06) was established by high-voltage paper electrophoresis. These data in conjunction with previously published pK_a values determined by high-voltage electrophoresis suggest that in wine (pH 3.2-3.8), 5-carboxypyranomalvidin-3-glucoside exists as a complex mixture of hydrated and non-hydrated, partially ionised species with the predominant species being the quinonoidal base (λ_max 498 nm).     

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.     

Synthesis and crystal structure of the Sr2MnGa(O,F)6 oxyfluorides

The fluorine-containing derivatives of Sr₂MnGaO_5.5 were prepared by treatment with XeF₂ at temperatures ranging from 300°C to 600°C. The compounds crystallize in a tetragonal unit cell with a_t≈a_p, c_t≈2a_p (a_p—the parameter of the perovskite subcell). An increase in fluorine content is accompanied by a reduction of the Mn oxidation state due to a partial replacement of oxygen by fluorine. The crystal structure of Sr₂MnGaO_4.78F_1.22 was determined by electron diffraction and X-ray powder diffraction (a=3.85559(2) Å, c=7.78289(6) Å, S.G. P4/mmm, R_I=0.012, R_P=0.019). The structure consists of alternating (MnO₂), (SrO) and (GaO_0.78F_1.22) layers. The Ga atoms are situated in slightly elongated octahedra, the MnO₆ octahedra are characterized by two short apical Mn-O distances of 1.876(8) Å and four long equatorial ones of 1.9278(1) Å. This is interpreted as an “apically compressed” type of Jahn-Teller distortion, in contrast to the “apically elongated” one in the Sr₂MnGaO_5+δ brownmillerites with different oxygen content. Possible structural reasons for the reversed Jahn-Teller effect are discussed.     

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.     

Determination of pKa values of fluoroalkanesulfonamides and investigation of their nucleophilicity

The pK_a values of a series of fluoroalkanesulfonylamides were measured by potentiometric titration. Different kinds of alkyl halides and tosylates were employed to investigate the nucleophilicity of fluoroalkanesulfonylamides. Fluoroalkanesulfonylamides with longer fluoroalkyl chain have weaker nucleophilicity.     

A DFT study of lithium battery materials: application to the β-VOXO4 systems (X=P, As, S)

VOXO₄ systems have been considered as potential lithium battery electrodes. They mainly present two distinct structural types: the tetragonal “α” type with a two-dimensional framework, and the three-dimensional orthorhombic “β”. DFT calculations were performed on this latter system for several β-Li_xVOXO₄ compounds (x=0, 1; X=P, As, S). They allowed to propose structural models for VOAsO₄ and LiVOSO₄, not fully crystallographically well described yet. Based on an experimental model of two-phase processes, these calculations led also to a good simulation of electrochemical potential values. A density of states analysis put in evidence the “inductive effect” and the role played by (XO₄)ⁿ⁻ groups inside the host frameworks on these potentials.     

Development of ratiometric fluorescent pH sensors based on chromenoquinoline derivatives with tunable pKa values for bioimaging

In this work, we first studied the pH-dependent characteristic of chromenoquinoline. Based on this, we then designed and synthesized two novel chromenoquinoline derivatives that can act as fluorescent pH sensors. The pK_a values of two novel chromenoquinoline derivatives can be modulated from 2.32 to 4.38 and 6.27 by introducing EDG on the backbone of chromenoquinoline. Furthermore, we demonstrate that the sensor 4 can be used as a ratiometric fluorescent pH sensor for fluorescence imaging in living cells.     

Cyclopropenimine as a hydrogen bond acceptor—towards the strongest non-phosphorus superbases

Utilizing dialkylamino cyclopropenimines as hydrogen bond acceptors in tri-substituted guanidines and cyclopropenimines, we computationally designed the most basic superbases possessing intramolecular hydrogen bonds (IHB-superbases) so far. The values of proton affinity in the gas phase range between 296.6 and 306 kcal mol⁻¹, with estimated pK_a values in acetonitrile between 35.5 and 39.7. The obtained PAs of five new IHB-superbases surpass the basicity of the paradigmatic P4-tBu Schwesinger phosphazene, whereas pK_a values come close to that of P4-tBu. None of the designed superbases contain phosphorus, which puts them among few most basic non-phosphorus superbases desiged so far.     

Capillary zone electrophoresis of basic drugs in non-aqueous acetonitrile with buffers based on a conventional pH scale

Summary The pK _a ^* values of 10 nitrogen-containing basic drugs in non-aqueous acetonitrile were determined from the pH^* dependence of their electrophoretic mobilities. The pH^* scale in the organic solvent was established using background electrolytes with known conventional pK _a ^* values, making further calibration with reference pH electrodes unnecessary. In acetonitrile the pK _a ^* values of analytes (or their conjugated cation acids, BH⁺, respectively) were 5.2±8.9 pK units>those in water. The observed change in pK _a ^* values of cationic analytes was, however, much less than the known respective change for neutral acids type HA. From the pK _a ^* values and the actual mobilities, it is possible to predict pH^* conditions to enable separation of analytes, and this was demonstrated for two pairs of common drugs.     

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.     

Synthesis, properties, and oxidizing function of 6-substituted 7,9-dimethylcyclohepta[b]pyrimido[5,4-d]pyrrole-8(7H),10(9H)-dionylium tetrafluoroborates

Uracil-annulated heteroazulenes, 6-substituted 7,9-dimethylcyclohepta[b]pyrimido[5,4-d]pyrrole-8(7H),10(9H)-dionylium tetrafluoroborates 7a,b·BF₄⁻, which are the isoelectronic compounds of 5-dezazaflavin, were synthesized. X-Ray crystal analysis and MO calculations were carried out to clarify the structural characteristics of 7a,b·BF₄⁻. The stability of cations 7a,b is expressed by the pK_R+ values which were determined spectrophotometrically to be 10.9 and 11.2, respectively. The electrochemical reduction of 7a,b exhibited high reduction potentials at −0.84 and −0.87 (V vs Ag/AgNO₃) upon cyclic voltammetry (CV). A good linear correlation between the pK_R+ values and reduction potentials (E1_red) of 7a,b·BF₄⁻ and reference compounds 4·BF₄⁻ and 5·BF₄⁻ was obtained. In a search of the reactivity, reactions of 7a,b·BF₄⁻ with some nucleophiles, hydride and diethylamine, were carried out to clarify that the introduction of nucleophiles to give regio-isomers is dependent on the nucleophile. The photo-induced oxidation reactions of 7a,b·BF₄⁻ toward some alcohols under aerobic conditions were carried out to give the corresponding carbonyl compounds in more than 100% yield [based on compounds 7a,b·BF₄⁻], suggesting the oxidizing function of 7a,b·BF₄⁻ toward alcohols in the autorecycling process.     

Benchmarking and validating algorithms that estimate p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> values of drugs based on their molecular structures

The REGDIA regression diagnostics algorithm in S-Plus is introduced in order to examine the accuracy of pK _a predictions made with four updated programs: PALLAS, MARVIN, ACD/pKa and SPARC. This report reviews the current status of computational tools for predicting the pK _a values of organic drug-like compounds. Outlier predicted pK _a values correspond to molecules that are poorly characterized by the pK _a prediction program concerned. The statistical detection of outliers can fail because of masking and swamping effects. The Williams graph was selected to give the most reliable detection of outliers. Six statistical characteristics (F _exp, R ², , MEP, AIC, and s(e) in pK _a units) of the results obtained when four selected pK _a prediction algorithms were applied to three datasets were examined. The highest values of F _exp, R ², , the lowest values of MEP and s(e), and the most negative AIC were found using the ACD/pK _a algorithm for pK _a prediction, so this algorithm achieves the best predictive power and the most accurate results. The proposed accuracy test performed by the REGDIA program can also be applied to test the accuracy of other predicted values, such as log P, log D, aqueous solubility or certain physicochemical properties of drug molecules.     

The coulometric titration of acids and bases in m-cresol medium

A method is described for the coulometric titration of acids and bases in the solvent m-cresol. The method is suitable for bases with pK_a values greater than 11 in m-cresol, or for acids with pK_a values below 13 in m-cresol. Amounts of 5–50 μeq of acid or base can be determined with a relative accuracy of ±1%.     

Determination of pKa values of some hydroxylated benzoic acids in methanol-water binary mixtures by LC methodology and potentiometry

An accurate estimation of pK_a values in methanol-water binary mixtures is very important for several separation techniques such as liquid chromatography and capillary electrophoresis that use these solvent mixtures. In this study, the pK_a values of 11 polyphenolic acids have been determined in methanol-water binary mixtures (10%, 20% and 30% (v/v)) by potentiometry, liquid chromatography (LC) and LC-DAD methodology.The results show a similar trend for the pK_a values of all the studied compounds, as they increase with increasing concentration of organic modifier, which allows a linear relationship between pK_a values and mole fraction of methanol to be obtained. The pK_a values obtained in aqueous medium have been compared with those given in the literature, and also with the values predicted by the SPARC on-line pK_a calculator. The data obtained have been used to test the feasibility of an estimation of dissociation constants in a methanol-water medium from the relationship between pK_a values and the organic cosolvent fraction in the mixtures.     

A fluorine scan of non-peptidic inhibitors of neprilysin: Fluorophobic and fluorophilic regions in an enzyme active site

This article describes the synthesis and in vitro biological affinities of (poly)fluorinated neprilysin inhibitors. Two series of inhibitors with F-substitution of the central benzimidazole platform of the ligands and the benzylic vector to fill the S1’ pocket of NEP were investigated. The S1’ pocket was found to be highly fluorophobic, and F-substitution led to significantly decreased binding affinities of inhibitors. This result is explained by electrostatically unfavorable close contacts of organic fluorine with the negatively polarized π-surfaces of surrounding aromatic amino acid side chains. In contrast, the protein environment around the benzimidazole platform, with three electropositive guanidinium side chains of Arg residues, was found to provide a fluorophilic environment. Overall, the data support that organic fluorine, with its high negative charge density prefers to orient into electropositive regions of receptor sites. pK_a measurements of fluorinated ligands provided several simple patterns for the prediction of pK_a values of benzimidazoles, important building blocks in medicinal chemistry.     

Selective separation of hydroxy polychlorinated biphenyls (HO-PCBs) by the structural recognition on the molecularly imprinted polymers: direct separation of the thyroid hormone active analogues from mixtures

We developed novel separation media for hydroxy polychlorinated biphenyls (HO-PCBs) using the molecular imprinting techniques. The results of evaluation for the molecularly imprinted polymers (MIPs) by the liquid chromatography (LC) suggested that MIPs had selective separation ability for certain HO-PCB analogues. The results of the LC evaluations and molecular modeling indicated that the molecular volumes and pK_a values of template molecules were related with the retention factor of HO-PCBs. Additionally, according to the detail evaluation toward the selective separation behaviors of MIPs, these HO-PCB analogues have low pK_a values dependent on their chemical structures. In other words, the prepared MIPs had selective recognition ability against the analogues, which have an OH group on a phenyl carbon and two chlorine atoms on the both neighboring carbons of the carbon attached with the OH group. Moreover, these analogues may have a potential for thyroid hormone activities so that we attempted to separate these analogues directly from mixtures of HO-PCBs using a prepared MIP.     

What are the pKa values of C-H bonds in aromatic heterocyclic compounds in DMSO?

A first-principle method has been successfully developed for the prediction of pK_a values of aromatic heterocyclic compounds in DMSO solution with a precision of 1.1 pK_a units. Comparison of theoretical results and experimental data (where available) also shows excellent consistency. Armed with this useful approach, the pK_a values for a series of aromatic heterocycles were calculated in DMSO. Moreover, a discussion of the relationships between hydrogen acidities and molecular structures is conducted for the first time (determinants of C-H acidities, substituent effects, and some practical use of dehydrometalation). These statistics could be useful for synthetic chemists to design proper routes for introduction of aromatic heterocyclic moiety, especially when dehydrometalation reactions are used.