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.     

Synthesis and spectrophotometric studies of water-soluble amino[bis(ethanesulfonate)] azobenzene pH indicators

Three azobenzene pH indicators with amino[bis(ethanesulfonate)] substituents were synthesized and studied by UV–visible absorption spectroscopy in aqueous solution. The indicators exhibit brilliant and distinct colour changes with transitions between pH 1 and 4. Significant changes were observed in the UV–visible spectra on titration with acid with pK_a values ranging from 2.2 to 2.8. The indicators demonstrate individual changes in colour as a function of pH. These novel pH indicators complement the existing library of azobenzene indicator dyes and may be useful for environmental situations with high proton concentrations.     

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.     

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.     

Acid-base chemistry of omeprazole in aqueous solutions

Omeprazole is a potent anti-acid drug. Its absorption and mode of action are closely related to its prototropic behavior. In the present study, omeprazole samples from different sources and in different forms were studied spectrophotometrically to obtain pK_a values. In the neutral to alkaline pH region, two consistent pK_a values of 7.1 and 14.7 were obtained from various samples. The assignment of these pK_a values was realized by comparison with the prototropic properties of N(1)-methylated omeprazole substituted on the nitrogen at the 1-position of the benzimidazole ring, which was found to have a pK_a of 7.5. The omeprazole pK_a of 14.7 is assigned to the dissociation of the hydrogen from the 1-position of the benzimidazole ring and the pK_a of 7.1 is assigned to the dissociation from the protonated pyridine nitrogen of omeprazole. The results presented are at variance with those of earlier work.     

Uncertainty estimation in measurement of pKa values in nonaqueous media: A case study on basicity scale in acetonitrile medium

The difficulties in estimating uncertainty of pK_a values determined in nonaqueous media are reviewed and two different uncertainty estimation approaches are presented and applied to the pK_a values of the compounds on a previously established self-consistent spectrophotometric basicity scale in acetonitrile. One approach is based on the ISO GUM methodology (the “ISO GUM” approach) and involves careful analysis of the uncertainty sources and quantifying the respective uncertainty components. The second approach is based on the standard-deviation-like statistical parameter that has been used for characterization of the consistency of the scale (the “statistical” approach). It is demonstrated that the ISO GUM approach somewhat overestimates the uncertainty. The statistical approach is based on long-term within-laboratory statistical data and it is demonstrated that it underestimates the uncertainty. In particular it neglects the laboratory bias effects that are taken into account at least to some extent by the ISO GUM approach. Thus, together these two approaches allow to “bracket” the uncertainties of the pK_a values on the scale. The uncertainties of the pK_a values are defined in two different ways. Definition (a) includes the uncertainty of the pK_a of the reference base (anchor base of the scale) pyridine. Definition (b) excludes it. It is demonstrated that both definitions have their virtues. Definition (a) leads to the uncertainty ranges of 0.12-0.22 and 0.12-0.14 pK_a units at standard uncertainty level for different bases using the ISO GUM and statistical approach, respectively. Definition (b) leads to the uncertainty ranges of 0.04-0.19 and 0.02-0.08 pK_a units, respectively. The uncertainty of the pK_a of a given base is dependent on the quality of the measurements involved and on the distance from the reference base on the scale. The importance of the correlation between the pK_a values of bases belonging to the same scale is stressed.     

Ionization of some derivatives of benzamide, oxamide and malonamide in DMF-water mixture

The ionization of six compounds of bis-phenolic amides was studied spectrophotochemically in DMF-water mixture. The compounds showed two pK_a values in the range of 5.97-7.32 for pK_a1 and 7.61-8.44 for pK_a2. The obtained values of K_a were normalized using the distribution diagrams of the different species and found to be in the range of 5.81-7.42 for pK_a1 and 7.48-8.27 for pK_a2.     

Determination of dissociation constants of sparingly soluble phenothiazine derivatives by second-derivative spectrophotometry

The dissociation constants (pK_a) for sparingly soluble phenothiazines (promazine, chlorpromazine, trifluoropromazine) in water were measured by second-derivative spectrophotometry. The intense background signals in the absorption spectra due to the turbidity caused by the precipitation of insoluble free base of the phenothiazine derivatives were eliminated in the second-derivative spectra, and the solubilities of the phenothiazine derivatives could be easily determined from the peak-to-trough lengths (D values) of the second-derivative signals. The pK_a values were calculated from the pH dependence of the D values. The pK_a values obtained agreed well with reported values and the standard deviations for 6–10 determinations were ? 0.02. The solubilities of the free bases of the phenothiazines were also determined.     

Laser raman and infrared spectrum of poly-p-xylylene

The dipole moments μ_ab of some forty complexes between substituted phenols and substituted pyridines were determined, using the Onsager relation. The dipole increment Δμ, vector difference between μ_ab and the dipole moments μ_a and μ_b of the components, show a coherent evolution with the pK_a of the donor and of the acceptor and with the complexation enthalpy, when such orientations of the molecules which correspond to a hydrogen bond between the O-H group of the phenol and the lone pair of electrons of the nitrogen atom of the base are chosen. This evolution with respect to the ΔpK_a is given by a unique curve for all the complexes. This shows that the difference in pK_a between the donor and the acceptor is the main factor determining Δμ for these complexes. This curve presents a sigmoidal aspect in agreement with a model assuming a tautomeric equilibrium between two forms of the hydrogen bond: A-H·B ? A^?·H⁺-B. The corresponding equilibrium constant K_s was computed for the complexes lying in the transition region and obeys the linear relation, log K_s = 0.7pK_a-2.25. The data also permit the evaluation of the angle θ_a between the O-H direction and the dipole moment of the 3,4-dinitrophenol. This angle is of the order of magnitude of 70°, showing the presence of appreciable amounts of different rotamers around the C-O direction in the complexes composed of this acid with pyridines.     

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.     

Kinetics and mechanisms of the reactions of S-methyl chlorothioformate with pyridines and secondary alicyclic amines

The pyridinolysis of S-methyl chlorothioformate shows a biphasic Brønsted-type plot, in agreement with a stepwise mechanism and a change in the rate-limiting step, from formation of a zwitterionic tetrahedral intermediate (T^±) at high pK_a to its breakdown at low pK_a. The reaction of the same substrate with secondary alicyclic amines shows a linear Brønsted-type plot of slope 0.23, which is in accordance with a stepwise mechanism where formation of T^± is the rate-determining step for the whole pK_a range examined.     

Fluorimetric determination of dissociation constants of aryl-substituted alkylammonium ions

Although the absorption spectra of aryl-substituted alkylammonium ions are insensitive to prototropic dissociation, the fluorescence quantum yields of these ions are often very different from those of their uncharged conjugate bases. This is shown to be the result of different rates of non-radiative deactivation in excited acid and conjugate base and is analytically useful for the determination of pK_a values. The pK_a values of six drugs (procaine, butacaine, benoxinate, cinchonine, propranolol and dibucaine) which are aryl-substituted alkylammonium ions were evaluated fluorimetrically and are presented here.     

Tributylphosphine, excellent organocatalyst for conjugate additions of non-nucleophilic N-containing compounds

Conjugate additions of non-nucleophilic N-containing compounds such as amides, thioamides, sulfonamides, and electron-poor anilines with different Michael acceptors can be promoted through the use of tributylphosphine. The range of useful pK_a's of nucleophiles has been established (pK_a<25) and new insights into the mechanism proposed.     

Acid-base and tautomeric equilibria of fluorescein dyes in water micellar solutions of zwitterionic sulfobetaine surfactant

Ionization constants of fluorescein and six its derivatives in water micellar solutions of zwitterionic surfactant, N-cetyl-N,N-dimethyl-3-ammonium-1-propanesulfonate were evaluated spectrophotometrically. On the basis of absorption spectra of dyes conclusions concerning the tautomerism of molecular and ionic forms were made and the relationships between the pK _a values were explained.     

An Electron Diffraction and XRPD Study of Superlattice Ordering in the Elpasolite-Related Oxyfluoride K3MoO3F3

A detailed electron diffraction and XRPD study has been made of the room-temperature α polymorph of K₃MoO₃F₃. It is shown that the true symmetry of this polymorph is neither tetragonal, trigonal, nor triclinic as previously reported but rather monoclinic I1a1, a=2a_p−c_p, b=4b_p, c=a_p+2c_p when expressed in terms of the underlying elpasolite (ordered perovskite) parent structure type. A highly structured, three-dimensional, continuous diffuse intensity distribution (presumably arising from local O/F ordering and associated structural relaxation) is shown to coexist with the sharp satellite reflections characteristic of the monoclinic supercell.     

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%.     

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.     

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.     

pKa values in organic chemistry – Making maximum use of the available data

Acids and bases are ubiquitous. Sometimes, it is essential to know the accurate strength (pK_a values) of the acids/bases to work with, but sometimes just acidity/basicity order is enough. We often receive requests to measure pK_a values of different substances in different solvents for answering questions like “what acids can be used to protonate this substance” or “what base is able to deprotonate that compound?” Such questions can, in fact, often be answered using published pK_a data in different solvents. This digest/tutorial will give an overview of how to make efficient use of the existing pK_a data.     

SAMPL6: calculation of macroscopic p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> values from ab initio quantum mechanical free energies

Macroscopic pK_a values were calculated for all compounds in the SAMPL6 blind prediction challenge, based on quantum chemical calculations with a continuum solvation model and a linear correction derived from a small training set. Microscopic pK_a values were derived from the gas-phase free energy difference between protonated and deprotonated forms together with the Conductor-like Polarizable Continuum Solvation Model and the experimental solvation free energy of the proton. pH-dependent microstate free energies were obtained from the microscopic pK_as with a maximum likelihood estimator and appropriately summed to yield macroscopic pK_a values or microstate populations as function of pH. We assessed the accuracy of three approaches to calculate the microscopic pK_as: direct use of the quantum mechanical free energy differences and correction of the direct values for short-comings in the QM solvation model with two different linear models that we independently derived from a small training set of 38 compounds with known pK_a. The predictions that were corrected with the linear models had much better accuracy [root-mean-square error (RMSE) 2.04 and 1.95 pK_a units] than the direct calculation (RMSE 3.74). Statistical measures indicate that some systematic errors remain, likely due to differences in the SAMPL6 data set and the small training set with respect to their interactions with water. Overall, the current approach provides a viable physics-based route to estimate macroscopic pK_a values for novel compounds with reasonable accuracy.