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.     

Facile, aprotic degradation of η-CpZrCl3·dme by ternary sodium/group 14 tert-butoxides: From η-CpZrCl3·dme back to NaCp in two easy steps

CpZrCl₃·dme was treated with Na[El(O^tBu)₃], El = Ge, Sn, Pb, respectively. The addition of Na[Sn(O^tBu)₃] to CpZrCl₃·dme caused rapid cyclopentadienide loss and the equally rapid appearance of CpSnCl, half of which crystallized as the trinuclear complex {[ZrCl(O^tBu)₃]₂·CpSnCl}. Pristine CpSnCl reacted almost instantly with NaO^tBu to give NaCp and Na[Sn(O^tBu)₃], which co-crystallized as a coordination polymer. Na[Ge(O^tBu)₃] also displaced Cp from zirconium, but with a different product distribution, giving Cp₂Ge, fac-[Ge(μ-^tBuO)₃ZrCl(O^tBu)₂], and ZrCl(O^tBu)₃. By contrast, Na[Pb(O^tBu)₃] only exchanged its tert-butoxide groups with zirconium to furnish CpZr(O^tBu)₃ and PbCl₂. The solid-state structures of {[ZrCl(O^tBu)₃]₂·CpSnCl}, fac-[Ge(μ-^tBuO)₃ZrCl(O^tBu)₂], and {NaCp·Na[Sn(O^tBu)₃]}_n were determined.     

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.     

Activating Pronucleophiles with High pKa Values: Chiral Organo‐Superbases

Direct deprotonation represents an extremely simple, straightforward, and atom‐economic strategy to activate pronucleophiles bearing an acidic proton. However, the difficulty often arises in activating pronucleophiles with high pK_a values by using conventional chiral tertiary amines. To overcome this challenge, a handful of novel chiral Brønsted superbases, including amidines, guanidines, cyclopropenimines, and iminophosphoranes, have been discovered in recent years. This minireview focuses on the application of these organo‐superbases in the catalytic asymmetric reactions of weakly acidic pronucleophiles, and highlights their comparison to the conventional tertiary amines, demonstrating the highly efficient deprotonation processes and stereoselectivity controlled conversions of the superbases. The advantage of these new superbases brings a great opportunity for developing more asymmetric transformations of weakly acidic pronucleophiles.     

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.     

Activating Pronucleophiles with High pKa Values: Chiral Organo-Superbases

Direct deprotonation represents an extremely simple, straightforward, and atom-economic strategy to activate pronucleophiles bearing an acidic proton. However, the difficulty often arises in activating pronucleophiles with high pK_a values by using conventional chiral tertiary amines. To overcome this challenge, a handful of novel chiral Brønsted superbases, including amidines, guanidines, cyclopropenimines, and iminophosphoranes, have been discovered in recent years. This minireview focuses on the application of these organo-superbases in the catalytic asymmetric reactions of weakly acidic pronucleophiles, and highlights their comparison to the conventional tertiary amines, demonstrating the highly efficient deprotonation processes and stereoselectivity controlled conversions of the superbases. The advantage of these new superbases brings a great opportunity for developing more asymmetric transformations of weakly acidic pronucleophiles.     

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.     

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.     

Molecular solvent effect on the acidity constant of protic ionic liquids

In this work how the microscopic properties of a molecular solvent affect the chemical environment of the protic ionic liquids (PILs) was analyzed. Using Reichardt’s dye as indicator of acidity, new acidity constant values for eight PILs (pK_a^PILs) were determined by spectrophotometric titration. Modifying the character hydrogen bonding donor of the molecular solvent it is possible to handle the PIL acid strength. Thus, we can turn basic PILs into acidic ones thereby the molecular solvent could be used as ‘additive’ for PILs, which allowed us to tune PILs design.     

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).     

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.     

Synthesis and properties of bis(heteroazulen-3-yl)methyl cations and bis(heteroazulen-3-yl)ketones

The synthesis and properties of a novel type of bis(heteroazulen-3-yl)methyl cations, bis(2-oxo-2H-cyclohepta[b]furan-3-yl)methyl cation salt and nitrogen analogues, (9a-c·PF₆⁻) and (9a-c·BF₄⁻), as well as bis(heteroazulen-3-yl)ketones (12a-d) are studied. The synthetic method was based on a TFA-catalyzed electrophilic aromatic substitution on the heteroazulenes (6a-d) with paraformaldehyde to afford the corresponding disubstituted methane derivatives 7a-d, followed by oxidative hydrogen abstraction with DDQ, and subsequent exchange of the counter-anion by using aq. HPF₆ or aq. HBF₄. In addition, the reaction of 7a-d with 2.2 equiv. amounts of DDQ afforded carbonyl compounds 12a-d. The delocalization of the positive charge of 9a-c was evaluated by the ¹H and ¹³C NMR spectral data. The thermodynamic stability of cations 9a-c was evaluated to be in the order 9a<9b<9c on the basis of their reduction potentials measured by cyclic voltammetry (CV) and pK_R+ values (2.6-10.3) obtained spectrophotometrically. The reduction waves of cations 9a-c were irreversible, suggesting the dimerization of the radical species generated by one-electron reduction. This was demonstrated by the reduction of 9a·BF₄⁻ with Zn powder to give dimerized product 14a. In addition, the quenching of 9a·BF₄⁻ with MeOH/NaHCO₃ gives ether derivative 15a, which is proposed for the precursor for synthesizing tris(heteroazulene)-substituted methyl cations bearing two different heteroazulene-units.     

Syntheses and structures of zinc and tin(II) compounds with hemilabile N-silyl-tert-butylamido and N-silyl-p-tolylamido ligands that contain pendent tert-butoxy groups

Syntheses and solid-state structures of zinc and tin(II) compounds, containing the N-silyl-amide ligands (O^tBu)(NR)SiMe₂, R = ^tBu (L^tBu), or R = p-tolyl (L^pTol), are reported. The N-silyl amines were synthesized by modified published procedures from commercially available Me₂SiCl₂, ^tBuOH, and ^tBuNH₂, or p-Me-C₆H₄NH₂, respectively. Treatment of SnCl₂ with LiL^pTol furnished Sn(L^pTol)₂, which was X-ray structurally characterized and shown to contain two covalent Sn-N bonds and two asymmetrical O → Sn donor bonds. The single-crystal X-ray structure of Sn(L^tBu)₂ revealed a much more symmetrically-coordinated, pseudo-trigonal-bipyramidal tin atom. Aminolysis of diethylzinc with HL^pTol produced [EtZn(L^pTol)]₂, which crystallized as a centrosymmetric dimer, containing four-coordinate zinc atoms connected by bridging amides. Zinc dichloride, by contrast, reacted with two equivalents of LiL^tBu to produce the homoleptic, pseudo-spirocyclic Zn(L^tBu)₂.     

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.     

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.     

A facile method for the synthesis of steroidal and nonsteroidal 5-methyl pyrazolo[1,5-a]pyrimidines

The steroidal and nonsteroidal 5-methyl pyrazolo[1,5-a]pyrimidines were synthesized by the reaction of steroidal/nonsteroidal α,β-unsaturated ketones and 3-amino-1H-pyrazoles/5-amino-1H-pyrazoles in the presence of KO^tBu in ethanol under reflux condition.     

Synthesis and hybridization affinity of oligodeoxyribonucleotides incorporating 4-N-(N-arylcarbamoyl)deoxycytidine derivatives

Modified oligodeoxynucleotides incorporating 4-N-(N-arylcarbamoyl)-dC derivatives 1a-c were synthesized. The ¹H NMR spectra of 1a-c suggest that the carbamoyl group forms an intramolecular hydrogen bond with the cytosine ring nitrogen atom so that formation of a Watson-Crick base pair with the complementary guanine base is inhibited. The hybridization properties of oligodeoxynucleotides containing 1a-c were investigated by use of T_m analysis. The hybridization properties of 4-N-(N-phenylcarbamoyl)-dC (1a) were similar to those of 4-N-(N-alkylcarbamoyl)-dC derivatives reported previously. In sharp contrast to 1a, it turned out that 4-N-(N-napht-1-yl) and (N-quionol-5-yl)-dC (1b,c) have a unique property as a universal base.     

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.     

High basicity of tris-(tetramethylguanidinyl)-phosphine imide in the gas phase and acetonitrile—a DFT study

It is shown by reliable density functional theory (DFT) calculations that compounds 4 and 6 are very powerful neutral organic superbases as evidenced by the calculated proton affinities in the gas phase 305.4 kcal mol⁻¹ (44.8) and 287.8 kcal mol⁻¹ (37.8), respectively, and the corresponding calculated pK_a values in acetonitrile given within parentheses.     

Syntheses and crystal structures of mono- and bi-metallic zinc compounds of symmetrically- and asymmetrically-substituted bis(amino)cyclodiphosph(V)azanes

The dioxocyclodiphosph(V)azane cis-[(^tBuHN)OP(μ-N^tBu)₂PO(NH^tBu)] reacted with two equivalents of diethylzinc to form the centrosymmetric dimer {[(OPN^tBu)₂(N^tBu)₂ZnEt](ZnEt · THF)}₂ (1) while under identical conditions, the sulfur and selenium analogues afforded only the monoethylzinc compounds {[(^tBuHN)EP(μ-N^tBu)₂PE(N^tBu)](ZnEt · THF)}ES(2), Se (3). To further probe the apparent ligand effects on coordination number and coordination site, cis-[(PhHN)SP(μ-N^tBu)₂PS(NH^tBu)] (5) was synthesized from cis-[ClP(μ-N^tBu)₂P(NH^tBu)] (4) and both were characterized by single-crystal X-ray diffraction. Two equivalents of 5 reacted with diethylzinc to produce the homoleptic, trispirocyclic complex {[(^tBuHN)SP(μ-N^tBu)₂PS(NPh)]₂Zn} (6). A second asymmetrically-substituted cyclodiphosph(V)azane, namely [(^tBuNH)SP(μ-N^tBu)₂PNp-tol(NH^tBu)] (7), was also synthesized and structurally characterized. In contrast to 5, only one equivalent of this ligand reacted with excess diethylzinc, via its N,N^′, rather than its N,S side, to afford {[(^tBuHN)SP(μ-N^tBu)₂PNp-tolyl(N^tBu)](ZnEt)} (8).