Polynuclear Branched Tetrazole Systems. 2. New 2-(5-Tetrazolyl)ethylpodands and Their NH-Acidity

Nine new polynuclear 2-(5-tetrazolyl)ethyl podands have been obtained by the azidation of the corresponding nitriles. Using Bjerrum distribution functions, the values of pK _a ¹, pK _a ², pK _a ³, and pK _a ⁴ have been determined by a potentiometric method for 14 polynuclear tetrazoles in aqueous and aqueous methanolic solution. The found values lie in the range from 3.5 to 7.5 pH units. The overall rules and the sequence of the ionization of the spatially separated tetrazole fragments in these podand systems are discussed.     

Basicity of some aliphatic amines in mixed H2O?CH3CN solvents

The values of pK_a^ms (K_a^ms represents ionization constant of conjugate acid of amine base in mixed water–acetonitrile solvent) for all amines, except for charged amine bases, show a mild decrease (ca. 0.1–0.4 pK units) with the increase in CH₃CN content from 2 to ∼60% v/v. However, the pK_a^ms values at 70% v/v CH₃CN become nearly equal or slightly larger (by ≤0.7 pK units) than the corresponding pK_a^ms at 2% v/v CH₃CN for all neutral and charged amines. The values of pK_a^ms for phenol increase from 10.17 to 13.38 with the increase in the content of CH₃CN from 2 to 70% v/v in mixed aqueous solvent. Taft reaction constants, ρ*, obtained from the plots of pK_a^ms against ∑σ* for primary and secondary amines decrease by ca. 0.8 ρ* units with the increase in the CH₃CN content from 2 to 70% v/v. The values of pK_a^ms show an empirical linear relationship with the corresponding values of pK_a^w (where pK_a^w represents the pK_a obtained in aqueous solvent containing 2% v/v CH₃CN), which allows the estimation of a pK_a in mixed H₂O CH₃CN solvents from that in water. © 2000 John Wiley & Sons, Inc. Int J Chem Kinet 32: 146–152, 2000     

Determination of pKa values using 15N and 13C nuclear magnetic resonance spectroscopy. The case of apramycin

By comparison of pK^a values derived from ¹⁵N and ¹³C nuclear magnetic resonance (NMR) spectroscopies, the assignment of the ¹⁵N resonances of apramycin is completed. ¹³C NMR spectra appear to provide accurate pK_a determinations with this aminoglycoside. Hydroxylation adjacent to one of the basic nitrogens of apramycin appears to change the pK_a values of all five amines of the molecule.     

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.     

EFFECT OF THE BROMINE ATOM UPON THE DISSOCIATION CONSTANTS OF BROMOPYRIDINES,BROMOQUINOLINES AND 4-BROMOISOQUINOLINE IN THEIR LOWEST EXCITED SINGLET AND TRIPLET STATES*

Abstract— The lowest excited singlet-state dissociation constants (pK^S_a) of bromosubstituted pyridines, quinolines, and isoquinolines were determined from the pH-dependent shifts in their electronic absorption spectra. The lowest excited triplet-state dissociation constants (pK^T_a) of bromosubstituted quinolines and 4-bromoisoquinoline were obtained from the shifts of the 0–0 phosphorescence bands measured in rigid aqueous solution at 77 K. The pK^S_a values indicate that the basicity of these brominated nitrogen heterocycles is increased in the lowest excited singlet state by 2 to 10 orders of magnitude as compared with the ground state. The pK^T_a values are found to be significantly different from the corresponding ground-state pK_a values, indicating that the basicity of bromoquinolines is increased in the lowest excited triplet state by 1.7 to 3.0 pK units. The enhancement of the excited singlet-and triplet-state basicity of brominated nitrogen heterocycle derivatives as compared with the unsuhstituted parent compounds is attributed to the increased electron-donor conjugative interactions of the bromine atom pπ orbitals with π orbitals in the lowest excited singlet and triplet state.     

Reaction of α,β-unsaturated ketones with guanidine. Substituent effects on the protonation constants of 2-amino-4,6-diarylpyrimidines

1,3-Diaryl-2-propen-1-ones, I, reacted with guanidine hydrochloride (II) in the presence of 3 moles of sodium hydroxide to give the corresponding 2-amino-4,6-diarylpyrimidines, III. The structure and configuration of the products are based on chemical and spectroscopic evidence. The protonation constants of these compounds (series A and series B) have been determined in 50 volume percent ethanol-water medium. Excellent linear correlations are obtained when pK_a values of the two series of 2-amino-4,6-diarylpyrimidines, IIIa-j and IIIk-r, are plotted against the substituent constant, ^σx, and the polar substituent constant, ^σ* xC₆H₄, for substituted phenyl groups. The pK_a values have also been correlated with the extended Hammett equation. The correlation follows the equations: Series A; pK_a = 3.273 - 0.820σI,X - 0.662σR,X Series B; pK_a = 3.169 - 0.424σI,X - 0.137σR,X     

The Derivation of Inductive Substituent Constants from pKa Values of 4-Substituted Quinuclidines. Polar effects. Part I

Thermodynamic pK_a-values have been determined for 38 4-substituted quinuclidinium perchlorates. They are remarkably sensitive to the polar effect of the substituent and cover a range of 3.63 pK_a units. Furthermore, they vary linearly and almost equally with temperature since the contribution of the TΔS° term to the free energy of ionization is relatively small and constant. The magnitude of the polar effect of the 4-cyano group varies with the solvent and appears to depend on its ability to form hydrogen bonds to the substituent rather than its dielectric constant. New inductive substituent constants σ_I^q are derived from the pK_a values. Their correlation with known inductive constants is only fair or unsatisfactory, especially as regards the relative order of hydrogen and the alkyl groups. The discrepancies can be ascribed mainly to the different models used to derive the substituent constants.     

Determination of acidity constants,ionic mobilities,and hydrodynamic radii of carborane-based inhibitors of carbonic anhydrases by capillary electrophoresis

Capillary electrophoresis (CE) has been applied for determination of the thermodynamic acidity constants (pK_a) of the sulfamidoalkyl and sulfonamidoalkyl groups, the actual and limiting ionic mobilities and hydrodynamic radii of important compounds, eight carborane-based inhibitors of carbonic anhydrases, which are potential new anticancer drugs. Two types of carboranes were investigated, (i) icosahedral cobalt bis(dicarbollide)(1-) ion with sulfamidoalkyl moieties, and (ii) 7,8-nido-dicarbaundecaborate with sulfonamidoalkyl side chains. First, the mixed acidity constants, pK_a^mix, of the sulfamidoalkyl and sulfonamidoalkyl groups of the above carboranes and their actual ionic mobilities were determined by nonlinear regression analysis of the pH dependences of their effective electrophoretic mobility measured by capillary electrophoresis in the pH range 8.00−12.25, at constant ionic strength (25 mM), and constant temperature (25°C). Second, the pK_a^mix were recalculated to the thermodynamic pK_as using the Debye–Hückel theory. The sulfamidoalkyl and sulfonamidoalkyl groups were found to be very weakly acidic with the pK_as in the range 10.78−11.45 depending on the type of carborane cluster and on the position and length of the alkyl chain on the carborane scaffold. These pK_as were in a good agreement with the pK_as (10.67−11.27) obtained by new program AnglerFish (freeware at https://echmet.natur.cuni.cz ), which provides thermodynamic pK_as and limiting ionic mobilities directly from the raw CE data. The absolute values of the limiting ionic mobilities of univalent and divalent carborane anions were in the range 18.3−27.8 TU (Tiselius unit, 1 × 10⁻⁹ m²/Vs), and 36.4−45.9 TU, respectively. The Stokes hydrodynamic radii of univalent and divalent carborane anions varied in the range 0.34−0.52 and 0.42−0.52 nm, respectively.     

Microscopic Protonation/Deprotonation Equilibria of the Anti-Inflammatory Agent Piroxicam

The microscopic ionization behavior of piroxicam was investigated using two different approaches, i.e., direct UV spectroscopy and an indirect analogue approach (deductive method). The best microscopic pK_a values (pK_a12 = 4.60, pK_a21 = 5.40, pK_a22 = 2.72, and pK_a11 = 1.92) were obtained by the deductive method using as pK_a22 the pK_a of the enolic O-methylated piroxicam 2 . The results show remarkable electrostatic effects in the protonation/deprotonation equilibria, a marked increase in the acidity of the enolic function (2.68 pK_a units) being caused by the pyridinium group. The electronic structure of piroxicam was studied based on ¹H-NMR chemical shifts at various ionization states, indicating an extended electron conjugation through the molecule. The partition measurements in octan-1-ol/H₂O of zwitterionic compound 3 (the pyridyl N-methyl derivative of piroxicam ( 1 )) suggest that the two opposite charges in zwitterionic piroxicam are indeed in a close intramolecular proximity.     

Investigations on the dissociation behavior of hydrolyzed alternating copolymers of maleic anhydride and alkenes: 13C-NMR spectra and potentiometric titrations

The pK_a values of the succinic acid moieties of hydrolyzed alternating ethene- and isobutene-maleic anhydride copolymers were determined in D₂O. The pD-dependence on the ¹³C chemical shift of selected signals was analyzed for these copolymers. Four different pK_as were determined for the copolymer with ethene due to the existence of both the erythro- and threo-configuration of the succinic acid moiety: pK_01,erythro = 4.2, pK_0.1,threo = 4.1, pK_02,erythro = 6.1, pK_02,threo = 6.8. The isobutene-maleic anhydride copolymer contains only threo-units. Therefore, only two dissociation steps with pK₀₁ = 3.0 and pK₀₂ = 8.7 were observed for the hydrolyzed form. © 1996 John Wiley & Sons, Inc.     

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.     

Heterylation of 3-R1-5-R2-1,2,4-Triazoles with Derivatives of 3,5-Dinitro-1,2,4-Triazole

Heterylation of 3-R¹-5-R²-1'2'4-triazoles (pK _a 3-12) with N-alkyl-, N-alkenyl-, N-alkoxy-carbonyl-, N-oxoalkyl-, N-nitroxyalkyl, N-nitroaminoalkyl-3'5-dinitro-1'2'4-triazoles results insubstitution of a nitro group in 5 position of the dinitro compound yielding 1-R-methyl-3-nitro-5-(3-R¹-5-R²-1,2,4-triazolyl)-1,2,4-triazoles. The side processes: Hydroxide-ion attack on C⁵ and (or) N¹ of the ring both in the substrate and in the target compound afford 1-R-methyl3-nitro-1,2,4-triazol-5-ones, 3,5-dinitro-1,2,4-triazole and NH-acids of N-C-bitriazole series. Optimal reaction media are aprotic dipolar substances, and for compounds prone to heterolysis ethyl acetate-water systems. The azole pK _a is the decisive factor controlling the composition and the ratio of reaction products. The process is promising for azoles with pK _a > 5, and the optimal range of pK _a is 8-10.     

A reliable and efficient first principles‐based method for predicting pKa values. 4. organic bases

The ionization (dissociation) constant (pK_a) is one of the most important properties of a drug molecule. It is reported that almost 68% of ionized drugs are weak bases. To be able to predict accurately the pK_a value(s) for a drug candidate is very important, especially in the early stages of drug discovery, as calculations are much cheaper than determining pK_a values experimentally. In this study, we derive two linear fitting equations (pK_a = a × ΔE + b; where a and b are constants and ΔE is the energy difference between the cationic and neutral forms, i.e., ΔE = E_neutral?E_cationic) for predicting pK_as for organic bases in aqueous solution based on a training/test set of almost 500 compounds using our previously developed protocol (OLYP/6‐311+G**//3‐21G(d) with the the conductor‐like screening model solvation model, water as solvent; see Zhang, Baker, Pulay, J. Phys. Chem. A 2010 , 114, 432). One equation is for saturated bases such as aliphatic and cyclic amines, anilines, guanidines, imines, and amidines; the other is for unsaturated bases such as heterocyclic aromatic bases and their derivatives. The mean absolute deviations for saturated and unsaturated bases were 0.45 and 0.52 pK_a units, respectively. Over 60% and 86% of the computed pK_a values lie within ±0.5 and ±1.0 pK_a units, respectively, of the corresponding experimental values. The results further demonstrate that our protocol is reliable and can accurately predict pK_a values for organic bases. © 2012 Wiley Periodicals, Inc.     

pKa prediction for acidic phosphorus‐containing compounds using multiple linear regression with computational descriptors

Ninety‐six acidic phosphorus‐containing molecules with pK_a 1.88 to 6.26 were collected and divided into training and test sets by random sampling. Structural parameters were obtained by density functional theory calculation of the molecules. The relationship between the experimental pK_a values and structural parameters was obtained by multiple linear regression fitting for the training set, and tested with the test set; the R² values were 0.974 and 0.966 for the training and test sets, respectively. This regression equation, which quantitatively describes the influence of structural parameters on pK_a, and can be used to predict pK_a values of similar structures, is significant for the design of new acidic phosphorus‐containing extractants. © 2016 Wiley Periodicals, Inc.     

Thermodynamic dissociation constants of risedronate using spectrophotometric and potentiometric pH-titration

Risedronate inhibits bone resorption in diseases like osteoporosis, Paget’s disease, tumor bone diseases or the malfunction of phosphocalcium metabolism. The acid-base properties of risedronate in an aqueous solution have been studied in a pH range from 2 to 12 and can be described in terms of four dissociation steps: pK _a,2, pK _a,4, pK _a,5 (related to the dissociation of POH groups) and pK _a,3 related to the dissociation of protonated amino group NH₃ ⁺. The mixed dissociation constants were determined at different ionic strengths I = 0.02 to 0.20 mol dm⁻³ KCl and of 25°C and 37°C using pH-spectrophotometric and pH-potentiometric titration methods. Determination of group parameters L ₀, H _T might lead to false estimates of common parameters p K _a;therefore, the computational strategy employed is important. A comparison between the two programs ESAB and HYPERQUAD demonstrated that the ESAB program provides a better fit of potentiometric titration curve. The thermodynamic dissociation constants pK _a^T were estimated by a nonlinear regression of (pK _a, I) data and a Debye-Hückel equation at 25°C and 37°C, pK _a,2^T = 2.37(1) and 2.44(1), pK _a,3^T = 6.29(3) and 6.26(1), pK _a,4^T = 7.48(1) and 7.46(2) and pK _a,5^T = 9.31(7) and 8.70(3) at 25°C and 37°C using pH-spectroscopic data and pK _a,2^T = 2.48(3) and 2.43(1), pK _a,3^T= 6.12(2) and 6.10(2), pK _a,4^T = 7.25(2) and 7.23(1) and pK _a,5^T = 12.04(5) and 11.81(2) at 25°C and 37°C. The ascertained estimates of three dissociation constants pK _a,3, pK _a,4, pK _a,5 are in agreement with the predicted values obtained using PALLAS      

Determination of thermodynamic pKa values of pharmaceuticals from five different groups using capillary electrophoresis

A determination of the thermodynamic acid dissociation constants (pK_a) of 22 frequently used pharmaceuticals using capillary electrophoresis in aqueous media is presented in this work. The investigated pharmaceuticals belong to different pharmacological groups: macrolides, fluoroquinolones, sulfonamides, β‐lactams, tetracyclines, and other miscellaneous pharmaceuticals. The electrophoretic mobilities of the investigated analytes were monitored in a pH range from 2.00 to 10.82. The data were fitted with an appropriate mathematical model using a nonlinear regression analysis to obtain pK_a values. Experimentally obtained data were well described by the mathematical model chosen for each analyte that was confirmed by r² values higher than 0.99 for most of the investigated analytes. Extrapolations to zero ionic strength were used to determine the thermodynamic pK_a values. Experimentally obtained acid dissociation constants were interpreted using structural formulae of investigated analytes and the moieties corresponding to specific pK_a were identified.     

Thermodynamic Estimate of pKa Values of the Carboxylic Acids in Aqueous Solution with the Density Functional Theory

The 96 pK_a values of 85 carboxylic acids in aqueous solution were calculated with the density functional theory method at the level of B3LYP/6‐31+G(d,p) and the polarizable continuum model (PCM) was used to describe the solvent. In the calculations of pK_a values, the dissociation Gibbs free energies were directly calculated using carboxylic acid dissociation reactions in aqueous solution, i. e., no thermodynamic cycle was employed, which is different from the previous literatures. A highly significant correlation of R²=0.95 with a standard deviation (SD) of 0.36 between the experimental pK_a values and the calculated dissociation Gibbs free energies [ΔG(calc.)] was found. The slope of pK_a vs. (G(calc.)/(20303RT) is only 47.6% of the theoretically expected value, which implies that the ΔG(calc.) value from the theoretical calculation is larger than the actual one for all 85 carboxylic acids studied. Thus, by adding the 0.476 scaling‐factor into the slope, we can derive a reliably procedure that can reproduce the experimental pK_a values of carboxylic acids. The pK_a values furnished by this procedure are in good agreement with the experimental results for carboxylic acids in aqueous solution.     

Enantioselective Synthesis and Physicochemical Properties of Libraries of 3‐Amino‐ and 3‐Amidofluoropiperidines

The enantioselective syntheses of 3‐amino‐5‐fluoropiperidines and 3‐amino‐5,5‐difluoropiperidines were developed using the ring enlargement of prolinols to access libraries of 3‐amino‐ and 3‐amidofluoropiperidines. The study of the physicochemical properties revealed that fluorine atom(s) decrease(s) the pK_a and modulate(s) the lipophilicity of 3‐aminopiperidines. The relative stereochemistry of the fluorine atoms with the amino groups at C3 on the piperidine core has a small effect on the pK_a due to conformationnal modifications induced by fluorine atom(s). In the protonated forms, the C?F bond is in an axial position due to a dipole–dipole interaction between the N?H⁺ and C?F bonds. Predictions of the physicochemical properties using common software appeared to be limited to determine correct values of pK_a and/or differences of pK_a between cis‐ and trans‐3‐amino‐5‐fluoropiperidines.     

The salt–cocrystal spectrum in salicylic acid–adenine: the influence of crystal structure on proton‐transfer balance

At one extreme of the proton‐transfer spectrum in cocrystals, proton transfer is absent, whilst at the opposite extreme, in salts, the proton‐transfer process is complete. However, for acid–base pairs with a small ΔpK_a (pK_a of base ? pK_a of acid), prediction of the extent of proton transfer is not possible as there is a continuum between the salt and cocrystal ends. In this context, we attempt to illustrate that in these systems, in addition to ΔpK_a, the crystalline environment could change the extent of proton transfer. To this end, two compounds of salicylic acid (SaH) and adenine (Ad) have been prepared. Despite the same small ΔpK_a value (≈1.2), different ionization states are found. Both crystals, namely adeninium salicylate monohydrate, C₅H₆N₅⁺·C₇H₅O₃^?·H₂O, I , and adeninium salicylate–adenine–salicylic acid–water (1/2/1/2), C₅H₆N₅⁺·C₇H₅O₃^?·2C₅H₅N₅·C₇H₆O₃·2H₂O, II , have been characterized by single‐crystal X‐ray diffraction, IR spectroscopy and elemental analysis (C, H and N) techniques. In addition, the intermolecular hydrogen‐bonding interactions of compounds I and II have been investigated and quantified in detail on the basis of Hirshfeld surface analysis and fingerprint plots. Throughout the study, we use crystal engineering, which is based on modifications of the intermolecular interactions, thus offering a more comprehensive screening of the salt–cocrystal continuum in comparison with pure pK_a analysis.