NMR determination of pKa values of indoloquinoline alkaloids

Malaria is one of the most serious global health problems. Isolating new therapeutic agents with potential antimalarial activity from natural sources or preparing such agents either semisynthetically or synthetically is one strategy for solving the problem of resistance constantly evolving to the drugs currently in use. For alkaloids, the acid–base dissociation constant, pK_a, is an important characteristic, thought to be associated with biological activity. In this contribution, pK_a values for several indoloquinoline alkaloids were determined by using ¹H NMR spectroscopy in a mixture of solvents. The data were recalculated for water solutions using the correction factors reported previously. The structural dependence of the pK_a values for cryptolepine and its isomers neocryptolepine, isocryptolepine and isoneocryptolepine as well as some substituted neocryptolepine derivatives is discussed. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis,microwave‐promoted catalytic activity in Suzuki–Miyaura cross‐coupling reactions and antimicrobial properties of novel benzimidazole salts bearing trimethylsilyl group

A mixture of benzimidazole salts (2–7), Pd(OAc)₂ and K₂CO₃ in DMF–H₂O catalyzes the Suzuki–Miyaura cross‐coupling reactions promoted by microwave irradiation resulting in high yield within a short time. In particular, the yield of the Suzuki–Miyaura reactions with aryl bromides was found to be nearly quantitative. The synthesized benzimidazole salts (2–7) were identified by ¹H‐¹³C, NMR, IR spectroscopic methods and microanalysis. The molecular structure of 1 was determined by X‐ray crystallography. The antibacterial and antifungal activities of the novel benzimidazole derivatives (1–7) were also tested against standard strains. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis,characterization and microwave‐assisted catalytic activity of novel benzimidazole salts bearing piperidine and morpholine moieties in Heck cross‐coupling reactions

A mixture of novel benzimidazole salts (2a–f), Pd(OAc)₂ and K₂CO₃ in DMF? H₂O catalyzes, in high yield, the Heck cross‐coupling reaction assisted by microwave irradiation in a short time. All synthesized novel benzimidazole derivatives were characterized by elemental analysis and NMR spectroscopy. In addition, the molecular structure of 2a was determined by X‐ray crystallography. Copyright © 2011 John Wiley & Sons, Ltd.     

Determination of thermodynamic pKa values of benzimidazole and benzimidazole derivatives by capillary electrophoresis

Thermodynamic pK_a values for benzimidazole and several substituted benzimidazoles were determined by CE. Electrophoretic mobilities of benzimidazoles were determined by CE at different pH levels and ionic strengths. The dependence of electrophoretic mobilities on pH was used to obtain pK_a values at different ionic strengths. Extrapolations to zero ionic strength were used to determine the thermodynamic pK_a values. Using this method the thermodynamic pK_a values of 15 benzimidazoles were determined and found to range from 4.48 to 7.38. Results from the CE measurements were compared with spectrophotometric measurements which were evaluated at wavelengths where the highest absorbance difference for varying pH was recorded. The two analytical techniques were in good agreement.     

Basicity of azoles. 5—Experimental gas phase basicities determined by mass spectrometry towards ab initio calculated protonation energies

Using Cooks' method, the relative gas phase proton affinities of six azoles (imidazole, benzimidazole, pyrazole, indazole, 1-methylindazole and 2-methylindazole) have been determined. Ab initio calculations have been carried out for these six molecules and the corresponding cations, thus allowing the determination of protonation energies. Even the correlation between these quantities (-log K = 0.438+0.0744δΔE_p) is far from perfect (r² = 0.863), the order of basicity is the same. Aqueous basicities, pK_a values, are totally uncorrelated.     

Synthesis and microwave‐assisted catalytic activity of novel bis‐benzimidazole salts bearing furfuryl and thenyl moieties in Heck and Suzuki cross‐coupling reactions

A mixture of bis‐benzimidazole salts ( 1–7 ), Pd(OAc)₂ and K₂CO₃ in DMF ? H₂O catalyzes, in high yield, the Suzuki and Heck cross‐coupling reactions assisted by microwave irradiation in a short time. In particular, the yields of the Heck and Suzuki reactions with aryl bromides were found to be nearly quantative. The synthesized bis‐benzimidazole salts ( 1 – 7 ) were identified by ¹H? ¹³C NMR, IR spectroscopic methods and micro analysis. Copyright © 2010 John Wiley & Sons, Ltd.     

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.     

Acidity of Several Anilinium Derivatives in Pure Tetrahydrofuran

The acidity constant (pK _a) of eleven substituted anilinium ions and the dissociation constants of their perchlorate salts (pK _salt) were determined in pure tetrahydrofuran by potentiometry and conductometry. The pK _a values of the studied aniliniums extend downward the range of previously determined pK _a values. The resolution of acid strength for cationic acids in tetrahydrofuran was compared with those obtained in other amphiprotic and aprotic solvents. It is shown that the resolution in tetrahydrofuran is higher than the ones in water and methanol, similar to those in acetone, dimethyl sulfoxide and isobutylmethylketone, but lower than those in acetonitrile and nitromethane.     

Determination of chromatographic dissociation constants of some carbapenem group antibiotics and quantification of these compounds in human urine

The dissociation constant values (_s^spK_a) of some carbapenem group drugs (ertapenem, meropenem, doripenem) in different percentages of methanol–water binary mixtures (18, 20 and 22%, v/v) were determined from the mobile phase pH dependence of their retention factor. Evaluation of these data was performed using the NLREG program. From calculated pK_a values, the aqueous pK_a values of these subtances were calculated by different approaches. Moreover, the correlation established between retention factor and the pH of the water–methanol mobile phase was used to determine the optimum separation conditions. In order to validate the optimized conditions, these drugs were studied in human urine. The chromatographic separation was realized using a Gemini NX C₁₈ column (250 × 4.6 mm i.d., 5 µm particles) and UV detector set at 220 and 295 nm. Copyright © 2013 John Wiley & Sons, Ltd.     

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.     

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     

Protonation‐Dependent Base Flipping at Neutral pH in the Catalytic Triad of a Self‐Splicing Bacterial Group II Intron

NMR spectroscopy has revealed pH‐dependent structural changes in the highly conserved catalytic domain 5 of a bacterial group II intron. Two adenines with pK_a values close to neutral pH were identified in the catalytic triad and the bulge. Protonation of the adenine opposite to the catalytic triad is stabilized within a G(syn)–AH⁺(anti) base pair. The pH‐dependent anti‐to‐syn flipping of this G in the catalytic triad modulates the known interaction with the linker region between domains 2 and 3 (J23) and simultaneously the binding of the catalytic Mg²⁺ ion to its backbone. Hence, this here identified shifted pK_a value controls the conformational change between the two steps of splicing.     

1H NMR spectroscopic identification of protonable sites in cryptolepines with C‐11 substituents containing two amino functionalities

Knowledge of protonable sites and acid dissociation constants of cryptolepine derivatives having C‐11 substituents containing two amino functionalities is of great importance to the understanding of the mechanism of their antimalarial action, which may contribute to their further development as drug candidates. In this work, we applied ¹H NMR titration to investigate the acid–base characteristics of these polyprotic compounds in the pH range 3–13. We identified three acid–base equilibria with most acid dissociation constants (pK_a*) being greater than 10.5, which prevented us from using the potentiometric method. Overall, ¹H NMR titration was sensitive and suitable for the determination of pK_a values for these drug leads. Copyright © 2012 John Wiley & Sons, Ltd.     

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.     

Palladium catalyzed Mizoroki–Heck and Suzuki–Miyaura reactions using naphthalenomethyl-substituted imidazolidin-2-ylidene ligands in aqueous media

Naphthalenomethyl-substituted imidazolidinium salts (1a-g) were prepared and characterized by conventional spectroscopic methods, ¹H NMR, ¹³C NMR, FTIR, and elemental analysis techniques. The in situ prepared three component systems naphthalenomethyl-substituted imidazolidinium salts, Pd(OAc)₂, and K₂CO₃ catalyzed quantitatively the Mizoroki–Heck and Suzuki–Miyaura coupling of aryl halides under mild conditions in aqueous media.     

2-Phosphonobutane-1,2,4,-Tricarboxylic Acid (PBTC): pH-Dependent Behavior Studied by Means of Multinuclear NMR Spectroscopy

Although 2-phosphonobutane-1,2,4,-tricarboxylic acid, PBTC, has manifold industrial applications, relevant and reliable data on the protonation of PBTC are poor. However, these data are critical parameters for ascertaining PBTC speciation, especially with regard to a sound structural and thermodynamic characterization of its metal ion complexes. A rigorous evaluation of pH-dependent ¹H, ¹³C, and ³¹P chemical shifts along with accessible scalar spin–spin coupling constants (J) was performed in order to determine the pK_a values of PBTC in 0.5 molal NaCl aqueous solution by means of nuclear magnetic resonance (NMR) spectroscopy. The phosphonate group revealed pK_a values of 0.90 ± 0.02 and 9.79 ± 0.02, and the pK_a values associated with the carboxylic groups are 3.92 ± 0.02, 4.76 ± 0.03, and 6.13 ± 0.03. Supported by DFT-calculated structures revealing strong intramolecular hydrogen bonding, the sequence of deprotonation could be unambiguously determined.     

Efficient and green catalytic system incorporating new benzimidazolium salts for the Sonogashira cross‐coupling reaction

A number of novel benzimidazole salts were synthesized and their structures were determined using ¹H NMR, ¹³C NMR and infrared spectroscopic techniques and elemental analysis. A catalyst system consisting of Pd(OAc)₂ and copper nanoparticles in the presence of Cs₂CO₃ and incorporating the novel benzimidazole salts in poly(ethylene glycol) solvent significantly improved the yields of Sonogashira reactions between aryl halides and phenylacetylene under microwave irradiation in 10 min.     

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.     

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.     

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.