Potentiometric and ab initio studies of acid-base interactions of substituted 4-halo(Cl, Br)pyridine N-oxide systems

By using the potentiometric method, acidity constants have been determined in systems of tri- and tetra-substituted pyridine N-oxides. The potentiometric measurements in systems of four 4-chloropyridine N-oxide derivatives containing the chlorine atom at position 4 to the NO₂ group and four bromine counterparts were carried out in polar non-aqueous solvents, viz. amphiprotic methanol (MeOH) and aprotic protophilic dimethyl sulfoxide (DMSO). It was found that in all the systems studied the pK_a values were readily determinable (as indicated by small standard deviations) in MeOH, whereas in DMSO large standard deviations were obtained making the pK_a values either hardly determinable or indeterminable from potentiometric measurements. Furthermore, it was demonstrated that the acidity constants of protonated N-oxides studied in MeOH changed according to the sequence of their acidity constants in water. It was also found that in the polar solvents studied, i.e. in the amphiprotic methanol and the highly basic aprotic dimethyl sulfoxide, the cationic homo-conjugation equlibrium constants could not be determined using potentiometric method. Also, by using ab initio methods at the RHF and MP2 levels and the PCM model, utilizing the Gaussian 6-31++G^∗∗ basis set, energies and Gibbs free energies of the protonation reactions of the N-oxides have been determined. The energy parameters have been compared with acidity constants of the protonated N-oxides determined by potentiometric titration in methanol to establish a correlation between these approaches.     

The basicity of pyridine and its tendency towards cationic homoconjugation in non‐aqueous media

Acid dissociation constant, pK_a, of protonated pyridine, determined in the polar protophobic aprotic solvent, acetone, has been compared with pK_a values of the pyridinium ion in a variety of other polar solvents including aprotic protophobic ones, acetonitrile, benzonitrile, nitrobenzene, nitromethane, and propylene carbonate, in the protophilic aprotic dimethyl sulfoxide and N,N‐dimethylformamide, as well as in the amphiprotic methanol. On the basis of the set of these pK_a values, the effect of the medium on the basicity of pyridine is discussed. Further, based on the cationic homoconjugation constants of pyridine conjugated with the pyridinium cation in the non‐aqueous solvents, the tendency of pyridine towards homoconjugation reactions has also been discussed. Finally, both the basicity of pyridine and its tendency towards cationic homoconjugation has been compared with analogous properties of pyridine N‐oxide.     

Base Equilibria of Substituted Pyridines in Nitromethane

In the framework of our studies on acid=nbase equilibria in systems comprisingsubstituted pyridines and nonaqueous solvents, acid dissociation constants havebeen determined potentiometrically for a variety of cationic acids conjugatedwith pyridine and its derivatives in the polar protophobic aprotic solvent nitromethane. The potentiometric method enabled a check as to whether and to whatextent cationic homoconjugation equilibria of the BH⁺/B type, as well as cationicheteroconjugation equilibria in BH⁺/B₁ systems without proton transfer, are setup in nitromethane. The equilibrium constants were compared with thosedetermined in water and two other polar protophobic aprotic solvents, propylenecarbonate and acetonitrile. The pK _a values of acids conjugate to the N-bases innitromethane fall in the pK _a range of 5.84 to 17.67, i.e., 6 to 7 pK _a units, onaverage, higher than in water, 1 to 2 units higher than in propylene carbonate,and less than 1 unit lower than in acetonitrile. This means that the basicity ofthe pyridine derivatives increases on going from propylene carbonate throughnitromethane to acetonitrile. Further, it was found that the sequence of the pK _achanges of the protonated amines was consistent in all three media, thus providingthe basis for establishing linear correlations among these values. In the majorityof the BH⁺/B systems in nitromethane, cationic homoconjugation equilibria havebeen established. The cationic homoconjugation constants, log K _BHB+, arerelatively low, falling in the range 1.60–2.89. A comparison of the homoconjugationconstants in nitromethane with those in propylene carbonate and acetonitrile showsthat nitromethane is a more favorable solvent for the cationic homoconjugationequilibria than the other two solvents. Moreover, results of the potentiometricmeasurements revealed that cationic heteroconjugation equilibria were not presentin the majority of the BH⁺/B₁ systems in nitromethane. The heteroconjugationconstant could be determined in one system only, with logdiK _BHB1 + = 2.56.     

Solvent Effects in Acid‐Catalyzed Biomass Conversion Reactions

Reaction kinetics were studied to quantify the effects of polar aprotic organic solvents on the acid‐catalyzed conversion of xylose into furfural. A solvent of particular importance is γ‐valerolactone (GVL), which leads to significant increases in reaction rates compared to water in addition to increased product selectivity. GVL has similar effects on the kinetics for the dehydration of 1,2‐propanediol to propanal and for the hydrolysis of cellobiose to glucose. Based on results obtained for homogeneous Brønsted acid catalysts that span a range of pK_a values, we suggest that an aprotic organic solvent affects the reaction kinetics by changing the stabilization of the acidic proton relative to the protonated transition state. This same behavior is displayed by strong solid Brønsted acid catalysts, such as H‐mordenite and H‐beta.     

Basicity comparison for di-substituted 4-nitropyridine derivatives in polar non-aqueous media

Acid dissociation, as well as cationic homoconjugation equilibria have been studied potentiometrically in systems involving four di-substituted 4-nitropyridines and conjugate cationic acids in the polar non-aqueous solvents - aprotic protophobic acetonitrile (AN) and propylene carbonate (PC), the amphiprotic methanol (MeOH), and in the aprotic protophilic dimethyl sulfoxide (DMSO). The influence of solvent effect on the obtained acidity constants has been discussed. The acidity constants (expressed as pK_a values) were compared with those previously determined in another polar protophobic aprotic solvent - acetone (AC), and obtained for the unsubstituted pyridine (Py). A comparison of the acid dissociation constants determined in all media studied has proved that the strength of the cationic acids increases on going from acetonitrile through propylene carbonate, acetone, and methanol to dimethyl sulfoxide. Furthermore, the values of acidity constants in the non-aqueous media have shown that in all the solvents studied they change according to the substituent effects. It has been also found that substituted 4-nitropyridine derivatives studied exhibit no tendency towards cationic homoconjugation in acetonitrile, propylene carbonate, and methanol and dimethyl sulfoxide. Moreover, it has been demonstrated that the acid dissociation constants determined by potentiometric titration method in all the solutions investigated correlate well with the calculated energy parameters of the protonation reactions in the gaseous phase.     

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.     

1H NMR studies of solvent and substituent effects on strong intramolecular hydrogen bonds

Chemical shifts of H-bonded protons in tetrabutylammonium hydrogen maleate and 14-substituted picolinic acid N-oxides have been measured in a number of dry solvents, of different activity, in order to distinguish between symmetrical single minimum and asymmetrical hydrogen bonds. In tetrabutylammonium hydrogen maleate the resonance was observed at 20.70 ppm and its was independent of the nature of the solvent used. The chemical shift value of picolinic acid N-oxide varies with the solvent. These observations suggest that the hydrogen bond is symmetrical in tetrabutylammonium hydrogen maleate but that it is asymmetrical in picolinic acid N-oxide. The chemical shifts of substituted picolinic acid N-oxides were correlated with σ_p, σ_m and Δ_pK_a. The substituent and solvent effects are compared and the position of the intramolecular H-bonded protons in picolinic acid N-oxides are estimated and discussed.     

New description of the substituent effect on electronic spectra by means of substituent constants—VI. Utraviolet spectra of 4-substituted pyridine N-oxides and blue shifted iodine bands of their EDA complexes with iodine

Electronic spectra of 4-substituted pyridine N-oxides and their EDA complexes with iodine were studied. The substituent effect on the near u.v.¹A₁ intramolecular CT bands of the N-oxides and on the blue shifted iodine bands caused by CT complex formation are discussed in terms of a general equation, theoretically derived in order to describe the substituent effect on electronic spectra by means of substituent constants. The results are quite successful and supported by semi-empirical SCFMO-CI calculations. Based on the results mentioned above, the character of n-σ type N-oxide—iodine CT complexes is also examined. The complex formation constants (log K) and pK_a values of the N-oxides correlate especially well, indicating that the CT interaction mechanism cannot be neglected in proton addition reactions such as hydrogen bonding and pK_a values.     

Simple methods for the estimation of ionization constants of substituted pyridine N-oxides in polar aprotic solvents and water

A direct method for the determination of the pK _a values of acids conjugated to substituted pyridine N-oxides has been proposed which is based on the pH measurement of the solution of the basic salt. It has been experimentally shown that the method is reliable when applied to N-oxides of not too low basicity (pK _a >5). Correlation has been performed between the pK _a values in aqueous and aprotic media solutions which shows the great influence of the solvation effect on the acid-base equilibria. The good correlation between the pK _a values in aqueous and non-aqueous solutions enables the pK _a values in water to be estimated with sufficient accuracy, even in the cases when the experimental limitations make the determination impossible which is shown on the basis of selected examples.     

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.     

Acid-base equilibria of substituted pyridine N-oxides in methanol

Acid dissociation constants in methanol for eight substituted pyridine N-oxides having a wide range of acid-base properties, [quinoline N-oxide (bi-cyclic amine N-oxide) and pyridine (heterocyclic amine)] have been determined using the potentiometric titration method. A linear correlation between ourmethanol data and aqueous pK _a values from the literature has been found. As in polar aprotic solvents cationic homoconjugation phenomenon has been found to be present for sufficiently basic N-oxides. The tendency of substituted pyridine N-oxides towards cationic homoconjugation in methanol is weaker than in polar aprotic solvents and increases with increasing basicity of N-oxides. It has also been found that, in contrast to polar aprotic solvents, the cationic homoconjugation phenomenon in methanol is much more pronounced for heterocyclic amines than their N-oxides.     

A New Approach to Analysis of the Nonlinearity of the Brønsted Relationship: I. Role of Solvation Factors in Variations of the Kinetic and Thermodynamic Acidity of CH Acids

A procedure for eliminating the electrostatic component from pK _a of CH acids in DMSO wassuggested, substantiated in detail, used to construct the most suitable pK _a scale from the viewpoint of thechoice of standard, solvent-independent states of species participating in acid-base equilibria. Deviationsfrom the linearity of the Brönsted relationship are explained using a corrected scale of pK _a cor in combination with the concept of hard and soft acids and bases. The reactions of hydrogen exchange of CH acids of various structures in media of various protolytic activities were chosen as critical objects when checking in what cases and why derivations from the Brönsted relationship should be expected. Hard electrostatiuc interaction of carbanions with an aprotic polar solvent, nonequivalent to a less hard interaction between the transition state of the reaction and a protic solvent, is one of the factors responsible for deivations from the linearity.     

Determination of acid dissociation constants of histidine-containing peptides by proton magnetic resonance spectroscopy

The acid dissociation constant of the imidazolium ring of the decapeptide luliberin has been determined by ¹H NMR-followed titration in D₂O. The normal procedure for the analysis of the titration curve, i.e. direct use of the Henderson-Haselbalch equation, is still applicable in this case, but for more complex peptides a modified calculation procedure is proposed. Results obtained when both methods were applied to luliberin are compared. The influence of D₂O when used as the solvent in this type of determination has been studied using N^α-acetyl-L -histidine methyl ester as a model compound. The difference between the acid dissociation constant of this molecule determined in H₂O and in D₂O implies that a correction of ?.25 unit is needed for those pK_a values calculated by plotting the chemical shifts in D₂O vs the apparent pH meter readings. The pK_a found for N^α-acetyl-L-histidine methyl ester, 6.30 ± 0.04, can be taken as a standard value for histidine-containing peptides.     

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.     

Interaction of pyrimethamine and sulfadiazine with ionic and neutral micelles: Electronic absorption and fluorescence studies

The binding of two antitoxoplasmosis drugs, pyrimethamine (PYR) and sulfadiazine (SDZ) to cationic cetyltrimethylammonium chloride (CTAC), anionic sodium dodecylsulfate (SDS), zwiterionic N-hexadecyl-N,N-dimethyl-2-ammonium-1-propanesulfonate (HPS) and neutral polyoxyethylene-dodecyl-ether (Brij-35^®) micelles was studied using absorption and fluorescence spectroscopic methods. The pK_a of PYR changed in the presence of charged anionic, cationic and zwiterionic micelles, indicating that interaction is influenced by the micellar charge. For SDZ, pK_a changes were lower than 1 for all micelles, suggesting the occurrence of low binding constants in addition to a reasonable influence of the micellar charge. The values of binding constants K_b, obtained from fluorescence measurements, for PYR to CTAC micelles were very low at pH 4.0, where the drug is in a complete protonated state, increasing at pH 9.0 to long-chained CTAC and HPS micelles since this factor also favors accomodation of the neutral drug in the hydrophobic compartments. For SDZ the binding constants were determined from optical absorption measurements. Low binding constants were observed to charged surfactant micelles, with influence of micellar charge. It must be stated however that those values can be underestimated due to the relatively low sensitivity of the method based on absorption measurements.     

Relative pKa of some anilinium derivatives in methanol,acetonitrile, and tetrahydrofurane solvents

In this study, the relative pK_a values of nine anilinium derivatives in methanol (MeOH), acetonitrile (AN), and tetrahydrofurane (THF) solutions were successfully calculated with mean absolute deviations of 0.63, 0.68, and 0.75 pK_a units, respectively. To this aim, their gas‐phase basicities were computed using the CBS‐QB3 composite method. Also, conductor‐like polarizable continuum model (CPCM) with UAHF, UAKS and UA0 cavities and SM8 solvation models at HF/6‐31+G(d) level of theory were applied for the calculation of the solvation Gibbs free energies. The obtained results indicate that there is reliable correlation between the experimental and computed pK_a values in the studied solutions. Therefore, to extend the pK_a database for anilines, correlation equations were used to predict the pK_a values in the investigated solvents.     

Studies on acid–base equilibria of 4-R-2,6-dimethylpyridine N-oxide systems in non-aqueous solvents

Acid–base equilibrium constants, i.e. acid dissociation, cationic homoconjugation and cationic heteroconjugation constants in 4-R-2,6-dimethylpyridine N-oxide systems (where R denotes methoxy-, methyl-, chloro- or nitro-group) in polar non-aqueous solvents: protophobic aprotic nitromethane, acetonitrile and acetone, protophilic aprotic N,N-dimethylformamide and amphiprotic methanol have been determined. The acidity constant values of protonated N-oxides in solvents studied have been found to change according to the substituent effect and to the sequence of acidity changes in water. This finding allowed to correlate the pK_a values determined in water with those determined in the solvents studied. Further, it was found that the cationic homo- and heteroconjugation constant values increased with decreasing solvent basicity and with increasing basicity of the N-oxide, and in the case of heteroconjugating systems, with increasing basicity of the the proton acceptor.     

Structure-Property Relationships in the Basicity and Lipophilicity of Arylalkylamine Oxides

Homologous N,N-dimethyl-phenylalkylamine oxides and N,N-dimethyl-diphenylalkylamine oxides were prepared. Their basicity and lipophilicity (octan-1-ol/H₂O) were compared to those of the parent amines. In contrast to the amines, the basicity of all N,N-dimethyl-arylalkylamine oxides showed very limited pK_a variations (range 4.65 – 5.01) with increasing chain length and number of Ph groups. The N-oxides in their neutral form had a log P^N value lower by 2.77±0.34 (n=9) units than that of the parent amine. The log P^C of the cationic N,N-dimethyl-diphenylalkylamines was lower than that of their neutral form, with a decrement diff(log P^N−C) that increased from 3.25 to 4.21 in the homologous series. Unexpectedly, the decrement diff(log P^N−C) for the N-oxides was much smaller than for the tertiary amines, being 0.23 for the aliphatic N,N-dimethyl-pentylamine oxide, 0.47±0.13 for the phenylalkylamine oxides, and 0.80±0.07 for the diphenylalkylamine oxides. In fact, the protonated N-oxides had log P^C values that were quite comparable to those of the protonated parent amines. Because of the differences in basicity, the difference in distribution coefficients at physiological pH (log D^7.4) between a tertiary arylalkylamine and its N-oxide was 0.82±0.66 (n=9). The pharmacokinetic implication is that N-oxygenation may have a smaller effect on the urinary excretion of tertiary amines than usually assumed.