Article pubs.acs.org/jced
Determination of the Dissociation Constants of 5‑Substituted 1H‑Tetrazoles and Amino Acids by the Concentration Spectrophotometric Method: A New Approach Tatiana Aleksandrovna Skripnikova,*,† Svetlana Sergeevna Lysova,† and Yuriy Eduardovich Zevatskii†,‡,§ †
Saint-Petersburg State University of Industrial Technologies and Design, Bolshaya Morskaya str. 18, 191186, Saint-Petersburg, Russian Federation ‡ NOVBYTCHIM Company, Zheleznovodskaya 45, Gatchina, 188350, Leningrad Region, Russian Federation § Saint Petersburg Electrotechnical University “LETI” 197376, ul. Professora Popova 5, 197376 St. Petersburg, Russian Federation ABSTRACT: A new theoretical and experimental approach to determination of the thermodynamic dissociation constants of a number of active pharmaceutical compounds, such as 5-substituted-1H-tetrazoles and amino acids, has been proposed. We obtained our experimental data from A (absorbance) to C/mol·dm−3 (concentration of weak electrolyte) without either measuring pH during the experiment or using buffer solutions with a constant ionic strength. Thermodynamic dissociation constants were obtained by extrapolating the calculated dissociation constants to zero concentration of the investigated compound. We determined the previously unknown values of thermodynamic dissociation constants of three 5-substituted1H-tetrazoles with poorly resolved spectra of the protonated and unprotonated forms.
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INTRODUCTION The thermodynamic dissociation constant is an essential parameter for a drug development; it can be used for the prognostication of pharmacodynamical and pharmokinetical properties of substances: absorption, distribution, metabolism, solubility, and elimination, the so-called ADMET profile.1,2 The pKT value has vital importance for understanding the transport of drugs into cells and across membranes. In addition, dissociation constants of selected components (acid and base) can be usefull in forming salts (cocrystals) with required solid-state characteristics and obtaining new biopharmaceutical substances.3 The main purpose of the pharmaceutical industry is the introduction of new drug compounds and their manufacturing methods. The new developments in pharmacology call for the improvement of traditional methods and finding new ones for the accurate determination of the thermodynamic dissociation constants pKT. Therefore, the determination of pKT is still relevant. There are methods for determining the dissociation constants of various organic compounds; for example, see refs 4 and 5. In most cases, the multiwavelength spectrophotometric pH titration, combined with various approaches to experimental data processing, is used for the determination of pKT. For example, a number of authors used the following approaches and programs: MCR-ALS, PLS, and PCR,6 SPECFIT and SQUAD,6−9 and so forth.10,11 For the primary experimental data these authors used A (absorbance) − pH dependence, obtained from the spectra of the investigated compound at a © 2017 American Chemical Society
constant concentration in a set of buffer solutions with various pH values, at a constant ionic strength. Because of that, the determination accuracy of the dissociation constants comes to depend not only on the selected approach to the processing of spectrophotometric data, but on the errors of pH measurements too. Another challenge associated with spectrophotometric methods is the very slight difference between the absorption spectra of the protonated and unprotonated forms. This problem prevents the determination of thermodynamic dissociation constant values for these substances. Previously, in our paper,12 we determined the thermodynamic dissociation constants of weak monobasic organic acids in the binary electrolyte−solvent systems through the application of concentration spectrophotometric measurements in combination with the numerical extrapolation methods. In the proposed method as the primary experimental data we used the next dependence: A (absorbance) − C/mol·dm−3 (concentration of weak electrolyte), obtained from the spectra of the investigated substance at different concentrations with the addition of a strong acid (HCl) or base (NaOH) at a constant concentration. It should be noted that the concentration of the strong electrolyte is constant during the experiment and, in many cases, no more than 10−3 mol·dm−3. In such solutions Received: March 31, 2017 Accepted: June 29, 2017 Published: July 17, 2017 2400
DOI: 10.1021/acs.jced.7b00308 J. Chem. Eng. Data 2017, 62, 2400−2405
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with a very low ionic strength (I → 0) intermolecular interactions and association are usually neglected, considering such solutions are close to ideal. We are able to show that within the concentration range of 10−5 to 10−2 mol·dm−3 of the compound solution the dissociation constants (pKiC) depend on concentration. Through a number of simple-composition acids and bases, we have shown that, at Ci → 0, pKiC → pKT. We noted that the thermodynamic dissociation constants pKT can be determined by extrapolation of the dissociation constants to zero concentration of the investigated compound in water solutions. Therefore, the proposed approach has several advantages compared with a standard spectrophotometric pH titration: • it does not require the measurement of pH values of the investigated solutions; • it does not require the use of buffer solutions with a constant ionic strength; • it does not require correction on the ionic strength. The aim of our paper is to improve the concentration spectrophotometry method and to customize this approach for the determination of thermodynamic dissociation constants of biologically active compounds (5-substituted-1H-tetrazoles and amino acids). We assume that the study of these compounds’ biological activity is impossible without studying their acid− base properties. Tetrazoles are important heterocyclic NH acids of medium strength; they do not occur in nature and therefore do not get metabolized in a specific way. Their use as synthetic bioisosteres of various functional groups of the active compounds increases the drugs’ metabolic stability.13 Despite the abundance of papers devoted to the tetrazoles, the data on their physical and chemical properties are fragmented.14,15 For case studies, we took two 5-substituted-1H-tetrazoles and three amino acids, whose pKT values have been previously reported, to show the applicability viability of concentration spectrophotometry. Also, in that paper we have identified previously unknown values of pKaT for three 5-substituted-1H-tetrazoles.
forms of the molecule, respectively, obtained experimentally; εi/dm·mol−1·cm−1 were determined by the Bouguer−Lambert− Beer law:
εi =
Ai C il
(4)
where Ci/mol·dm−3 is the molar concentration of the i-solution of the investigated compound; Ai is the absorbance of the investigated compound; l/cm is the optical length layer. For the cases where the dissociation degree of the 5-substituted-1H-tetrazole ranged from 0.2 ≤ αi ≤ 0.8, the experimental values of the dissociation constants pKiex we obtained by Ostwald dilution law: ⎛ Cα2 ⎞ pKiex = −log⎜ i i ⎟ ⎝ 1 − αi ⎠
(5)
If the dissociation degree of the 5-substituted-1H-tetrazole ranged from αi > 0.8, we added a small amount of a constant concentration of a strong acid (CHCl). The experimental values of the dissociation constants pKiex for 5-substituted-1Htetrazole in the presence of a constant concentration of hydrochloric acid was obtained from Ostwald dilution law and from the law of electrical neutrality: ⎛ α (C + C iαi) ⎞ pK iex = −log⎜ i HCl ⎟ 1 − αi ⎠ ⎝
(6)
The addition of a strong electrolyte (strong acid, as HCl, or strong alkali, as NaOH) is necessary for the shifting the protolytic equilibrium and the resulting increase of the dissociation degree of a form (cationic or anionic). The strong electrolyte was added to a point, where the dissociation degree of the investigated compound became 0.2 ≤ αi ≤ 0.8. The equilibrium content of carbon dioxide in fresh distilled water is ∼1.3 × 10−5 mol·dm−3;16 therefore, the concentration of NaOH exceeds the concentration of carbon dioxide. Thus, in this paper the thermodynamic dissociation constants pKT were obtained by extrapolating the calculated values of (pKiC) to zero concentration of the solution of the investigated compound by using the linear dependence.
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THEORETICAL SECTION Procedure for the Determination of the Protonation/ Dissociation Constants. 5-Substituted-1H-tetrazoles dissociate in water solutions according to the following scheme:
pK iC = pKT + bC i
(7)
−3
where Ci/mol·dm is the molar concentration of the i-solution of the investigated compound, b coefficient, that was found numerically by Mathcad 14, by minimization of the sum of the squared deviation S of the calculated values of the dissociation constant (pKiC) by eq 8 from the corresponding experimental values (pKiex):17
The thermodynamic dissociation constant of 5-substituted1H-tetrazole is a −a + K aT = A H aAH (2)
S=
i
where aA−, aH+, and aAH are the activities of the respective particles. The dissociation degrees of the 5-substituted-1H-tetrazoles were determined by ε − ε0 αi = i εA− − ε0 (3) εA−/dm·mol−1·cm−1
−1
∑ (pK iC − pK iex)2 → min
(8)
Amino acids in aqueous solutions exist mainly as a zwitterion and, in minor amounts, as a neutral form (RH0±), as a cation (RH2+) in the presence of strong acids (HCl), and as an anion (R−) in the presence of strong alkalis (NaOH), according to the dissociation scheme: −H +
−H +
+H K1T
+H K 2T
RH+2 Xoooo+Y [RH±0 ]Xoooo+YR−
−1
where and ε0/dm·mol ·cm are the molar absorption coefficients for the unprotonated and protonated 2401
(9) DOI: 10.1021/acs.jced.7b00308 J. Chem. Eng. Data 2017, 62, 2400−2405
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where K1T and K2T are the first and the second thermodynamic dissociation constants of amino acids; thus: aRH±0 a H+ K1T = a RH+2 (10)
K 2T =
a R−a H+ a RH±0 −
+
Instruments and Spectrophotometric Measurements. Water solutions were prepared from deionized water. The concentration range of the investigated compounds was 10−5 to 10−4 mol·dm−3, which is sufficient for the spectrophotometric measurements. All of the investigated compounds were soluble in water and did not require the addition of an organic solvent. Concentration Spectrophotometry. A series of working solutions with different mass fractions of each substance was prepared by a weight method of dilution. Sample of the test substance and its solutions were weighted on the analytical balance MV 210-A with the electronic precision of ±0.1 mg. The densities of the aqueous solutions of the investigated compounds were measured by a density meter DMA-5000 M Anton Paar (Austria) with the electronic precision of ±5 × 10−5 g·cm−3. UV spectra of each aqueous solution with different concentrations of the investigated compounds were recorded by spectrophotometer Shimadzu UV 2700. Quartz cuvettes 1.001 cm were used during the spectrophotometric measurements. Temperatures of the investigated solution were monitored by the cuvette holder “Shimadzu TCC-100” Peltier temperature control with the accuracy of ±0.1 °C. All measurements were carried out at the temperature of 25 °C. The analytical wavelength corresponded to the largest difference between the optical absorbance of the solutions of the protonated and unprotonated forms. The molar absorption coefficients of the protonated and unprotonated forms were determined experimentally, by added the strong acid solution, e.g., HCl (pH ≈ 1), and strong alkaline solution, e.g., NaOH (pH ≈ 13). The experimental data were processed by using Mathcad 14 and the discussed approach, which has been developed in our laboratory.
(11)
aRH0±,
aRH2+
where aR , aH , and are the activities of the corresponding particles. The dissociation degrees of the amino acid were determined: αi(εRH±0 ) = −
εi − εRH±0 εR−(RH+2 ) − εRH±0 −1
−1
(12)
εRH2+/dm·mol−1·cm−1
where εR /dm·mol ·cm and are the molar absorption coefficients for the unprotonated and protonated forms of the molecule respectively, experimentally obtained; εi/dm·mol−1·cm−1 were determined according to eq 4; εRH0±/dm·mol−1·cm−1 is the calculated value of the molar absorption coefficient of the molecule. For amino acids, this method allows to calculate not only the pKT values and the coefficient b by eqs 7 and 8, but the molar absorption coefficients for the neutral forms εRH0±/dm·mol−1·cm−1, necessary for 12 too. This reduces the time for spectrophotometric measurements; even though the calculation of the thermodynamic dissociation constants is thus made more complicated, for another free parameter, the molar absorption coefficient for the neutral form εRH0±/ dm·mol−1·cm−1 has to be introduced to eq 8. The experimental values of the dissociation constants pK1iex and pK2iex of amino acids in the presence of a constant concentration of hydrochloric acid (CHCl/mol·dm−3) were obtained by the equation: ⎛ (1 − αi)(C HCl − C iαi) ⎞ pK1iex = −log⎜ ⎟ αi ⎠ ⎝
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RESULTS AND DISCUSSION As it has been previously noted, the problem of the poorly resolved absorption spectra of the protonated and unprotonated forms is still relevant. For all of the investigated 5-substituted-1H-tetrazoles, except 5-(4-nitrophenyl)-1H-tetrazole, the difference between the absorption spectra of the protonated and unprotonated forms is negligible, which complicates the use of the spectrophotometric pH titration. As a case study (Figure 1), we presented the absorption spectra of 5-phenyl-1H-tetrazole, obtained by spectrophotometric pH titration. As seen, the difference between the absorption spectra of 5-phenyl-1H-tetrazole at various pH values is slight. This poses
(13)
in the presence of a constant concentration of sodium hydroxide (CNaOH/mol·dm−3) by the following equation, which we obtained from the Ostwald dilution law and from the law of electrical neutrality: ⎛ α(C iαi − C NaOH) ⎞ pK 2iex = −log⎜ ⎟ (1 − αi) ⎠ ⎝
(14)
The experimental values of the dissociation constants pK2iex of 4-aminobenzenesulfonic acid were obtained by the eq 6 in the presence of a constant concentration of hydrochloric acid.
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EXPERIMENTAL SECTION Materials and Solutions. The following 5-substituted-1Htetrazoles [5-phenyl-1H-tetrazole, 5-(4-nitrophenyl)-1H-tetrazole, 5-(methylthio)-1H-tetrazole, 5-(phenoxymethyl)-1H-tetrazole, 5-(4-chlorobenzyl)-1H-tetrazole] and amino acids (nicotinic acid, 4-aminobenzenesulfonic acid, 2-aminobenzoic acid) were selected for the investigation. Compounds with a mass fraction of 98−99% were used to determine the pKT. Their purity was assessed by melting point for solids, by density for liquids. All of the compounds passed the quality test and did not require further purification.
Figure 1. Absorption spectra of 5-phenyl-1H-tetrazole (C = 5 × 10−5 mol·dm−3) as a function of pH, between 0.72 and 10.43. 2402
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certain challenges in determining pKaT. The main problem is the choice of analytical wavelengths and the processing of the results.18 In our paper we analyze the absorption spectra of the investigated substances at various concentrations by the concentration spectrophotometry method. In Figure 2 we present the
The thermodynamic dissociation constants of 5-phenyl-1Htetrazole, as well as the b coefficient, were calculated according to the theoretical model (2.1). Calculation results are shown in Table 1 in comparison with the previously published data. The values of pKaT and b for the other 5-substituted-1H-tetrazoles were calculated through the same procedure. The Table 1 also features the values of the standard deviations σ: N
σ=
∑i (pK iC − pK iex )2 N−1
(15)
where N is the number of the concentration constant values of the investigated compound. The average difference between the experimental and the calculated dissociation constant values: M=
1 × N
N
∑ (pK iC − pK iex)
(16)
i
The values of the thermodynamic dissociation constant of 5-phenyl-1H-tetrazole are consistent with the published data. We also determined the new values of the thermodynamic dissociation constants of three 5-substituted-1H-tetrazoles with poorly resolved absorption spectra of the protonated and unprotonated forms. For all of the investigated compounds, the resulting values of the average difference between the experimental and the calculated dissociation constant values are at least several orders of magnitude below the values of the standard deviation. It confirms the viability of this method for determining the thermodynamic dissociation constants of other tetrazoles. Thermodynamic dissociation constants for amino acids were determined through similar procedures. Table 2 shows obtained values of thermodynamic dissociation constants for amino acids versus the previously published data, as well as the range of the concentrations of the investigated compounds and the concentration of the strong electrolyte (HCl or NaOH). It also contains the values of the standard deviations (σ) and the average difference between the experimental and the calculated dissociation constant values (M). We succeeded in calculating thermodynamic dissociation constants for nicotinic acid that had not been defined with any precision earlier. The values of thermodynamic dissociation constants for amino acids are consistent with published data.
Figure 2. Absorption spectra of 5-phenyl-1H-tetrazole at various concentrations in aqueous solution C/mol·dm−3: between 1.0 × 10−4 and 3.7 × 10−5 mol·dm−3.
absorption spectra of 5-phenyl-1H-tetrazole at various concentrations in aqueous solution. Figure 3 shows the dependence of the dissociation constants of 5-phenyl-1H-tetrazole on its concentrations.
Figure 3. Values of the dissociation constants of 5-phenyl-1H-tetrazole in aqueous solution (λ = 238 nm): experimental valuespKiex; calculated valuespKic.
Table 1. Thermodynamic Dissociation Constants (pKaT) of 5-Substituted 1H-Tetrazoles in Comparison with the Previously Published Data, Standard Deviations (σ), and the Average Difference between the Experimental and the Calculated Dissociation Constant Values (M) 5-substituted-1H-tetrazoles
solventa
λb (nm)
5-(4-nitrophenyl)-1Htetrazole 5-phenyl-1H-tetrazole
HCl, 3 × 10−4 M H2O
295.0
5-(methylthio)-1Htetrazole 5-(4-chlorobenzyl)-1Htetrazole 5-(phenoxymethyl)-1Htetrazole
H2O
230.6
H2O
267.5
H2O
269.0
238.0
Cic (mol·dm−3) 10−4 to −5
1× 3 × 10 1 × 10−4 to 3 × 10−5 3 × 10−4 to 1 × 10−4 8 × 10−4 to 3 × 10−4 9 × 10−4 to 2 × 10−4
αid
pKaT
σ × 102 M × 1010
be
0.43−0.48
3.51
3.15 × 10
0.58−0.62
4.72
0.43−0.66
2
0.42
0.61
−7.13 × 103
2.39
−0.46
3.84
3.40 × 102
0.83
0.38
0.49−0.59
3.70
−3.48 × 102
0.62
0.02
0.59−0.73
3.41
−2.92 × 102
1.19
−1.95
pKa (lit.) 3.45 ± 0.06 [ref 14] 4.86 ± 0.02 [ref 19]
a Measured absorption of the investigated compounds in solution with the constant concentration of the solvent or in water solutions. bThe wavelength for the pKa determination. cConcentration range of the 5-substituted-1H-tetrazole. dThe degree of dissociation of the 5-substituted-1Htetrazole. eEstimated coefficient.
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Table 2. Thermodynamic Dissociation Constants (pKT) of Amino Acids in Comparison with the Previously Published Data, Standard Deviations (σ), and the Average Difference between the Experimental and the Calculated Dissociation Constant Values (M) amino acids nicotinic acid
2-aminobenzoic acid
4-aminobenzene sulfonic acid
solventa HCl, 5 × 10−3 M NaOH, 5 × 10−5 M HCl, 1 × 10−2 M NaOH, 5 × 10−5 M HCl, 10−3 M
λb (nm) 261.3
309.3
248.5
Cic (mol·dm−3) 10−4 to −5
3× 8 × 10 2 × 10−4 to 5 × 10−5 3 × 10−3 to 9 × 10−4 9 × 10−4 to 3 × 10−4 3 × 10−4 to 1 × 10−4
αid
pKT
σ × 103
be
2.72 (1)
−1.32 × 10
0.20−0.45
4.12 (2)
2.52 × 10
0.47−0.52
2.06 (1)
−1. 29 × 101
2.16
0.20−0.29
4.80 (2)
−1.52 × 102
4.30
0.33−0.35
3.25 (2)
−1.86 × 101
0.76
0.70−0.72
2
3
4.22 19.8
M × 109 0.42 0.69 761 0.86 −19.0
pK (lit.) 1.87−3.60 (1) [ref 20] 4.67−5.12 (2) [ref 20] 2.18 ± 0.05 (1) [ref 21] 4.84 ± 0.01 (2) [ref 21] 3.227 ± 0.006 (2) [ref 22]
a c
Measured absorption of the investigated compounds in solution with a constant concentration of solvent. bThe wavelength for pKa determination. Concentration range of the amino acids. dDegree of dissociation of the amino acids. eEstimated coefficient. (4) Pathare, B.; Tambe, V.; Patil, V. A review on various analytical methods used in determination of dissociation constant. Int. J. Pharm. Pharm. Sci. 2014, 6 (8), 26−34. (5) Reijenga, J.; van Hoof, A.; van Loon, A.; Teunissen, B. Development of Methods for the Determination of pKa Values. Anal. Chem. Insights 2013, 8, 53−71. (6) Amador-Hernández, J.; Rojas-Hernández, A.; Colunga-Urbina, E. M.; De La Garza Rodríguez, I. M.; Velazquez-Manzanares, M.; Medina-Vallejo, L. F. New chemometric strategies in the spectrophotometric determination of pKa. Eur. J. Chem. 2014, 5 (1), 1−5. (7) Meloun, M.; Ferencikova, Z.; Javurek, M. Reliability of dissociation constants and resolution capabilyti of SQUAD (84) and SPECFIT/32 in the regression of multiwavelenght spectrophotometric pH-titration data. Spectrochim. Acta, Part A 2012, 86, 305−314. (8) Meloun, M.; Necasova, V.; Javurek, M.; Pekarek, T. The dissociation constants of the cytostatic bosutinib by nonlinear leastsquares regression of multiwavelenght spectrophotometric and potentiometric pH-titration data. J. Pharm. Biomed. Anal. 2016, 120, 158−167. (9) Meloun, M.; Bordovska, S.; Syrovy, T. A novel computational strategy for the pKa estimation by non-linear regression of multiwavelenght spectrophotometric pH-titration data exhibiting small spectral changes. J. Phys. Org. Chem. 2007, 20, 690−701. (10) Vidal Salgado, L. E.; Vargas-Hernández, C. Spectrophotometric Determination of the pKa, Isosbestic Point and Equation of Absorbance vs. pH for a Universal pH Indicator. Am. J. Anal. Chem. 2014, 5, 1290−1301. (11) Musil, K.; Florianova, V.; Bucek, P.; Dohnal, V.; Kuca, K.; Musilek, K. Development and validation of a FIA/UV-Vis method for pKa determination of oxime based acetylcholinesterase reactivators. J. Pharm. Biomed. Anal. 2016, 117 (5), 240−246. (12) Lysova, S. S.; Starikova, T. A.; Zevatskii, Yu.E. Limit of Concentration Constant of Protolytic Equilibrium. Russ. J. Gen. Chem. 2014, 84 (8), 1634−1635. (13) Ostrovskii, V. A.; Trifonov, R. E.; Popova, E. A. Medicinal chemistry of tetrazoles. Russ. Chem. Bull. 2012, 61 (4), 768−780. (14) Trifonov, R. E.; Ostrovskii, V. A. Protolytic Equilibria in Tetrazoles. Russ. J. Org. Chem. 2006, 42 (11), 1585−1605. (15) Boraei, A. A. A. Acidity Constants of Some Tetrazole Compounds in Various Aqueous-Organic Solvent Media. J. Chem. Eng. Data 2001, 46, 939−943. (16) Korenman, I. M. Analytical chemistry of small concentrations. Moskow: Chemistry 1966, 111. (17) Meloun, M.; Militky, J.; Forina, M. Chemometrics for analytical chemistry, V.1: PC-Aided Statistical data analysis,; Ellis Horwood: Chichester, 1992. (18) Frans, S. D.; Harris, J. M. Selection of analytical wavelengths for multicomponent spectrophotometric determinations. Anal. Chem. 1985, 57 (13), 2680−2684.
For the investigated compounds, the resulting values of the average difference between the experimental and calculated dissociation constant values (M) are at least several orders of magnitude below the values of the standard deviation (σ). This testifies to the efficiency of the proposed approach. A valid point is that the method allows to determine not only thermodynamic dissociation constants and coefficient b but also the value of the molar absorption coefficient of the molecule (εRH0±/dm·mol−1·cm−1), without using the spectrophotometric pH titration.
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CONCLUSION The new approach to determining thermodynamic constants for 5-substituted-1H-tetrazoles and amino acids, by using concentration spectrophotometric method that does not require pH measurement or use of buffer solutions, was proposed. In this paper we have shown the concentration dependence of the values of pKiex in weak electrolytes with various structures and strengths in the range of 10−5 to 10−2 mol·dm−3. The value of the thermodynamic constants of the investigated substances is consistent with the previously published data. This is a valid proof that concentration spectrophotometry is readily applicable to the studies of acid−base equilibria. In this paper we determined the previously unknown values of thermodynamic dissociation constants of three 5-substituted-1H-tetrazoles with poorly resolved spectra of the protonated and unprotonated forms.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel.: 8-911-231-29-64. ORCID
Tatiana Aleksandrovna Skripnikova: 0000-0002-9945-6854 Notes
The authors declare no competing financial interest.
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REFERENCES
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(19) Ostrovskii, V. A.; Koldobskii, G. I.; Shirokova, N. P.; Poplavskii, V. S. Acid-base properties of 5-substituted-1H-tetrazoles. Chem. Heterocycl. Compd. 1981, 4, 559−562. (20) Goncalves, E. M.; Rego, T. S.; Minas da Piedade, M. E. Thermochemistry of aqueous pyridine-3-carboxylic acid (nicotinic acid). J. Chem. Thermodyn. 2011, 43, 974−979. (21) Zapała, L.; Woznicka, E.; Kalembkiewicz, J. Tautomeric and microscopic protonation equilibria of anthranilic acid and its derivatives. J. Solution Chem. 2014, 43 (6), 1167−1183. (22) MacLaren, R. O.; Swinehart, D. F. The Ionization Constant of Sulfanilic Acid from 0 to 50° by Means of E.m.f. Measurements. J. Am. Chem. Soc. 1951, 73 (4), 1822−1824.
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