Acid-dissociation constant bases

Semiquinone radical anions can undergo protonation steps to form neutral semiquinone or in very strongly acidic solution, a semiquinone cation radical. On the other hand, semiquinone radical anions containing ionisable H can undergo deprotonation to form dianion, trianion or even polyanion. An example is the case of naphthazarin (5,8-dihydroxy-l,4-naphthoquinone)(NzH2) [31] where 5 different states of protonation of the semiquinone radicals are possible. 

Studies on pK(-l) are rare [44], It is probably befieved that in very strong acidic solutions, semiquinone radicals can remain in the cationic form. Except some ESR studies [45-47], very little research has been oriented to this direction. Irradiation of p-benzoquinone in a CFCI3 matrix at 77 K and subsequent ESR studies [48] established a symmetric o-radical cation. In situ UV photolysis of p-benzoquinone in CF3COOH at room temperature apparently gave a symmetric 7t-cation radical [49,50]. The question of the nature of the radical cation still remains unresolved. 

Mayer and Kiaslukianis [44] carried out pulse radiolysis of p-benzoquinone, 1,4-naphthoquinone, naphthazarin, 9,10-anthraquinone and quinizaiin, in fi-eon 113 (CF2CI-CFCI2) solution at room temperature. Blue shifted UV-visible absorption spectra were assigned to the radical cations. High formation rate constants ( 10 ° dm mof s ) have been reported. The value of pK(l) is the most important parameter as pK(2) and pK(3) are normally measurable in very strongly alkaline solutions only [31]. 

As the absorption spectra of neutral and anionic semiquinones differ considerably, it has been possible to estimate pK(l) and in many cases, even pK(2), by choosing appropriate wavelengths and a modified Hendersen s equation [40]  

In the case of benzo-semiquinone the pK(l) value is 4.1 in aqueous solution [9] and 4.7 in the aqueous-organic mixed solvent [28], However, in substituted quinones, especially OH-substituted quinones, the anion is more stabilized due to the intramolecular H-bonding. As a result, pK(l) values are lower, as shown in Table 1. 

---

Two useful characterization applications involving acid-base titrimetry are the determination of equivalent weight, and the determination of acid-base dissociation constants. 

The initial goal of the kinetic analysis is to express k as a function of [H ], pH-independent rate constants, and appropriate acid-base dissociation constants. Then numerical estimates of these constants are obtained. The theoretical pH-rate profile can now be calculated and compared with the experimental curve. A quantitative agreement indicates that the proposed rate equation is consistent with experiment. It is advisable to use other information (such as independently measured dissociation constants) to support the kinetic analysis. 

The use of capillary electrophoresis (CE) during the synthetic drug development is described from the preclinical development phase to the final marketed stage. The chapter comprises the determination of physicochemical properties, such as acid—base dissociation constants (pKJ, octanol—water distribution coefficients (logP), and analysis of pharmaceutical counterions and functional excipients. 

Izutzu, K. (1990). Acid-Base Dissociation Constants in Dipolar Aprotic Solvents, Chemical Data Series No. 35 Blackwell Scientific Publications, Oxford... 

From Izutsu, K. Acid-base Dissociation Constants in Dipolar Aprotic Solvents, Blackwell Science, Oxford 1990, and others. 

L. Finston and A. C. Rychtman A New View of Current Acid-Base Theories, Wiley, Chichester, 1982. [108] F. Strohbusch Neue Erkenntnisse der Sdure-Basen-Theorie, Chemie in unserer Zeit 16, 103 (1982). [109] R. A. Cox and K. Yates Acidity Eunctions - An Update, Can. J. Chem. 61, 2225 (1983). [110] (a) E. P. Serjeant and B. Dempsey Ionisation Constants of Organic Acids in Aqueous Solution, Pergamon Press, Oxford/U.K., 1979 (b) K. Izutsu Acid-Base Dissociation Constants in Dipolar Aprotic Solvents, Blackwell Scientific Publishers, Oxford/U.K., 1990. 

In order to determine to what extent these speculations have validity, it is necessary to be able to evaluate more quantitatively the relative contributions of these interactions to the free energies of protein and nucleic acid molecules in water and nonaqueous solvents. For this purpose, a substantial body of quantitative data is required concerning the properties of suitable model compounds in a variety of solvents, including their solubilities, acid-base dissociation constants, and thermodynamics of hydrogen bond formation. The dearth of pertinent data on hydrogen bonds in solvents of interest is particularly frustrating to even a semiquantitative evaluation of the scheme presented in Fig. 7. 

Tanaka H, Tachibana T. Determination of acid/base dissociation constants based on a rapid detection of the half equivalence point by feedback-based flow ratiometry. Anal Sci 2004 Jun 20(6) 979-981. 

There are indications that free energies of formation of hydrogen bonds vary substantially with the structural type of the partners in ways that are not correlated with acid-base dissociation constants. If such a variation is incorporated in it would be sufficient to account for the observation that acids covering a variety of structural types do not fit on a single Bronsted plot. ... 

Description of key chemical and physical properties/ characteristics—A physical description of the compound (color, form, and appearance) should be stated. A discussion should be provided on existence of pol3miorphic forms, solvates or hydrates of the molecule supported by appropriate data (e.g., thermal analyses or x-ray powder diffraction testing). Available solubility data, specific (optical) rotation values for chiral compounds, the partition (distribution) coefficient, acid/base dissociation constants, pH, and hygroscopi-city data are generally also included for the selected form of the API. 

The acidity constant is a measure of the strength of the acid. Base dissociation constants (K),) are similarly defined. The expression ... 

Consistent with the structure, lovastatin exhibits no acid/base dissociation constants. Potentiometric titration of a sample in 50% aqueous methanol revealed no observable buffering action in the pH range of 2-11. 

Although hy definition, a pK value is determined in water, analogous "pKa values have been determined in other solvents, too. See for instance K. Izutsu (Ed.), Acid-base dissociation constants in dipolar aprotic solvents. Chemical Data Series No. 35, International Union of Pure and Apphed Chemistry, pubhshed hy BlackweU Scientific Pubhcations, Oxford, London, Edinburgh, Boston, Melbourne, 1990. 

Solinova V., Kasicka V., Koval D., Cesnek M., Holy A., Determination of acid—base dissociation constants of amino- and guanidinopurine nucleotide analogs and related compounds by capillary zone electrophoresis. Electrophoresis, 27, 1006—1019 (2006). 

We start by using Eq. (3.9) to define the different chemical species that are assumed to be present and then we will proceed to substitute secondary equilibrium expressions governed by acid/base dissociation constants or... 

Figure 8.2 Predicted retention of a zwitterion (pK and pK are acid-base dissociation constants in water and micellar solution, respectively, and [S] is surfactant concentration), as a function of pH and micelle concentration with nonionic micelles (top) solute-micelle association constants for cation, zwitterion and anion are 3, 0.1 and 3, respectively, cmc = 2.4x10 M and with anionic micelles (bottom) solute-micelle association constants are 10,000, 10 and 0.1, respectively, cmc = 8.3x10 M. The derivatives of the sigmoidal curves at each micelle concentration are also shown to give the apparent dissociation constants. Reprinted from Ref 6 with permission of the American Chemical Society.

The second relationship is of particular interest because extended compilations of pa are accessible in the form of PA (proton affinities in the gas phase) and (acid-base dissociation constants in aqueous solution). With this in mind, the proton-affinity difference becomes... 

It should be noted that the minimum data set, namely molecular mass, Henry coefficient, the octanol/water partitioning ratio and the acid-base dissociation constant, is the same for all environmental fate submodels. 

Izutsu, K. Acid-base dissociation constants in dipolar aprotic solvents, Blackwell Scientific Publications, Oxford, 1990. 

---