Ionization constants discussion

As examples of applications, we present the overall accuracy of predicted ionization constants for about 50 groups in 4 proteins, changes in the average charge of bovine pancreatic trypsin inhibitor at pH 7 along a molecular dynamics trajectory, and finally, we discuss some preliminary results obtained for protein kinases and protein phosphatases. 

The tautomeric equilibrium 151 152 has been discussed by Cromwell and David.Ultraviolet spectral data indicate that 151 predominates in neutral aqueous solution, and infrared data are in essential agreement. It was further concluded that in acid solution the equilibrium favors 152, but no ionization constants were reported,... 

For reasons discussed in Section VI, a survey of the purine series (29) is being made in this Department, but so far no example (including 2-hydroxy- and 8-trifluoromethyl-2-hydroxy-purine) of covalent hydration has come to light. An examination of ionization constants disclosed no apparent anomalies, although the interpretation is made more difficult by the ease of anion formation in the 9-position, which often competes with that from other anionic substituents. The only abnormal spectrum seems to be that of the anion of 2-mercaptopurine which is being further examined. 

None of the other reactions so far discussed involve interaction between a pair of charged species. This is but another instance of the electrostatic effect shown by Kirkwood and Westheimer to be responsible for the disparity between the first and second ionization constants of dibasic acids, for the effect of the carboxylate ion on the basicity of an a-amino acid, and for the difference in reactivity of ionic compounds compared with analogous nonionic species in acid- or base-catalyzed reactions. ... 

All equilibrium constants in the present discussion are based on the concentration (not activity) scale. This is a perfectly acceptable thermodynamic scale, provided the ionic strength of the solvent medium is kept fked at a reference level (therefore, sufficiently higher than the concentration of the species assayed). This is known as the constant ionic medium thermodynamic state. Most modern results are determined at 25 °C in a 0.15 M KCl solution. If the ionic strength is changed, the ionization constant may be affected. For example, at 25 °C and 0.0 M ionic strength, the pXj of acetic acid is 4.76, but at ionic strength 0.15 M, the value is 4.55 [24]. 

The link between UpophiUcity and point charges is given by intermolecular electrostatic interactions (Sections 12.1.1.2, 12.1.3 and 12.1.4 address this topic) and ionization constants. The mathematical relationships between Upophilicity descriptors and pKjS are discussed in detail in Chapter 3 by Alex Avdeef. Here, we recall how pKj values are related to the molecular electron flow by taking the difference between the pfCj of aromatic and aUphatic amines as an example. The pfCa of a basic compound depends on the equilibrium shown in Fig. 12.2(A). A chemical effect produces the stabilization or destabiUzation of one of the two forms, the free energy difference (AG) decreases or increases and, consequently. 

The book is organized into eight chapters. Chapter 1 describes the physicochemical needs of pharmaceutical research and development. Chapter 2 defines the flux model, based on Fick s laws of diffusion, in terms of solubility, permeability, and charge state (pH), and lays the foundation for the rest of the book. Chapter 3 covers the topic of ionization constants—how to measure pKa values accurately and quickly, and which methods to use. Bjerrum analysis is revealed as the secret weapon behind the most effective approaches. Chapter 4 discusses experimental... 

Hydroxy-2//-thiopyran as a pseudobase was determined by UV spectrophotometry and discussed with HMO calculations together with other heterocycles.287 Ionization constants of 2//-thiopyran 1,1-dioxides 484 (R = H R1 = Ph R2 = H, Me) were determined spectrophotometrically in H20 and MeOH at 25°C.4S8a... 

It is usual to discuss the ionization of a base B in terms of its conjugate acid BH+ in order to use the same set of equations for both acids and bases. The ionization constant Ka is defined by... 

Potentiometric titration is a commonly used technique determination (Albert and Serjeant, 1984). The PCA101 chemical analyzer, developed and manufactured by Sirius Analytical Instruments Ltd., is the rst commercial instrument designed specilly to determine ionization constants (Avdeef, 1993). The theory and applications of the method have been discussed byAvdeef (Avdeef, 1993), and the reader is directed to that excellent review for a detailed discussion. 

The discussion in the previous sections concerning solvated species indicates that a complete knowledge of the chemical reactions that take place in a system is not necessary in order to apply thermodynamics to that system, provided that the assumptions made are applied consistently. The application of thermodynamics to sulfuric acid in aqueous solution affords another illustration of this fact. We choose the reference state of sulfuric acid to be the infinitely dilute solution. However, because we know that sulfuric acid is dissociated in aqueous solution, we must express the chemical potential in terms of the dissociation products rather than the component (Sect. 8.15). Either we can assume that the only solute species present are hydrogen ion and sulfate ion (we choose to designate the acid species as hydrogen rather than hydronium ion), or we can take into account the weak character of the bisulfate ion and assume that the species are hydrogen ion, bisulfate ion, and sulfate ion. With the first assumption, the effect of the weakness of the bisulfate ion is contained in the mean activity coefficient of the sulfuric acid, whereas with the second assumption, the ionization constant of the bisulfate ion is involved indirectly. 

As mentioned by Tipson,10 the question arises as to whether ultraviolet absorption spectra of the type described112-114 can serve as proof for the positional assignment of the carbohydrate moiety on the pyrimidine ring of nucleosides. The increasing usage of spectrophotometry in the isolation, and in structural and enzymic studies, of nucleosides and nucleotides warrants a detailed consideration of this technique. The studies described above,112 114 for example, may be open to question (despite the fact that the conclusions were correct), since the pH of the curves selected was not predicated upon the ionization constants of the compounds under investigation. A series of comprehensive spectral studies of nucleosides of nucleic acids, their parent pyrimidines, and related compounds have been reported,87-110 and much of the following discussion is derived from them. 

In dilute aqueous solutions, the three halides, HC1, HBr, and HI, are essentially fully ionized, but in the poorer ionizing solvent, methanol, ionization is partial. In the latter solvent, HC1 is the most weakly ionized of the three whereas HI is the most strongly ionized this order of acidities has already been discussed (p. 90 see also Exercise 14). The ionization constant for hydrofluoric acid in dilute solutions is 7.2 X 10 4, but in very concentrated solutions the degree of ionization appears to rise sharply, a behavior opposite to that of almost all other weak electrolytes. This increase in acid strength is almost certainly due to the increase in concen-... 

In Chapter 4, the ionization constant (i.e., the reaction constant of dissolution) for weak acids and acid phosphates was defined. The concept of the ionization constant is very general and useful while discussing dissolution of sparsely soluble oxides in acid-base reactions. We assign the symbol K for this constant. 

Some ionizing solvents are of major importance in analytical chemistry whilst others are of peripheral interest. A useful subdivision is into protonic solvents such as water and the common acids, or non-protonic solvents which do not have protons available. Typical of the latter subgroup would be sulphur dioxide and bromine trifluoride. Non-protonic ionizing solvents have little application in chemical analysis and subsequent discussions will be restricted to protonic solvents. Ionizing solvents have one property in common, self-ionization, which reflects their ability to produce ionization of a solute some typical examples are given in table 3.2. Equilibrium constants for these reactions are known as self-ionization constants. 

These are only the theoretical dependencies real behavior of actual molecule usually is significantly altered due to different types of intermolecular interactions. Molecular solvation, association, hydrogen bonding, and counterions all have a significant effect on drug ionization constant and partitioning and distribution coefficients. Detailed and comprehensive discussion of these effects could be found in the book by Avdeef [22]. 

Methods for evaluating the microconstants are discussed in the paper by Martin et al. (1958), and by Edsall et al. (1958). Martin et al. (1958) found pfci2 = 9.63 0.02 (phenolic ionization constant for tyrosine carrying ammonium and carboxylate ions) and pkm = 10.04 0.03 (phenolic ionization constant for tyrosine carrying uncharged amino group and carboxylate ion), at 25°C and ionic strength 0.16. 

Some less reliable H bond interpretations of dissociation data have been made. For example, Dippy (526) proposed that a G—H- -O bond from 7 carbon to C=0 formed a ring in C4-Cg acids, to account for the fact that their ionization constants do not fall as rapidly as do those of C2 and Cs acids. A case in aromatic compounds is given by Arnold and Sprung (64). Some later work (907) makes use of the same idea to explain the Ka of a partially fluorinated valeric acid, (CF8(GH2)sGOOH). This scheme of H bonding hzis not been substantiated, and there is still controversy—the discussion at the end of one of Katch2ilsky s papers is illustrative (1089). 

In discussing the permanent polarization of single bonds we cannot help wondering how far along a carbon chain this factor exerts its influence. From an examination of the ionization constants of the aliphatic chloroacids we see (Table 2) that two methylene groups interposed between the carboxyl group and the carbon to which the chlorine atom is attached almost destroy the effect of the permanent polarization of the carbon-chlorine bond upon the carboxyl group. 

We have discussed strong acids and strong bases. There are relatively few of these. Weak acids are much more numerous than strong acids. For this reason you were asked to learn the list of common strong acids (see Table 18-1). You may assume that nearly all other acids you encounter in this text will be weak acids. Table 18-4 contains names, formulas, ionization constants, and pK values for a few common weak acids Appendix F contains a longer list of values. Weak acids ionize only slightly in dilute aqueous solution. Our classification of acids as strong or weak is based on the extent to which they ionize in dilute aqueous solution. 

Discuss the acidity of the aqueous Group VIA hydrides, including the relative values of acid ionization constants. What is primarily responsible for the order of increasing acidities in this series ... 

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