Dissociation constant evaluation

The CIP dissociation constants evaluated according to Eq. (6) are listed in Table V for some typical charge-transfer salts in t oth polar and nonpolar solvents. The values of Kop measured conductometrically (39) for the related ionic salts PPN+ Co(CO)4, PPN+ V(CO)6", and Na+ BPh4 are included in Table V for comparison. Two features in Table V are particularly noteworthy. First, the magnitudes of Aqp in the nonpolar solvents (THF and CH2C12) are smaller by at least a factor of 100 compared with those in the polar MeCN. Thus, at the concentrations employed in the IR... 

To evaluate the dissociation constants it would be necessary to measure the equDibrium constant for the reaction in Scheme 4. The dissociation of thiazolecarboxylic acids has been studied principally by Erlenmeyer et al. (47, 48). It seems that no systematic and reliable determination of the acidity dissociation constants have been realized until now. 

This dependence of pHi n on the rate constants as well as the dissociation constant has sometimes been overlooked by authors evaluating log A -pH curves, and the literature contains examples of such plots that have been erroneously used to estimate p/c . 

The dissociation constant is most accurately estimated from kinetic data when all of the data points are used in the evaluation. There are several ways to do this. The Henderson-Hasselbalch equation... 

Another approach to evaluating cri was taken by Roberts and Moreland,who defined inductive substituent constants in terms of the acid dissociation constants of 4-substituted bicyclof2.2.2]octane-l-carboxylic acids, 3. 

The forces that stabilize quaternary structure have been evaluated for a few proteins. Typical dissociation constants for simple two-subunit associations... 

Reference must be made to textbooks of physical chemistry (see Bibliography, Section 3.39) for details of the methods used to evaluate true dissociation constants of acids. 

It is worth mentioning that an attempt was made by Tsao and Willmarth to determine the acid dissociation constant of HO2. The reaction between hydrogen peroxide and peroxydisulphate was used for the generation of the HO2 radical. However, these experiments, like others where the HO2 radical is studied under steady-state conditions, could yield only a value of acidity constant multiplied by a coefficient consisting of a ratio of kinetic parameters. Unfortunately, in this case there are no independent data for the kinetic coefficient, and the value of cannot be evaluated. Considering the kinetic analogue of the titration curve it can be stated only that ionization of HO2 becomes important in the pH range from 4.5-6.5. The value of acidity constant of HO2 obtained by Czapski and Dorfman is (3.5 + 2.0)x 10 mole.l. . ... 

In this chapter, the voltammetric study of local anesthetics (procaine and related compounds) [14—16], antihistamines (doxylamine and related compounds) [17,22], and uncouplers (2,4-dinitrophenol and related compounds) [18] at nitrobenzene (NB]Uwater (W) and 1,2-dichloroethane (DCE)-water (W) interfaces is discussed. Potential step voltammetry (chronoamperometry) or normal pulse voltammetry (NPV) and potential sweep voltammetry or cyclic voltammetry (CV) have been employed. Theoretical equations of the half-wave potential vs. pH diagram are derived and applied to interpret the midpoint potential or half-wave potential vs. pH plots to evaluate physicochemical properties, including the partition coefficients and dissociation constants of the drugs. Voltammetric study of the kinetics of protonation of base (procaine) in aqueous solution is also discussed. Finally, application to structure-activity relationship and mode of action study will be discussed briefly. 

As the acid content within the GI tract is known to change as the body ages, it is also important to evaluate the dissociation constant(s) (Ka) of the drug(s) to be used. From the Henderson-Hasselbach equation of weak acids ... 

In this chapter we described the thermodynamics of enzyme-inhibitor interactions and defined three potential modes of reversible binding of inhibitors to enzyme molecules. Competitive inhibitors bind to the free enzyme form in direct competition with substrate molecules. Noncompetitive inhibitors bind to both the free enzyme and to the ES complex or subsequent enzyme forms that are populated during catalysis. Uncompetitive inhibitors bind exclusively to the ES complex or to subsequent enzyme forms. We saw that one can distinguish among these inhibition modes by their effects on the apparent values of the steady state kinetic parameters Umax, Km, and VmdX/KM. We further saw that for bisubstrate reactions, the inhibition modality depends on the reaction mechanism used by the enzyme. Finally, we described how one may use the dissociation constant for inhibition (Kh o.K or both) to best evaluate the relative affinity of different inhibitors for ones target enzyme, and thus drive compound optimization through medicinal chemistry efforts. 

By plotting the measured rate constant versus the undissociated acid concentration, one obtains for this type of catalysis a straight line with intercept kx and slope ax = (/cHA + kA-/q). If the procedure is repeated for other ratios, enough information is obtained to permit evaluation of /cHA and kA-. The hydrogen and hydroxide ion concentrations corresponding to a given ratio q may be determined from equation 7.3.12 and the dissociation constant for water. 

In a series of papers (Cohen and Lach, 1963 Lach and Cohen, 1963 Lach and Chin, 1964a,b Pauli and Lach, 1965 Lach and Pauli, 1966), Lach and co-workers used a similar technique to evaluate the effect of the cycloamyloses on the solubilities of a variety of pharmaceuticals. Plots of the solubility of the pharmaceutical against the concentration of added cycloamylose were usually linear with slopes ranging from 0 to 2.25. In theory, these slopes can be related to the dissociation constants for the cycloamylose-substrate complexes if the stoichiometries of the complexes can be determined (Thoma and Stewart, 1965). This technique, however, is inferior to the spectrophotometric method to be discussed presently. 

From scheme I, together with the experimentally observed first-order dependence on the total ester concentration, the rate relationship illustrated in Eq. (1) may be derived. In applying this equation, the cycloamylose concentration must be at least tenfold greater than the initial substrate concentration to ensure first-order conditions. Equation (1) may be rearranged in two ways to yield linear forms which permit graphical evaluation of fa, the maximal rate constant for release of phenol from the fully com-plexed ester and Kd, the cycloamylose-substrate dissociation constant (defined in Scheme I as A i/fa). These two methods are illustrated in Eqs. (2) and (3) and may be attributed to Lineweaver and Burk (1934) and to Eadie (1942), respectively. Although in theory both methods should give... 

In summary, the physical-chemical and environmental fate data listed result in the tabulated selected values of solubility, vapor pressure, Kow, dissociation constant where appropriate and reaction half-lives at the end of each chapter. These values are used in the evaluative environmental calculations. 

It is convenient to evaluate a4, which may be done by substituting into equation (5.11) from expressions for the dissociation constants Kv K2, K3, K4... 

The marked changes in the carbonyl IR bands accompanying the solvent variation from tetrahydrofuran to MeCN coincide with the pronounced differences in colour of the solutions. For example, the charge-transfer salt Q+ Co(CO)F is coloured intensely violet in tetrahydrofuran but imperceptibly orange in MeCN at the same concentration. The quantitative effects of such a solvatochromism are indicated by (a) the shifts in the absorption maxima and (b) the diminution in the absorbances at ACT. The concomitant bathochromic shift and hyperchromic increase in the charge-transfer bands follow the sizeable decrease in solvent polarity from acetonitrile to tetrahydrofuran as evaluated by the dielectric constants D = 37.5 and 7.6, respectively (Reichardt, 1988). The same but even more pronounced trend is apparent in passing from butyronitrile, dichloromethane to diethyl ether with D = 26, 9.1 and 4.3, respectively. The marked variation in ACT with solvent polarity parallels the behaviour of the carbonyl IR bands vide supra), and the solvatochromism is thus readily ascribed to the same displacement of the CIP equilibrium (13) and its associated charge-transfer band. As such, the reversible equilibrium between CIP and SSIP is described by (14), where the dissociation constant Kcip applies to a... 

Conventional absorptiometric and fluorimetric pH indicators show a shift of band positions in absorption and emission spectra between the protonated and deprotonated forms. This feature allows the spectroscopic measurement of the acid dissociation constant in the ground state, Ka, and also the evaluation of the dissociation constant in the excited state, Ka (Eq. (5.5)), from the Forster cycle under the assumption of equivalent entropies of reaction in the two states.<109 112)... 

While this model explained the action of the brain enzyme on a number of hexose substrates and nonsubstrate inhibitory analogs, the mode had its weaknesses. It assumed that the other conformations of a hexose that are in equilibrium with the active conformer act as competitive inhibitors relative to this conformer. One cannot evaluate the effect of a competitive inhibitor which is present in a constant proportion relative to the active substrate by initial velocity measurements. Moreover, the use of apparent Michaelis constants may not provide accurate estimates of affinity, which is more directly related to a dissociation constant. The chief limitation of the model, however, is that an equally great number of experimental facts can be satisfactorily explained in terms of a simpler scheme involving the binding and phosphorylation of the Cl conformer. Furthermore, one can understand more directly how the enzyme can phosphorylate glucopyranose and fructofuranose equally well. 

Reaction conditions permitting a catalyst to pass through many catalytic rounds. Multiple-turnover conditions are usually obtained by maintaining the substrate concentration in excess over the concentration of active catalyst. This technique usually allows one the opportunity to evaluate the catalytic rate constant ka,t, which is the first-order decay rate constant for the rate-determining step for each cycle of catalysis, and one can evaluate the magnitude of other parameters such as the substrate s dissociation constant or Michaehs constant. 

Evaluating the magnitude of dissociation constants of products can provide useful information on enzyme interactions of products. In most cases, these values are true dissociation constants, not Michaehs constants. Initial rate studies of the reverse reaction will provide values and enable one to compare and An, values. This can aid in identifying key rate constants or steps in the reaction scheme. 

While the latter measurements, strictly speaking, evaluate the state of dissociation of the initiator ions only, they also provide at least a guide as to the degree of dissociation of the propagating polymeric ion pairs. In the case of vinyl polymerisations, where no living cations have been observed to date, direct evaluation of the dissociation constant Kd, of the growing ion pair is not possible. However, in a number of cyclic monomer polymerisations living characteristics are observed, and direct measurements have been possible (27). 

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