Dissociation constant compounds

Hammen equation A correlation between the structure and reactivity in the side chain derivatives of aromatic compounds. Its derivation follows from many comparisons between rate constants for various reactions and the equilibrium constants for other reactions, or other functions of molecules which can be measured (e g. the i.r. carbonyl group stretching frequency). For example the dissociation constants of a series of para substituted (O2N —, MeO —, Cl —, etc.) benzoic acids correlate with the rate constant k for the alkaline hydrolysis of para substituted benzyl chlorides. If log Kq is plotted against log k, the data fall on a straight line. Similar results are obtained for meta substituted derivatives but not for orthosubstituted derivatives. 

Determination of the dissociation constants of acids and bases from the change of absorption spectra with pH. The spectrochemical method is particularly valuable for very weak bases, such as aromatic hydrocarbons and carbonyl compounds which require high concentrations of strong mineral acid in order to be converted into the conjugate acid to a measurable extent. 

Table 1 6 VSEPR and Molecular Geometry Table 1 7 Dissociation Constants (pK ) of Acids Table 2 5 Oxidation Numbers in Compounds with More Than One Carbon...

The compound is odorless with a faintly acidic taste it is practically insoluble in water, ethanol and dilute acids but freely soluble in dilute aqueous alkaU with dissociation constants, pfC, 3.73, 7.9, 9.3. The compound is prepared by sodium hydrosulfite reduction of 3-nitro-4-hydroxyphenylarsonic acid [121 -19-7] and then acetylation in aqueous suspension with acetic anhydride at 50—55°C for 2 h (174,175). 

Amino-2-hydroxybenZOiC acid. This derivative (18) more commonly known as 4-aminosa1icy1ic acid, forms white crystals from ethanol, melts with effervescence and darkens on exposure to light and air. A reddish-brown crystalline powder is obtained on recrystallization from ethanol —diethyl ether. The compound is soluble ia dilute solutioas of nitric acid and sodium hydroxide, ethanol, and acetone slightly soluble in water and diethyl ether and virtually insoluble in benzene, chloroform or carbon tetrachloride. It is unstable in aqueous solution and decarboxylates to form 3-amiaophenol. Because of the instabihty of the free acid, it is usually prepared as the hydrochloride salt, mp 224 °C (dec), dissociation constant p 3.25. 

Hydroxyacetanilide. This derivative (21), also known as 4-acetamidophenol, acetaminophen, or paracetamol, forms large white monoclinic prisms from water. The compound is odorless and has a bitter taste. 4-Hydroxyacetani1 ide is insoluble in petroleum ether, pentane, and ben2ene slightly soluble in diethyl ether and cold water and soluble in hot water, alcohols, dimethylformamide, 1,2-dichloroethane, acetone, and ethyl acetate. The dissociation constant, pfC, is 9.5 (25°C). 

Alternatively, instabiUty or dissociation constants are sometimes used to describe compounds, and caution is necessary when comparing values from different sources. 

Analogous plots for many other reactions of aromatic compounds show a similar linear correlation with the acid dissociation constants of the corresponding benzoic acids. 

Hydrogen cyanide, mp —13.3° bp 25.7°, is an extremely poisonous compound of very high dielectric constant (p. 55). It is miscible with H2O, EtOH and Et20. In aqueous solution it is an even weaker acid than HE, the dissociation constant Ka being 7.2 x 10 ° at 25°C. It was formerly produced industrially by acidifying NaCN or Ca(CN)2 but the most modem catalytic processes are based on direct reaction between... 

A determination of the dissociation constants of the compounds reveals that 5-azauracil (pi a = 6.73) is practically of the same acidity as 6-azauracil and considerably more acidic than uracil, A fundamental difference between 5-azauracil, on the one hand, and 6-azauracil and uracil, on the other, lies in the low stability of 5-azauracil toward acid and especially to alkaline hydrolysis. This fact appears to be in agreement with the differences in electron densities of these substances computed by the simple MO-LCAO method. ... 

The course of alkylations of 6-azauracil is in good agreement with the results of determination of the dissociation constants of 6-azauracil and of its two monomethyl derivatives. On the assumption that a methyl group does not much affect the dissociation constant, and on the basis of the lactam structure, it may be concluded from the values of the dissociation constants iKa of 6-azauracil = 7.00, of l-methyl-6-azauracil = 6.99, and of 3-methyl-6-azauracil = 9.52) that dissociation takes first place at the NH group in position 3. The same results are obtained independently by comparing the pH dependence of the XJV spectra of these compounds. These results represent an exact confirmation of the older observation by Cattelain that the monoalkyl derivatives of 6-substituted dioxotriazines possess different acidity. 

It was found already by Cattelain that the 3-thioxo derivatives behave as monobasic acids that can be titrated on phenolphthalein and he considered them as more acid than the analogous 3,5-dioxo-triazines. This assumption was recently confirmed by determining the dissociation constants. Just as with 6-azauracil, it was possible to demonstrate, by comparing the dissociation constants of the V-methyl derivatives of all the thioxo analogs, that with the 3-thioxo compounds too, dissociation proceeds first at the NH group in position 3 122... 

The determination of pi a values is probably the most generally useful method for the investigation of tautomerism. This method was first employed in the heterocyclic field in the early 1950 s by Tucker and Irvin and by Angyal and Angyal. There are two empirical dissociation constants, and K2, for the conjugate acid (HXH+) of a tautomeric compound. Constants Kt and K2 are, in effect, a summation of the true dissociation constants Ka, Kb, Kc, and Kd of the individual tautomeric forms (see scheme 43, where XH and HX are tautomers) and the tautomeric constant, Kt] these constants are related by the following equations ... 

Attempts have been made to deduce the structure of the predominant form of a potentially tautomeric compound from the shifts which occur in the ultraviolet spectrum of the compound in question on passing from neutral to basic or acidic solutions. The fact that no bathochromic shifts were observed for 2- and 4-hydroxy quinoline and 1-hydroxyisoquinoline under these conditions was taken as evidence that they existed in the oxo form [similar work on substituted quinol-4-ones led to no definite conclusions ]. A knowledge of the dissociation constants is essential to studies of this type, and the conclusions can, in any case, be only very tentative. A further dif-... 

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

Separate experiments on the iodine-catalysed bromination of these compounds revealed a rate maximum at [I2]/[Br2] = 0.35, from which it follows that the concentrations of molecular bromine and iodine monobromide are equal, i.e. the latter catalyses bond-breaking in the former in the intermediate. Since iodine monobromide is dissociated into iodine and bromine, dissociation constant K, [Br2]VAT is proportional to [IBr] and hence equation (152) may be rewritten in the form... 

A final point to bear in mind is that, when a reaction involves fully dissociated ionic compounds in solution, then the equilibrium constant should be written for the net ionic equation, by using the activity for each type of ion. 

From Table III we see that the difference between the free radical resonance energies of tribiphenylmethyl and triphenylmethyl is 0.07a. Hence X]/X2 = 37 = 2.2 X103. Ziegler and Ewald8 found that at 20°C the value of the dissociation constant for hexaphenylethane in benzene solution is 4.1 X10-4 and consequently we calculate for hexabiphenylethane a value of X = 2.2X103 X4.1 X 10 4 = 0.90. This value is probably too low as the compound is reported to be completely dissociated the error may not be large, however, since a dissociation constant of 0.90 would lead to 91 percent dissociation in 0.05M solution. 

The inactivation is normally a first-order process, provided that the inhibitor is in large excess over the enzyme and is not depleted by spontaneous or enzyme-catalyzed side-reactions. The observed rate-constant for loss of activity in the presence of inhibitor at concentration [I] follows Michaelis-Menten kinetics and is given by kj(obs) = ki(max) [I]/(Ki + [1]), where Kj is the dissociation constant of an initially formed, non-covalent, enzyme-inhibitor complex which is converted into the covalent reaction product with the rate constant kj(max). For rapidly reacting inhibitors, it may not be possible to work at inhibitor concentrations near Kj. In this case, only the second-order rate-constant kj(max)/Kj can be obtained from the experiment. Evidence for a reaction of the inhibitor at the active site can be obtained from protection experiments with substrate [S] or a reversible, competitive inhibitor [I(rev)]. In the presence of these compounds, the inactivation rate Kj(obs) should be diminished by an increase of Kj by the factor (1 + [S]/K, ) or (1 + [I(rev)]/I (rev)). From the dependence of kj(obs) on the inhibitor concentration [I] in the presence of a protecting agent, it may sometimes be possible to determine Kj for inhibitors that react too rapidly in the accessible range of concentration. ... 

Binding assays for the saxitoxins were conducted with homogenized rabbit brain and saxitoxin exchange-labelled with tritium at C-11 (92, 93). If the various saxitoxins were available with suitably intense radiolabels, then the equilibrium dissociation constant, K, could be measured directly for each. Since only saxitoxin is currently available with the necessary label, the binding experiments instead measure the ability of a compound to compete with radiolabelled saxitoxin for the binding site. The value obtained, Kj, corresponds to the uilibrium dissociation constant, K, that would be observed for the compound if it were measured directly. Affinity is defined for this assay as the reciprocal of Kj. The affinities of several of the saxitoxins (94) are summarized in Figure 11, expressed relative to saxitoxin and plotted on a logarithmic scale. 

Figure 15. Data from single channel experiments, plotted to show the relationship between kinetic and equilibrium parameters for several of the saxitoxins, tetrodotoxin, and Conus geographus toxin GIIIA. Compound numbering corresponds to that in Figure 1. The vertical axis is and the horizontal axis is dwell time, the reciprocal of k j. The dissociation constant, the ratio of k jj/k, therefore corresponds to distance along the diagonal. Data primarily from Ref. 95.

Figure 17.8 Comparison of the antagonist potencies of some neuroleptics on different NT receptors. Data are shown for haloperidol (HAL), chlorpromazine (CPZ), clozapine (CLOZ) and risperidone (RISP) acting on dopamine Dj and D2, 5-HT2 (S2), alpha (0(2) adrenoceptors and cholinergic muscarinic receptors (M). The height of each column shows an average of the dissociation constants obtained from a number of publications (see Seeman 1990). The values, which can vary some fiftyfold, are expressed as the negative logarithms (i.e. 9 = 10 M,lnM) so that the higher the column, the more potent the compound. The order of potency of the four compounds at each receptor is shown alongside...

From these equations it is possible to predict the effective lipophilicity (log D) of an acidic or basic compound at any pH value. The data required in order to use the relationship in this way are the intrinsic lipophilicity (log P), the dissociation constant (pKa) and the pH of the aqueous phase. The overaU effect of these relahonships is the effechve hpophilicity of a compound, at physiological pH, is approximately the log P value minus one unit of hpophilicity, for every unit of pH the pKa value is below (for acids) and above (for bases) pH 7.4. Obviously for compounds with mul-hfunchonal ionizable groups the relahonship between log P and log D, as weU as log D as a function of pH become more complex [65, 68, 70]. For diprotic molecules there are already 12 different possible shapes of log D-pH plots. 

Tam, K. Y. Multiwavelength spectrophotometric determination of add dissociation constants. Part VI. Deconvolution of binary mixtures of ionizable compounds. Anal. Lett. 2000, 33, 145-161. 

The following physico-chemical properties of the analyte(s) are important in method development considerations vapor pressure, ultraviolet (UV) absorption spectrum, solubility in water and in solvents, dissociation constant(s), n-octanol/water partition coefficient, stability vs hydrolysis and possible thermal, photo- or chemical degradation. These valuable data enable the analytical chemist to develop the most promising analytical approach, drawing from the literature and from his or her experience with related analytical problems, as exemplified below. Gas chromatography (GC) methods, for example, require a measurable vapor pressure and a certain thermal stability as the analytes move as vaporized molecules within the mobile phase. On the other hand, compounds that have a high vapor pressure will require careful extract concentration by evaporation of volatile solvents. 

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. 

---