Dissociation constant benzoic acid derivatives

The ionization of monoprotic acids and bases and hence their solubility and absorption is dependent on their pK, the pH at which the drug is 50% ionized. First developed by Hammett and published in 1940, the relation between the dissociation constants of benzoic acid derivatives and the longer range electronic (inductive, mesomeric and field) effects is linear and additive. 

The earliest and best known relationship was devised by Hammett [2] and is based on such an equilibrium, namely the dissociation constants of nuclear substituted benzoic acids. Hammett substituent constants a are given by Equation (8), where Kq represents the dissociation constant for benzoic acid and K represents the dissociation constant for a derivative of benzoic acid substituted by the group to which the substituent constant belongs. 

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. 

The influence of NH., and CO, on the chromatographic behaviour of benzoic acid and its derivatives (o-, m-, p-hydroxybenzoic, nitrobenzoic, aminobenzoic, chlorobenzoic acids) was studied. The work was carried out by means of upgoing TLC on Sorbfil plates. Isopropanol- and ethyl acetate-containing water-organic eluents were used as mobile phases in the absence or presence of gaseous modifiers in the MP. The novel modification of TLC has been found to separate benzoic acids with different values of their dissociation constants more effectively than water-organic mobile phases. 

A significant contribution to the uncertainty interval assigned to the O-H bond dissociation enthalpy in benzoic acid comes from the estimate of the activation enthalpy for the radical recombination. The experimental determination of this quantity is not easy because diffusion-controlled recombination rate constants are very high (109 mol-1 dm3 s 1 or larger) [180]. Therefore, most thermochemical data derived from kinetic experiments in solution rely on some similar assumptions. 

The DSP approach nicely answers the controversial question about which substituent parameters should be employed to correlate pKa data for 4-substituted pyridinium ions. Statistically, the best correlation is given by Eq. (9), which has values to measure the resonance contribution of a substituent, a result in keeping with chemical intuition. This correlation is statistically superior to a Hammett treatment, where both resonance and inductive effects of a group are combined into a single parameter, p or ap.53,54 Moreover, now it is possible to rationalize why a simple Hammett treatment using ap works so well. Equation (9) reveals that the protonation equilibrium is much more sensitive to an inductive effect (p, — 5.15) than to a resonance effect (p = 2.69). Hence, substituent parameters, such as erp, which are derived from a consideration of the dissociation constants for benzoic acids where resonance contributions are small serve as a useful approximation. The inductive effect is said to have a larger influence on pKa values for pyridinium ions than for benzoic acids because the distance between the substituent and the reactive site is shorter in the pyridine series.53... 

The alternative approach is the attempt to quantify substituent effects, and this has been most successfully done by the Hammett equation and its various extensions (Hammett, 1970). Here one set of free energy data is compared with another set. One set is taken as standard (originally the dissociation constants of benzoic acids) and other rate or equilibrium data are compared (by logarithmic plots). So much has been written about this treatment that discussion here is unnecessary. Absolute values of a (the substituent constant) are not to be expected, in fact one would expect a different a for every reaction (i.e. for every p). In the present context it is important to note that both the Hammett equation and the closely related Taft treatment are based on systems where solvation is known to be important and therefore the application of these treatments using parameters derived from solution phase studies to reactions in the gas phase may be of uncertain value. 

The original Hammett substituent constants [Hammett, 1937 Hammett, 1970] measuring the overall electronic effect of the meta- and paro-substituents of benzene derivatives having the functional group in the side chain. They were originally calculated from the variation of the acid dissociation constant of substituted benzoic acids (m-, P-XC6H4COOH) in water at 25°C, with respect to the unsubstituted compound (i.e. benzoic acid) ... 

Inversion of hindered alcohols. In the Mitsunobu reaction a positive relationship between dissociation constant of the acid component (nucleophile) with reaction efficiency is indicated. Product yields are higher when using acids of lower pK . Among substituted benzoic acids, 4-nitro, 4-methanesulfonyl, and 4-cyano derivatives give better results. 

A. Hammett Substitution Constant (o). It is a measure of either the electron-withdrawing or electron-donating capability of a substituent i.e., the functional moiety). Hammet substitution constant may be determined conveniently by actual measurement of the dissociation of a series of benzoic acid substituted derivatives vis-a-vis the dissociation of pure benzoic acid itself. 

In 1934 Saxton and Meier [1] published a report in which they described measurements of the acid dissociation constants of benzoic acid and its three monochloro derivatives. The results showed an interesting pattern all of the chloro-derivatives were more acidic than the parent compound, with the ortlio-substituted compound most acidic and the meta-chloro derivative least acidic. However, the authors closed their report with the lament that at present, there is no adequate theoretical method of calculating the ionization of a weak electrolyte from its structure. ... 

The concept of Hammett substituent constants is based on his observation that there were simple quantitative relationships when two series of equilibrium constants were compared. Thus for example, a good linear plot can be obtained when the logarithms of the dissociation constants of m- and p-substituted phe-noxyacetic acids are plotted against the logarithms of the dissociation constants of the corresponding substituted benzoic acids (Figure 5.1). He derived equation... 

Kq is the dissociation constant of benzoic acid and that of the p-substituted derivative. is the resonance substituent constant and is a measure of the resonance effect of the group it represents. It has been shown [15] by measurements on 46 substituted benzoic acids, that the resonance effect of a p-group, determined as (Up-aj) is on average three times that of the same group in the m-position (o, -aj), which leads to Equation (14). Combination of equations... 

Acidity and Basicity Measurements. Nishiguchi and Iwakura have determined the Hammett and o- values of the 3-ethylthioureido, 3-ethylureido, thioacetamido, acetamido, methylaminothiocarbonyl, and methylaminocarbonyl groups by measuring the dissociation constants of the relevant meta and pam-substituted benzoic acids. The investigators, on the basis of a comparison of the subsequently derived ai and on values... 

Fig. 2. Derivation of the Hammett equation for the linear correlation of logarithm of rate constant for ester hydrolysis and logarithm of acidity constant of benzoic acids with equivalent substitution. This equation is thus a linear correlation of the free activation energy for hydrolysis with the free energy of add dissociation.

Based on a large experimental material, L. Hammett in 1937 proposed the known prate constant of the reaction of an aromatic compound to the dissociation constant of the corresponding benzoic acid. A year later, M. Evans and M. Polanyi derived the empirical correlation A = oAH for the reaction of sodium atoms with alkyl halides. In 1954 N. N. Semenov considered and showed the applicability of this correlation to many reaction of radical abstraction. Simultaneously (1952-1953) R. Taft advanced a postulate about the additive influence of structural factors. A diverse experimental material on various reactions of aromatic and aliphatic compounds and application of the Hammett, Taft, and Polanyi-Semenov equations to them was obtained in fifties-seventies. 

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