Dissociation constant substituent effect

It is always important to keep in mind the relative nature of substituent effects. Thus, the effect of the chlorine atoms in the case of trichloroacetic acid is primarily to stabilize the dissociated anion. The acid is more highly dissociated than in the unsubstituted case because there is a more favorable energy difference between the parent acid and the anion. It is the energy differences, not the absolute energies, that determine the equilibrium constant for ionization. As we will discuss more fully in Chapter 4, there are other mechanisms by which substituents affect the energy of reactants and products. The detailed understanding of substituent effects will require that we separate polar effects fiom these other factors. 

It is of interest to consider the form of the Bronsted plot or Eigen plot to be expected for reaction of a series of related intramolecularly hydrogen-bonded acids with hydroxide ion by the mechanisms in Schemes 5 and 6. The effect of a substituent on the value of the dissociation constant of an intramolecularly hydrogen-bonded acid (8 log K) will be two-fold. The stability of the undissociated acid will be modified because of a substituent effect on the... 

Addition of a second crown produces the loose ion pair A, Cr,K, Cr. However, the complexation constant for adding the second crown is 1800 M 1 for the fluorenyl carbanion and only 200 M 1 for the picrate salt. The lower value for picrate may in part be due to less charge delocalization, e.g., the free ion dissociation constant for potassium fluorenyl in TEF is 1.6 x 10 7M (18) as compared to 9.2 x 10 M for potassium picrate (17). The two N02 substituents close to the 0 bond in picrate may also hinder the enlargement of this ionic bond and the insertion of a crown ether molecule because of electronic or sterlc effects. 

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. 

Beranek et ai.314 report a 600-fold enhancement in equilibrium constant for methoxide addition to pyridinium cations in 1 1 dimethyl sulfoxide-methanol relative to methanol. These workers have also measured the rates of dissociation of the methoxide adducts of N-phenylpyridinium cations (163) in dimethyl sulfoxide-methanol mixtures and have used the observation that the relative rates of dissociation appear to be independent of dimethyl sulfoxide content of the solvent to extrapolate these data to pure methanol. The rates of dissociation for all substituents other than X = 3-N02 or 4-NOz are too rapid in 100% methanol to allow direct determination by stopped-flow spectrophotometry. The presence of dimethyl sulfoxide shifts the equilibrium toward the adduct both by enhancing the rate of methoxide addition and by decreasing the rate of adduct dissociation. These solvent effects on pseudobase formation are similar to those observed... 

The overall effect of the radicals of the substituents can be a essed by comparing the dissociation constants of the corr ponding substituted acids data on the degree of substitution of various cdlulose esters prepared by the trans-esterihcation reaction are presented in Table 11. 

J This polarization along aliphatic chains forms the only explanation of the dissociation constants of organic acids, in particular of the effect of substituents, and must also, according to N. Bjerrum Zeitschr. f. phys. Chemie 106, 220 (1923)), be taken into account in the theoretical explanation of the dissociation constants of poly basic acids. Quantitative limits to the magnitude of this effect may be obtained by experimenting with different solvents (L. Ebert, Ber. d. dtsch. chem. Ges., 175 (1925)) for short chains its value is fgund to be considerable. 

Dissociation constants of heteroannularly disubstituted ferrocenoic acids have been employed as a means of measuring the effect of a substituent in one ring on the electron distribution in the other. One would expect those substituents which withdraw electron density to stabilize the anion formed on ionization, thereby increasing the acidity of the substituted ferrocenoic acid. This is indeed the result observed by Nesmeyanov and Reutov 52). Over a decade ago these authors found that T-acetylferrocenoic acid was 2.4 times as strong an acid as ferrocenoic acid itself, whereas the latter is 3.3 times stronger than T-ethylferrocenoic acid. 

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) ... 

Phosphorus electronic constants or are electronic substituent constants derived from the dissociation constants of dialkylphosphinic acids for substituent groups directly bonded to a phosphorus atom [Mastryukova and Kabachnik, 1971]. Assuming the alkyl groups exert only an inductive effect, these electronic constants can be distinguished as Oy inductive constant and o resonance constant [Charton and Charton, 1978]. 

The relationship in equation 72 indicates that the enthalpic and the entropic contributions to the substituent effect are not independent. Therefore, the assumption that "Og and Og are independent substituent constants accounting for the enthalpic and entropic contributions (22) is not valid. However, for the separation of these contributions, this assumption is not needed, since the enthalpic and entropic contributions to the free energy of dissociation can be obtained experimentally in an independent fashion. In fact, the relationship between the enthalpic and the entropic contributions on one hand with the inductive and resonance effects (which are assumed to be independent) on the other hand can be obtained only by using the relationship between enthalpic and entropic contributions. 

Charton made use of the dissociation constants of the readily available substituted acetic acids (Equation 22) stable for a wide range of X-substituents. There are negligible resonance and steric components to the transmission of the polar effect to the reaction centre in the equilibrium of Equation (22) and the pXg values fit Equation (23). The Gj value may be determined according to Equation (23) obtained from the dissociation which is very accurately documented for a very large number and variety of X-substituents and pj = 3.95. Other equilibria and rates (such as in Equations 17, 19 and 21) may be used as secondary standards to define Gj on the basis of Equation (23). 

The literature on proton binding by humic substances indicates that statistical effects, delocalization effects, and, probably most importantly, the effects of dipolar groups on the acidity of a functional group have generally been ignored. An attempt has been made in this chapter to provide the reader with a rather detailed discussion of the nature of substituent effects on the dissociation constants of organic acids. Statistical, electrostatic, and delocalization effects have been treated separately. 

---