Proton acidities substituent effects

Several theories have been proposed to account for substituent-induced changes in the acidities of organic acids. Substituent effects are most clearly illustrated in a symmetrical proton tr sfer reaction such as... 

Orientation in azole rings containing three or four heteroatoms Effect of azole ring structure and of substituents Proton acids on neutral azoles basicity of azoles Proton acids on azole anions acidity of azoles Metal ions... 

In the El cb mechanism, the direction of elimination is governed by the kinetic acidity of the individual p protons, which, in turn, is determined by the polar and resonance effects of nearby substituents and by the degree of steric hindrance to approach of base to the proton. Alkyl substituents will tend to retard proton abstraction both electronically and sterically. Preferential proton abstraction from less substituted positions leads to the formation of the less substituted alkene. This regiochemistry is opposite to that of the El reaction. 

The 1,3-xylyl trick was also used for the incorporation of phenols into crown ethers. Three classes of phenols [46a]-[46c] have been investigated. They differ by their substituents in the 4-position. In Table 22 the pX a values of different macrocyclic phenols [46a]-[46c] are compared. The data obtained for the phenol-containing crowns [46a] and [46b] show very little evidence for a macrocyclic effect. No extra stabilization of the protonated (acidic) form by a macrocycle of appropriate ring size was found. The acidities of the macrocyclic phenols [46a] and [46b] were independent of the ring size and comparable to non-macrocyclic analogues. However, the azo-substituted crowns [46c] showed a difference of 0.8 pACg units which was not expected from the pAfa values of [46a] and [46b]. TTiis different behaviour of [46c] is not yet understood. 

The maximum rate reported at very high acidity accords with protonation of the ester °. To summarise, the ester meehanism has gained general acceptance, although the substituent effects have yet to be explained wholly satisfactorily and the exact nature of the transition state, i.e. whether it is of considerable or only slight carbonyl character, remains a contentious issue ... 

The new treatment had its origins partly in ab initio molecular orbital calculations of substituent effects and partly in extensive studies of gas-phase proton transfer reactions from about 1980 (Section V.A). Various aspects of this work essentially drew attention to the importance of substituent polarizability. In 1986 Taft, Topsom and their colleagues252 developed a scale of directional substituent polarizability parameters , oa, by ab initio calculations of directional electrostatic polarization potentials at the 3-21G//3-31G level for a large set of CH3X molecules. The oa values were shown to be useful in the correlation analysis of gas-phase acidities of several series of substrates252, and such work has subsequently been extended by Taft and Topsom151. 

The accurate determination of gas-phase basicities and gas-phase acidities opened the way to analyses of the effect of solvation on proton acidities, and on hydrogen-bond acidities and basicities, as well as on substituents effects. 

The early experiments concerned with proton transfer from hydrogen-bonded acids did not provide information which permitted a choice between the two mechanisms (Kresge, 1973). These experiments included the measurement of kinetic isotope effects (Haslam et al., 1965b Eyring and Haslam, 1966 Haslam and Eyring, 1967), activation parameters (Haslam et ai, 1965a), the effect of different solvents (Jensen et al., 1966) and substituent effects in the intramolecularly hydrogen-bonded acid (Miles et al.,... 

Craze and Kirby (1974) have recently proposed that hydrolysis of methoxymethoxybenzoic acids proceeds with intramolecular general acid catalysis with little proton transfer from the carboxyl group and aleurge amount of bond breaking in the transition state. This suggestion was, however, based solely on substituent effects and a graphical analysis using the extended 4-parameter Hammett Equation (see Section 2). 

Further evidence for nitrogen as the site of protonation of amides in largely aqueous acid comes from studies of substituent effects on the p/Sfa Value of benzamide (Edward et al., 1960 Yates and Stevens, 1965). It has been observed that the pi g-values are correlated with a-constants of the substituents, rather than with o. This means that the structure of the dominant form of the cation is N-protonated as in [112], because resonance interactions of para-substituents in this kind of cation are similar to those in benzoic acid. The p-value (0 92)... 

The study of the relationships between the acidity (N—H) and the basicity ( N ) of azoles has shown that both properties display essentially the same sensitivity to substituent effects (58JA148 69JOC3315). Analogous behavior has been reported for tetrazoles (81KGS559), and, more generally, for all azoles protonated on a pyridine nitrogen (80BSF30). 

The reported 2 e reductive cleavage of phenylsulphonylacetonitrile (PhSO CH CN) and the observation that in protic media the products were PhSO and CH CN, suggested that this reaction could be a useful source of CHjCN. However, careful re-examination showed that in acetonitrile solution the reaction is pseudo one-electron, analogous to the phosphonium and sulphonium salts (Scheme 8), and that phenylsulphonylacetonitrile is sufficiently acidic rapidly to protonate "CHjCN assuming additivity of substituent effects an estimate of pK 14-16 was made for PhSOjCHjCN, cf. pK 31 for CH,CN... 

Substituent effects on the acidity of pyridinium ions46,47 have been extensively studied in order to learn about the ability of a hetero-aromatic ring to transmit electronic effects and to determine how and to what extent substituents influence the protonation of an annular nitrogen atom. No other series of heteroaromatic compounds has been studied as carefully and as thoroughly as these model compounds. Yet, interpretations are far from being universally accepted. Single-parameter Hammett treatments will be considered before dual-substituent parameter (DSP) approaches. 

Substituent effects on the A,u I reaction have been studied by Bender and Chen55. These authors measured the rates of hydrolysis of a series of 4-substituted 2,6-dimethylbenzoates in 9.70 M sulphuric acid at 25°C, and found that the values for the first-order coefficients with 4-methoxy, 4-methyl, 4-unsubstituted and 4-bromo-compounds (5.0, 0.37, 0.033 and 0.01 x I0 4 sec-1, respectively) are satisfactorily correlated by the Hammett equation, following cr+ with a slope p = —3.22. Since the esters are not fully protonated in 9.70 M H2SOj, part of this factor is due to the effects of the 4-substituent on the protonation equilibrium, p for the protonation of substituted benzoic acids is about — l35, but is likely to be considerably smaller for di-ortho-substituted compounds, since the conjugative interaction of the p-substituents with the protonated carboxyl group requires coplanarity with the ring. 

---