Linear free energy relationships substitution reactions

The applicability of the two-parameter equation and the constants devised by Brown to electrophilic aromatic substitutions was tested by plotting values of the partial rate factors for a reaction against the appropriate substituent constants. It was maintained that such comparisons yielded satisfactory linear correlations for the results of many electrophilic substitutions, the slopes of the correlations giving the values of the reaction constants. If the existence of linear free energy relationships in electrophilic aromatic substitutions were not in dispute, the above procedure would suffice, and the precision of the correlation would measure the usefulness of the p+cr+ equation. However, a point at issue was whether the effect of a substituent could be represented by a constant, or whether its nature depended on the specific reaction. To investigate the effect of a particular substituent in different reactions, the values for the various reactions of the logarithms of the partial rate factors for the substituent were plotted against the p+ values of the reactions. This procedure should show more readily whether the effect of a substituent depends on the reaction, in which case deviations from a hnear relationship would occur. It was concluded that any variation in substituent effects was random, and not a function of electron demand by the electrophile. ... 

Quite early on (p. 361) in this discussion of linear free energy relationships consideration was restricted to the side-chain reactions of m- and p-substituted benzene derivatives. The reactions of o-substituted benzene derivatives, and indeed of aliphatic compounds, were excluded because of the operation of steric and other effects, which led to non-linear, or even to apparently random, plots. 

Non-Marcusian linear free energy relationships (if I may again be permitted that barbarism) provide direct evidence for this type of potential surface in octahedral ligand substitution reactions. Both dissociative (e.g., the chloropentaamine of cobalt(III)) and associative systems (e.g., chloropentaaquo chromium(III)) may have values of slopes for the linear free energy relationships indicating non-Marcusian behavior. 

Modification of Chemical Structure of Drug The use of a Hammett linear free-energy relationship to investigate the effects of substituents on the rates of aromatic side-chain reactions such as hydrolysis of esters has been alluded to earlier vis-a-vis attainment of optimum stability [9,10]. Degradation of erythromycin under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl as found for the acid stability of clathromycin, which is 340 times greater than that of erythromycin [70]. 

The kinetics of the acid catalyzed hydrolysis of ethoxysilanes has been studied. Each of the silanes that were used had a phenyl or para-substituted phenyl group attached to the silicon atom. This permitted a study of the linear free energy relationships of this reaction. The reaction is of interest because of its role in silane coupling agent chemistry, in the preparation of zinc-rich silicate coatings, in the sol-gel process and in the preparation of silicones in general. 

In the 1950s Taft devised a method of extending linear free-energy relationships to aliphatic systems.16 He suggested that, since the electronic nature of substituents has little effect on the rate of acid-catalyzed hydrolysis of meta- or para-substituted benzoates (p values are near 0, see Table 2.3), the electronic nature of substituents will also have littie effect on acid-catalyzed hydrolysis of aliphatic esters. All rate changes due to substituents in the latter reactions are, therefore, probably due to steric factors.17 Taft defined Es, a steric substituent constant, by Equation 2.16... 

Because of the bulk of comparable material available, it has been possible to use half-wave potentials for some types of linear free energy relationships that have not been used in connection with rate and equilibrium constants. For example, it has been shown (7, 777) that the effects of substituents on quinone rings on their reactivity towards oxidation-reduction reactions, can be approximately expressed by Hammett substituent constants a. The susceptibility of the reactivity of a cyclic system to substitution in various positions can be expressed quantitatively (7). The numbers on formulae XIII—XV give the reaction constants Qn, r for the given position (values in brackets only very approximate) ... 

The oxidation of meta- and para-substituted anilines with imidazolium fluorochro-mate (IFC)18 and nicotinium dichromate (NDC),19 in several organic solvents, in the presence of p-toluenesulfonic acid (TsOH) is first order in the oxidant and TsOH and is zero order with respect to substrate. A correlation of rate data in different solvents with Kamlet-Taft solvatochromic parameters suggests that the specific solute-solvent interactions play a major role in governing the reactivity, and the observed solvent effects have been explained on the basis of solute-solvent complexation. The oxidation rates with NDC exhibited negative reaction constants, while the oxidation with IFC did not correlate well with any linear free energy relationships. 

The extension of a linear free-energy relationship to substitution reactions of the aromatic nucleus has received much attention in the past decade. The problems encountered and the procedures employed in the development of a free-energy treatment for the quantitative rate and equilibrium data for direct substitution processes are the substance of this review. 

Experimental studies of the reactivity of other aniline derivatives in substitution reactions are far more limited, de la Mare and Hassan (1958) and Bradfield and Jones (1928) examined the influence of acyl substituents on the amino function on the rate of halogenation at the para position. These interesting data are too limited to be useful for the evaluation of a linear free-energy relationship and are not included in Table 4. 

Hammett, after illustrating the existence of linear relationships among the data for a variety of side-chain reactions, defined the (7-constants to characterize the behavior of substituent groups. In the application of the Hammett equation the cr-parameters are assumed to be constant. The assessment of the validity of this same assumption for substituents in aromatic substitution reactions is the major problem which must be considered prior to the adoption of a simple two-parameter linear free-energy relationship for these reactions. Preliminary evaluations of linear relationships were undertaken through somewhat modified procedures as discussed in Section IV. Now, however, with many quantitative data available it is no longer necessary to rely on the less direct Selectivity Relationship. Rather, the more straightforward conventional Hammett approach is applicable. This procedure requires the adoption of the a1 -constants derived from the study of substituted phenyldimethylcarbinyl chlorides and the assumption of constancy of the values. This assumption is shown to be fully justified in subsequent tests of the relationship. 

The procedure adopted to portray the scope and utility of a linear free-energy relationship for aromatic substitution involves first a determination of the p-values for the reactions. These parameters are evaluated by plotting the values of log (k/ka) for a series of substituted benzenes against the values based on the solvolysis studies (Section IV, B). The resultant slope of the line is p, the reaction constant. The procedure is then reversed to assess the reliability and validity of the Extended Selectivity Treatment. In this approach the log ( K/ H) observations for a single substituent are plotted against p for a variety of reactions. This method assays the linear or non-linear response of each substituent to variations in the selectivity of the reagents and conditions. Unfortunately, insufficient data are available to allow the assignment of p for many reactions. It is more practical in these cases to adopt the Selectivity Factor S as a substitute for p and revert to the more empirical Selectivity Treatment for an examination of the behavior of the substituents. 

The reaction constants obtained in the previous section for numerous substitution reactions permit the examination of the applicability of a linear free-energy relationship by the Extended Selectivity Procedure. The utility of this approach is demonstrated by application to a series of data for side-chain reactions which are correlated with good precision by the Hammett equation. The variations as detected by the procedure serve as a convenient frame of reference for the behavior to be anticipated in other treatments. 

The problem was first approached in 1954, when de la Mare pointed out a major discrepancy in the observations for the para chlorination of biphenyl in an attempted correlation based on the Hammett equation. Subsequently, Eabom and his students examined the behavior of biphenyl in several additional reactions (Deans et al., 1959 Eaborn and Taylor, 1961b) concluding that reactivity in the para position of hiphenyl did not conform to a linear free-energy relationship. Moreover, the p-phenyl group did not accelerate the substitution to the anticipated extent. The peculiar behavior of the phenyl group prompted several investigations of the substitution reactions. These data are summarized in Table 7. 

Figure 29 presents an analysis of the data for p-phenyl groups in the Extended Selectivity Treatment. The reactivity of the para position increases significantly with an increase in the electron demand of the substitution reaction. This result is confirmed by an analysis of the data through the Selectivity Relationship in which a linear relationship is predicted for a diagram of log pfh against S (Fig. 30). Again, curvature is evident. It must be concluded that the substitution reactions of biphenyl do not adhere to a linear free-energy relationship (Eabom and Taylor, 1961b Stock and Brown, 1962a).

The Selectivity Relationship was shown to be applicable for substitution in the meta and para positions of toluene (Section II). The fine adherence of the -methyl group to a linear free-energy relationship (Fig. 37) is apparently typical of the behavior of the other alkyl substituents, as illustrated for the p-ethyl, p-i-propyl, and p-t-butyl groups (Figs. 38-40). Indeed, the data for electrophilic substitution in toluene are better correlated by a linear relationship than are the data for ordinary side-chain reactions of p-tolyl derivatives (Stock and Brown, 1959a). In the Extended Selectivity Treatment (Fig. 25) the side-chain reactions show a slightly greater scatter from the correlation line than the aromatic substitution reactions. 

The partial rate factors for many substituents in many substitution reactions have been explored in the previous sections. Analyses of these data by the Selectivity and Extended Selectivity Treatments indicate the adherence of the data to the predictions of a linear free-energy relationship, and only two groups, p-phenyl andp-fluoro, deviate significantly. Several comparisons of the applicability of a linear relationship for substitution and for Hammett side-chain reactions reveal the... 

---