Relative Rates of Electrophilic Aromatic Substitution

Electrophilic aromatic substitution reactions (Sec. 15.1) are among the best understood of all organic reactions. The qtuilitative aspects of the reactions that are discussed in textbooks include the effect substituents have on the reactivity of arenes toward electrophiles and the orientation, ortho, meta, or para, of their attack on the ring. However, relatively Httle information is given in textbooks about the quantitative differences in rates and reactivities of substituted aromatic compounds. The experimental procedures of this section provide both semiquantitative and quantitative measures of the differences in reactivity of a series of arenes toward the bromo-nium ion, Br, to produce the corresponding aryl bromides (Eq. 15.20). 

Studies of electrophilic substitutions on arenes are reported in which the experimental conditions allow a direct comparison of the relative reaction rates. For example, the relative reactivities of benzene and toluene toward halogenation, acetylation, sulfonation, nitration, and methylation have been determined. In all cases, electrophilic aromatic substitution was more rapid with toluene. For example, bromina-tion of toluene is some 600 times faster than that of benzene. Such studies have led to the classification of substituents as ring activators or deactivators, depending on whether the substituted arene reacts faster or slower than benzene itself. Thus, the methyl group of toluene is a ring activator. 

You will be measuring the relative rates of bromination of six monosubstituted arenes 27-32. This particular electrophilic aromatic substitution is selected because the relative rates may be measured both qualitatively and quantitatively. The results should allow you to determine the order of ring activation associated with the various substituents that you will investigate. 

The qualitative measurements are easier to perform because they simply rely on your observing the disappearance of the characteristic reddish color of molecular bromine as a function of time. You should be able to rank-order the substituent effects, but the results will be subject to the vagaries of human judgment with respect to knowing when all of the color has been discharged from the reaction mixture. 

In order to analyze the data from the quantitative measurements, we start by considering the rate expression for an Se2 reaction that is given in Equation 15.21 this equation is identical to Equation 15.2 (Sec. 15.1) except that [Br2], the precursor to Br , has replaced [E ]. This expression could be more complex if a Lewis acid catalyst were required to promote formation of the electrophile, which is the case when the arene is less reactive toward electrophilic aromatic substitution than the ones we ve selected. The rate is seen to be first-order in both reagents and therefore is second-order overall (Sec. 14.6). 

---

On the whole the effect of substituents on the relative stability of isomeric arenium ions (for details see Sect. IV, 1) is described in the same terms as those used to explain the influence of substituents on the orientation and relative rates of electrophilic aromatic substitution. However, the isomeric composition of electrophilic substitution products is often controlled by kinetic factors while the equilibrium composition of isomeric arenium ions formed in aromatic compound protonation is determined by thermodynamic equilibrium. Therefore, no quantitative agreement may be observed between the relative hydrogen substitution rates at different positions of this compound and the ratio of equilibrium concentrations of the respective arenium ions formed in protonating the same compound even under identical conditions (cf. Sect. IV, 7). 

Specify sources of error in this procedure for determining the relative rates of electrophilic aromatic substitution. 

Whether the nonplanarity of single-boundary three-dimensional aromatic hydrocarbons is reflected in predictable changes in physical or chemical properties remains to be established. Good test cases could be the rates of electrophilic aromatic substitutions (39) or the relative rates of Diels-Alder reactions (40). A comparison of the predicted rates with experimental measurements, perhaps by using the procedures of Szentpaly and Herndon (17) summarized in this book, might provide some new insights into the relationships among molecular structure, strain, and reactivity. 

Those substituents with a +/ effect or a +/ and a +M effect increase the rate of electrophilic aromatic substitution relative to benzene and are said to be activating substituents.273 Since ortho and para products should predominate with these activating groups, activators are also said to be ortho/para directors. When 2-methylanisole was treated with bromine in chloroform, for example, a 94% yield of 368 was obtained as part of Vyvan s synthesis of heliannuol D.274 Note that the presence of two activating groups allowed the reaction to proceed without adding a Lewis acid, which is typical of very activated benzene derivatives. 

Table 10.11 shows the relative rates of nitration of a few benzene derivatives, and these demonstrate the electron donating (activating) and withdrawing (deactivating) effect of several substituents. In fact, most chemist s intuition as to what groups are electron donating and withdrawing is derived from rates of electrophilic aromatic substitution, as well as the (T constants associated with Hammett plots. 

Thus the absence of isotope effects establishes not only the two-step nature of electrophilic aromatic substitution, but also the relative speeds of the steps. Attachment of the electrophile to a carbon atom of the ring is the difficult step (see Fig. 11.2) but it is equally diflicult whether the carbon carries protium or deuterium. The next step, loss of hydrogen ion, is easy. Although it occurs more slowly for deuterium than for protium, this really makes no difference slightly faster or slightly slower, its speed has no effect on the overall rate. 

By use of especially selected aromatic substrates—highly hindered ones—isotope effects can be detected in other kinds of electrophilic aromatic substitution, even in nitration. In certain reactions the size of the isotope can be deliberately varied by changes in experimental conditions- and in a way that shows dependence on the relative rates of (2) and the reverse of (I). There can be little doubt that all these reactions follow the same two-step mechanism, but with differences in the shape of potential energy curves. In isotope effects the chemist has an exceedingly delicate probe for the examination of organic reaction mechanisms. 

The relative basicities of aromatic hydrocarbons, as represented by the equilibrium constants for their protonation in mixtures of hydrogen fluoride and boron trifluoride, have been measured. The effects of substituents upon these basicities resemble their effects upon the rates of electrophilic substitutions a linear relationship exists between the logarithms of the relative basicities and the logarithms of the relative rate constants for various substitutions, such as chlorination and... 

Rate data are also available for the solvolysis of l-(2-heteroaryl)ethyl acetates in aqueous ethanol. Side-chain reactions such as this, in which a delocalizable positive charge is developed in the transition state, are frequently regarded as analogous to electrophilic aromatic substitution reactions. In solvolysis the relative order of reactivity is tellurienyl> furyl > selenienyl > thienyl whereas in electrophilic substitutions the reactivity sequence is furan > tellurophene > selenophene > thiophene. This discrepancy has been explained in terms of different charge distributions in the transition states of these two classes of reaction (77AHC(21)119>. 

The table below gives first-order rate constants for reaction of substituted benzenes with w-nitrobenzenesulfonyl peroxide. From these data, calculate the overall relative reactivity and partial rate factors. Does this reaction fit the pattern of an electrophilic aromatic substitution If so, does the active electrophile exhibit low, moderate, or high substrate and position selectivity ... 

Individual substitutions may not necessarily be true electrophilic aromatic substitution reactions. Usually it is assumed that they are, however, and with this assumption the furan nucleus can be compared with others. For tri-fluoroacetylation by trifluoroacetic anhydride at 75 C relative rates have been established, by means of competition experiments 149 thiophene, 1 selenophene, 6.5 furan, 1.4 x 102 2-methylfuran, 1.2 x 105 pyrrole, 5.3 x 107. While nitrogen is usually a better source of electrons for an incoming electrophile (as in pyrrole versus furan) there are exceptions. For example, the enamine 63 reacts with Eschenmoser s salt at the 5-position and not at the enamine grouping.150 Also amusing is an attempted Fischer indole synthesis in which a furan ring is near the reaction site and diverted the reaction into a pyrazole synthesis.151... 

Substituents already bonded to an aromatic ring influence both the rate of electrophilic substitution and the position of any further substitution. The effect of a particular substituent can be predicted by a consideration of the relative stability of the first-formed arenium cation, formation of which constitutes the rate-lintiting step. In general, substituents that are electron releasing activate the ring to further substitution - they help to stabilize the arenium ion. Substituents that are electron withdrawing destabilize the arenium ion, therefore, are deactivating and hinder further substitution. 

The effect of monofluorination on alkene or aromatic reactivity toward electrophiles is more difficult to predict Although a-fluonne stabilizes a carbocation relative to hydrogen, its opposing inductive effect makes olefins and aromatics more electron deficient. Fluorine therefore is activating only for electrophilic reactions with very late transition states where its resonance stabilization is maximized The faster rate of addition of trifluoroacetic acid and sulfuric acid to 2-fluoropropene vs propene is an example [775,116], but cases of such enhanced fluoroalkene reactivity in solution are quite rare [127] By contrast, there are many examples where the ortho-para-dueeting fluorine substituent is also activating in electrophilic aromatic substitutions [128]... 

A far more serious consideration is the adequacy of the solvolysis of phenyldimethylcarbinyl chlorides as a model reaction for electrophilic substitution. As will be shown, the cr -parameters derived from the phenyldimethylcarbinyl chloride studies are in good agreement with the a+-values deduced from the data for electrophilic substitution. Not all model reactions would have proved as satisfactory. As this research developed, it became clear that the influences of substituents on aromatic substitution reactions are quite accurately described by the other hand, the relative rates for electrophilic side-chain reactions of which the phenyldimethylcarbinyl chloride solvolysis is characteristic are not as adequately correlated by these constants. 

Reference should also be made to a superdelocalizability index Sp derived within the frame of the simple FEMO model [35], Goodness of fit of correlations of SfE values with relative rate constants for electrophilic aromatic substitution was found to be comparable with those based on CNDO/2 calculations. 

Early examples of reactivity-selectivity relationships in aromatic substitutions are limited since, in the absence of absolute rate data, it is often difficult to assign relative reactivity to the different electrophiles. For certain cases where the relative reactivity order may be assumed, a reactivity-selectivity relationship was noted. For example, bromina-tion with the reactive species Br+ results in lower selectivity than with the less reactive species Br2 (de la Mare and Harvey, 1956 Brown, 1957). However, it appears that no general reactivity-selectivity relationship exists in electrophilic aromatic substitution reactions, for there exist slow, unselective reactions such as aromatic... 

Perdenteration of the methylene hnker affords a relatively kinetically stable complex, which allows for the monitoring of exogenons snbstrate oxidations. When (7) is exposed to cold (-95 °C) acetone solntions of the lithium salts of para-substituted phenolates, clean conversion to the corresponding o-catechols is observed. Deuterium kinetic isotope effects (KIEs) for these hydroxylation reactions of 1.0 are observed, which is consistent with an electrophilic attack of the peroxo ligand on the arene ring. An electrophilic aromatic substitution is also consistent with the observation that lithium jo-methoxy-phenolate reacts substantially faster with (7) than lithium / -chloro-phenolate. Furthermore, a plot of observed reaction rates vs. / -chloro-phenolate concentration demonstrated that substrate coordination to the metal center is occurring prior to hydroxylation, and thus may be an important feature in these phenolate o-hydroxylation reactions. 

---