Electrophilic aromatic substitution relative rates

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. 

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 ... 

These relative rate data per position are experimentally detennined and are known as partial rate factors. They offer a convenient way to express substituent effects in electrophilic aromatic substitution reactions. 

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... 

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]... 

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. 

To understand why some substituents make a benzene ring react faster than benzene itself (activators), whereas others make it react slower (deactivators), we must evaluate the rate-determining step (the first step) of the mechanism. Recall from Section 18.2 that the first step in electrophilic aromatic substitution is the addition of an electrophile (E ) to form a resonance-stabilized carbo-cation. The Hammond postulate (Section 7.15) makes it pos.sible to predict the relative rate of the reaction by looking at the stability of the carbocation intermediate. 

The electronic effect of the butadiynyl group in electrophilic aromatic substitutions has been determined by measuring the rates of acid-catalyscd cleavage of the aryl-tin bonds in the aryltrimethylstannancs 4 The reaction (equation 2) proceeds by way of the benzenonium intermediate 5, and the relative rates (Table 2) give an indication... 

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 propensity for C-N vs. N-H activation correlates well with substituent Hammet parameters groups that increase the basicity of aniline increase the relative rate of N-H activation, suggesting that nucleophilic attack by the amine at an empty d /dy orbital of Ta(silox)3 preceeds oxidative addition. On the other hand, electron-withdrawing substituents decrease the rate of N-H activation and increase the rate of C-N activation, similarly to the effects observed on electrophilic aromatic substitution. Nucleophilic attack by the filled d a orbital of Ta(silox)3 is expected to occur at the arylamine ipso carbon preceding C-N oxidative addition. The carbon-heteroatom cleavages can be accomodated by mechanisms using both electrophilic and nucleophilic sites on the metal center. 

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

TABLE 9. Relative rates and directing effects of the Me3Si group in electrophilic aromatic substitution of ArSiMe3... 

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. 

All of these effects are observed when comparing the rates of various electrophilic aromatic substitution reactions. Activating substituents increase the rate of reaction relative to benzene. The rate of reaction for the nitration of anisole, for example, was 9.7 x 10 times faster than nitration of benzene. The reaction of anisole with nitric and sulfuric acids, gave 44% of o-nitroanisole, 56% of p-nitroanisole and < 1% of m-nitro-anisole.2 9 contrasts with reactions involving deactivating substituents, where selectivity for the meta -product is usually very good. Nitration of nitrobenzene, for example, gave 1,3-dinitrobenzene in 94% yield, with only 6% of the ortho product and < 1% of the para product. ... 

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). 

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