Electrophilic aromatic substitution example mechanism

The scope of electrophilic aromatic substitution is quite large both the aromatic com pound and the electrophilic reagent are capable of wide variation Indeed it is this breadth of scope that makes electrophilic aromatic substitution so important Elec trophilic aromatic substitution is the method by which substituted derivatives of benzene are prepared We can gam a feeling for these reactions by examining a few typical exam pies m which benzene is the substrate These examples are listed m Table 12 1 and each will be discussed m more detail m Sections 12 3 through 12 7 First however let us look at the general mechanism of electrophilic aromatic substitution... 

A historically important method, first used about 1900, is sulfonation of benzene followed by desulfonation with caustic. This is classic aromatic chemistry. In 1924 a chlorination route was discovered. Both the sulfonation and chlorination reactions are good examples of electrophilic aromatic substitution on an aromatic ring. Know the mechanism of these reactions. These routes are no longer used commercially. 

At least two other special mechanisms exist that are not considered in this chapter. The first is electrophilic aromatic substitution via a carbanion. This pathway is sometimes followed if a strong base is present or if the substrate is a metal-substituted aromatic. For example, Mach and Bunnett have found that the presence of i-BuOK, i-BuOBr brominates 1,3,5-tribromobenzene by the mechanism shown below ... 

A few examples are known in which the second step of an electrophilic aromatic substitution is rate-determining. For example, 67 is brominated by Br2 and BrOH at approximately the same rate, even though the latter is usually much the more reactive reagent. Moreover, the rate of reaction is first-order in base. These facts point to the two-step mechanism of Equation 7.70 with the second step ratedetermining.169... 

Although discussed in terms of a Pd°/Pdn versus PdII/PdIV mechanism, the lack of regioselectivity suggests an electrophilic aromatic substitution. Other examples, as well as competitive experiments, also supported such a mechanism (see text below). 

All of the electrophilic aromatic substitution reactions follow this same general mechanism. The only difference is the structure of the electrophile and how it is generated. Let s look at a specific example, the nitration of benzene. This reaction is accomplished by reacting benzene with nitric acid in the presence of sulfuric acid ... 

The reaction presented in this problem is known as a Friedel-Crafts acylation. Technically, this example belongs to a class of reactions referred to as electrophilic aromatic substitutions. Furthermore, the actual mechanism associated with this reaction, utilizing Lewis acid reagents as catalysts, proceeds through initial formation of an electrophilic acyl cation followed by reaction with an aromatic ring acting as a nucleophile. This mechanism, shown below, reflects distinct parallels to standard addition-elimination reaction mechanisms warranting introduction at this time. 

These two brominations are examples of the mechanism of electrophilic aromatic substitution, which, in many different guises, will return again and again during this chapter. In its most general form the mechanism has two stages attack by an electrophile to give an intermediate cation and loss of a proton from the cation to restore the aromaticity. 

Five specific examples of electrophilic aromatic substitution are shown in Figure 18.1. The basic mechanism, discussed in Section 18.2, is the same in all five cases. The reactions differ only in the identity of the electrophile, E. ... 

The general mechanism outlined in Mechanism 18.1 can now be applied to each of the five specific examples of electrophilic aromatic substitution shown in Figure 18.1. For each mechanism we must learn how to generate a specific electrophile. This step is different with each electrophile. Then, the electrophile reacts with benzene by the two-step process of Mechanism 18.1. These two steps are the same for all five reactions. 

Rearrangements can occur even when no free carbocation is formed initially. For example, the 1° alkyl chloride in Equation [2] forms a complex with AICI3, which does not decompose to an unstable 1° carbocation, as shown in Mechanism 18.9. Instead, a 1,2-hydride shift forms a 2° carbocation, which then serves as the electrophile in the two-step mechanism for electrophilic aromatic substitution. 

This reaction is another example of electrophilic aromatic substitution, with the diazonium salt acting as the electrophile. Like all electrophilic substitutions (Section 18.2), the mechanism has two steps addition of the electrophile (the diazonium ion) to form a resonance-stabilized carbocation, followed by deprotonation, as shown in Mechanism 25.4. 

The most common mechanism of C-H bond cleavage in the arylation examples discussed above has been assumed to be electrophilic aromatic substitution involving reaction of an electrophilic palladium catalyst with an electron rich, nucleophilic aromatic ring. In order to effect direct arylation on simple, electron deficient arenes, a basic directing group or intramolecular reaction is usually necessary to enable formation of a metalocycle. As a brief introduction to the effect of this area on the functionalization of indoles and pyrroles, we provide an overview of the mechanistic... 

The reader is directed to several excellent reviews for further details. Hassner and Fischer s general review of oxazoles covers both electrophilic aromatic substitution (EAS) reactions and addition reactions. Belen kii and Chuvylkin surveyed EAS reactions of oxazoles as part of a larger review for azoles. Larina and co-workers published two extensive reviews of nitration of azoles, including oxazoles. The articles cover kinetics and the mechanism of nitrations as well as the synthesis of nitroazoles via heterocyclization and ring transformations and direct methods of nitration. In light of these reviews, only a few selected examples of EAS reactions of oxazoles are described in this section. 

After realizing that our hypotheses about oxidative cross-coupling reactions were not as unique as assumed, we quickly turned our attentirai to intermolecular oxidative amination reactions. In the carbazole example, regioselectivity was coti-trolled by the presence of a Lewis base that was attached near the C—H bmid that would be cleaved, resulting in a metallacyle intermediate. For die development of an intramolecular reaction, we chose to take advantage of the selectivity that is often observed in the selective metalation of electron-rich heteroarenes. At the time, the palladation of indoles was presumed to operate by an electrophilic aromatic substitution mechanism. (This has since been demonstrated to be incorrect, vide infra.) We hypothesized that regioselective palladation of an indole substrate could be followed by a subsequent C—N bond reductive elimination. At the time, the exact mechanism by which the intermediate containing Pd—C and Pd—N bonds could be formed was not clear, nor was the order of the two metalation steps, but the overall process seemed plausible. 

This chapter is concerned with reactions that introduce or interchange substituent groups on aromatic rings. The most important group of such reactions are the electrophilic aromatic substitutions, but there are also significant reactions that take place by nucleophilic substitution mechanisms, and still others that involve radical mechanisms. Examples of synthetically important reactions from each group will be discussed. Electrophilic aromatic substitution has also been studied in great detail from the point of view of reaction mechanism and structure-reactivity relationships these mechanistic studies received considerable attention in Part A, Chapter 9. In this chapter, the synthetic aspects of electrophilic aromatic substitutions will be emphasized. 

In choosing the Key Mechanisms, I ve used two major criteria. If the mechanism is one of the fundamental mechanisms that make up the longer, more complex mechanisms, then it must be a Key Mechanism. Examples are S l, 5 2, El, E2, nucleophilic acyl substitution, electrophilic aromatic substitution, and so forth. The other criterion is more subjective. If the mechanism is one of the ones I routinely expect students to do on exams, then it is a Key Mechanism. Examples are formation of imines and acetals, aldol and Claisen condensations, and so oa If you feel I have left one out or included one that should not be a Key Mechanism, please let me know. 

Substitution processes are diverse in both scope and mechanism. Upon detailed investigation, even those reactions that seem most familiar to us offer degrees of complexity that confound our attempts to fit all of organic chemistry into a few distinct compartments. As one author put it, "in summary, nitration—the classic example of electrophilic aromatic substitution—is not always an electrophilic aromatic substitution." ... 

Isotope effects are also useful in providing insight into other aspects of the mechanisms of individual electrophilic aromatic substitution processes. In particular, since primary isotope effects are expected only when the breakdown of the rate-determining, the observation of a substantial kn/ko points to rate-determining deprotonation. Some typical isotope effects are summarized in Table 9.7. While isotope effects are rarely observed for nitration and halogenation, Friedel-Crafts acylation, sulfonation, nitrosation, and diazo coupling provide examples in which the rate of proton abstraction can control the rate of substitution. 

An electrophilic aromatic substitution mechanism has been usually favored for the arylation of electron-rich heterocydes [61, 62]. Thus, for example, no kinetic... 

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