Aromatic Electrophilic Substitution Mechanism

Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL, USA 

Arene Chemistry Reaction Mechanisms and Methods for Aromatic Compounds First Edition. Edited by Jacques Mortier. 

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The azo coupling reaction proceeds by the electrophilic aromatic substitution mechanism. In the case of 4-chlorobenzenediazonium compound with l-naphthol-4-sulfonic acid [84-87-7] the reaction is not base-catalyzed, but that with l-naphthol-3-sulfonic acid and 2-naphthol-8-sulfonic acid [92-40-0] is moderately and strongly base-catalyzed, respectively. The different rates of reaction agree with kinetic studies of hydrogen isotope effects in coupling components. The magnitude of the isotope effect increases with increased steric hindrance at the coupler reaction site. The addition of bases, even if pH is not changed, can affect the reaction rate. In polar aprotic media, reaction rate is different with alkyl-ammonium ions. Cationic, anionic, and nonionic surfactants can also influence the reaction rate (27). 

You can summarize this particular electrophilic aromatic substitution mechanism like this ... 

Nucleophilic aromatic substitutions have been studied in detail. Either of two mechanisms may be involved, depending on the reactants. One mechanism is similar to the electrophilic aromatic substitution mechanism, except that nucleophiles and carban-ions are involved rather than electrophiles and carbocations. The other mechanism involves benzyne, an interesting and unusual reactive intermediate. 

Often the most difficult part of electrophilic aromatic substitution mechanisms is working out the generation of the reactive electrophile. The first task is always to map changes on a balanced reaction. The medium is almost always acidic because reactive electrophiles are present. The electrophilic addition to the aromatic ring is just a two-step process, Ag then Dg (usually a proton). Make sure you draw the arrows correcdy, keep track of charge balance, and use the known electron flow paths. 

Section 4.6.2 Approaches to Electrophilic Aromatic Substitution Mechanisms... 

Scheme 3 A plausible electrophilic aromatic substitution mechanism for palladium-catalyzed direct arylation...

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. 

As before, the exploration of the metal-free oxidative amination was a competitive process. Both Chang" and Antonchick" simultaneously discovered nearly identical I(III)-mediated aminations. They both proposed that the reactions operated by generating an electrophilic nitrogen source in situ. This new species then acted as an R2N equivalent and aminated the arene via an electrophilic aromatic substitution mechanism. This hypothesis seemed appealing, but their data could not be directly compared to ours, as neither Chang nor Antonchick performed reactions on arene substrates that could provide mixtures of regiomers (e.g., toluene). 

A reminder electrophilic aromatic substitution mechanisms are easier to follow if you draw in the H at the point of substitution. 

Results on the intramolecular arylation on a 5H-indeno[l,2-b]pyridine derivative, which proceeded selectively at the pyridine ring, are also inconsistent with an electrophilic aromatic substitution mechanism for this reaction [37]. 

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

The Houben-Hoesch reaction proceeds via a straightforward electrophilic aromatic substitution mechanism. Following protonation or Lewis acid activation of the alkyl nitrile, nucleophilic attack by the electron-rich pyrrole selectively at C(2) produces the resonance stabilized intermediate 1. Elimination of H" reestablishes the aromaticity of the pyrrole, resulting in imine 2, which is rapidly hydrolyzed to produce the ketone 3. ... 

In this section and the next, we will present experimental evidence that supports the electrophilic aromatic substitution mechanism just described. We will do this by examining how substituents already present on an aromatic ring affect further substitution reactions. 

However, the mechanistic scheme for this catalytic cycle (Shilov system) is a topic of debate and there have been alternative proposals for of oxidative addition pathways that have been put forth, and experimental evidence provided to support the theory. Excellent review articles have focused on catalytic oxidation of alkanes, however herein we will discuss only those examples for the synthesis of bi(hetero)aryls involving an electrophilic aromatic substitution mechanism. 

Besides the examples that have been discussed in the earlier section involving an electrophilic aromatic substitution mechanism there are many others that suggest a similar pathway for C H bond functionalization. 

Under acidic conditions, phenol reacts with formaldehyde by an electrophilic aromatic substitution mechanism. This in turn can react with another phenol to give a methylene bridged bisphenol and then with more formaldehyde and phenol to give the novolak. The novolak is not specifically the compound shown, but rather a mixture of that and similar structures. 

We noted earlier that with the exception of the halogens ortho, para directors activate the ring toward electrophilic substitution by supplying eleetton density to the ring. But why are the ortho and para positions especially susceptible to attack To answer this question, consider the stability of the cyclohexa-dienyl carbocation that forms in the first step of the electrophilic aromatic substitution mechanism. The r ioselectivity of the reaction is controlled by the stability of the carbocation. To determine the stability of a cydohexadienyl carbocation, we must compare all the possible resonance forms. Thus, we compare the stabihty of the intermediate carbocations resulting from attack at the ortho and para positions with those resulting when an electrophile attacks at the meta position. 

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