Electrophilic aromatic substitution mechanisms, process

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. 

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). 

Finally, we ask, if the reactive triads in Schemes 1 and 19 are common to both electrophilic and charge-transfer nitration, why is the nucleophilic pathway (k 2) apparently not pertinent to the electrophilic activation of toluene and anisole One obvious answer is that the electrophilic nitration of these less reactive [class (ii)] arenes proceeds via a different mechanism, in which N02 is directly transferred from V-nitropyridinium ion in a single step, without the intermediacy of the reactive triad, since such an activation process relates to the more conventional view of electrophilic aromatic substitution. However, the concerted mechanism for toluene, anisole, mesitylene, t-butylbenzene, etc., does not readily accommodate the three unique facets that relate charge-transfer directly to electrophilic nitration, viz., the lutidine syndrome, the added N02 effect, and the TFA neutralization (of Py). Accordingly, let us return to Schemes 10 and 19, and inquire into the nature of thermal (adiabatic) electron transfer in (87) vis-a-vis the (vertical) charge-transfer in (62). 

The hydroarylation of olefins is relatively uncommon in photochemistry, despite a high interest in this process which allows the formation of an aryl-carbon bond via the direct activation of an aromatic, with no need for leaving groups in both components of the reaction. The process follows a photo-EOCAS (Electrophile-Olefin Combination Aromatic Substitution) mechanism [32], and is initiated by a PET reaction between an electron-rich aromatic and an electron-poor olefin, as illustrated in Scheme 3.14. 

A general mechanism for the electrophilic aromatic substitution reaction is outlined in Figure 17.1. The process... 

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. 

These steps illustrate how to generate the electrophile E for nitration and sulfonation, the process that begins any mechanism for electrophilic aromatic substitution. To complete either of these mechanisms, you must replace the electrophile by either or S03H in the general mechanism (Mechanism 18.1). Thus, the two-step sequence that replaces H by E is the same r ardless of E. This is shown in Sample Problem 18.1 u.sing the reaction of benzene with the nitronium ion. 

Media pH errors and media pH span errors are common. Since electrophilic aromatic substitution is almost exclusively an acidic media process, do not make any strong bases during the mechanism. The proton on the aromatic ring becomes very acidic after the electrophile attaches and forms the carbocationic sigma-complex. However, before the electrophile attacks, the aromatic H is not acidic at all, p Ta = 43, so do not get your steps out of order and try to pull the H off first. 

The mechanism of the reaction has been studied in some detail by Hogberg i2,7i,72) jn contrast to the base-catalyzed oligomerization, the acid catalyzed process involves electrophilic aromatic substitutions by cations, as outlined in Fig. 8. Although formaldehyde does not react with resorcinol to produce cyclic oligomers, other aldehydes such as acetaldehyde and benzaldehyde give excellent yields of... 

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." ... 

The general mechanistic framework outlined in the preceding paragraphs must be further elaborated by other details to fully describe the mechanisms of the individual electrophilic substitutions. The question of the identity of the active electrophile in each reaction is important. We have discussed the case of nitration, in which, under many circumstances, the electrophile has been established to be the nitronium ion. Similar questions arise in many of the other substitution processes. Other matters that are important include the ability of the electrophile to select among alternative positions on a substituted aromatic ring. The relative reactivity of different substituted benzenes toward various electrophiles has also been important in developing a firm understanding of electrophilic aromatic substitution. The next section considers the structure-reactivity relationships that have proved most informative. 

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. 

Although the results of these experiments suggest that the palladation proceeds by an electrophilic aromatic substitution, the transformations are probably more complex than the above results suggest. Indeed, the reaction of alkyl palladium complex 6a with KOPh in MeCN was almost completely inhibited by the addition of lequiv. of PPhs [29], which indicates that ligand substitution, presumably by an associative mechanism, occurs during the C—H bond-activation process. Biden-... 

The mechanism of direct arylation has been studied experimentally and computationally and possible pathways include electrophilic aromatic substitution, Heck-type coupling and concerted metalation-deprotonation (CMD). The reaction pathway is dependent on the substrate and the catalytic system employed,however, most electron-rich (hetero)arenes seem to follow a base-assisted CMD pathway. Two catalytic cycles for the coupling of bromo-benzene and thiophene are shown in Schemes 19.5 and 19.6. Scheme 19.5 depicts a carboxylate-mediated process where C-H activation occurs... 

---