Pyrroles electrophilic substitution mechanism

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

Attempts to correlate reaction mechanisms, electron density calculations and experimental results have met with only limited success. As mentioned in the previous chapter (Section 4.06.2), the predicted orders of electrophilic substitution for imidazole (C-5 > -2 > -4) and benzimidazole (C-7>-6>-5>-4 -2) do not take into account the tautomeric equivalence of the 4- and 5-positions of imidazole and the 4- and 7-, 5- and 6-positions of benzimidazole. When this is taken into account the predictions are in accord with the observed orientations of attack in imidazole. Much the same predictions can be made by considering the imidazole molecule to be a combination of pyrrole and pyridine (74) — the most likely site for electrophilic attack is C-5. Furthermore, while sets of resonance structures for the imidazole and benzimidazole neutral molecules (Schemes 1 and 2, Section 4.06.2) suggest that all ring carbons have some susceptibility to electrophilic attack, consideration of the stabilities of the expected tr-intermediates (Scheme 29) supports the commonly observed preference for 5- (or 4-) substitution. In benzimidazole attack usually occurs first at C-5 and a second substituent enters at C-6 unless other substituent effects intervene. 

The chemical reactivity of simple heterocyclic aromatic compounds varies widely in electrophilic substitution reactions, thiophene is similar to benzene and pyridine is less reactive than benzene, while furan and pyrrole are susceptible to polymerization reactions conversely, pyridine is more readily susceptible than benzene to attack by nucleophilic reagents. These differences are to a considerable extent reflected in the susceptibility of these compounds and their benzo analogues to microbial degradation. In contrast to the almost universal dioxygenation reaction used for the bacterial degradation of aromatic hydrocarbons, two broad mechanisms operate for heterocyclic aromatic compounds ... 

Pyrrole reacts in electrophilic substitution reactions about 10 faster than furan under similar conditions. This is in spite of the fact that its resonance energy is greater than that of furan it should, therefore, react more slowly. The discrepancy can be explained by considering the mechanism described on... 

Now we need an explanation. The mechanisms for both 2- and 3-substitutions look good and we will draw both, using a generalized as the electrophile. Both mechanisms can occur very readily. Reaction in the 2-position is somewhat better than in the 3-position but the difference is small. Substitution is favoured at all positions. Calculations show that the HOMO of pyrrole does indeed have a larger coefficient in the 2-position, and one way to explain this result is to look at the structure of the intermediates. The intermediate from attack at the... 

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. ... 

The chemistry of pyrrole is rich in substitution reactions which can readily be recognized to involve attack by an electrophilic reagent. On the other hand, little is known of the reactions of pyrroles with radicals or with nucleophilic reagents. With regard to the electrophilic substitutions it should be realized that whilst their general character is usually immediately apparent, in hardly any case is anything known about the detailed mechanism. 

Whatever the detailed mechanism of the reaction between formaldehyde, secondary or primary amines and a suitably reactive aromatic compound, it is clear that essentially the Mannich aminomethylation is an electrophilic substitution. It is therefore not surprising that pyrrole reacts very readily with formaldehyde and secondary amines to give Mannich bases . If an excess of pyrrole is not maintained during the reaction, more highly substituted products result" 4, 1-Methylpyrrole reacts, if anything, more readily... 

With substitutions effected in acid media, the possible role of pyrrole cations has not been elucidated. However, in electrophilic substitutions it seems most improbable that any entity other than the neutral molecule should be involved. Not only must it be more reactive to electrophilic attack than are the cations, but also it is difficult to formulate any other mechanism such as, for example, nucleophilic attack upon the cation, followed by electrophilic attack and elimination. The consequences of nucleophilic attack upon the j8-protonated pyrrole cation are seen in the trimerization of pyrrole. 

Write the mechanism of electrophilic aromatic substitution reactions of pyrrole, furan, and thiophene. 

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 arylation of pyrroles, furans, and thiophenes, which are generally susceptible to electrophiles, may be considered to proceed through an electrophilic mechanism involving the attack of ArPd(II) species, as judged by the usual substitution pattern [128]. However,other mechanisms seem to be capable of participating as in the above aromatic arylation. 

A palladium-catalyzed oxidative cyclization of tertiary enamines 7 to pyrroles 8 using copper acetate was reported by Guan and co-workers. Trifluo-roacetic acid as a stoichiometric additive was proven to be integral to the improvement of yield. The mechanism is proposed to go through electrophilic paUadation on the C—H of a tertiary enamine under acidic conditions which tri ers a cascade to form pyrroles 8. This method was used to synthesize a range of differentially functionalized 1,3,4-tri-substituted pyrroles (14OL3360). 

PROBLEM 14.24 In addition to the mechanism following the path shown for pyrrole in Rgure 14.61, there is another reasonable mechanism for aromatic substitution of furan. Suggest one. Hint Think simple What are the possible reactions between electrophiles and double bonds (Chapters 9 and 10) Use the chlorination of furan as an example. 

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