Pyrroles electrophilic aromatic substitution

Electrophilic Aromatic Substitution. The Tt-excessive character of the pyrrole ring makes the indole ring susceptible to electrophilic attack. The reactivity is greater at the 3-position than at the 2-position. This reactivity pattern is suggested both by electron density distributions calculated by molecular orbital methods and by the relative energies of the intermediates for electrophilic substitution, as represented by the protonated stmctures (7a) and (7b). Stmcture (7b) is more favorable than (7a) because it retains the ben2enoid character of the carbocycHc ring (12). 

Pyrrole, furan, and thiophene, on the other hand, have electron-rich aromatic rings and are extremely reactive toward electrophilic aromatic substitution— rnore like phenol and aniline than benzene. Like benzene they have six tt electrons, but these tt electrons are delocalized over five atoms, not six, and ar e not held as strongly as those of benzene. Even when the ring atom is as electronegative as oxygen, substitution takes place readily. 

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... 

Hence the positional selectivity is different from that of the furan additions to 417 (Scheme 6.90). Assuming diradical intermediates for these reactions [9], the different types of products are not caused by the nature of the allene double bonds of 417 and 450 but by the properties of the allyl radical subunits in the six-membered rings of the intermediates. Also N-tert-butoxycarbonylpyrrole intercepted 450 in a [4 + 2]-cycloaddition and brought about 455 in 29% yield. Pyrrole itself and N-methylpyr-role furnished their substituted derivatives of type 456 in 69 and 79% yield [155, 171b]. Possibly, these processes are electrophilic aromatic substitutions with 450 acting as electrophile, as has been suggested for the conversion of 417 into 442 by pyrrole (Scheme 6.90). 

In a similar fashion, hydroformylation of N-allyl-pyrrols leads to 5,6-dihydroindolizines via a one-pot hydroformylation/cyclization/dehydration process (Scheme 27) [81,82]. The cyclization step represents an intramolecular electrophilic aromatic substitution in a-position of the pyrrole ring. This procedure was expanded to various substrates bearing substituents in the al-lyl and in the pyrrole unit. 

As described in the previous sections, a variety of nucleophiles attack the Cy atom of ruthenium-allenylidene intermediates. Aromatic compounds should also be suitable candidates and this was found to be the case [30]. Thus, reactions of propargylic alcohols with heteroaromatic compounds such as furans, thiophenes, pyrroles, and indoles in the presence of a diruthenium catalyst such as la proceeded smoothly to afford the corresponding propargylated heteroaromatic compounds in high yields with complete regioselectivity (Scheme 7.25). The reaction is considered to be an electrophilic aromatic substitution if viewed from the side of aromatic compounds. 

Electrophilic aromatic substitution Electrophilic aromatic substitution of indole occurs on the five-membered pyrrole ring, because it is more reactive towards such reaction than a benzene ring. As an electron-rich heterocycle, indole undergoes electrophilic aromatic substitution primarily at C-3, for example bromination of indole. 

Annelation of 2,5-disubstituted pyrroles provides a useful route to isoindoles as shown in reactions (140)-(142). These reactions can be formulated as electrophilic aromatic substitutions of the pyrrole ring and proceed under the influence of acid catalysts (66T2481, 68JCS(C)3036, 72JCS(P1)904). 

Alkylation of the C(2) or C(3) carbons of the pyrrole ring can be accomplished by electrophilic aromatic substitution. Such substitution reactions may be carried out on the neutral heterocycle or on a metal salt. The magnesium salts are of most synthetic importance for the alkylation of both pyrroles and indoles. As discussed in Section 3.05.1.2.7, there is a reversal of the preferred site of electrophilic substitution between pyrroles and indoles. Thus Friedel-Crafts-type substitution of pyrroles gives 2-aIkylpyrroles while similar reaction... 

The text states that electrophilic aromatic substitution in furan, thiophene, and pyrrole occurs at C-2. The sulfonation of thiophene gives thiophene-2-sulfonic acid. 

Predict the product expected from electrophilic aromatic substitution reactions of pyrrole, furan, and thiophene. 

Pyrrole undergoes electrophilic aromatic substitution more readily than benzene, and mild reagents and conditions are sufficient. These reactions normally occur at the 2-position rather than the 3-position, as shown in the following example. 

The other simple five-membered heterocycles are furan, with an oxygen atom instead of nitro- pyrrole gen, and thiophene with a sulfur atom. They also undergo electrophilic aromatic substitution very Ft ft readily, though not so readily as pyrrole. Nitrogen is the most powerful electron donor of the three, 1 J> oxygen the next, and sulfur the least. Thiophene is very similar to benzene in reactivity. N... 

Indole has a pyrrole-like nitrogen and undergoes electrophilic aromatic substitutions in the heterocyclic ring. 

In our study of electrophilic aromatic substitution (Sec. 11.19 and Sec. 30.9), we found that we could account for orientation on the following basis the controlling step is the attachment of the electrophilic reagent to the aromatic ring, which takes place in .uch a way as to yield the most stable intermediate carbonium ion. Let us apply this approach to the reactions of pyrrole. 

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... 

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