Pyrrole, reactivity compared benzene

Thiophene is far more reactive than benzene in electrophilic substitution reactions. Reaction with bromine in acetic acid has been calculated to be 1.76 x 109 times faster than with benzene (72IJS(C)(7)6l). This comparison should, of course, be treated with circumspection in view of the fact that the experimental conditions are not really comparable. Benzene in the absence of catalysts is scarcely attacked by bromine in acetic acid. More pertinent is the reactivity sequence for this bromination among five-membered aromatic heterocycles, the relative rates being in the order 1 (thiophene) and 120 (furan) or, for trifluoroacetylation, 1 (thiophene), 140 (furan), 5.3 xlO7 (pyrrole) (B-72MI31300, 72IJS(C)(7)6l). Among the five-membered heteroaromatics, thiophene is definitely the least reactive. 

Pyrrole is highly reactive, compared with benzene, because of contribution from the relatively stable structure 111. In 111 every atom has an octet of electrons nitrogen accommodates the positive charge simply by sharing four pairs of electrons. It is no accident that pyrrole resembles aniline in reactivity both owe their high reactivity to the ability of nitrogen to share four pairs of electrons. 

This reaction sequence is much less prone to difficulties with isomerizations since the pyridine-like carbons of dipyrromethenes do not add protons. Yields are often low, however, since the intermediates do not survive the high temperatures. The more reactive, faster but less reliable system is certainly provided by the dipyrromethanes, in which the reactivity of the pyrrole units is comparable to activated benzene derivatives such as phenol or aniline. The situation is comparable with that found in peptide synthesis where the slow azide method gives cleaner products than the fast DCC-promoted condensations (see p. 234). 

In addition to electrophilic attack on the pyrrole ring in indole, there is the possibility for additions to the fused benzene ring. First examine the highest-occupied molecular orbital (HOMO) of indole. Which atoms contribute the most What should be the favored position for electrophilic attack Next, compare the energies of the various protonated forms of indole (C protonated only). These serve as models for adducts formed upon electrophilic addition. Which carbon on the pyrrole ring (C2 or C3) is favored for protonation Is this the same as the preference in pyrrole itself (see Chapter 15, Problem 2)1 If not, try to explain why not. Which of the carbons on the benzene ring is most susceptible to protonation Rationalize your result based on what you know about the reactivity of substituted benzenes toward electrophiles. Are any of the benzene carbons as reactive as the most reactive pyrrole carbon Explain. 

For the so-called jt-excessive heterocycles, furan, pyrrole, and thiophene, where the heteroatom contributes two electrons to the aromatic sextet, the HOMO is of relatively high energy, compared to that in benzene, which fact confers the familiar high reactivity of these species toward electrophiles. Correspondingly, ionization to give cation-radicals is facile however, such species are not persistent without stabilizing substitution or annelation (see Section III,D,3). Anion-radicals are also known, particularly for thiophene-containing systems (see Part Two this Series, Volume 27, in press). 

A cyclic conjugated system containing An + 2)ji electrons has an extra stability over that of a comparable number of isolated double bonds. This extra stabilization, known as aromaticity, leads to a characteristic pattern of reactivity which distinguishes the reactions of benzene (1.8) from, for example, the linear hexatriene (1.9) or cyclooctatetraene (1.10) An electrons, n = 2). The aromatic sextet may arise not just from the overlap of three double bonds as in benzene (1.8) or pyridine (1.11) but also from the participation of the lone pair of electrons on a heteroatom. Thus pyrrole (1.12), with effectively six n-electrons, shows some aromatic character. In allene (1.13) the double bonds are at 90° to each other and conjugation does not occur. 

Electrophilic substitution in the azoles is intermediate in facility between pyridine on the one hand and pyrroles, thiophenes and furans on the other the presence of the electron-withdrawing imine unit has an effect on the flve-membered aromatic heterocycles just as it does when incorporated into a six-membered aromatic framework, i.e. the comparison is like that between benzene and pyridine (Chapter 7). The order of reactivity - pyrrole > furan > thiophene - is echoed in the azoles, though the presence of the basic nitrogen complicates such comparisons. The regiochemistry of electrophilic attack can be rationalised nicely by comparing the character of the various ring positions - those that are activated in being flve-membered in character and those that are deactivated by their similarity to a- and y- positions in pyridine. 

Heterocyclic aromatic derivatives also undergo electrophilic aromatic substitution reactions. Pyrrole, for example, reacts with nitric acid in acetic anhydride, at 0°C, to give 509r of 2-nitropyrrole and 15% of 3-nitro-pyrrole. Pyrrole is more reactive in these reactions when compared to benzene, and the mild reaction conditions described are sufficient. One caution is that the products may decompose with prolonged exposure to a powerful Lewis acid. The preference for substitution at C2 in pyrrole is seen in other five-membered ring... 

This includes heteroannulenes, which comply with the HUCKEL rule, i.e. which possess An + 2) -electrons delocalized over the ring. The most important group of these compounds derives from [6]annulene (benzene). They are known as heteroarenes, e.g. furan, thiophene, pyrrole, pyridine, and the pyrylium and thiinium ions. As regards stability and reactivity, they can be compared to the corresponding benzenoid compounds [1]. 

Haas and coworkers performed a series of studies on the reactivity of the perituoroalkyl sulfenyl chlorides with electron rich heterocyclic compounds, to give CFjS derivatives. Pyrroles are good substrates for reaction with trifluoromethyl sulfenyl chloride due to higher nucleophilicity compared to benzene [45]. An excess of reagent gives bis-CCFjS) pyrrole derivatives as shown in Scheme 16. 

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