Pyrrole, reactivity toward electrophiles

The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

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. 

The chemistry of pyrrole is similar to that of activated benzene rings. In general, however, the heterocycles are more reactive toward electrophiles than benzene rings are, and low temperatures are often necessary to control the reactions. Halogenation, nitration, sulfonation, and Friedel-Crafts acylation can all be accomplished. For example ... 

Heteroaromatics very reactive toward electrophilic species, such as furan and pyrrole, are not suitable for homolytic aminations owing to their low stability under the reaction conditions. Thiophene, however, can be aminated, leading to 2-dialkylamino derivatives. ... 

Pyrrole is very reactive towards electrophiles. For example, treatment with bromine leads to substitution of all four positions. 

Pyrrole is very reactive towards electrophiles charge distribution from the nitrogen makes either C-2 (or C-3) electron rich. Thus, a second porphobilinogen acts as the nucleophile towards the methylidene pyrrolium cation in a conjugate addition reaction. It is now possible to see that two further identical steps will give us the required linear tetrapyrrole, and that one more time will then achieve ring formation. 

Pyrrole is very reactive towards electrophiles. With bromine in ethanol at 0 C, for example, it gives 2,3,4,5-tetrabromopyrrole, whereas sulfuryl chloride (SO-,Cl.,) in diethyl ether at 0 °C yields 2-chloropyrrole. 

Problem 20.22 Compare, and explain the difference between, pyridine and pyrrole with respect to reactivity toward electrophilic substitution. 

Bromination The five-membered aromatic heterocycles are all more reactive toward electrophiles than benzene is, and the reactivity is similar to that of phenol. These compounds undergo electrophilic bromination. However, reaction rates vary considerably, and for pyrrole, furan and thiophene the rates are 5.6 x 10, 1.2 x 10 and 1.00, respectively. While unsubstituted five-membered aromatic heterocycles produce a mixture of bromo-derivatives, e.g. bromothiphenes, substituted heterocycles produce a single product. 

Like 1,3-azoles, due to the presence of a pyridine-like nitrogen atom in the ring, 1,2-azoles are also much less reactive towards electrophilic substitutions than furan, pyrrole or thiophene. However, 1,2-azoles undergo electrophilic substitutions under appropriate reaction conditions, and the main substitution takes place at the C-4 position, for example bromination of 1,2-azoles. Nitration and sulphonation of 1,2-azoles can also be carried out, but only under vigorous reaction conditions. 

It is convenient to consider heteroaromatic ligands in two classes - 7t-excessive, five membered rings typified by pyrrole, furan and thiophen, and TC-deficient six-membered rings typified by pyridine. The 7i-excessive heterocycles are usually extremely reactive towards electrophilic attack and, with the exception of thiophen, do not exhibit the chemical inertness often associated with aromatic benzene derivatives. Conversely, the TT-deficient heterocycles are extremely inert with respect to electrophilic attack. Paradoxically, it is the high reactivity of the five-membered rings and the inertness of the six-membered rings that give rise to common synthetic problems. The usual methods for the... 

Pyrrole is extremely reactive towards electrophiles while thiophene, the most aromatic of the trio, is much less reactive. At a very rough approximation, the reactivity of thiophene is of the order of a heteroatom-substituted benzene derivative such as phenol. Despite large differences in the rates of electrophilic substitutions there are some important aromatic substitution reactions common to all three heterocycles. 

The presence of a pyridine-like nitrogen in the 1,2-azoles makes them markedly less reactive towards electrophilic substitution than furan, pyrrole, and thiophene. (The same effect was noted for the 1,3-azoles in Chapter 3.) Nevertheless, electrophilic substitution is known in 1,2-azoles, occurring principally at the C4 position. This selectivity is reminiscent of pyridine chemistry where the position meta to the electronegative nitrogen atom is the least deactivated (see Chapter 5). 

The NMR of pyrrole is slightly less convincing as the two types of proton on the ring resonate at higher field (6.5 and 6.2 p.p.m.) than those of benzene or pyridine but they still fall in the aromatic rather than the alkene region. Pyrrole is also more reactive towards electrophiles than benzene or... 

Notice that the regioselectivity is the same as it was with pyrrole—the 2-position is more reactive than the 3-position in both cases. The product ketones are less reactive towards electrophiles than the starting heterocycles and deactivated furans can even be nitrated with the usual reagents used for benzene derivatives. Notice that reaction has occurred at the 5-position in spite of the presence of the ketone. The preference for 2- and 5-substitution is quite marked. 

Heteroaromatics have high reactivity toward electrophilic palladation and show good regioselectivity. Reactions with pyrrole,thiophene, furan, and indole have been reported (equation 3). The use of stoichiometric copper(II) ion gives a process catalytic in Pd. 

Nitrogen s extra pair of electrons, which is responsible for the usual basicity of nitrogen compounds, is involved in the tt cloud, and is not available for sharing with acids. In contrast to most amines, therefore, pyrrole is an extremely weak base (ATj, -- 2.5 X 10 14). By the same token, there is a high electron density in the ring, which causes pyrrole to be extremely reactive toward electrophilic substitution it undergoes reactions like nitrosation and coupling with diazonium salts which are characteristic of only the most reactive benzene derivatives, phenols and amines. 

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