Pyrroles side-chain reactivity

In Table II the pK s of the 2- and 3-carboxylic acids of thiophene, furan, and pyrrole are reported. While pyrrole carboxylic acids, like the alkoxy- and amino-substituted benzoic acids, are weaker, thiophene- and furan carboxylic acids, like the chloro-and bromobenzoic acids, are stronger than unsubstituted benzoic acid. This behavior is confirmed by other side-chain reactivity data.41... 

This synthesis of this widely used model compound uses a Knorr sequence as the first step the oligomerisation steps and the final cyclisation rest on side-chain reactivity of pyrrolylammonium salts (section 13.12) and the easy decarboxylation of pyrrole acids (section 13.14). 

We still have to make the pyrrole with the alkyl side chain for this acylation reaction. Friedel-Crafts alkylation is not an option but pyrroles are reactive enough to do the Mannich reaction. Formaldehyde and an amine combine to give another iminium salt 107 that reacts with A-methyl pyrrole to give, after rearomatisation 109 the substituted pyrrole 110. 

The only available data concern some a-carbonium ion side-chain reactions (hydrolysis of <-cumyl chlorides and p-nitrobenzoates) they reveal that the substitution of nitrogen for a CH group, in furan, thiophene, or pyrrole, leads to a fairly uniform reduction in reactivity at the 2-position.211... 

Pyrrole reacts with halogens so readily that unless controlled conditions are used, tetrahalo-pyrroles are the only isolable products, and these are stable. Attempts to mono-halogenate simple alkyl-pyrroles fail, probably because of side-chain halogenation and the generation of extremely reactive pyrryl-alkyl halides (16.11). 

Pyrroles (10) can be made the same way, the cyclisation being carried out with ammonia, but an alternative strategy is particularly valuable for carbonyl-substituted pyrroles. Pyrrole esters such as (15) are needed for the synthesis of porphyrins (as in haemoglobin), chlorins (as in chlorophyll), and corrins (vitamin B 2). Ester (IS) has the haem side chain and can be converted by hydrolysis and decarboxylation into a pyrrole (16) with a reactive free position (H in 16). 

By contrast, pyrroles are sufficiently reactive that formylation normally proceeds both on nucleus and side chain. An unusual result is shown in the reaction of compound 95 (Eq. 89). ... 

Because of the occurrence of isomers, the synthesis from pyrroles is only useful for porphyrins with eight identical /8-pyrrolic and four identical methine bridge substituents. Famous examples are the syntheses of chloroform-soluble /8-octaethyl-porphyrin and meso-tetraphenylporphyrin which have been used in innumerable studies on porphyrin reactivity (K.M. Smith, 1975). Porphyrins with four long meso-alkyl side-chains can be obtained by use of analogous reactions. These porphyrins have melting points below 100 °C and are readily soluble in petroleum ether. Sulfonation of olefinic double bonds leads to highly charged, water soluble porphyrins (J.-H. Fuhrhop, 197 ). 

Side chain lithiation is a major source of reactivity in terms of the elaboration of pyrroles and indoles, and new examples and developments continue to be reported. One major development has been the lithiation of 2-alkyl groups of 2-alkylindole-1 -carboxylate lithium salts. The carboxyl group protects the nitrogen atom, directs the lithiation, and can easily be removed after alkylation (Scheme 121) <86JA6808>. Similarly, lithiation of 2,3-dialkylindoles takes place at the 2-methylene position via the C,7V-dilithio derivative, using three equivalents of butyllithium <9UOC2256>. 

Concerning the function of the other side chains around the porphin ring, namely, the methyl groups, no direct evidence is available. From the chemical point of view a reasonable postulate is that they function as a protection for the reactive pyrrole rings, preventing them from entering into undesirable side reactions which might occur in the cells. 

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