Pyrrole, aromaticity electrophilic substitution reactions

Although pyrrole appears to be both an amine and a conjugated diene, its chemical properties are not consistent with either of these structural features. Unlike most other amines, pyrrole is not basic—the pKa of the pyrrolin-ium ion is 0.4 unlike most other conjugated dienes, pyrrole undergoes electrophilic substitution reactions rather than additions. The reason for both these properties, as noted previously in Section 15.5, is that pyrrole has six 77 electrons and is aromatic. Each of the four carbons contributes one... 

The benzo-l,3-dithiole derivative 153, a precursor of a 1,3-dithiolium cation, was used to synthesize substituted 155 and 3,4-disubstituted-pyrrole-2,5-dicarbaldehydes 156 (Scheme 14) <1996J(P1)2365>. Thus, in the aromatic electrophilic substitution reaction of pyrrole with 153, the symmetrical 2,5-disubstituted pyrrole 154 was obtained, from which, following functionalization of positions 3 and/or 4, then the final removal of benzo-l,3-dithiole moieties under hydrolytic conditions using the HgO-HBF4-DMSO, the corresponding 155 and 156 were formed, respectively (DMSO = dimethyl sulfoxide). 

Iron Porphyrins. Porphyrias (15—17) are aromatic cycHc compouads that coasist of four pyrrole units linked at the a-positions by methine carbons. The extended TT-systems of these compounds give rise to intense absorption bands in the uv/vis region of the spectmm. The most intense absorption, which is called the Soret band, falls neat 400 nm and has 10. The TT-system is also responsible for the notable ring current effect observed in H-nmr spectra, the preference for planar conformations, the prevalence of electrophilic substitution reactions, and the redox chemistry of these compounds. Porphyrins obtained from natural sources have a variety of peripheral substituents and substitution patterns. Two important types of synthetic porphyrins are the meso-tetraaryl porphyrins, such as 5,10,15,20-tetraphenylporphine [917-23-7] (H2(TPP)) (7) and P-octaalkylporphyrins, such as 2,3,7,8,12,13,17,18-octaethylporphine [2683-82-1] (H2(OEP)) (8). Both types can be prepared by condensation of pyrroles and aldehydes (qv). 

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. 

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

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 ... 

The formation of the C = O radical can be explained by considering the fact that pyrrole is a heterocyclic compound, considered as aromatic because of the delocalisation of the jr-electrons wich stabilize the ring. These delocalized 7r-electrons are very reactive and they can promote aromatic electrophilic substitution, wich produces to nitration reactions. Usually aromatic nitriles are obtained by means of nitrogen salts (N24), wich comes from aromatic amines, pyrrole in our case. The final step of the overall reaction is the production of the radical carbonyl. However, the polymerization of conductive PPy it must be avoided. Plays de role of TFB as electrolyte acts as activator of the reaction. 

Furthermore, porphyrins react like extremely electron-rich aromatic compounds, comparable to phenol, aniline, or pyrrole. Central metal ions, in particular zinc(II) and copper(II), further activate them in electrophilic substitution reactions, l pical examples of the di- and tetrachlorination, mono- and dinitration, and most important Vilsmeier mono me o-formylation are given (Scheme 6.4.3) (Bonnett and Stephenson, 1965). Vilsmeier formylation of tetraphenylpor-phyrins gives mono (3-formyl products, which have been used to attach side chains to an imidazole end. Five coordinated metal complexes thus become accessible (not shown). 

Furan is the least aromatic of the N, O, S heterocycles, and special conditions are required to preserve the ring in electrophilic substitution reactions. The ring is also sensitive to acidic conditions. When substitutions are successful, it is the 2-position that is entered, for the same reasons described for pyrrole substitutions. Some processes that are useful for furan are described as follows ... 

Reactivity First and foremost, porphyrins are aromatic molecules. For example, they undergo some of the electrophilic substitution reactions characteristic of aromatic compounds—nitration, halogenation, sulphona-tion, formylation, acylation, and deuteration. Porph)nins differ from molecules such as benzene, in that there are two different sites on the macrocycle where electrophilic substitution can take place with different reactivities the meso-position and the pyrrole p-position. Which of these... 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

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... 

Heterocycles with conjugated jr-systems have a propensity to react by substitution, similarly to saturated hydrocarbons, rather than by addition, which is characteristic of most unsaturated hydrocarbons. This reflects the strong tendency to return to the initial electronic structure after a reaction. Electrophilic substitutions of heteroaromatic systems are the most common qualitative expression of their aromaticity. However, the presence of one or more electronegative heteroatoms disturbs the symmetry of aromatic rings pyridine-like heteroatoms (=N—, =N+R—, =0+—, and =S+—) decrease the availability of jr-electrons and the tendency toward electrophilic substitution, allowing for addition and/or nucleophilic substitution in yr-deficient heteroatoms , as classified by Albert.63 By contrast, pyrrole-like heteroatoms (—NR—, —O—, and — S—) in the jr-excessive heteroatoms induce the tendency toward electrophilic substitution (see Scheme 19). The quantitative expression of aromaticity in terms of chemical reactivity is difficult and is especially complicated by the interplay of thermodynamic and kinetic factors. Nevertheless, a number of chemical techniques have been applied which are discussed elsewhere.66... 

The fact that benzene derivatives are much more generally accessible than pyrroles has relegated pyrrole annelation to a relatively minor role in indole synthesis. Nevertheless the concept provides a viable synthetic approach and the existing methods serve as useful prototypes. One strategy is to build up an appropriately functionalized side-chain and complete indole formation by electrophilic substitution-aromatization. Reactions (135)-(137) illustrate this type of approach (79TL3477, 79JA257, 73JPR295). 

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... 

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