Pyrrole electrophilic substitution into

The following rules pertain to electrophilic substitution in pyrroles (35) (/) an electron-withdrawing substituent in the a-position directs substitution to the P and a -positions, (2) an electron-releasing substituent in the a-position directs substitution to the neighboring -position or to the a -position, (J) an electron-withdrawing substituent in the -position leads to substitution in the a -position, and (4) an electron-releasing substituent in the P-position tends to direct substitution into the neighboring a-position. 

The preparation of -substituted derivatives is more difficult and different methods have been used in the various series. 2-Tritylpyrrole undergoes electrophilic substitution selectively at the 3-position (Section 3.3.1.4.3) and the trityl group can then be removed. Again, in the pyrrole series the selective hydrolysis of a-C02Et in alkali and of (3-C02Et in acid, followed by decarboxylation, allows the introduction of (3-substituents into compounds such as 2,4-dialkylpyrrole-3,5-dicarboxylic esters to afford 3-substituted 2,4-dialkylpyrroles (Section 33.3.3.1). 

Nevertheless, this collection of heterocycles does share certain characteristics. The trend we have seen of decreasing tendency towards electrophilic substitution on going from furan, pyrrole, and thiophene to the azoles is continued into these series. The presence of additional pyridine-like nitrogen atoms renders these systems particularly electron-deficient, and electrophilic substitution is of little importance. 

Attempts to correlate reaction mechanisms, electron density calculations and experimental results have met with only limited success. As mentioned in the previous chapter (Section 4.06.2), the predicted orders of electrophilic substitution for imidazole (C-5 > -2 > -4) and benzimidazole (C-7>-6>-5>-4 -2) do not take into account the tautomeric equivalence of the 4- and 5-positions of imidazole and the 4- and 7-, 5- and 6-positions of benzimidazole. When this is taken into account the predictions are in accord with the observed orientations of attack in imidazole. Much the same predictions can be made by considering the imidazole molecule to be a combination of pyrrole and pyridine (74) — the most likely site for electrophilic attack is C-5. Furthermore, while sets of resonance structures for the imidazole and benzimidazole neutral molecules (Schemes 1 and 2, Section 4.06.2) suggest that all ring carbons have some susceptibility to electrophilic attack, consideration of the stabilities of the expected tr-intermediates (Scheme 29) supports the commonly observed preference for 5- (or 4-) substitution. In benzimidazole attack usually occurs first at C-5 and a second substituent enters at C-6 unless other substituent effects intervene. 

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. 

Reactions of Pyrroles. 1,3-Di-t-butylpyrrole forms the first stable protonated pyrrole, the salt (104). Electrophilic substitution of pyrrole with MeaC or Me FC in the gas phase occurs mainly at the j3-position, as does nitration and Friedel-Crafts acylation of l-phenylsulphonylpyrrole2 Pyrrole-2,5-dialdehyde has been prepared by Vilsmeier-Haack formylation of the ester (105), followed by hydrolysis. A similar method has been used to convert the di-acetal (106) into pyrrole-2,3,5-tricarbaldehyde. AT-Benzoyl-pyrrole reacts with benzene in the presence of palladium(II) acetate to yield a mixture of l-benzoyl-2,5-diphenylpyrrole, the bipyrrolyl (107), and compound (108). Treating lithiated A-methylpyrrole with nickel(II) chloride results in the polypyrrolyls (109 = 0-4). 2-Aryl-1-methylpyrroles are obtained by cross-coupling of l-methylpyrrol-2-ylmagnesium bromide with aryl halides in the presence of palladium(0)-phosphine complexes. ... 

Pyrrole, furan, and thiophene are all more reactive than benzene toward electrophilic substitution because they are better able to stabilize the positive charge on the carbocation intermediate, since the lone pair on the hetereoatom can donate electrons into the ring by resonance (Figure 21.1). 

The NH-acidity of carbazole = 17.06 corresponds approximately to that of indoles and pyrroles. For this reason, carbazole is convertible into A -metallated compounds which can be subjected to electrophilic substitution on nitrogen. 

Organometallic intermediates continue to be important in the synthetic methodology for substitution of pyrroles and indoles. Numerous lithiation techniques have been reported and provide a range of useful reaction conditions. The pyrrolyl dimer (120) (really a dimeric equivalent of pyrrole-2-carbaldehyde) can be lithiated at the 5- and 5 -positions. Electrophilic substitution then yields 5-substituted pyrrole-2-carbaldehydes (121) (Scheme 34) <88TL777>. The related monomeric ald-iminium salts (122) yield similar products after anion formation, bromination, lithiation, and electrophilic attack (Scheme 35) <88HCA2053>. In a similar process, the dimer (120) can be brominated at C-4 and converted into 4-substituted pyrrole-2-carbaldehydes <88TL3215>. 

Carbazoles behave like o,o -disubstituted diphenylamines. However, the basicity of carbazole, pKa = —4.94, is much lower than that of diphenylamine (pfCo = 0.78), and also lower than that of indole and pyrrole. As a consequence, carbazole is insoluble in dilute acids but only soluble in concentrated H2SO4 with protonation of the N-atom. On pouring the solution into water, carbazole precipitates without polymerization. The N-H-acidity of carbazole (pfCA = 17.06) corresponds approximately to that of indoles and pyrroles. For this reason, carbazole is convertible into N-metalated compounds which can be subjected to electrophilic substitution on nitrogen. 

Sufficiently electrophilic aromatic compounds can effect substitution into pyrroles. Thus, acylpyridinium compounds give products formulated in the manner of (14), though the evidence for attachment at C(4> in the pyridine nucleus, rather than at C(2), is not conclusive - . In contrast, the product from 2-ethoxy-3,4-dimethylpyrrole, ethyl chloroformate and pyridine is formulated as the fully aromatized 3,4-dimethyl-2,5-di(4-pyridyl)pyrrole. Pyrroles react with acridine, giving either complexes of 9-(2-pyrrolyl)acridan with acridine, or 9-(2-pyrrolyl)acridine2 . 1-Methylpyrrole does not react with acridine, but 2,5-dimethylpyrrole reacts at both j8-positions. 

As stated already, the observed orientations of electrophilic substitution can be accounted for, in the pyrrole molecule, in terms of electrophilic localization energies, without invoking an auxiliary inductive parameter, for positive values of A. However, pyrrole is very reactive, and for this reason orientation would be expected to follow 7r-electron densities. These fall into line (when the acceptable value A = + 2 is used) if A >0 19. The orientation of electrophilic substitution is satisfactorily accounted foi s when A = 2 and A = 0 25. 

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). 

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