Pyrrole, acylation nitration

The first three reactions are all electrophilic substitution a bromination of a pyrrole, the nitration quinoline, and a Friedel-Crafts acylation of thiophene. Bromination occurs on the pyrrole at only remaining site. Nitration of quinoline occurs on the benzene rather than the quinoline r-fi (actually giving a mixture of 5- and 8-nitroquinolines, but don t worry if you didn t see t- Mi p. 1174), and the acylation would occur next to sulfur. 

In many ways the chemistry of indole is that of a reactive pyrrole ring with a relatively unreactive benzene ring standing on one side—electrophilic substitution almost always occurs on the pyrrole ring, for example. But indole and pyrrole differ in one important respect. In indole, electrophilic substitution is preferred in the 3-position with almost all reagents whereas it occurs in the 2-position with pyrrole. Halogenation, nitration, sulfonation, Friedel—Crafts acylation, and alkylation all occur cleanly at that position. 

Frontier orbital theory predicts that electrophilic substitution of pyrroles with soft electrophiles will be frontier controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles will be charge controlled and occur at the 3-position. These predictions may be illustrated by the substitution behaviour of 1-benzenesulfonylpyr-role. Nitration and Friedel-Crafts acylation of this substrate occurs at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N=CH2), in formylation under Vilsmeier conditions (R2N=CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO=CHCl) effect substitution mainly in the 2-position (81TL4899, 81TL4901). Formylation of 2-methoxycarbonyl-l-methylpyrrole with... 

Grignard reagent from, acylation, 4, 237 nitration, 4, 211 reactivity, 4, 71-72 synthesis, 4, 149, 237, 341, 360 Pyrrole-3-carboxylic acids acidity, 4, 71 decarboxylation, 4, 286 esterification, 4, 287 esters... 

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 ... 

Typical electrophilic reactions, such as nitration, halogenation with a Lewis acid (as a carrier ), Friedel-Crafts C-alkylation and -acylation, that work well with benzene, cannot be applied to pyrrole, because heating with strong acids, or a Lewis acid, destroys the heterocycle. However,... 

The monosubstitution products of the Friedel-Crafts reaction and of the nitration reaction have been interrelated to show that the substituent group is introduced at the same position in each case. A further correlation with the adduct (Id) from indolizine and methyl propiolate provides evidence that this is the 1-position as predicted.56 Acylation of 2-methoxycarbonyl-3-phenylcycl[3,2,2]azine (Is) takes place in the pyrrole part of the molecule.51... 

The synthesis of a pyrrole segment common to netropsin and distamycin is shown in Scheme 2ji°l Friedel-Crafts acylation of 1-methylpyrrole (1) followed by nitration at C4 provides 3 in 54% yield. After a haloform reaction, hydrogenolysis, N-protection with B0C2O, and saponification, the pyrrolecarboxylic derivative acid 7 was obtained in 30% overall yield from 3. This monomer is readily chain-extended to the pyrrole-imidazole derivative 9 (Scheme 3)J10 Furthermore, solid-phase synthesis with this and related pyrrole-containing building blocks leads to polyamides that have recently been used in the recognition of a 16 base-pair sequence in the minor groove of DNA.1" ... 

Instead, these heterocycles and their derivatives most commonly undergo electrophilic substitution nitration, sulfonation, halogenation. Friedel-Crafts acylation, even the Reimer-Tiemann reaction and coupling with diazonium salts. Heats of combustion indicate resonance stabilization to the extent of 22-28 kcal/ mole somewhat less than the resonance energy of benzene (36 kcal/mde), but much greater than that of most conjugateci dienes (about Tlccal/mole). On the basis of these properties, pyrrole, furan, and thiophene must be considered aromatic. Clearly, formulas I, II, and III do not adequately represent the structures of these compounds. 

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. ... 

Electrophilic substitution is less useful on pyrroles and furans than on benzenes (see Chapters 2 and 3) as the less stable five-membered rings are destroyed by strong acids. Nitrations and Friedel-Crafts acylations can still be carried out under mild conditions the a-positions are attacked first, or, if these are blocked, thejS-positions are attacked almost equally as well. 

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... 

Like benzene derivatives, porphyrins will undergo Friedel-Crafts reactions. Thus, deuterohemin dimethyl ester acylates at its 3- and 8-pyrrole positions [Figure 3.17(a)]. Nitration [Figure 3.17(b)] occurs, unexpectedly, only at the meso-carbons, even when the less electrophilic 3-pyrrole positions are vacant. 

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