Pyrrol rings

In the heaviest fractions such as resins and asphaltenes (see article 1.2), metal atoms such as nickel and vanadium are found. They belong in part to molecules in the porphyrine family where the basic pattern is represented by four pyrrolic rings, the metal being at the center of this complex in the form Wi - or V0+ (< 3)... 

This synthesis of the pyrrole ring system, due to Knorr, consists in the condensation of an a-aminoketone with a 1,3-diketone or the ester of a p-keto-acid, a-Aminoketones are unstable in the free state, readily undergoing self-condensation consequently they must be prepared, by the reduction of an a-nitroso (or oximino) ketone, in the presence of the 1,3-diketone or p-ketoester, to ensure rapid interaction. 

Heteroaromatics such as furan, thiophene, and even the 2-pyridone 280 react with acrylate to form 281(244-246]. Benzene and heteroaromatic rings are introduced into naphthoquinone (282) as an alkene component[247]. The pyrrole ring is more reactive than the benzene ring in indole. 

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. 

As illustrated in Scheme 8.1, both 2-vinylpyrroles and 3-vinylpyiroles are potential precursors of 4,5,6,7-tetrahydroindolcs via Diels-Alder cyclizations. Vinylpyrroles are relatively reactive dienes. However, they are also rather sensitive compounds and this has tended to restrict their synthetic application. While l-methyl-2-vinylpyrrole gives a good yield of an indole with dimethyl acetylenedicarboxylate, ot-substitiients on the vinyl group result in direct electrophilic attack at C5 of the pyrrole ring. This has been attributed to the stenc restriction on access to the necessary cisoid conformation of the 2-vinyl substituent[l]. 

Indole is a heteroaromatic compound consisting of a fused benzene and pyrrole ring, specifically ben2o[ ]pyrrole. The systematic name, IJT-indole (1) distinguishes it from the less stable tautomer 3JT-indole [271-26-1] (2). Iff-Indole [120-72-9] is also more stable than the isomeric ben2o[ ] pyrrole, which is called isoindole, (2H, (3) and IH (4)). A third isomer ben2o[i ]pyrrole is a stable compound called indoli2idine [274-40-8] (5). 

Indole is a heterocycHc analogue of naphthalene. The basic reactivity patterns of indole can be understood as resulting from the fusion of an electron-rich pyrrole ring with a ben2ene ring. 

Electrophilic Aromatic Substitution. The Tt-excessive character of the pyrrole ring makes the indole ring susceptible to electrophilic attack. The reactivity is greater at the 3-position than at the 2-position. This reactivity pattern is suggested both by electron density distributions calculated by molecular orbital methods and by the relative energies of the intermediates for electrophilic substitution, as represented by the protonated stmctures (7a) and (7b). Stmcture (7b) is more favorable than (7a) because it retains the ben2enoid character of the carbocycHc ring (12). 

Endo adducts are usually favored by iateractions between the double bonds of the diene and the carbonyl groups of the dienophile. As was mentioned ia the section on alkylation, the reaction of pyrrole compounds and maleic anhydride results ia a substitution at the 2-position of the pyrrole ring (34,44). Thiophene [110-02-1] forms a cycloaddition adduct with maleic anhydride but only under severe pressures and around 100°C (45). Addition of electron-withdrawiag substituents about the double bond of maleic anhydride increases rates of cycloaddition. Both a-(carbomethoxy)maleic anhydride [69327-00-0] and a-(phenylsulfonyl) maleic anhydride [120789-76-6] react with 1,3-dienes, styrenes, and vinyl ethers much faster than tetracyanoethylene [670-54-2] (46). 

NH2)50s(2,3-T -L)], where L = furan, pyrrole, and thiophene. Although neither the furan nor thiophene complexes react with maleic anhydride over a period of 10 days, the pyrrole complex (15) reacts rapidly at room temperature and 101.3 kPa to form a mixture of endo (17) and exo (16) complexes. An a2omethine ylide intermediate was postulated as the key intermediate through which maleic anhydride added to the 2- and 5-positions of the coordinated pyrrole ring. 

Phthalocyanines. The pyrrole ring system is also the fundamental stmctural unit of the important group of blue and blue-green pigments known as the phthalocyanines (see Phthalocyanine compounds). 

Reduction of isoindoles with dissolving metals or catalytically occurs in the pyrrole ring. Reduction of indolizine with hydrogen and a platinum catalyst gives an octahydro derivative. With a palladium catalyst in neutral solution, reduction occurs in the pyridine ring but in the presence of acid, reduction occurs in the five-membered ring (Scheme 38). Reductive metallation of 1,3-diphenylisobenzofuran results in stereoselective formation of the cw-1,3-dihydro derivative (Scheme 39) (80JOC3982). 

The reactions of pyrroles with dienophiles generally follow two different pathways involving either a [4 + 2] cycloaddition or a Michael-type addition to a free a-position of the pyrrole ring. Pyrrole itself gives a complex mixture of products with maleic anhydride or maleic acid and with benzyne reacts to give 2-phenylpyrrole rather than a product of cycloaddition (Scheme 47). 

This procedure provides a method for functionalizing the pyrrole ring in the 3-position, normally a difficult synthetic step when conventional electrophilic substitution is used, The technique has been extended to... 

Oxidation of the 3-(hydroxyalkyl)pyrrole derivative gives a pure 3-acylpyrrole derivative which is difficult to obtain by direct substitution in the pyrrole ring. Acylation of pyrrole yields 1- and/or 2-acetyl pyrrole, whereas acylation of 1-methyl pyrrole forms both 2- and 3-acetyl-1-methyl-... 

Apart from the A-methyl group, three double-bond equivalents and three multiplets remain in the chemical shift range appropriate for electron rich heteroaromatics, Sh = 6.2 to 6.9. A-Methyl-pyrrole is such a compound. Since in the multiplets at Sh = 6.25 and 6.80 the Jhh coupling of 4.0 Hz is appropriate for pyrrole protons in the 3- and 4-positions, the pyrrole ring is deduced to be substituted in the 2-position. 

The free 2-position in the pyrrole ring (B) explains the indole colour reactions given by these acids and the parent alkaloids. 

Several alkaloids have been recorded for plants of this sub-order. From Nymphoea alba Linn., Bures and Plzik isolated nymphoeine, C14H23O2N it is amorphous, has m.p. 76-7°, gives a hydrochloride, m.p. 230° (dec.), contains a hydroxyl group, appears to be a secondary base, and to contain a pyrrole ring. It is toxic to frogs and produces tetanus-like symptoms. 

In addition to electrophilic attack on the pyrrole ring in indole, there is the possibility for additions to the fused benzene ring. First examine the highest-occupied molecular orbital (HOMO) of indole. Which atoms contribute the most What should be the favored position for electrophilic attack Next, compare the energies of the various protonated forms of indole (C protonated only). These serve as models for adducts formed upon electrophilic addition. Which carbon on the pyrrole ring (C2 or C3) is favored for protonation Is this the same as the preference in pyrrole itself (see Chapter 15, Problem 2)1 If not, try to explain why not. Which of the carbons on the benzene ring is most susceptible to protonation Rationalize your result based on what you know about the reactivity of substituted benzenes toward electrophiles. Are any of the benzene carbons as reactive as the most reactive pyrrole carbon Explain. 

The pyrrole ring in numerous natural products has been constructed using a PK synthesis. Examples include lamellarin L, funebrine, magnolamide, and... 

NMR speetroseopy. According to these data the protonation occurs at the amino group with no evidence for protonation of the pyrrole ring (87T5225). 

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