Pyrrole carbon substitutions

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 thiophene ring can be elaborated using standard electrophilic, nucleophilic, and organometallic chemistry. A variety of methods have been developed to exploit the tendency for the thiophene ring (analogous to that of furan and pyrrole) to favor electrophilic substitution and metallation at its a-carbons. Substitution at the p-carbons is more challenging, but this problem can also be solved by utilizing relative reactivity differences. 

All haem-containing compounds are derivatives of porfihin (Fig. 1), which does not itself occur naturally. AO. porphyrins and metalloporphyrins which are found in living systems are fully substituted at the pyrrole carbon... 

Kaneko extended the early work of Schild on tuberostemonine, demonstrating the presence of a C-ethyl group and two lactone rings (1). Edwards et al. 2) used spectroscopic methods to elaborate this picture. Bisdehydrotuberostemonine, the product of silver oxide oxidation 3,4), was shown to contain a pyrrole ring substituted as in I. The NMR-spectrum of this compound confirmed the presence of the C-ethyl group. In addition it was deduced that the second lactone ring was substituted as in II, with a possible further carbon-carbon bond at position 3. 

Here we see that the macrocycle consists of two pyrrole units and two pyrrolenine units. After a ir-electron count, the great American chemist, R.B. Woodward, pointed out that the two pyrrole units could be considered to have their own aromatic sextet of electrons. Each pyrrolenine unit, on the other hand, is one electron short of the aromatic sextet, having only five tt-electrons. In order to make up this deficiency, they can be thought of as borrowing electron density from the neighbouring meso-carbons. This means that, compared with the pyrrole carbons, the meso-carbons will have a tendency to be electron deficient and, therefore, would be less enthusiastic about electrophilic substitution. 

Reactivity patterns of pyrrole carbons are determined by delocalization of the nitrogen lone pair. The electron-rich nature of this heterocycle means that reactions with electrophiles are facile and preferentially occur at the C2 (or C5) position unless it is already substituted. This innate reactivity means that C—H activation by metal insertion preferentially occurs at the position adjacent to the heteroatom. 

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). 

Hydroxypyrroles. Pyrroles with nitrogen-substituted side chains containing hydroxyl groups are best prepared by the Paal-Knorr cyclization. Pyrroles with hydroxyl groups on carbon side chains can be made by reduction of the appropriate carbonyl compound with hydrides, by Grignard synthesis, or by iasertion of ethylene oxide or formaldehyde. For example, pyrrole plus formaldehyde gives 2-hydroxymethylpyrrole [27472-36-2] (24). The hydroxymethylpyrroles do not act as normal primary alcohols because of resonance stabilization of carbonium ions formed by loss of water. 

The high reactivity of pyrroles to electrophiles is similar to that of arylamines and is a reflection of the mesomeric release of electrons from nitrogen to ring carbons. Reactions with electrophilic reagents may result in addition rather than substitution. Thus furan reacts with acetyl nitrate to give a 2,5-adduct (33) and in a similar fashion an adduct (34) is obtained from the reaction of ethyl vinyl ether with hydrogen bromide. 

It is also of significance that in the dilute gas phase, where the intrinsic orientating properties of pyrrole can be examined without the complication of variable phenomena such as solvation, ion-pairing and catalyst attendant on electrophilic substitution reactions in solution, preferential /3-attack on pyrrole occurs. In gas phase t-butylation, the relative order of reactivity at /3-carbon, a-carbon and nitrogen is 10.3 3.0 1.0 (81CC1177). 

Carbon tetrachloride was also found to react with pyrryl potassium to give 3-chloropyridine, however the mechanism is obscure and would justify further investigation. In a preparatively useful reaction, pyrrole and chloroform in the vapor phase at 500-550° gave 3-chloro-pyridine (33%) and a little 2-chloropyridine (2-5%). No interconversion of the isomers occurred under these conditions, though pyrolytic rearrangement of N-alkylpyrrole to 3-substituted pyridines is considered to involve 2-alkylpyrroles as intermediates. There is some independent evidence that dichlorocarbene is formed in the vapor phase decomposition of chloroform. ... 

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... 

Porphyrins are formally derived from the porphin (1) nucleus by substitution of some or all peripheral positions with various side chains. In the classical system of nomenclature T, introduced by H. Fischer,Sc the peripheral /5-pyrrolic positions are numbered front 1 to 8 and the methine positions (also named meso positions) between the pyrrole rings are designated a, //, y, and 5. The rings are lettered clockwise A, B, C, and D. The classical nomenclature was in the past more and more displaced by a nomenclature which numbers all the carbon... 

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