Pyrroles, carbon atom reactivity

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. 

Inspection of the three cations shows that (13) and (14) would be expected to be quito active as electrophilic reagents by reason of delocalization of the positive charge by mesomerism leading to the transfer of electrophilic character to the carbon atom. Cation (12), on the other hand, would show electrophilic reactivity at carbon only by induction. Since neutral pyrrole is so susceptible to electrophilic attack, it is extremely likely that it would react with one or other of the three cations. 

Pyrrole is thus referred to as a n-excessive heterocycle and behaves rather like a reactive benzene derivative, e.g. aniline (p. 153), undergoing very ready electrophilic attack. This may be complicated by the fact that in strongly acid solution protonation (69) is forced even on the weakly basic pyrrole (it takes place on the 2-carbon atom rather than on N, cf. p. 73) ... 

Rearrangement Formation of Pyrroles. 7 Reactivity of Substituents Attached to Ring Carbon Atoms. 8 Reactivity of Substituents Attached to Ring Heteroatoms... 

Although MO calculations do give an indication of the relative reactivity of the a- and /3-positions, no satisfactory explanation has been proposed for the relatively unreactive character of the nitrogen atom. In all theoretical calculations, the charge density on the nitrogen atom is considerably higher than on the carbon atoms. This anomaly may only be explained when we have more detailed information on the mechanism of pyrrole substitution reactions. 

M—1 sec-1) (Hart et al., 1964a). It has been pointed out that the replacement of a carbon atom of a double bond by a tertiary nitrogen atom increases the reactivity of the compound by two orders of magnitude (Anbar, 1965). This is true in the cases of pyrrole and imidazole, benzene and pyridine, as well as in the cases of thioazole and thiophene (k = 2-5 x 10° and 6-5 x 107, respectively) (Anbar andNeta, 1967a). 

The reactivity sequence furan > selenophene > thiophene > benzene has also been observed in the nucleophilic substitutions of the halogenonitro derivatives of these rings.21,22 This shows that the observed trend does not depend on the effectiveness of lone-pair conjugation of the heteroatoms NH, O, Se, and S and the 77-electron density at the carbon atoms. It is interesting to note that a good correlation is observed between molecular ionization potentials (determined from electron impact measurements) and reactivity data in electrophilic substitution, in that higher reactivities correspond to lower ionization potentials182 pyrrole furan < selenophene < thiophene benzene (see Table VII). This is expected in view of a... 

If the nucleophile is very reactive, the preferred agent for trifluoromethylation is the dimethyl derivative 229b, which is not very powerful. Less reactive substrates were trifluoromethylated in reasonably good yields by the more powerful dinitro salt 230. The unsubstituted salt 229a is intermediate in its trifluoromethylating power. Carbanions, enamines, enol trimethylsilyl ethers, aniline, phenol, and pyrrole have all been successfully trifluoromethylated at their respective nucleophilic carbon atoms (Equations 112-117). 

When the imidazole ring is considered to be something resembling a pyrrole-pyridine combination (1) it would appear that any electrophilic attack should take place preferably at C-5 (pyrrole-or, pyridine-j8). Such a model, though, fails to take account of the tautomeric equivalence of C-4 and C-5 (Section 4.06.5.1). The overall reactivities of imidazole and benzimidazole can be inferred from sets of resonance structures in which the dipolar contributors have finite importance (Section 4.06.2) or by mesomeric structures such as (2). These predict electrophilic attack in imidazole at N-3 or any ring carbon atom, nucleophilic attack at C-2 or C-1, and also the amphoteric nature of the molecule. In benzimidazole the acidic and basic properties, the preference for nucleophilic attack at C-2 and the tendency for electrophiles to react at the fused benzene ring can be readily rationalized. 

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