Reactivity of the Pyrrole Ring

This low substrate selectivity and the low positional selectivity (see Section III,B) are in keeping with a transition state little perturbed with respect to the initial state. This was to be expected, on the basis of the Hammond postulate,183 in view of the very great reactivity of the pyrrole ring. 

In a series of papers spanning 20 years, Natsume, Muratake, and coworkers reported a versatile synthesis of indoles exploiting the reactivity of the pyrrole ring toward intramolecular electrophilic attack at the C-2 or C-3 position [1-16], In their seminal paper, Natsume and... 

After this work, the more challenging synthesis of arene-alkynylated indoles was investigated. Because of the enhanced reactivity of the pyrrole ring, the direct functionalization of indoles on the benzene ring is highly challenging. A domino process to access these compounds would therefore be very useful. They were able... 

Calculations of ru-electron densities of indole using the Huckel method, when appropriate parameters are introduced into the calculation to take into account the electronegativity of the nitrogen atom, give a 7i-density order of3>2>4 5 6 7 (57). The method employed predicts correctly the order of positional reactivity of the pyrrole ring, whereas it has not predictive value for positions in the benzene ring. 

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]. 

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). 

Antibodies also well catalyze the reactions where a molecule should he forced to adopt a particular and reactive conformation, thanks to privileged interactions with the amino acids of the binding site. For example, ahzymes with a ferrochelatase activity, 7G12, force the mesoporphyrin IX ring to adopt a distorted conformation favorable to the insertion of a Cu ion in the center of the macrocycle,thanks to an interaction with the HlOOc methionine which constrains one of the pyrrole rings to be left outside the plane of porphyrin (Figure 24). 

Alekseeva et al. (1972b) have carried out a comparison of calculated values of localization energies and free valency indices of pyrrolo[ 1,2-a] imidazole, pyrrolo[l,2-a] benzimidazole and indolizine. In all these molecules the a-position of the pyrrole ring is calculated to be more reactive than the / -position. The free valence indices increase in the order indolizine < pyrrolobenzimidazole < pyrroloimidazole, which is also the order of increasing basicity. 

The reactivity of radical-cations of porphins with various nucleophiles has been studied the reaction afforded the corresponding meso-substituted porphins 373-375 or substitution in the / -position of the pyrrole rings in the porphins.376... 

As mentioned earlier (Section 3.18.4) thienopyrroles have been studied much more than other azaheteropentalenes. Thieno[2,3-f ]pyrrole (32) undergoes Vilsmeier formylation to yield a mixture of two products (43) and (44) in 90% and 10% yields, respectively. The major product is the C-5 substituted isomer (43) which is not surprising in view of the higher reactivity of pyrrole compared to thiophene. Upon deactivation of the pyrrole ring by the introduction of an ester function at C-5 as in (45) formylation occurs exclusively at C-2 to give aldehyde (46) in 95% yield (Scheme 8) (78AHC(22)183>. 

The two earliest structures (14, 20) shown in Figure 3 were based on the reactivity of these compounds to the Ehrlich reagent. The pyrrole-2-carboxylic acid of the second formula was presumed to be attached to protein by the hydroxyl group at the 4-position of the pyrrole ring. 

The reactivity of iodylbenzene was increased in the presence of trifluoroacetic acid for example, PhSCH2CH2N02 was converted into its sulphoxide (97%) at room temperature [11]. 4-t-Butyliodylbenzene in hot chlorobenzene oxidized tetralin to a-tetralone (97%) [12] it also brought about the opening of the pyrrole ring in a derivative of tryptophan [13]. 

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