Reactivity of pyrrole

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. 

The reactivity sequence furan > tellurophene > selenophene > thiophene is thus the same for all three reactions and is in the reverse order of the aromaticities of the ring systems assessed by a number of different criteria. The relative rate for the trifluoroacetylation of pyrrole is 5.3 x lo . It is interesting to note that AT-methylpyrrole is approximately twice as reactive to trifluoroacetylation as pyrrole itself. The enhanced reactivity of pyrrole compared with the other monocyclic systems is also demonstrated by the relative rates of bromination of the 2-methoxycarbonyl derivatives, which gave the reactivity sequence pyrrole>furan > selenophene > thiophene, and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3] (35) with a further selection of heteroaromatic substrates (Scheme 5). The comparative rates of reaction from this substitution were 2-methylindole == AT-methylindole>indole > pyrrole > furan > thiophene (73CC540). 

The main feature of the reactivity of pyrrole-2-carboxylic acids is the ease with which the carboxyl group is removed. Thermal decarboxylation is a preparatively useful reaction. 

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of iV-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive... 

Pyrazoles and imidazoles exist partly as anions (e.g. 108 and 109) in neutral and basic solution. Under these conditions they react with electrophilic reagents almost as readily as phenol, undergoing diazo coupling, nitrosation and Mannich reactions (note the increased reactivity of pyrrole anions over the neutral pyrrole species). 

The pyrrole ring is widely distributed in nature. It occurs in both terrestrial and marine plants and animals [1-3]. Examples of simple pyrroles include the Pseudomonas metabolite pyrrolnitrin, a recently discovered seabird hexahalogenated bipyrrole [4], and an ant trail pheromone. An illustration of the abundant complex natural pyrroles is konbu acidin A, a sponge metabolite that inhibits cyclin-dependent kinase 4. The enormous reactivity of pyrrole in electrophilic substitution reactions explains the occurrence of more than 100 naturally occurring halogenated pyrroles [2, 3]. 

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of Af-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive to hydroxide addition at the carbonyl carbon than A-methylpyrrole-2-carbaldehyde (76JOC1952). Pyrrole-2-aldehydes fail to undergo Cannizzaro and benzoin reactions, which is attributed to mesomerism involving the ring nitrogen (see 366). They yield 2-hydroxymethylpyrroles (by NaBH4 reduction) and 2-methylpyrroles (Wolff-Kishner reduction). The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

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>. 

Doak and Corwin94 have studied the kinetics of the iodination of some trisubstituted derivatives of pyrrole and A-methylpyrrole. Both free iodine and hypoiodous acid are supposed to be the iodinating agents in this reaction. The similar reactivity exhibited by pyrrole and A-rn ethyl py rrole contradicts the hypothesis previously proposed,95 that the great reactivity of pyrroles in iodination may be due to a reaction either of the dissociated anion or the pyrrolenine tautomer. 

The relative reactivities of all four unsubstituted rings have been subsequently determined in another electrophilic substitution trifluoroacetylation by trifluoroacetic anhydride in dichloroeth-ane.142 143 The relative rates, obtained by a competitive procedure, are in good agreement with the bromination data (Table V) and confirm, in particular, the big jump in reactivity from furan to pyrrole. The great reactivity of pyrrole cannot be ascribed to a reaction involving the anion C4H4N, since V-methylpyrrole is still more reactive than pyrrole by a factor of about 2. 

The very high reactivity of pyrrole compared with furan in electrophilic substitutions is also confirmed by rate measurements of hydrogen-deuterium exchange in methanol-water-sulfuric acid mixtures53 (Table VI). The rate of exchange of pyrrole-2-d in 0.5%... 

Nitration of 2- and 3-nitropyrrole and their 1-methyl analogues by nitric acid-sulfuric acid at 25°C showed the nitro groups to deactivate by factors of 1.5 x 105 and 2.6 x 104, respectively this is less than that in benzene, which may reasonably be attributed to the higher reactivity of pyrrole. The l-methyl compounds were only 1.5 times more reactive (75CHE571), which is consistent with the results obtained in hydrogen exchange (see Section I.D.). 

The high basicity and consequent electrophilic reactivity that hinder the determination of the reactivity of pyrrole relative to other aromatics facilitates reaction with unreactive electrophiles. This was utilized by Butler and co-workers, who measured partial rate factors for methyl substituents (Table 6.10) in coupling with benzenediazonium ions [77JCS(P2) 1452] and in alkylation by 4-(Af,ALdimethylamino)benzalde-hyde [76JCS(P2)696]. The selectivities of both reactions are remarkably similar. Reaction with p-X-benzenediazonium ions (X = OMe, CN, NO,... 

The activation by a 5-methyl group on the 2-position was calculated as 170-fold (77G339) from unpublished data of Noyce et al. for solvolysis of I-arylethyl p-nitrobenzoates. This indicates a sensitivity to substituent effects greater than either those of furan or thiophene, despite the far higher reactivity of pyrrole. 

The decade passed since the mid-1990s has again shown a sustainable interest in the reactivity of pyrroles and their benzo derivatives <2002CRV4303> the research interest owes it to their important role in the living matter, drug design, and advanced materials. 

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