Pyrrole ring reactivity

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. 

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 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). 

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 /)-oxobilanc route to porphyrins 17->20 is more common since here the oxo function does not influence the reactivity of the terminal pyrrole rings at which the cyclization occurs. As with w-oxobilanes the oxo function has to be removed but here it can be done after cyclization at the porphyrin stage. 

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 same authors <2000J(P1)3584> studied the reactivity of 2 toward benzenediazonium (chloride or tetrafluoro-borate) salts. No diazo coupling took place under neutral or slightly acidic conditions. However, under basic conditions (NaOH in H20/MeOH), a mixture of 62 and 63 was obtained. This result clearly indicates that the diazo coupling takes place through the anion of 62 which arises from the base-catalyzed methanolysis of amide 2 in which the pyrrole ring is obviously not nucleophilic enough. 

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. 

With an electron-withdrawing N-substituent the pyrrole ring is more reactive as a diene towards acetylenic dienophiles, and the Diels-Alder... 

The first step is formation of a pyrrole ring system from two identical aminoketones. It is actually a Knorr pyrrole synthesis, but we do not need to identify it as such, just approach it logically. In fact, if we look back at the Knorr pyrrole synthesis, we shall see that, under chemical conditions, the reagents used here are not sufficiently reactive for the pyrrole synthesis we need a more activated compound, like ethyl acetoacetate. Furthermore, we could not possibly proceed without masking the carboxyls as esters. This underlines how a biosynthetic sequence might differ somewhat from a purely chemical synthesis. 

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

Electrophilic aromatic substitution Electrophilic aromatic substitution of indole occurs on the five-membered pyrrole ring, because it is more reactive towards such reaction than a benzene ring. As an electron-rich heterocycle, indole undergoes electrophilic aromatic substitution primarily at C-3, for example bromination of indole. 

Pyrroles and fiirans were prepared by the intramolecular carbon-carbon bond formation between pendant acetylene and nitrile or carbonyl functions. The process, running in acetic acid, starts by the fraw-acetoxypalladation of the acetylene moiety, which initiates a series of further transformations. The nature of the ring formed is determined by heteroatom bridging the two reactive units. The propargylamine derivative in 3.88., for example gave a pyrrole ring.112... 

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>. 

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