Pyrrole-2-carboxylic acid, mechanism

Scheme 9 Mechanism of decarboxylation via addition of water to the carboxyl group of pyrrole-2-carboxylic acid. Reprinted with permission from Reference 73. Copyright 2009 American Chemical Society.

We have presented evidence that pyrrole-2-carboxylic acid decarboxylates in acid via the addition of water to the carboxyl group, rather than by direct formation of C02.73 This leads to the formation of the conjugate acid of carbonic acid, C(OH)3+, which rapidly dissociates into protonated water and carbon dioxide (Scheme 9). The pKA for protonation of the a-carbon acid of pyrrole is —3.8.74 Although this mechanism of decarboxylation is more complex than the typical dissociative mechanism generating carbon dioxide, the weak carbanion formed will be a poor nucleophile and will not be subject to internal return. However, this leads to a point of interest, in that an enzyme catalyzes the decarboxylation and carboxylation of pyrrole-2-carboxylic acid and pyrrole respectively.75 In the decarboxylation reaction, unlike the case of 2-ketoacids, the enzyme cannot access the potential catalysis available from preventing the internal return from a highly basic carbanion, which could be the reason that the rates of decarboxylation are more comparable to those in solution. Therefore, the enzyme cannot achieve further acceleration of decarboxylation. In the carboxylation of pyrrole, the absence of a reactive carbanion will also make the reaction more difficult however, in this case it occurs more readily than with other aromatic acid decarboxylases. 

The reaction of cyclohexenamides with nucleophiles such as water, alcohols, or thiols, produced carboxylic acid, esters, or thioesters. Reaction with acetylenic dipolarophiles in acidic conditions produced highly functionalized pyrroles via a complex mechanism, implying as intermediates 1,3-dipoles and bycyclic cycloaddition products. Reaction of cyclohexenamides containing protected hydroxylic functions with AcCl/MeOH produced < -lactones, while cyclohexenamides, bearing in Ri an o-aminophenyl group, easily cyclized to 1, 4-benzodiazepine-2, 5-diones. 

Acidic hydrolysis of the reactive enamide led to the corresponding carboxylic acids 14 whereas alcoholysis gave esters 16 and aminolysis amides 15. The mechanism of the hydrolysis was shown to proceed via miinchnone derivatives 20 which, instead of being opened with a nucleophile, reacted as a 1,3-dipole in [3+2] cycloaddition reactions with propiolic esters or acetylene dicarboxylic esters to give after elimination of carbon dioxide protected pyrroles 19 (Scheme 3.2.4)... 

The mechanisms of the acid-catalysed decarboxylation of pyrrole-2-carboxylic acid and mesitoic acid have been investigated at the B3LYP/6-311G (d, p) level of theory. A polarizable continuum model has been established in order to evaluate the effects of solvents on these reactions. The results of the calculations indicate that the first step of the acid-catalysed decarboxylation of the pyrrole-2-carboxylic acid has two possible pathways the proton of H30 attacks either the a-carbon atom or the carboxyl oxygen atom. The subsequent process of forming a four-membered ring TS is the ratedetermining step. The computational results show that both pathways are favoured. 

CMD mechanism (transition state 3). A similar carboxylate-assisted mechanism was proposed for pyrrole C2-arylation with a ruthenium(I) catalyst and a bnlky carboxylic acid cocatalyst however, this method required a 2-pyridyl snbstitnent directing group at the pyrrole C3 position in order to facilitate the C—H activation reaction. ... 

Pyrrole aldehydes and ketones are important sources of alkylpyrroles, formed from them by WolfF-Kishner reduction 232 -3, 33i, More recently, lithium aluminium hydride has been used for this purpose32 233, 332 -5 Direct addition of the carbonyl compound to the reagent gives the alkyl-pyrrole, whilst inverse addition allows preparation of the carbinol. Carboxylic acids and their esters are also reduced by lithium aluminium hydride to alkylpyrroles. In contrast to pyrrole aldehydes unsubstituted at nitrogen, 2-and 3-formyl-1-methylpyrroles are reduced by lithium aluminium hydride only to the carbinol stage sa. The difference is explained by the mechanism... 

B. Ethyl pyrrole-2-carboxylate. In a 1-1. three-necked round-bottomed flask equipped with a sealed mechanical stirrer and powder funnel are place 1.0 g. of sodium and 300 ml. of anhydrous ethanol. When the sodium is dissolved, 75 g. (0.35 mole) of pyrrol-2-yl trichloromethyl ketone from Part A is added portionwise over a 10-minute period (Note 4). After the addition is complete, the solution is stirred 30 minutes, then concentrated to dryness using a rotary evaporator. The oily residue is partitioned between 200 ml. of ether and 25 ml. of 3 N hydrochloric acid. The ether layer is separated, and the aqueous layer is washed once with 100 ml. of ether. The ether solutions are combined, washed once with 25 ml. of saturated sodium bicarbonate solution, dried with magnesium sulfate, and concentrated by distillation. The residue is fractionated at reduced pressure to give 44.0-44.5 g. (91-92%) of ethyl pyrrole-2 carboxylate as a pale yellow oil, b.p. 125-128° (25 mm.) (Note 5). The yield based on pyrrole is 70-74%. Upon standing at room temperature the product crystallizes, m.p. 40-42°. 

It was mentioned above that the carboxyl carbon is lost in the conversion of anthranilic acid to indole. Consequently, two additional carbon atoms must be supplied to complete the pyrrole ring of the indole. The observation that various ribose derivatives could be the source of these two carbons provided the clue that led to the elucidation of the mechanism of indole synthesis in the tryptophan biosynthetic pathway (232). Yanofsky determined that sonic extracts of a tryptophan auxotroph of E. cdi (that also grew on anthranilic acid or indole) could utilize ribose, ribose 5-phosphate, and 5-phosphoribosylpyrophosphate to form indole from anthranilic acid. With the two former compounds, ATP was essential for the reaction, with the latter compound it was not. This result made it appear evident that 5-phosphoribosylpyrophosphate was the more immediate reactant in the condensation with anthranilic acid. 

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