Pyrrole is a heterocyclic, aromatic, organic compound, a five-membered ring with the formula . It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, . Porphobilinogen, a trisubstituted pyrrole, is the biosynthetic precursor to many natural products such as heme.
Pyrroles are components of more complex macrocycles, including the porphyrinogens and products derived therefrom, including porphyrins of heme, the chlorins, bacteriochlorins, and chlorophylls.
Properties, structure, bonding
Pyrrole is a colorless volatile liquid that darkens readily upon exposure to air, and is usually purified by distillation immediately before use. Pyrrole has a nutty odor. Pyrrole is a 5-membered aromatic heterocycle, like furan and thiophene. Unlike furan and thiophene, it has a dipole in which the positive end lies on the side of the heteroatom, with a dipole moment of 1.58 D. In CDCl3, it has chemical shifts at 6.68 (H2, H5) and 6.22 (H3, H4). Pyrrole is an extremely weak base for an amine, with a conjugate acid pKa of −3.8. The most thermodynamically stable pyrrolium cation (C4H6N+) is formed by protonation at the 2 position. Substitution of pyrrole with alkyl substituents provides a more basic molecule—for example, tetramethylpyrrole has a conjugate acid pKa of +3.7. Pyrrole is also weakly acidic at the N–H position, with a pKa of 16.5. As a hydrogen bonding Lewis acid it is classified as a hard acid and the ECW model lists its acid parameters as EA = 1.38 and CA = 0.68.
Pyrrole has aromatic character because the lone pairs of electrons on the nitrogen atom is partially delocalized into the ring, creating a 4n + 2 aromatic system (see Hückel's rule). In terms of its aromaticity, pyrrole's is modest relative to benzene but comparable to related heterocycles thiophene and furan. The resonance energies of benzene, pyrrole, thiophene, and furan are, respectively, 152, 88, 121, and 67 kJ/mol (36, 21, 29, and 16 kcal/mol). The molecule is flat.
History
Pyrrole was first detected by F. F. Runge in 1834, as a constituent of coal tar. In 1857, it was isolated from the pyrolysate of bone. Its name comes from the Greek pyrrhos (, “reddish, fiery”), from the reaction used to detect it—the red color that it imparts to wood when moistened with hydrochloric acid.
Occurrence in nature
Pyrrole itself is not naturally occurring, but many of its derivatives are found in a variety of cofactors and natural products. Common naturally produced molecules containing pyrroles include vitamin B12, bile pigments like bilirubin and biliverdin, and the porphyrins of heme, chlorophyll, chlorins, bacteriochlorins, and porphyrinogens. Other pyrrole-containing secondary metabolites include PQQ, makaluvamine M, ryanodine, rhazinilam, lamellarin, prodigiosin, myrmicarin, and sceptrin. The syntheses of pyrrole-containing haemin, synthesized by Hans Fischer was recognized by the Nobel Prize.
Pyrrole is a constituent of tobacco smoke and may contribute to its toxic effects.
Synthesis
Pyrrole is prepared industrially by treatment of furan with ammonia in the presence of solid acid catalysts, like SiO2 and Al2O3.
Pyrrole can also be formed by catalytic dehydrogenation of pyrrolidine.
Several syntheses of the pyrrole ring have been described. Three routes dominate, but many other methods exist.
Hantzsch pyrrole synthesis
The Hantzsch pyrrole synthesis is the reaction of β-ketoesters (1) with ammonia (or primary amines) and α-haloketones (2) to give substituted pyrroles (3).
Knorr pyrrole synthesis
The Knorr pyrrole synthesis involves the reaction of an α-amino ketone or an α-amino-β-ketoester with an activated methylene compound. The method involves the reaction of an α-aminoketone (1) and a compound containing a methylene group α to (bonded to the next carbon to) a carbonyl group (2).
Paal–Knorr pyrrole synthesis
In the Paal–Knorr pyrrole synthesis, a 1,4-dicarbonyl compound reacts with ammonia or a primary amine to form a substituted pyrrole.
Other methods
Van Leusen reaction pyrroles are produced by reaction of tosylmethyl isocyanide (TosMIC) with an enone in the presence of base, in a Michael addition. A 5-endo cyclization then forms the 5-membered ring, which reacts to eliminate the tosyl group. The last step is tautomerization to the pyrrole.
By the Barton–Zard synthesis, an isocyanoacetate reacts with a nitroalkene in a 1,4-addition, followed by 5-endo-dig cyclization, elimination of the nitro group, and tautomerization.