Pyrrole
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 and 6.22. Pyrrole is an extremely weak base for an amine, with a conjugate acid pKa of −3.8. The most thermodynamically stable pyrrolium cation 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. 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. 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, 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.Image:Pyrrolsynthese1.svg|200px|center|class=skin-invert-image|Synthesis of pyrrole from furan
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 with ammonia and α-haloketones to give substituted pyrroles.Image:Hantzsch Pyrrole Synthesis Scheme.png|center|300px|class=skin-invert-image|The Hantzsch pyrrole synthesis
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 and a compound containing a methylene group α to a carbonyl group.Image:Knorr Pyrrole Synthesis Scheme.png|center|350px|class=skin-invert-image|The Knorr pyrrole synthesis
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
pyrroles are produced by reaction of tosylmethyl isocyanide 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.
Image:Barton-Zard reaction.svg|center|class=skin-invert-image|400px
The starting materials in the Piloty–Robinson pyrrole synthesis, named for Gertrude and Robert Robinson and Oskar Piloty, are two equivalents of an aldehyde and hydrazine. The product is a pyrrole with substituents at the 3 and 4 positions. The aldehyde reacts with the diamine to an intermediate di-imine. In the second step, a -sigmatropic rearrangement takes place between. Addition of hydrochloric acid leads to ring closure and loss of ammonia to form the pyrrole. The mechanism was developed by the Robinsons.
In one modification, propionaldehyde is treated first with hydrazine and then with benzoyl chloride at high temperatures and assisted by microwave irradiation:
Image:Piloty-Robinson reaction.png|center|400px|class=skin-invert-image|Piloty–Robinson reaction
Pyrroles bearing multiple substituents have been obtained from the reaction of münchnones and alkynes. The reaction mechanism involves 1,3-dipolar cycloaddition followed by loss of carbon dioxide by a retro-Diels–Alder process. Similar reactions can be performed using azalactones.
Pyrroles can also be prepared by silver-catalyzed cyclization of alkynes with isonitriles, where R2 is an electron-withdrawing group, and R1 is an alkane, aryl group, or ester. Examples of disubstituted alkynes have also been seen to form the desired pyrrole in considerable yield. The reaction is proposed to proceed via a silver acetylide intermediate. This method is analogous to the azide–alkyne click chemistry used to form azoles.
One synthetic route to pyrrole involves the decarboxylation of ammonium mucate, the ammonium salt of mucic acid. The salt is typically heated in a distillation setup with glycerol as a solvent.
The Trofimov reaction allows for the synthesis of 2,3-disubstituted pyrroles from ketoximes and acetylene in basic medium.
Biosynthesis
The biosynthesis of pyrrole rings begins with aminolevulinic acid, which is synthesized from glycine and succinyl-CoA. ALA dehydratase catalyzes the condensation of two ALA molecules via a Knorr-type ring synthesis to form porphobilinogen. This later reacts to form, for example, the macrocycles heme and chlorophyll..
Proline is biosynthetically derived from the amino acid L-glutamate. Glutamate-5-semialdehyde is first formed by glutamate 5-kinase and glutamate-5-semialdehyde dehydrogenase. This can then either spontaneously cyclize to form 1-pyrroline-5-carboxylic acid, which is reduced to proline by pyrroline-5-carboxylate reductase, or turned into ornithine by ornithine aminotransferase, followed by cyclisation by ornithine cyclodeaminase to form proline.
Proline can be used as precursor of aromatic pyrroles in secondary natural products, as in prodigiosins.
The biosynthesis of Prodigiosin involves the convergent coupling of three pyrrole type rings from L-proline, L-serine, L-methionine, pyruvate, and 2-octenal.
Ring A is synthesized from L-proline through the nonribosomal peptide synthase pathway, wherein the pyrrolidine ring of proline is oxidized twice through FAD+ to yield pyrrole ring A.
Ring A is then expanded via the polyketide synthase pathway to incorporate L-serine into ring B. Ring A fragment is transferred from the peptidyl carrier protein to the Acyl Carrier Protein by a KS domain, followed by transfer to malonyl-ACP via decarboxylative Claisen condensation. This fragment is then able to react with the masked carbanion formed from the PLP mediated decarboxylation of L-serine, which cyclizes in a dehydration reaction to yield the second pyrrole ring. This intermediate is then modified by methylation and oxidation of the primary alcohol to the aldehyde to yield the core A–B ring structures.
Reactions and reactivity
Due to its aromatic character, pyrrole is difficult to hydrogenate, does not easily react as a diene in Diels–Alder reactions, and does not undergo usual olefin reactions. Its reactivity is similar to that of benzene and aniline, in that it is easy to alkylate and acylate. Under acidic conditions, pyrroles oxidize easily to polypyrrole, and thus many electrophilic reagents that are used in benzene chemistry are not applicable to pyrroles. In contrast, substituted pyrroles have been used in a broad range of transformations.Reaction of pyrrole with electrophiles
Pyrroles generally react with electrophiles at the α position, due to the highest degree of stability of the protonated intermediate.Pyrroles react easily with nitrating, sulfonating, and halogenating agents. Halogenation generally provides polyhalogenated pyrroles, but monohalogenation can be performed. As is typical for electrophilic additions to pyrroles, halogenation generally occurs at the 2-position, but can also occur at the 3-position by silation of the nitrogen. This is a useful method for further functionalization of the generally less reactive 3-position.