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 (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

150px|thumb|left|class=skin-invert-image|Structure of Heme B

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.

Synthesis

Pyrrole is prepared industrially by treatment of furan with ammonia in the presence of solid acid catalysts, like SiO2 and Al2O3. 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).

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 (1) and a compound containing a methylene group α to (bonded to the next carbon to) a carbonyl group (2).

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.

center|300px|class=skin-invert-image|The Paal–Knorr pyrrole synthesis

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.

:center|700px|class=skin-invert-image|Mechanism of the Van Leusen reaction to form pyrroles

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.

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 (R−C=N−N=C−R). In the second step, a [3,3]-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

center|class=skin-invert-image|Synthesis of pyrrole from ammonium mucate

The Trofimov reaction allows for the synthesis of 2,3-disubstituted pyrroles from ketoximes and acetylene in basic medium.

center|frameless|class=skin-invert-image|500x500px|Synthesis of pyrrole through the Trofimov reaction

Biosynthesis

The biosynthesis of pyrrole rings begins with aminolevulinic acid (ALA), 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 (PBG). This later reacts to form, for example, the macrocycles heme and chlorophyll.

center|class=skin-invert-image|Mechanism of biosynthesis of porphobilinogen.

Proline is biosynthetically derived from the amino acid L-glutamate. Glutamate-5-semialdehyde is first formed by glutamate 5-kinase (ATP-dependent) and glutamate-5-semialdehyde dehydrogenase (which requires NADH or NADPH). This can then either spontaneously cyclize to form 1-pyrroline-5-carboxylic acid, which is reduced to proline by pyrroline-5-carboxylate reductase (using NADH or NADPH), or turned into ornithine by ornithine aminotransferase, followed by cyclisation by ornithine cyclodeaminase to form proline.

thumb|left|260px|class=skin-invert-image|[[Zwitterionic structure of both proline enantiomers: (S)-proline (left) and (R)-proline]]

Proline can be used as precursor of aromatic pyrroles in secondary natural products, as in prodigiosins.

thumb|left|class=skin-invert-image|Figure 1: Structure of Prodigiosin 1 highlighting the A, B, and C pyrrole rings

The biosynthesis of Prodigiosin involves the convergent coupling of three pyrrole type rings (labeled A, B, and C in figure 1) from L-proline, L-serine, L-methionine, pyruvate, and 2-octenal.

Ring A is synthesized from L-proline through the nonribosomal peptide synthase (NRPS) pathway (figure 2), wherein the pyrrolidine ring of proline is oxidized twice through FAD+ to yield pyrrole ring A.

class=skin-invert-image|Figure 2: biosynthesis of pyrrole ring A

Ring A is then expanded via the polyketide synthase pathway to incorporate L-serine into ring B (figure 3). Ring A fragment is transferred from the peptidyl carrier protein (PCP) to the Acyl Carrier Protein (ACP) 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 (which incorporates a methyl group from L-methionine onto the alcohol at the 6 position) and oxidation of the primary alcohol to the aldehyde to yield the core A–B ring structures.

class=skin-invert-image|Biosynthesis of pyrrole ring B

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 (including protected pyrroles) have been used in a broad range of transformations. 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.

Acylation

Acylation generally occurs at the 2-position, through the use of various methods. Acylation with acid anhydrides and acid chlorides can occur with or without a catalyst. 2-Acylpyrroles are also obtained from reaction with nitriles, by the Houben–Hoesch reaction. Pyrrole aldehydes can be formed by a Vilsmeier–Haack reaction.

400px|center|class=skin-invert-image|Vilsmeier–Haack formylation of pyrrole

Reaction of deprotonated pyrrole

The NH proton in pyrroles is moderately acidic with a pKa of 17.5. Pyrrole can be deprotonated with strong bases such as butyllithium and sodium hydride. The resulting alkali pyrrolide is nucleophilic. Treating this conjugate base with an electrophile such as iodomethane gives N-methylpyrrole.

N-Metalated pyrrole can react with electrophiles at the N or C positions, depending on the coordinating metal. More ionic nitrogen–metal bonds (such as with lithium, sodium, and potassium) and more solvating solvents lead to N-alkylation. Nitrophilic metals, such as MgX, lead to alkylation at C (mainly C2), due to a higher degree of coordination to the nitrogen atom. In the cases of N-substituted pyrroles, metalation of the carbons is more facile. Alkyl groups can be introduced as electrophiles, or by cross-coupling reactions.

center|class=skin-invert-image|Pyrrole C-metalation

Substitution at C3 can be achieved through the use of N-substituted 3-bromopyrrole, which can be synthesized by bromination of N-silylpyrrole with NBS.

Reductions

Pyrroles can undergo reductions to pyrrolidines and to pyrrolines. For example, Birch reduction of pyrrole esters and amides produced pyrrolines, with the regioselectivity depending on the position of the electron-withdrawing group.

Cyclization reactions

Pyrroles with N-substitution can undergo cycloaddition reactions such as [4+2]-, [2+2]-, and [2+1]-cyclizations. Diels-Alder cyclizations can occur with the pyrrole acting as a diene, especially in the presence of an electron-withdrawing group on the nitrogen. Vinylpyrroles can also act as dienes.

center|class=skin-invert-image|300px|Pyrrole DA

Pyrroles can react with carbenes, such as dichlorocarbene, in a [2+1]-cycloaddition. With dichlorocarbene, a dichlorocyclopropane intermediate is formed, which breaks down to form 3-chloropyridine (the Ciamician–Dennstedt rearrangement).

500px|center|class=skin-invert-image|Ciamician–Dennstedt rearrangement

Commercial uses

Polypyrrole is of some commercial value. N-Methylpyrrole is a precursor to N-methylpyrrolecarboxylic acid, a building-block in pharmaceutical chemistry.

Analogs and derivatives

Structural analogs of pyrrole include:

Pyrroline, a partially saturated analog with one double bond
Pyrrolidine, the saturated hydrogenated analog

Derivatives of pyrrole include indole, a derivative with a fused benzene ring.

References

External links

Synthesis of pyrroles (overview of recent methods)
Substitution reaction mechanisms of nitrogen-containing heteroaromatics