Pyrrole

Pyrrole, or pyrrol, is a heterocyclic aromatic organic compound, a five-membered ring with the formula C₄H₄NH.^[1] Substituted derivatives are also called pyrroles. For example, C₄H₄NCH₃ is N-methylpyrrole. Porphobilinogen is a trisubstituted pyrrole, which is the biosynthetic precursor to many natural products.^[2]

Pyrroles are components of more complex macrocycles, including the porphyrins of heme, the chlorins and bacteriochlorins^[3] of chlorophyll, and porphyrinogens.

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Properties

Pyrrole has very low basicity compared to amines and other aromatic compounds like pyridine where the ring nitrogen is not bonded to a hydrogen atom. This decreased basicity is attributed to the delocalization of the lone pair of electrons of the nitrogen atom in the aromatic ring. Pyrrole is a very weak base with a pK_aH of about -4. Protonation results in loss of aromaticity and is therefore unfavorable.

Synthesis

Many methods exist for the organic synthesis of pyrrole and its derivatives. Classic named reactions are the Knorr pyrrole synthesis, the Hantzch pyrrole synthesis and the Paal-Knorr synthesis.

The starting materials in the Piloty-Robinson pyrrole synthesis are 2 equivalents of an aldehyde and hydrazine^[4][5]. The product is a pyrrole with specific substituents in the 3 and 4 positions. The aldehyde reacts with the diamine to an intermediate di-imine (R-C=N-N=C-R) which with added hydrochloric acid, gives ring-closure and loss of ammonia to the pyrrole.

In one modification propionaldehyde is reacted first with hydrazine and then with benzoyl chloride at high temperatures and assisted by microwave irradiation^[6]:

In the second step a [3,3]sigmatropic reaction takes place between two intermediates.

Reactivity

Both NH and CH protons in pyrroles are moderately acidic and can be deprotonated with strong bases such as butyllithium and the metal hydrides. The resulting "pyrrolides" are nucleophilic. Trapping of the conjugate base with an electrophile (e.g. an alkyl or acyl halide) reveals which sites were deprotonated based on which ring positions actually react as nucleophiles. The product distribution of such a reaction can often be complex and depends on the base used (especially the counterion, such as lithium from butyllithium or sodium from sodium hydride), existing substitution of the pyrrole, and the electrophile.

Pyrrole undergoes electrophilic aromatic substitution predominantly at the 2 and 5 positions, though the substitution product at positions 3 and 4 is obtained in low yields. Two such reactions that are especially significant for producing functionalized pyrroles are the Mannich reaction and the Vilsmeier-Haack reaction (depicted below) ^{[7] [8]}, both of which are compatible with a variety of pyrrole substrates. Reaction of pyrroles with formaldehyde form porphyrins.

Pyrrole compounds can also participate in cycloaddition (Diels-Alder) reactions under certain conditions, such as Lewis acid catalysis, heating, or high pressure.

Commercial Uses

In a 1994 report released by five top cigarette companies, pyrrole is one of the 599 additives to cigarettes. Its use or purpose, however, is unknown, like most cigarette additives. ^[9]

See also

• Arsole, a moderately-aromatic arsenic analog.
• Furan, an analog with an oxygen instead of the nitrogen.
• Indole, a derivative with a fused benzene ring.
• Phosphole, a non-aromatic phosphorus analog.
• Polypyrrole
• Pyroluria
• Pyrroline, a partially saturated analog with one double bond
• Pyrrolidine, the saturated hydrogenated analog
• Simple aromatic rings
• Thiophene, an analog with a sulfur instead of the nitrogen atom.

References

1. ^ # Loudon, Marc G. (2002). "Chemistry of Naphalene and the Aromatic Heterocycles.", Organic Chemistry, Fourth Edition, New York: Oxford University Press, 1135-1136. ISBN 0-19-511999-1. 
2. ^ Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.
3. ^ The aromatic pathways of porphins, chlorins and bacteriochlorins Jonas Juse lius and Dage Sundholm Phys. Chem. Chem. Phys., 2000, 2, 2145-2151 doi:10.1039/b000260g Open access
4. ^ Piloty, O. Chem. Ber. 1910, 43, 489.
5. ^ Robinson, R.; Robinson, G. M. J. Chem. Soc. 1918, 43, 639-644.
6. ^ Microwave-Assisted Piloty-Robinson Synthesis of 3,4-Disubstituted Pyrroles Benjamin C. Milgram, Katrine Eskildsen, Steven M. Richter, W. Robert Scheidt, and Karl A. Scheidt J. Org. Chem.; 2007; 72(10) pp 3941 - 3944; (Note) doi:10.1021/jo070389+
7. ^ Comparison of Benzene, Nitrobenzene, and Dinitrobenzene 2-Arylsulfenylpyrroles Jose R. Garabatos-Perera, Benjamin H. Rotstein, and Alison Thompson J. Org. Chem. 2007, 72, 7382-7385 doi:10.1021/jo070493r
8. ^ The 2-sulfenyl group in the pyrrole substrate acts as an activating group and as a protective group which can be removed with Raney nickel
9. ^ quitsmoking.about.com Link