Synthesis, Reactions, and Medicinal Uses of Pyrrole           

    Pyrrole is a five-membered heterocyclic compound having one nitrogen atom as a heteroatom.

Physical properties:

Colour                :  colorless

State                   :    liquid

Boiling point     : 131^oC

Melting point    :    -23^oC

Solubility           :    Insoluble in water, soluble in organic solvents

Structure & Aromaticity:

All atoms in the pyrrole ring are sp² hybridised, so the pyrrole contains a planar ring structure. the sp² hybrid orbitals overlap with each other and with "s" atomic orbital of the five hydrogens forming C-C, C-N, C-H, and N-H sigma bonds. all these sigma bonds lie in one plane.

Pyrrole also has unhybridized p orbitals and these are perpendicular to the plane of the ring. each p orbital on carbon atom contains one electron and the p orbital on nitrogen contains lone pair of electrons(two electrons). the p orbital overlap to form delocalized pi molecular orbital. Pyrrole shows aromaticity because the resulting pi molecular orbital (which contain 6 electrons) satisfies the Huckel's rule (n=1 in 4n+2).

Resonance structures:

Acidity: Pyrrole is a weak acid (p^k_a is 16.5). Pyrrolyl anion is a strong base.

Basicity: Pyrrole is a weak base (p^k_b is 13.6).

                                 

Synthesis:

1. From furan: Industrially pyrrole is synthesized by passing a mixture of furan and ammonia over alumina (catalyst)  at high temperatures.

2. Paal-Knorr synthesis: Condensation of 1,4- Dicarbonyl compounds with ammonia or primary amines to give pyrrole. the reaction is conducted under neutral or weakly acidic conditions.

Mechanism:

3. Hantzsch synthesis: Reaction of β-ketoesters with ammonia or primary amines and α-halo ketones give substituted pyrroles

Mechanism: 

4. Knorr synthesis: It is a condensation reaction of α-amino ketone and a compound containing an electron-withdrawing group to a carbonyl group in the presence of zinc and glacial acetic acid gives substituted pyrrole. 

Mechanism: 

Electrophilic substitution reactions:

Electrophile attack at 2^nd position gives more resonance structures than electrophile attack at the 3^rd position. More resonance structures mean more stable it is. 

So, electrophilic substitution reactions take place 2^nd position in pyrrole.

Substitution at "C":

1. Halogenation: Pyrrole reacts with halogens to give 2-Halo pyrrole(under controlled conditions). excess halogenation gives tetra halo pyrrole.

2. Nitration: Pyrrole reacts with concentrated nitric acid in acetic acid gives 2-nitro pyrrole.

3. Sulphonation: Pyrrole treated with sulfur trioxide in pyridine gives Pyrrole-2-sulfonic acid.

4. Acylation: Pyrrole reacts with Acetic anhydride at 200 ^oC give 2-Acyl pyrrole.

Substitution at "N":  

5. N-Alkylation: pyrrole reacts with an alkyl halide in Liq. ammonia to give N-alkyl pyrrole.

6. N-Acetylation: pyrrole reacts with Acetyl chloride and boron trifluoride gives N-acetyl pyrrole.

7. N-Metallation: Metallation takes place at Nitrogen in pyrrole.

Oxidation:

• Pyrrole oxidized with hydrogen peroxide and dihydropyran (DHP) gives 1,3-dihydro-2H-pyrrole-2-one.

• Pyrrole is oxidised by chromium trioxide in sulphuric acid to give maleic imide.

Reduction: 

• Pyrrole reduced with platinum and H₂ give pyrrolidine.

• Pyrrole reduced with zinc in acetic acid give 2,5-dihydro pyrrole.

ReimerTiemann reaction: pyrrole undergo Reimer Tiemann reaction to give 3-chloropyridine.

Medicinal uses:

Drugs containing a pyrrole ring:

1. Tolmetin is an NSAID drug used to treat pain, swelling, and tenderness in rheumatoid arthritis and osteoarthritis conditions.

2. Atorvastatin is an anti-hyperlipidemic and used to treat cardiovascular diseases.

3. Pyrrolnitrin is used as an anti-fungal antibiotic.

4. Ketorolac is an NSAID drug used to treat moderate to severe pain.

References (Latest editions):

Heterocyclic chemistry by Raj K. Bansal.

Heterocyclic chemistry by T.L. Gilchrist.

Organic chemistry by Morrison and Boyd.

A  textbook of organic chemistry - Arun Bahl. B.S. Bahl.