pyrrole

Pyrrole
IUPAC name	1H-pyrrole [1]
Other names	Pyrrol
Identifiers
CAS number	109-97-7 Y
SMILES	C1=CC=CN1
InChI	1/C4H5N/c1-2-4-5-3-1/h1-5H
Properties
Molecular formula	C4H5N
Molar mass	67.09 g/mol
Density	0.967 g/cm3
Melting point	−23 °C
Boiling point	129–131 °C
Y (what is this?)  (verify) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Pyrrole 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, bacteriochlorins chlorophyll, porphyrinogens.^[3]

Properties

Pyrrole has very low basicity compared to conventional amines and some other aromatic compounds like pyridine. 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.

Pyrrole being distilled.

Pyrrole after the distillation process. It is now transparent due to the removal of impurities such as Polypyrrole.

Synthesis

Pyrrole is prepared industrially from by treatment of furan with ammonia in the presence of solid acid catalysts.^[4]

Substituted pyrroles

Many methods exist for the organic synthesis of pyrrole derivatives. Classic "named reactions" are the Knorr pyrrole synthesis, the Hantzsch pyrrole synthesis, and the Paal-Knorr synthesis. More specialized methods are listed here.

The starting materials in the Piloty-Robinson pyrrole synthesis are 2 equivalents of an aldehyde and hydrazine.^[5][6] 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 treated first with hydrazine and then with benzoyl chloride at high temperatures and assisted by microwave irradiation:^[7]

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

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.^[8]

Reactivity

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

Resonance Contributors of Pyrrole

The resonance contributors of pyrrole provide insight to the reactivity of the compound. Like furan and thiophene, pyrrole is more reactive than benzene towards nucleophilic aromatic substitution because it is able to stabilize the negative charge of the intermediate carbanion.

Pyrrole undergoes electrophilic aromatic substitution predominantly at the 2 and 5 positions. Two such reactions that are especially significant for producing functionalized pyrroles are the Mannich reaction and the Vilsmeier-Haack reaction (depicted below)^[9][10] both of which are compatible with a variety of pyrrole substrates.

Formylation of a pyrrole derivative (Garabatos-Perera 2007^[9])

Pyrroles react with aldehydes to form porphyrins. For example, benzaldehyde condenses with pyrrole to give tetraphenylporphyrin. Pyrrole compounds can also participate in cycloaddition (Diels-Alder) reactions under certain conditions, such as under Lewis acid catalysis, heating, or high pressure.

Commercial Uses

Pyrrole has no significant commercial application, but N-methylpyrrole is a precursor to N-methylpyrrolecarboxylic acid, a building block in pharmaceutical chemistry.^[4]

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 Naphthalene and the Aromatic Heterocycles.". Organic Chemistry (Fourth ed.). New York: Oxford University Press. pp. 1135–1136. ISBN 0-19-511999-1. 
2. ^ Cox, Michael; Lehninger, Albert L; Nelson, David R. (2000). Lehninger principles of biochemistry. New York: Worth Publishers. ISBN 1-57259-153-6. 
3. ^ Jonas Jusélius and Dage Sundholm (2000). "The aromatic pathways of porphins, chlorins and bacteriochlorins" (Open access). Phys. Chem. Chem. Phys. 2: 2145–2151. doi:10.1039/b000260g. 
4. ^ ^{a b} Albrecht Ludwig Harreus "Pyrrole" in Ullmann's Encyclopedia of Industrial Chemistry, 2002, Wiley-VCH, Weinheim. doi:10.1002/14356007.a22_453
5. ^ Piloty, O. (1910). "Synthese von Pyrrolderivaten: Pyrrole aus Succinylobernsteinsäureester, Pyrrole aus Azinen". Chem. Ber. 43: 489. doi:10.1002/cber.19100430182. 
6. ^ Robinson, Gertrude Maud (1918). "LIV.—A new synthesis of tetraphenylpyrrole". J. Chem. Soc. 113: 639. doi:10.1039/CT9181300639. 
7. ^ Benjamin C. Milgram, Katrine Eskildsen, Steven M. Richter, W. Robert Scheidt, and Karl A. Scheidt (2007). "Microwave-Assisted Piloty-Robinson Synthesis of 3,4-Disubstituted Pyrroles" (Note). J. Org. Chem. 72 (10): 3941–3944. doi:10.1021/jo070389. 
8. ^ Practical Organic Chemistry, Vogel, Page 837, http://www.sciencemadness.org/library/books/vogel_practical_ochem_3.pdf
9. ^ ^{a b} Jose R. Garabatos-Perera, Benjamin H. Rotstein, and Alison Thompson (2007). "Comparison of Benzene, Nitrobenzene, and Dinitrobenzene 2-Arylsulfenylpyrroles". J. Org. Chem. 72: 7382–7385. doi:10.1021/jo070493r. 
10. ^ The 2-sulfenyl group in the pyrrole substrate serves as an activating group and as a protective group that can be removed with Raney nickel

External links

• General Synthesis and Reactivity of Pyrrole
• Synthesis of pyrroles (overview of recent methods)
• Substitution reaction mechanisms of nitrogen-containing heteroaromatics
• Recent Review on Pyrrole Protection