Pyrrole

Pyrrole
Names
Preferred IUPAC name
1H-Pyrrole
Other names
Azole
Identifiers
109-97-7 YesY
3D model (Jmol) Interactive image
Interactive image
1159
ChEBI CHEBI:19203 YesY
ChEMBL ChEMBL16225 YesY
ChemSpider 7736 YesY
ECHA InfoCard 100.003.387
EC Number 203-724-7
1705
PubChem 8027
RTECS number UX9275000
UNII 86S1ZD6L2C YesY
UN number 1992, 1993
Properties
C4H5N
Molar mass 67.09 g·mol−1
Density 0.967 g cm−3
Melting point −23 °C (−9 °F; 250 K)
Boiling point 129 to 131 °C (264 to 268 °F; 402 to 404 K)
Vapor pressure 7 mmHg at 23 °C
Viscosity 0.001225 Pa s
Thermochemistry
1.903 J K−1 mol−1
108.2 kJ mol−1 (gas)
2242 kJ mol−1
Hazards
Safety data sheet Chemical Safety Data
NFPA 704
Flammability code 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g., diesel fuel Health code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroform Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
2
2
0
Flash point 33.33 °C (91.99 °F; 306.48 K)
550 °C (1,022 °F; 823 K)
Explosive limits 3.1–14.8%
Related compounds
Related compounds
 Phosphole, arsole, bismole, stibole
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references

Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4H4NH.[1] It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3. Porphobilinogen, a trisubstituted pyrrole, is the biosynthetic precursor to many natural products such as heme.[2]

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

Properties

Pyrrole is a colorless volatile liquid that darkens readily upon exposure to air, and is usually purified by distillation immediately before use.[4] 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 weakly basic, 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 17.5.

Resonance contributors of pyrrole

History

Pyrrole was first detected by F. F. Runge in 1834, as a constituent of coal tar.[5] In 1857, it was isolated from the pyrolysate of bone. Its name comes from the Greek pyrrhos (πυρρός, “fiery”), from the reaction used to detect it—the red color that it imparts to wood when moistened with hydrochloric acid.[6]

Occurrence in nature

Heme b

Pyrroles are found in a variety of biological contexts, as parts 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.[3] Other pyrrole-containing secondary metabolites include PQQ, makaluvamine M, ryanodine, rhazinilam, lamellarin, prodigiosin, myrmicarin, and sceptrin. Pyrroles are also found in several drugs, including atorvastatin, ketorolac, and sunitinib.

One of the first syntheses of pyrrole-containing molecules was that of haemin, synthesized by Emil Fischer in 1929.[7]

Synthesis

Pyrrole is prepared industrially by treatment of furan with ammonia in the presence of solid acid catalysts, like SiO2 and Al2O3.[6]

Pyrrole can also be formed by catalytic dehydrogenation of pyrrolidine.

Laboratory routes

Several syntheses of the pyrrole ring have been described.[8]

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).[9][10]

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.[11][12][13] 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).[14]

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.[15][16]

Van Leusen reaction

Main article: Van Leusen reaction

The Van Leusen reaction can be used to form pyrroles, 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.

Barton–Zard synthesis

The Barton–Zard synthesis proceeds in a manner similar to the Van Leusen 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.[17]

Piloty–Robinson pyrrole synthesis

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.[18][19] 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:[20]

Cycloaddition-based routes

Pyrroles bearing multiple substituents are 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 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.

Other methods

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.[21]

Biosynthesis of pyrroles

The de novo 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.[22]

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 polymerize easily, 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.[8]

Reaction of pyrrole with electrophiles

Pyrroles generally react with electrophiles at the α position (C2 or C5), due to the highest degree of stability of the protonated intermediate.

Pyrroles react easily with nitrating (e.g. HNO3/Ac2O), sulfonating (Py·SO3), and halogenating (e.g. NCS, NBS, Br2, SO2Cl2, and KI/H2O2) 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.

Acylation

Acylation generally occurs at the 2-position, through the use of various methods. Acylation with acid anhydrides and acid chlorides can occur without a catalyst; alternatively, a Lewis acid may be used. 2-Acylpyrroles are also obtained from reaction with nitriles, by the Houben–Hoesch reaction. Pyrrole aldehydes can be formed by a Vilsmeier–Haack reaction. N-Acylation of simple pyrrole does not occur.

Alkylation

Electrophilic alkylation of simple pyrrole is uncommon. Alkylation to form enones at C2 has been seen.

Reaction of deprotonated pyrrole

The NH proton in pyrroles is moderately acidic with a pKa of 16.5. 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-Metallated pyrrole can react with electrophiles at the N or C positions, depending on the coordinating metal. More ionic nitrogen–metal bonds (such as with Li, Na, and K) 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, metallation of the carbons is more facile. Alkyl groups can be introduced as electrophiles, or by cross-coupling reactions.

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.

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).[23][24][25]

Commercial uses

Pyrrole is essential to the production of many different chemicals. N-Methylpyrrole is a precursor to N-methylpyrrolecarboxylic acid, a building-block in pharmaceutical chemistry.[6] Although there is a claim that pyrrole is used as an additive to cigarettes, it is typically listed as a constituent of tobacco smoke and not as an ingredient.[26]

Analogs and derivatives

Structural analogs of pyrrole include:

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

See also

References

  1. ↑ Loudon, Marc G. (2002). "Chemistry of Naphthalene and the Aromatic Heterocycles". Organic Chemistry (4th 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. 1 2 Jusélius, Jonas; Sundholm, Dage (2000). "The aromatic pathways of porphins, chlorins and bacteriochlorins". Phys. Chem. Chem. Phys. 2 (10): 2145–2151. doi:10.1039/b000260g.
  4. ↑ Armarego, Wilfred L. F.; Chai, Christina L. L. (2003). Purification of Laboratory Chemicals (5th ed.). Elsevier. p. 346.
  5. ↑ Runge, F. F. (1834). "Ueber einige Produkte der Steinkohlendestillation" [On some products of coal distillation]. Annalen der Physik und Chemie. 31: 65–78. See especially pages 67–68, where Runge names the compound Pyrrol (fire oil) or Rothöl (red oil).
  6. 1 2 3 Harreus, Albrecht Ludwig (2005), "Pyrrole", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a22_453
  7. ↑ Emil, Fischer. "Nobel Prize Lecture" (PDF).
  8. 1 2 Lubell, W.; Saint-Cyr, D.; Dufour-Gallant, J.; Hopewell, R.; Boutard, N.; Kassem, T.; Dörr, A.; Zelli, R. (2013). "1H-Pyrroles (Update 2013)". Science of Synthesis. 2013 (1): 157–388.
  9. ↑ Hantzsch, A. (1890). "Neue Bildungsweise von Pyrrolderivaten" [New methods of forming pyrrole derivatives]. Berichte der deutschen chemischen Gesellschaft. 23: 1474–1476. doi:10.1002/cber.189002301243.
  10. ↑ Feist, Franz (1902). "Studien in der Furan- und Pyrrol-Gruppe" [Studies in the furan and pyrrole groups]. Berichte der deutschen chemischen Gesellschaft. 35: 1537–1544. doi:10.1002/cber.19020350263.
  11. ↑ Knorr, Ludwig (1884). "Synthese von Pyrrolderivaten" [Synthesis of pyrrole derivatives]. Berichte der deutschen chemischen Gesellschaft. 17 (2): 1635–1642. doi:10.1002/cber.18840170220.
  12. ↑ Knorr, L. (1886). "Synthetische Versuche mit dem Acetessigester" [Synthesis experiments with the [ethyl] ester of acetoacetic acid]. Annalen der Chemie. 236: 290–332. doi:10.1002/jlac.18862360303.
  13. ↑ Knorr, L.; Lange, H. (1902). "Ueber die Bildung von Pyrrolderivaten aus Isonitrosoketonen" [On the formation of pyrrole derivatives from isonitrosketones]. Berichte der deutschen chemischen Gesellschaft. 35 (3): 2998–3008. doi:10.1002/cber.19020350392.
  14. ↑ Corwin, Alsoph Henry (1950). "Chapter 6: The Chemistry of Pyrrole and its Derivatives". In Elderfield, Robert Cooley. Heterocyclic Compounds. 1. New York, NY: Wiley. p. 287.
  15. ↑ Paal, C. (1884), "Ueber die Derivate des Acetophenonacetessigesters und des Acetonylacetessigesters", Berichte der deutschen chemischen Gesellschaft, 17: 2756–2767, doi:10.1002/cber.188401702228
  16. ↑ Knorr, Ludwig (1884), "Synthese von Furfuranderivaten aus dem Diacetbernsteinsäureester" [Synthesis of furan derivatives from the [diethyl] ester of 2,3-diacetyl-succinic acid], Berichte der deutschen chemischen Gesellschaft, 17: 2863–2870, doi:10.1002/cber.188401702254
  17. ↑ Li, Jie Jack (2013). Heterocyclic Chemistry in Drug Discovery. New York: Wiley. ISBN 9781118354421.
  18. ↑ Piloty, Oskar (1910). "Synthese von Pyrrolderivaten: Pyrrole aus Succinylobernsteinsäureester, Pyrrole aus Azinen" [Synthesis of pyrrole derivatives: pyrrole from diethyl succinyl succinate, pyrrole from azines]. Berichte der deutschen chemischen Gesellschaft. 43 (1): 489–498. doi:10.1002/cber.19100430182.
  19. ↑ Robinson, Gertrude Maud; Robinson, Robert (1918). "LIV.—A new synthesis of tetraphenylpyrrole". J. Chem. Soc. 113: 639. doi:10.1039/CT9181300639.
  20. 1 2 Milgram, Benjamin C.; Eskildsen, Katrine; Richter, Steven M.; Scheidt, W. Robert; Scheidt, Karl A. (2007). "Microwave-Assisted Piloty–Robinson Synthesis of 3,4-Disubstituted Pyrroles" (Note). J. Org. Chem. 72 (10): 3941–3944. doi:10.1021/jo070389+. PMC 1939979Freely accessible. PMID 17432915.
  21. ↑ Vogel (1956). Practical Organic Chemistry (PDF). p. 837.
  22. ↑ Walsh, Christopher T.; Garneau-Tsodikova, Sylvie; Howard-Jones, Annaleise R. "Biological formation of pyrroles: Nature's logic and enzymatic machinery". Natural Product Reports. 23 (4): 517. doi:10.1039/b605245m.
  23. ↑ Ciamician, G. L.; Dennstedt, M. (1881). "Ueber die Einwirkung des Chloroforms auf die Kaliumverbindung Pyrrols" [On the reaction of chloroform with the potassium compound of pyrrole]. Berichte der deutschen chemischen Gesellschaft. 14: 1153–1162. doi:10.1002/cber.188101401240.
  24. ↑ Corwin, Alsoph Henry (1950). Elderfield, Robert Cooley, ed. Heterocyclic Compounds. 1. New York, NY: Wiley. p. 309.
  25. ↑ Mosher, H. S. (1950). Elderfield, Robert Cooley, ed. Heterocyclic Compounds. 1. New York, NY: Wiley. p. 475.
  26. ↑ Fowles, Jefferson; Bates, Michael; Noiton, Dominique (March 2000). "The Chemical Constituents in Cigarettes and Cigarette Smoke: Priorities for Harm Reduction" (PDF). Porirua, New Zealand: New Zealand Ministry of Health. pp. 20, 49–65. Retrieved 2012-09-23.

Further reading

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