Pyrrole

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Pyrrole
Explicit structural formula of pyrrole, with aromaticity indicated by dashed bonds Numbered skeletal formula of pyrrole
Ball-and-stick model of the pyrrole molecule Space-filling model of the pyrrole molecule
Identifiers
CAS number 109-97-7 YesY
PubChem 8027
ChemSpider 7736 YesY
UNII 86S1ZD6L2C YesY
EC number 203-724-7
UN number 1992, 1993
ChEBI CHEBI:19203 YesY
ChEMBL CHEMBL16225 YesY
RTECS number UX9275000
Beilstein Reference 1159
Gmelin Reference 1705
Jmol-3D images Image 1
Image 2
Properties
Molecular formula 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
Specific
heat capacity
C
1.903 J k–1 mol k–1
Std enthalpy of
formation
ΔfHo298
108.2 kJ mol–1 (gas)
Std enthalpy of
combustion
ΔcHo298
2242 kJ mol–1
Hazards
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
Flash point 33.33 °C (91.99 °F; 306.48 K)
Explosive limits 3.1–14.8%
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 YesY (verify) (what is: YesY/N?)
Infobox references

Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4H4NH.[1] It is a colourless 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, porphyrinogens.[3]

Properties[edit]

Pyrrole is a colourless 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 a chemical shifts at 6.68 (H2, H5) and 6.22 (H3, H4). Pyrrole is weakly basic, with a pKa of -3.8. The most thermodynamically stable pyrrolium cation is formed by protonation at the 2 position. Substitution of pyrrole with alkyl substituents provides a more basic molecule—for example, tetramethylpyrrole has a pKa of +3.7. It is also weakly acidic at the N-H position, with a pKa of 17.5.

Resonance Contributors of Pyrrole

History[edit]

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 pyrros (“fiery”), from the reaction used to detect it—the red color that it imparts to wood when moistened with hydrochloric acid.[5]

Occurrence in nature[edit]

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.[6]

Biosynthesis of pyrroles[edit]

The de novo biosynthesis of pyrrole rings begins with α-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.[7]

Mechanism of biosynthesis of porphobilinogen

Synthesis[edit]

Pyrrole is prepared industrially by treatment of furan with ammonia in the presence of solid acid catalysts, like SiO2 and Al2O3.[5]

Synthesis of pyrrole from furan

Pyrrole can also be formed by catalytic dehydrogenation of pyrrolidine.

Laboratory routes[edit]

Several syntheses of the pyrrole ring have been described.

Hantzsch pyrrole synthesis[edit]

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).[8][9]

The Hantzch pyrrole synthesis

Knorr pyrrole synthesis[edit]

The Knorr pyrrole synthesis involves the reaction of an α-amino ketone or an α-amino-β-ketoester with an activated methylene compound.[10][11][12] The method involves the reaction of an α-amino-ketone (1) and a compound containing a methylene group α- to (bonded to the next carbon to) a carbonyl group (2).[13]

The Knorr pyrrole synthesis

Paal-Knorr pyrrole synthesis[edit]

In the Paal-Knorr pyrrole synthesis, a 1,4-dicarbonyl compound reacts with ammonia or a primary amine to form a substituted pyrrole.[14][15]

Paal–Knorr Pyrrole Synthesis

Van Leusen reaction[edit]

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.

Mechanism of Van Leusen reaction to form pyrroles

Barton-Zard synthesis[edit]

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.[16]

Barton-Zard reaction.png

Piloty–Robinson pyrrole synthesis[edit]

The starting materials in the Piloty–Robinson pyrrole synthesis are 2 equivalents of an aldehyde and hydrazine.[17][18] 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.

In one modification, propionaldehyde is treated first with hydrazine and then with benzoyl chloride at high temperatures and assisted by microwave irradiation:[19]

Piloty–Robinson reaction[19]

Cycloaddition-based routes[edit]

Various methods for the synthesis of pyrroles via two-component cycloaddition reactions are known. For example, dipolar cycloaddition of a oxido-oxazolium with an alkyne, followed by a retro-Diels-Alder reaction to expel CO2 provides pyrrole. Similar reactions can be performed using azalactones.

Synthesis of pyrroles via Diels-Alder cyclization

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 Ag-acetylide intermediate. This method is analogous to the azide-alkyne click chemistry used to form azoles.

Synthesis of pyrrole via silver click chemistry

Other methods[edit]

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.[20]

Synthesis of pyrrole from ammonium mucate

Reactions and reactivity[edit]

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.

Reaction of pyrrole with electrophiles[edit]

Pyrroles generally react with electrophiles at the α position (C2 or C4), due to the highest degree of stability of the protonated intermediate.

Pyrrole Electrophilic Substitution

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 α position, but can also occur at the β position by silation of the nitrogen. This is a useful method for further functionalization of the generally less reactive β position.

Acylation[edit]

Acylation generally occurs at the 2-position, through the use of various methods. Acylation with 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.

Vilsmeier-Haack formylation of pyrrole

Alkylation[edit]

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


Reaction of deprotonated pyrrole[edit]

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 methyl iodide gives N-methylpyrrole. N-metallated pyrrole can react with electrophiles at the N or C positions, depending on the coordinating metal. More ionic N-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.

Pyrrole C Metallation

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[edit]

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[edit]

Pyrroles with N-substitution can undergo cycloaddition reactions such as (4+2), (2+2), (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 N. Vinylpyrroles can also act as dienes.

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 (Ciamician-Dennstedt Rearrangement).[21]

Ciamician-Dennstedt Rearrangement

Commercial uses[edit]

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.[5] Although there is a claim that pyrrole is used as an additive to cigarettes[citation needed], it is typically listed as a constituent of tobacco smoke and not as an ingredient.[22]

Analogs and derivatives[edit]

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.

See also[edit]

References[edit]

  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. ^ a b Jonas Jusélius and Dage Sundholm (2000). "The aromatic pathways of porphins, chlorins and bacteriochlorins". Phys. Chem. Chem. Phys. (Open access) 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. ^ a b c Albrecht Ludwig Harreus "Pyrrole" in Ullmann's Encyclopedia of Industrial Chemistry, 2002, Wiley-VCH, Weinheim. doi:10.1002/14356007.a22_453
  6. ^ Emil, Fischer. "Nobel Prize Lecture". 
  7. ^ 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. 
  8. ^ Hantzsch, A. Ber. 1890, 23, 1474.
  9. ^ Feist, F. Ber. 1902, 35, 1538.
  10. ^ Knorr, L. (1884). "Synthese von Pyrrolderivaten". Berichte der deutschen chemischen Gesellschaft 17 (2): 1635. doi:10.1002/cber.18840170220.  edit
  11. ^ Knorr, L. (1886). Ann. 236: 290. 
  12. ^ Knorr, L.; Lange, H. (1902). "Ueber die Bildung von Pyrrolderivaten aus Isonitrosoketonen". Berichte der deutschen chemischen Gesellschaft 35 (3): 2998. doi:10.1002/cber.19020350392.  edit
  13. ^ Corwin, A. H. (1950). Heterocyclic Compounds 1: 287. 
  14. ^ Paal, C. (1884), Berichte der deutschen chemischen Gesellschaft 17: 2756, doi:10.1002/cber.188401702228 
  15. ^ Knorr, L. (1884), Berichte der deutschen chemischen Gesellschaft 17: 2863, doi:10.1002/cber.188401702254 
  16. ^ Jie Jack Li (2013). Heterocyclic Chemistry in Drug Discovery. New York: Wiley. ISBN 9781118354421. 
  17. ^ Piloty, O. (1910). "Synthese von Pyrrolderivaten: Pyrrole aus Succinylobernsteinsäureester, Pyrrole aus Azinen". Chem. Ber. 43: 489. doi:10.1002/cber.19100430182. 
  18. ^ Robinson, Gertrude Maud; Robinson, Robert (1918). "LIV.—A new synthesis of tetraphenylpyrrole". J. Chem. Soc. 113: 639. doi:10.1039/CT9181300639. 
  19. ^ a b 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. PMC 1939979. PMID 17432915. 
  20. ^ Practical Organic Chemistry, Vogel, 1956, Page 837, Link (12 MB)
  21. ^ Ciamician-Dennstedt Rearrangement, Ciamician, G. L. and Dennstedt, M. Ber. 14, 1153 (1881); Corwin, A. H. Heterocyclic Compounds 1, 309 (1950); Mosher, H. S. Heterocyclic Compounds 475
  22. ^ Fowles, Jefferson; Michael Bates and Dominique Noiton (March 2000). "The Chemical Constituents in Cigarettes and Cigarette Smoke: Priorities for Harm Reduction". Porirua, New Zealand: New Zealand Ministry of Health. pp. 20, 49–65. Retrieved 2012-09-23. 

External links[edit]