View source for Pyrrole

{{Short description|Organic ring compound (C4H4NH)}}
{{Chembox
| Watchedfields = changed 
| verifiedrevid = 464377778
| Name = Pyrrole
| ImageFileL1_Ref = {{chemboximage|correct|??}}
| ImageFileL1 = Pyrrole-2D-full.svg
| ImageClassL1 = skin-invert-image
| ImageNameL1 = Explicit structural formula of pyrrole, with aromaticity indicated by dashed bonds
| ImageFileR1_Ref = {{chemboximage|correct|??}}
| ImageFileR1 = Pyrrole-2D-numbered.svg
| ImageClassR1 = skin-invert-image
| ImageNameR1 = Numbered skeletal formula of pyrrole
| ImageFileL2 = Pyrrole-CRC-MW-3D-balls-A.png
| ImageClassL2 = bg-transparent
| ImageNameL2 = Ball-and-stick model of the pyrrole molecule
| ImageFileR2 = Pyrrole-CRC-MW-3D-vdW.png
| ImageClassR2 = bg-transparent
| ImageNameR2 = Space-filling model of the pyrrole molecule
| PIN = 1''H''-Pyrrole<ref>{{cite book |author=[[International Union of Pure and Applied Chemistry]] |date=2014 |title=Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 |publisher=[[Royal Society of Chemistry|The Royal Society of Chemistry]] |pages=141 |doi=10.1039/9781849733069 |isbn=978-0-85404-182-4}}</ref>
| OtherNames = {{Unbulleted list|Azole|Imidole<ref name="crc97">{{cite book | author=William M. Haynes | title=CRC Handbook of Chemistry and Physics | edition=97th | year=2016 | publisher=CRC Press | location=Boca Raton | isbn=978-1-4987-5429-3 | pages=3–478}}</ref>}}
|Section1={{Chembox Identifiers
| CASNo = 109-97-7
| CASNo_Ref = {{cascite|correct|CAS}}
| PubChem = 8027
| ChemSpiderID = 7736
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| UNII = 86S1ZD6L2C
| UNII_Ref = {{fdacite|correct|FDA}}
| UNNumber = 1992, 1993
| EINECS = 203-724-7
| RTECS = UX9275000
| SMILES = N1C=CC=C1
| SMILES1 = [nH]1cccc1
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 19203
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 16225
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C4H5N/c1-2-4-5-3-1/h1-5H
| InChI = 1/C4H5N/c1-2-4-5-3-1/h1-5H
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KAESVJOAVNADME-UHFFFAOYSA-N
| Beilstein = 1159
| Gmelin = 1705}}
|Section2={{Chembox Properties
| C = 4
| H = 5
| N = 1
| Appearance = colorless volatile liquid
| Density = 0.967&nbsp;g&nbsp;cm<sup>−3</sup>
| MeltingPtC = −23
| BoilingPtC = 129 to 131
| VaporPressure = 7&nbsp;mmHg at 23&nbsp;°C
| pKa = 17.5 (for the N−H proton)
| pKb = 13.6 (p''K''<sub>a</sub> 0.4 for [[Conjugate acid|C.A.]])
| MagSus = {{val|-47.6e-6|u=cm<sup>3</sup>&nbsp;mol<sup>−1</sup>}}
| Viscosity = 0.001225&nbsp;Pa&nbsp;s}}
|Section3={{Chembox Thermochemistry
| DeltaHf = 108.2&nbsp;kJ&nbsp;mol<sup>−1</sup> (gas)
| DeltaHc = 2242&nbsp;kJ&nbsp;mol<sup>−1</sup>
| HeatCapacity = 1.903&nbsp;J&nbsp;K<sup>−1</sup>&nbsp;mol<sup>−1</sup>
 }}
|Section7={{Chembox Hazards
| ExternalSDS = [http://www.sciencelab.com/msds.php?msdsId=9924774 Chemical Safety Data]
| NFPA-H = 2
| NFPA-F = 2
| NFPA-R = 0
| FlashPtC = 33.33
| AutoignitionPtC = 550
| ExploLimits = 3.1–14.8%
}}
|Section8={{Chembox Related
| OtherCompounds = [[Phosphole]], [[arsole]], [[bismole]], [[stibole]]}}
}}

'''Pyrrole''' is a [[heterocyclic]], [[Aromaticity|aromatic]], [[organic compound]], a five-membered [[Ring (chemistry)|ring]] with the [[chemical formula|formula]] {{chem2|C4H4NH}}.<ref>{{cite book
| last = Loudon
| first = Marc G.
| year = 2002
| title = Organic Chemistry
| chapter = Chemistry of Naphthalene and the Aromatic Heterocycles
| edition = 4th
| pages = 1135–1136
| publisher = Oxford University Press
| location = New York
| isbn = 978-0-19-511999-2
}}</ref> It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., ''N''-methylpyrrole, {{chem2|C4H4NCH3}}. [[Porphobilinogen]], a trisubstituted pyrrole, is the biosynthetic precursor to many natural products such as [[heme]].<ref>{{cite book |last1=Cox |first1=Michael |last2=Lehninger |first2=Albert L. |last3=Nelson |first3=David R. |title=Lehninger Principles of Biochemistry |publisher=Worth Publishers |location=New York |year=2000 |isbn=978-1-57259-153-0 |url-access=registration |url=https://archive.org/details/lehningerprincip01lehn }}</ref>

Pyrroles are components of more complex macrocycles, including the [[porphyrinogen]]s and products derived therefrom, including [[porphyrin]]s of [[heme]], the [[chlorin]]s, bacteriochlorins, and [[chlorophyll]]s.<ref name="Jonas Jusélius and Dage Sundholm 2000 2145–2151">{{cite journal | title = The aromatic pathways of porphins, chlorins and bacteriochlorins |first1=Jonas |last1=Jusélius |first2=Dage |last2=Sundholm | journal = [[Phys. Chem. Chem. Phys.]] | year = 2000 | volume = 2 | pages = 2145–2151 | doi = 10.1039/b000260g | issue = 10|bibcode=2000PCCP....2.2145J |url=https://zenodo.org/record/900813 }}{{open access}}</ref>

==Properties, structure, bonding==
Pyrrole is a colorless [[volatility (chemistry)|volatile]] liquid that darkens readily upon exposure to air, and is usually purified by [[distillation]] immediately before use.<ref>{{cite book | title = Purification of Laboratory Chemicals | edition = 5th |last1=Armarego |first1=Wilfred L. F. |last2=Chai |first2=Christina L. L. | year = 2003 | publisher = Elsevier | pages = 346}}</ref> Pyrrole has a nutty odor. 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&nbsp;[[Debye (unit)|D]]. In CDCl<sub>3</sub>, it has chemical shifts at 6.68 (H2, H5) and 6.22 (H3, H4). Pyrrole is an extremely weak base for an amine, with a conjugate acid p''K''<sub>a</sub> of −3.8. The most thermodynamically stable pyrrolium cation (C<sub>4</sub>H<sub>6</sub>N<sup>+</sup>) 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 p''K''<sub>a</sub> of +3.7. Pyrrole is also weakly acidic at the N–H position, with a p''K''<sub>a</sub> of 16.5.
As a hydrogen bonding Lewis acid it is classified as a [[HSAB|hard acid]] and the [[ECW model]] lists its acid parameters as ''E''<sub>A</sub> = 1.38 and ''C''<sub>A</sub> = 0.68.

Pyrrole has [[aromatic]] character because the [[lone pair]]s of [[electron]]s on the nitrogen atom is partially [[delocalized electron|delocalized]] into the ring, creating a 4''n''&nbsp;+&nbsp;2 aromatic system (see [[Hückel's rule]]).  In terms of its aromaticity, pyrrole's is modest relative to [[benzene]] but comparable to related heterocycles [[thiophene]] and [[furan]]. The [[resonance energy|resonance energies]] of benzene, pyrrole, [[thiophene]], and [[furan]] are, respectively, 152, 88, 121, and 67 kJ/mol (36, 21, 29, and 16 kcal/mol).<ref>{{March6th|page=62}}</ref>   The molecule is flat.

==History==
Pyrrole was first detected by [[Friedlieb Ferdinand Runge|F.&nbsp;F. Runge]] in 1834, as a constituent of [[coal tar]].<ref>{{cite journal|first=F. F. |last=Runge |date=1834 |url=http://babel.hathitrust.org/cgi/pt?id=wu.89048351654;view=1up;seq=81 |title=Ueber einige Produkte der Steinkohlendestillation |trans-title=On some products of coal distillation |journal=Annalen der Physik und Chemie |volume=31 |issue=5 |pages=65–78|doi=10.1002/andp.18341070502 |bibcode=1834AnP...107...65R }} {{open access}} See especially pages 67–68, where Runge names the compound ''Pyrrol'' (fire oil) or ''Rothöl'' (red oil).</ref> In 1857, it was isolated from the [[Dippel's oil|pyrolysate of bone]]. Its name comes from the Greek ''pyrrhos'' ({{lang|grc|πυρρός}}, "reddish, fiery"), from the reaction used to detect it—the red color that it imparts to wood when moistened with [[hydrochloric acid]].<ref name="Ullmann">{{Ullmann|first=Albrecht Ludwig |last=Harreus |title=Pyrrole |doi=10.1002/14356007.a22_453}}</ref>

==Occurrence in nature==
[[File:Heme B.svg|150px|thumb|left|class=skin-invert-image|Structure of Heme B]]
Pyrrole itself is not naturally occurring, but many of its derivatives are found in a variety of [[Cofactor (biochemistry)|cofactors]] and [[natural products]]. Common naturally produced molecules containing pyrroles include [[vitamin B12|vitamin B<sub>12</sub>]], bile pigments like [[bilirubin]] and [[biliverdin]], and the [[porphyrins]] of [[heme]], [[chlorophyll]], [[chlorin]]s, [[bacteriochlorin]]s, and porphyrinogens.<ref name="Jonas Jusélius and Dage Sundholm 2000 2145–2151"/> Other pyrrole-containing secondary [[metabolite]]s include PQQ, makaluvamine M, ryanodine, rhazinilam, lamellarin, prodigiosin, myrmicarin, and sceptrin. The syntheses of pyrrole-containing haemin, synthesized by [[Hans Fischer]] was recognized by the Nobel Prize.

Pyrrole is a constituent of tobacco smoke and may contribute to its toxic effects.<ref>{{cite web |url=http://www.moh.govt.nz/moh.nsf/pagescm/1003/$File/chemicalconstituentscigarettespriorities.pdf |title=The Chemical Constituents in Cigarettes and Cigarette Smoke: Priorities for Harm Reduction |first1= Jefferson|last1=Fowles |first2=Michael |last2=Bates |first3=Dominique |last3=Noiton |date=March 2000 |publisher= [[New Zealand Ministry of Health]] |location= Porirua, New Zealand |pages=20, 49–65 |access-date=2012-09-23}}</ref>

==Synthesis==
Pyrrole is prepared industrially by treatment of [[furan]] with [[ammonia]] in the presence of solid acid [[catalyst]]s, like [[silica|SiO<sub>2</sub>]] and [[alumina|Al<sub>2</sub>O<sub>3</sub>]].<ref name="Ullmann"/>

[[Image:Pyrrolsynthese1.svg|200px|center|class=skin-invert-image|Synthesis of pyrrole from furan]]

Pyrrole can also be formed by catalytic dehydrogenation of pyrrolidine.{{cn|date=September 2023}}

Several syntheses of the pyrrole ring have been described.<ref name="Lubell">{{cite journal|last1=Lubell |first1=W. |last2=Saint-Cyr |first2=D. |last3=Dufour-Gallant |first3=J. |last4=Hopewell |first4=R. |last5=Boutard |first5=N. |last6=Kassem |first6=T. |last7=Dörr |first7=A. |last8=Zelli |first8=R. |url=https://www.thieme.de/en/thieme-chemistry/sos-knowledge-updates-2013-58727.htm |title= 1''H''-Pyrroles (Update 2013) |journal=Science of Synthesis |date=2013 |volume=2013 |issue=1 |pages=157–388}}</ref>  Three routes dominate,<ref name=Gil>{{cite book |last1=Gilchrist |first1=Thomas L. |title=Heterocyclic Chemistry |date=1997 |publisher=Longman |location=Liverpool |page=194-196 |edition=3rd}}</ref> but many other methods exist.

===Hantzsch pyrrole synthesis===
{{Main|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''').<ref>{{cite journal | last1 = Hantzsch | first1 = A. | year = 1890 | title = Neue Bildungsweise von Pyrrolderivaten |trans-title=New methods of forming pyrrole derivatives | url = https://babel.hathitrust.org/cgi/pt?id=uc1.b3481786;view=1up;seq=1484 | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 23 | pages = 1474–1476 | doi=10.1002/cber.189002301243}} {{open access}}</ref><ref>{{cite journal | last1 = Feist | first1 = Franz | year = 1902 | title = Studien in der Furan- und Pyrrol-Gruppe |trans-title=Studies in the furan and pyrrole groups | url = https://babel.hathitrust.org/cgi/pt?id=uiug.30112025693646;view=1up;seq=305 | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 35 | issue = 2| pages = 1537–1544 | doi = 10.1002/cber.19020350263}} {{open access}}</ref>

[[Image:Hantzsch Pyrrole Synthesis Scheme.png|center|300px|class=skin-invert-image|The Hantzsch pyrrole synthesis]]

===Knorr pyrrole synthesis===
{{Main|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.<ref>{{Cite journal | doi = 10.1002/cber.18840170220| title = Synthese von Pyrrolderivaten |trans-title=Synthesis of pyrrole derivatives | journal = Berichte der Deutschen Chemischen Gesellschaft| volume = 17| issue = 2| pages = 1635–1642| year = 1884| last1 = Knorr | first1 = Ludwig | url = https://babel.hathitrust.org/cgi/pt?id=uc1.b3481769;view=1up;seq=65 }}  {{open access}}</ref><ref>{{cite journal| last=Knorr |first=L. | title = Synthetische Versuche mit dem Acetessigester |trans-title=Synthesis experiments with the [ethyl] ester of acetoacetic acid | journal=Annalen der Chemie | year=1886| volume=236|issue=3 | pages= 290–332 | url = https://babel.hathitrust.org/cgi/pt?id=hvd.hx3kie;view=1up;seq=702 | doi=10.1002/jlac.18862360303}} {{open access}}</ref><ref>{{Cite journal | doi = 10.1002/cber.19020350392| title = Ueber die Bildung von Pyrrolderivaten aus Isonitrosoketonen |trans-title=On the formation of pyrrole derivatives from isonitrosketones | journal = Berichte der Deutschen Chemischen Gesellschaft| volume = 35| issue = 3| pages = 2998–3008| year = 1902| last1 = Knorr | first1 = L.| last2 = Lange | first2 = H. | url = https://babel.hathitrust.org/cgi/pt?id=uc1.b3481898;view=1up;seq=470 }} {{open access}}</ref> 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''').<ref>{{cite book|last=Corwin |first=Alsoph Henry |chapter=Chapter 6: The Chemistry of Pyrrole and its Derivatives |editor-first=Robert Cooley |editor-last=Elderfield |title=Heterocyclic Compounds |volume=1 |location=New York, NY |publisher=Wiley |date=1950 |page=287}}</ref>

[[Image:Knorr Pyrrole Synthesis Scheme.png|center|350px|class=skin-invert-image|The Knorr pyrrole synthesis]]

===Paal–Knorr pyrrole synthesis===
{{Main|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.<ref name="Paal1">{{citation | last=Paal|first= C.| title= Ueber die Derivate des Acetophenonacetessigesters und des Acetonylacetessigesters | journal=Berichte der Deutschen Chemischen Gesellschaft| year=1884| volume=17|issue= 2| pages=2756–2767 | url=https://babel.hathitrust.org/cgi/pt?id=uc1.b3481769;view=1up;seq=1188 |doi=10.1002/cber.188401702228}} {{open access}}</ref><ref name="Knorr1">{{citation | last=Knorr|first= Ludwig| title=Synthese von Furfuranderivaten aus dem Diacetbernsteinsäureester |trans-title=Synthesis of furan derivatives from the [diethyl] ester of 2,3-diacetyl-succinic acid | journal=Berichte der Deutschen Chemischen Gesellschaft| year=1884| volume=17|issue= 2| pages=2863–2870| url=https://babel.hathitrust.org/cgi/pt?id=uc1.b3481769;view=1up;seq=1295 | doi=10.1002/cber.188401702254}} {{open access}}</ref>

[[File:Paal-Knorr Pyrrole Synthesis.svg|center|300px|class=skin-invert-image|The Paal–Knorr pyrrole synthesis]]

====Other methods====
[[Van Leusen reaction]] pyrroles are produced 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.{{citation needed|date=July 2016}}
:[[File:Van Leusen Mechanism.jpg|center|700px|class=skin-invert-image|Mechanism of the Van Leusen reaction to form pyrroles]]

By the [[Barton–Zard synthesis]], an isocyanoacetate reacts with a nitroalkene in a 1,4-addition, followed by 5-''endo''-''dig'' cyclization, elimination of the [[nitro group]], and [[tautomer]]ization.<ref>{{cite book | first=Jie Jack |last=Li | title =Heterocyclic Chemistry in Drug Discovery | publisher =Wiley | location =New York | year =2013 | isbn =9781118354421| url =https://books.google.com/books?id=p_fM6CuK6xcC}}</ref>

[[Image:Barton-Zard reaction.svg|center|class=skin-invert-image|400px]]

The starting materials in the Piloty–Robinson pyrrole synthesis, named for [[Gertrude Maud Robinson|Gertrude]] and [[Robert Robinson (organic chemist)|Robert Robinson]] and [[Oskar Piloty]], are two equivalents of an [[aldehyde]] and [[hydrazine]].<ref>{{cite journal | author-link= Oskar Piloty|last=Piloty |first=Oskar | journal = Berichte der Deutschen Chemischen Gesellschaft | year = 1910 | volume = 43 | issue = 1 | pages = 489–498 | doi = 10.1002/cber.19100430182 | title = Synthese von Pyrrolderivaten: Pyrrole aus Succinylobernsteinsäureester, Pyrrole aus Azinen |trans-title=Synthesis of pyrrole derivatives: pyrrole from diethyl succinyl succinate, pyrrole from azines | url = https://babel.hathitrust.org/cgi/pt?id=uc1.b3481273;view=1up;seq=499 }} {{open access}}</ref><ref>{{cite journal | journal = [[J. Chem. Soc.]] | year = 1918 | volume = 113 | pages = 639–645| doi = 10.1039/CT9181300639 | title = LIV. A new synthesis of tetraphenylpyrrole | last1 = Robinson|first1= Gertrude Maud | last2 = Robinson | first2 = Robert}}</ref> 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 [[Gertrude Maud Robinson#Piloty-Robinson Pyrrole Synthesis|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 chemistry|microwave irradiation]]:<ref name=milgram>{{cite journal | title = Microwave-Assisted Piloty–Robinson Synthesis of 3,4-Disubstituted Pyrroles |first1=Benjamin C.|last1= Milgram |first2=Katrine|last2= Eskildsen |first3=Steven M.|last3= Richter |first4=W. Robert |last4=Scheidt |first5=Karl A. |last5=Scheidt | journal = [[J. Org. Chem.]] | year = 2007 | volume = 72 | issue = 10 | pages = 3941–3944 | format = Note | doi =  10.1021/jo070389+| pmid = 17432915 | pmc = 1939979}}</ref>

[[Image:Piloty-Robinson reaction.png|center|400px|class=skin-invert-image|Piloty–Robinson reaction<ref name=milgram/>]]

Pyrroles bearing multiple substituents have been obtained from the reaction of [[münchnone]]s and [[alkyne]]s. 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.
 
[[File:DA Pyrrole Synthesis.jpg|center|350px|class=skin-invert-image|Synthesis of pyrroles via Diels–Alder cyclization]]

Pyrroles can also be prepared by [[silver]]-catalyzed cyclization of alkynes with [[isonitriles]], where R<sup>2</sup> is an electron-withdrawing group, and R<sup>1</sup> 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 Huisgen cycloaddition|azide–alkyne]] [[click chemistry]] used to form azoles.
 
[[File:Pyrrole Silver Cyclization.jpg|center|350px|class=skin-invert-image|Synthesis of pyrrole via silver click chemistry]]

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]].<ref>{{cite book|title=Practical Organic Chemistry |last=Vogel |first=Arthur I. |date=1956 |page=837 |url=http://www.sciencemadness.org/library/books/vogel_practical_ochem_3.pdf}}</ref>

[[File:Pyrrolesynthfromammoniummucate.svg|center|class=skin-invert-image|Synthesis of pyrrole from ammonium mucate]]

The [[Trofimov reaction]] allows for the synthesis of 2,3-disubstituted pyrroles from [[ketoxime|ketoximes]] and [[acetylene]] in basic medium.<ref>{{Cite journal |last=Trofimov |first=Boris A |date=1981-02-28 |title=Reactions of Acetylene in Superbasic Media |url=https://iopscience.iop.org/article/10.1070/RC1981v050n02ABEH002551 |journal=Russian Chemical Reviews |volume=50 |issue=2 |pages=138–150 |doi=10.1070/RC1981v050n02ABEH002551 |bibcode=1981RuCRv..50..138T |s2cid=250826279 |issn=0036-021X|url-access=subscription }}</ref>

[[File:Trofimov_Scheme_HD.png|center|frameless|500x500px|Synthesis of pyrrole through the Trofimov reaction]]

==Biosynthesis==
The 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 pyrrole synthesis|Knorr-type]] ring synthesis to form [[porphobilinogen]] (PBG). This later reacts to form, for example, the macrocycles [[heme]] and [[chlorophyll]].<ref>{{cite journal|last1=Walsh|first1=Christopher T.|last2=Garneau-Tsodikova |first2=Sylvie|author2-link= Sylvie Garneau-Tsodikova |last3=Howard-Jones |first3=Annaleise R. |title=Biological formation of pyrroles: Nature's logic and enzymatic machinery|journal=Natural Product Reports|volume=23|issue=4|pages=517–531|doi=10.1039/b605245m|year=2006|pmid=16874387}}</ref> 
 
[[File:Porphobilinogen Synthesis.jpg|center|class=skin-invert-image|Mechanism of biosynthesis of porphobilinogen]].

[[Proline]] is [[Biosynthesis|biosynthetically]] derived from the amino acid <small>L</small>-[[glutamate]].  [[Glutamate-5-semialdehyde]] is first formed by [[glutamate 5-kinase]] (ATP-dependent) and [[glutamate-5-semialdehyde dehydrogenase]] (which requires NADH or NADPH). This can then either spontaneously cyclize to form [[1-pyrroline-5-carboxylic acid]], which is reduced to proline by [[pyrroline-5-carboxylate reductase]] (using NADH or NADPH), or turned into [[ornithine]] by [[ornithine aminotransferase]], followed by cyclisation by [[ornithine cyclodeaminase]] to form proline.<ref>{{Lehninger3rd}}.</ref>

[[File:Betain-Proline.png|thumb|left|260px|class=skin-invert-image|[[Zwitterion]]ic structure of both proline enantiomers: (''S'')-proline (left) and (''R'')-proline]]

Proline can be used as precursor of aromatic pyrroles in secondary natural products, as in prodigiosins. 
[[File:Prodigiosin 1.png|thumb|left|class=skin-invert-image|Figure 1: Structure of Prodigiosin 1 highlighting the A, B, and C pyrrole rings]]
The biosynthesis of Prodigiosin<ref>{{cite journal | last1 = Walsh | first1 = C. T. | last2 = Garneau-Tsodikova | first2 = S. | last3 = Howard-Jones | first3 = A. R. | year = 2006 | title = Biological formation of pyrroles: Nature's logic and enzymatic machinery | journal = Nat. Prod. Rep. | volume = 23 | issue = 4 | pages = 517–531 | doi = 10.1039/b605245m | pmid = 16874387 }}</ref><ref name=Hu>{{cite journal | doi = 10.1021/acs.chemrev.6b00024 | volume=116 | title=Structure, Chemical Synthesis, and Biosynthesis of Prodiginine Natural Products | year=2016 | journal=Chemical Reviews | pages=7818–7853 | last1 = Hu | first1 = Dennis X. | issue=14 | pmid=27314508 | pmc=5555159}}</ref> involves the convergent coupling of three pyrrole type rings (labeled A, B, and C in figure 1) from <small>L</small>-proline, <small>L</small>-serine, <small>L</small>-methionine,  pyruvate, and 2-octenal.

Ring A is synthesized from <small>L</small>-proline through the nonribosomal peptide synthase (NRPS) pathway (figure 2), wherein the pyrrolidine ring of proline is oxidized twice through FAD<sup>+</sup> to yield pyrrole ring A.

[[File:Prodigiosin Ring A.png|class=skin-invert-image|Figure 2: biosynthesis of pyrrole ring A]]

Ring A is then expanded via the polyketide synthase pathway to incorporate <small>L</small>-serine into ring B (figure 3). Ring A fragment is transferred from the peptidyl carrier protein  (PCP) to the Acyl Carrier Protein (ACP) by a KS domain, followed by transfer to malonyl-ACP via decarboxylative Claisen condensation. This fragment is then able to react with the masked carbanion formed from the PLP mediated decarboxylation of <small>L</small>-serine, which cyclizes in a dehydration reaction to yield the second pyrrole ring. This intermediate is then modified by methylation (which incorporates a methyl group from <small>L</small>-methionine onto the alcohol at the 6 position) and oxidation of the primary alcohol to the aldehyde to yield the core A–B ring structures.

[[File:Prodigiosin Ring B.png|class=skin-invert-image|Biosynthesis of pyrrole ring B]]

==Reactions and reactivity==
Due to its [[Aromaticity|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 [[oxidize]] easily to [[polypyrrole]],<ref>{{cite book|editor1=Wang Jitao [王积涛]|editor2=Zhang Baoshen [张保申]|editor3=Wang Yongmei [王永梅]|editor4=Hu Qingmei [胡青眉]|year=2003|script-title=zh:有机化学|lang=zh|trans-title=Organic Chemistry|edition=2nd|publisher=Tianjin Nankai University|isbn=978-7-310-00620-5}}</ref> {{Citation needed|date=April 2025}}and thus many [[Electrophile|electrophilic]] reagents that are used in benzene chemistry are not applicable to pyrroles. In contrast, substituted pyrroles (including [[protecting group|protected]] pyrroles) have been used in a broad range of transformations.<ref name="Lubell"/>

===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. 
[[File:Pyrrole Electrophilic Substitution.png|500px|center|class=skin-invert-image|Pyrrole electrophilic substitution]]  Pyrroles react easily with [[Nitrate|nitrating]] (e.g. [[Nitric acid|HNO<sub>3</sub>]]/[[Acetic anhydride|Ac<sub>2</sub>O]]), [[Sulfonate|sulfonating]] ([[Sulfur trioxide pyridine complex|Py·SO<sub>3</sub>]]), and [[halogen]]ating (e.g. [[N-Chlorosuccinimide|NCS]], [[N-Bromosuccinimide|NBS]], [[Bromine|Br<sub>2</sub>]], [[Sulfonyl chloride|SO<sub>2</sub>Cl<sub>2</sub>]], and [[Potassium iodide|KI]]/[[Hydrogen peroxide|H<sub>2</sub>O<sub>2</sub>]]) agents.<ref>{{cite encyclopedia|entry=Pyrrol|encyclopedia=Römpp Lexikon Chemie|trans-title=Römpp's Chemical Lexicon|publisher=Thieme|lang=de}}</ref> 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.{{citation needed|date=July 2016}}

====Acylation====
[[Acylation]] generally occurs at the 2-position, through the use of various methods. Acylation with [[acid anhydride]]s and [[acid chloride]]s can occur with or without a catalyst.<ref>{{cite journal |doi=10.15227/orgsyn.051.0100 |title=Ethyl Pyrrole-2-Carboxylate |journal=Organic Syntheses |date=1971 |volume=51 |page=100|first1=Denis M.|last1=Bailey|first2=Robert E.|last2=Johnson|first3=Noel F.|last3=Albertson }}</ref> 2-Acylpyrroles are also obtained from reaction with nitriles, by the [[Houben–Hoesch reaction]]. Pyrrole aldehydes can be formed by a [[Vilsmeier–Haack reaction]].<ref>{{cite journal |doi=10.15227/orgsyn.036.0074 |title=2-Pyrrolealdehyde |journal=Organic Syntheses |date=1956 |volume=36 |page=74|first1=Robert M.|last1=Silverstein|first2=Edward E.|last2=Ryskiewicz|first3=Constance|last3=Willard
 }}</ref> 
[[File:PyrroleFormylation.png|400px|center|class=skin-invert-image|Vilsmeier–Haack formylation of pyrrole]]

===Reaction of deprotonated pyrrole===
The NH proton in pyrroles is moderately acidic with a [[Acid dissociation constant|p''K''<sub>a</sub>]] of 17.5.<ref>{{cite book|first1=C.&nbsp;W.|last1=Bird|first2=G.&nbsp;W.&nbsp;H.|last2=Cheeseman|title=Comprehensive Heterocyclic Chemistry|url=http://www.sciencedirect.com/science/article/pii/B9780080965192000527|publisher=Pergamon|year=1984|pages=39–88|isbn=978-0-08-096519-2|postscript=None}}, although note that {{cite journal|doi=10.1016/S0040-4020(01)89212-7|journal=Tetrahedron|volume=45|issue=23|pages=7501–7504|year=1989|publisher=Pergamon|location=Great Britain|title=The acid-base properties of pyrrole and its benzologs indole and carbazole: a re-examination from the excess acidity method|first1=M.|last1=Balón|first2=M.&nbsp;C.|last2=Carmona|first3=M.&nbsp;A.|last3=Muñoz|first4=J.|last4=Hidalgo|postscript=None}} suggests that figure's revision to 17.3.</ref> Pyrrole can be deprotonated with strong bases such as [[butyllithium]] and [[sodium hydride]].<ref>{{cite book|first1=Heinz-Gerhard|last1=Franck|first2=Jürgen&nbsp;Walter|last2=Stadelhofer|title=Industrielle Aromatenchemie: Rohstoffe, Verfahren, Produkte|trans-title=Industrial Chemistry of the Aromatics: Raw materials, processes, products|lang=de|publisher=Springer|location=Berlin|year=1987|isbn=978-3-662-07876-1|pages=403–404}}</ref> The resulting alkali pyrrolide is [[nucleophilic]]. Treating this conjugate base with an electrophile such as [[iodomethane]] gives ''N''-methylpyrrole. 

''N''-Metalated pyrrole can react with electrophiles at the N or C positions, depending on the coordinating metal. More ionic nitrogen–metal bonds (such as with lithium, sodium, and potassium) 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, metalation of the carbons is more facile. Alkyl groups can be introduced as electrophiles, or by cross-coupling reactions.{{citation needed|date=July 2016}} 
[[File:Pyrrole C Metallation.jpg|center|class=skin-invert-image|Pyrrole ''C''-metalation]]

Substitution at C3 can be achieved through the use of ''N''-substituted 3-bromopyrrole, which can be synthesized by bromination of ''N''-silylpyrrole with [[N-Bromosuccinimide|NBS]].{{citation needed|date=July 2016}}

===Reductions===
Pyrroles can undergo reductions to [[pyrrolidines]] and to [[pyrrolines]].<ref>{{cite book|author=Lyastukhin, Voronov [Ластухін, Воронов]|year=2006|script-title=uk:Органічна хімія|url=https://archive.org/details/isbn_9667022196|lang=uk|trans-title=Organic Chemistry|pages=781–782|isbn=966-7022-19-6}}</ref> For example, [[Birch reduction]] of pyrrole esters and amides produced pyrrolines, with the regioselectivity depending on the position of the electron-withdrawing group.{{citation needed|date=July 2016}}

===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.{{citation needed|date=July 2016}} 
[[File:Pyrrole DA.svg|center|class=skin-invert-image|300px|Pyrrole DA]]

Pyrroles can react with [[carbene]]s, such as [[dichlorocarbene]], in a [2+1]-cycloaddition. With [[dichlorocarbene]], a dichlorocyclopropane intermediate is formed, which breaks down to form [[3-Chloropyridine|3-chloropyridine]] (the Ciamician–Dennstedt rearrangement).<ref>{{cite journal|last1=Ciamician |first1=G. L. |last2=Dennstedt |first2=M. |title=Ueber die Einwirkung des Chloroforms auf die Kaliumverbindung Pyrrols |trans-title=On the reaction of chloroform with the potassium compound of pyrrole |journal=Berichte der Deutschen Chemischen Gesellschaft  |volume=14 |pages=1153–1162 |date=1881 |url=https://babel.hathitrust.org/cgi/pt?id=hvd.cl1hza;view=1up;seq=1223 |doi=10.1002/cber.188101401240}}</ref><ref>{{cite book|last=Corwin |first=Alsoph Henry |editor-first=Robert Cooley |editor-last=Elderfield |title=Heterocyclic Compounds |volume=1 |location=New York, NY |publisher=Wiley |date=1950 |page=309}}</ref><ref>{{cite book|last=Mosher|first=H. S.  |editor-first=Robert Cooley |editor-last=Elderfield |title=Heterocyclic Compounds |volume=1 |location=New York, NY |publisher=Wiley |date=1950 |page=475}}</ref> 
[[File:Ciamician-Dennstedt Rearrangement.png|500px|center|class=skin-invert-image|Ciamician–Dennstedt rearrangement]]

==Commercial uses==
Polypyrrole is of some commercial value.  ''N''-Methylpyrrole is a precursor to ''N''-methylpyrrolecarboxylic acid, a building-block in pharmaceutical chemistry.<ref name="Ullmann" />  Pyrroles are also found in several drugs, including [[atorvastatin]], [[ketorolac]], and [[sunitinib]].  Pyrroles are used as lightfast red, scarlet, and carmine pigments.<ref>{{cite web|url=http://dyes-pigments.standardcon.com/dpp-pigments.html|title=DPP Pigments,Diketopyrrolopyrrole Pigments,DPP Pigments Wholesaler,Diketopyrrolopyrrole Pigments Suppliers|website=dyes-pigments.standardcon.com}}</ref><ref>{{cite journal|author1=Kaur, Matinder|author2=Choi, Dong Hoon|title= Diketopyrrolopyrrole: brilliant red pigment dye-based fluorescent probes and their applications|journal=Chemical Society Reviews|year=2015|pages=58–77|volume=44|issue=1|doi=10.1039/C4CS00248B|pmid=25186723}}</ref>

==Analogs and derivatives==
[[Structural analog]]s 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==
{{Commons category}}
* [[Simple aromatic ring]]s
* [[Tetrapyrrole]]
* [[Polypyrrole]]
* [[Azonine]]

==References==
{{Reflist}}

==Further reading==
* {{cite book|editor1-last=Jones|editor1-first=R. Jones|title=Pyrroles. Part I. The Synthesis and the Physical and Chemical Aspects of the Pyrrole Ring|journal=Recueil des Travaux Chimiques des Pays-Bas|series=The Chemistry of Heterocyclic Compounds|volume=48|issue=7–8|pages=351|publisher=John Wiley & Sons|location=Chichester|year=1990|isbn=978-0-471-62753-1|doi=10.1002/recl.19911100712}}
* {{cite journal | doi = 10.1016/j.tet.2006.08.071 | title = Pyrrole protection | year = 2006 | last1 = Jolicoeur | first1 = Benoit | last2 = Chapman | first2 = Erin E. | last3 = Thompson | first3 = Alison | last4 = Lubell | first4 = William D. | journal = Tetrahedron | volume = 62 | issue = 50 | pages = 11531–11563}}

==External links==
* [https://www.organic-chemistry.org/synthesis/heterocycles/pyrroles.shtm Synthesis of pyrroles (overview of recent methods)]
* [https://web.archive.org/web/20060908222256/http://users.ox.ac.uk/~mwalter/web_05/year2/arom2/hetarom_rxn_mech.shtml Substitution reaction mechanisms of nitrogen-containing heteroaromatics]

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[[Category:Pyrroles| ]]