Editing Pyrrole (section)

===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 |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}}</ref>

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