View source for Chemistry:Paal–Knorr synthesis

{{Short description|Chemical reaction}}
{{Reactionbox
| Name = Paal-Knorr synthesis
| Type = Ring forming reaction
| NamedAfter = Carl Paal <br/> Ludwig Knorr
| Section3 = {{Reactionbox Identifiers
   | RSC_ontology_id = 0000161
 }}
}}
In [[Chemistry:Organic chemistry|organic chemistry]], the '''Paal–Knorr synthesis''' is a reaction used to synthesize substituted [[Chemistry:Furan|furan]]s, [[Chemistry:Pyrrole|pyrrole]]s, or [[Chemistry:Thiophene|thiophene]]s from [[Chemistry:Diketone|1,4-diketones]]. It is a synthetically valuable method for obtaining substituted furans and pyrroles, which are common structural components of many natural products. It was initially reported independently by German chemists Carl Paal and Ludwig Knorr in 1884 as a method for the preparation of furans, and has been adapted for pyrroles and thiophenes.<ref name="Paal1">{{citation | author=Paal, 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|doi=10.1002/cber.188401702228|url=https://zenodo.org/record/1425359 }}</ref><ref name="Knorr1">{{citation | author=Knorr, L. |title=Synthese von Furfuranderivaten aus dem Diacetbernsteinsäureester |journal=Berichte der deutschen chemischen Gesellschaft|year=1884|volume=17|issue=2 |pages=2863–2870|doi=10.1002/cber.188401702254|url=https://zenodo.org/record/1425367 }}</ref> Although the Paal–Knorr synthesis has seen widespread use, the mechanism wasn't fully understood until it was elucidated by V. Amarnath ''et al.'' in the 1990s.<ref name="Amarnath1">{{citation |author1=Amarnath, V. |author2=Amarnath, K. |title=Intermediates in the Paal-Knorr Synthesis of Furans |journal=The Journal of Organic Chemistry|year=1995|volume=60|issue=2 |pages=301–307|doi=10.1021/jo00107a006}}</ref><ref name="Amarnath2">{{citation |author1=Amarnath, V. |author2=Anthony, D. C. |author3=Amarnath, K. |author4=Valentine, W. M. |author5=Wetterau, L. A. |author6=Graham, D. G. |title=Intermediates in the Paal-Knorr synthesis of pyrroles |journal=The Journal of Organic Chemistry|year=1991|volume=56|issue=24 |pages=6924–6931|doi=10.1021/jo00024a040}}</ref>

The furan synthesis requires an acid catalyst:<ref>{{cite book |author=Thomas L. Gilchrist |title=Heterocyclic Chemistry |year=1987 |publisher=Longman Scientific |location=Harlow |isbn=0-582-01421-2}}</ref>

:[[File:Paal-Knorr furan synthesis.svg|center|300px|Paal–Knorr furan synthesis]]

In the pyrrole synthesis a primary [[Chemistry:Amine|amine]] participates:

:[[File:Paal-Knorr Pyrrole Synthesis.svg|center|300px|Paal–Knorr Pyrrole Synthesis]]

and in that of [[Chemistry:Thiophene|thiophene]] for instance the compound [[Chemistry:Phosphorus pentasulfide|phosphorus pentasulfide]]:
 
:[[File:Paal-Knorr thiophene.svg|center|300px|Paal-Knorr thiophene synthesis]]

==Mechanisms==

===Furan synthesis===
{{Reactionbox
| Name = Paal-Knorr furan synthesis
| | Section3 = {{Reactionbox Identifiers
   | OrganicChemistryNamed = paal-knorr-furan-synthesis
   | RSC_ontology_id = 0000162
 }}
}}
The acid catalyzed furan synthesis proceeds by protonation of one carbonyl which is attacked by the forming enol of the other carbonyl. Dehydration of the hemiacetal gives the resultant furan.<ref name="Kürti">{{citation|surname1=László Kürti|surname2=Barbara Czakó|title=Strategic Applications of Named Reactions in Organic Synthesis |publisher=Elsevier Science & Technology Books|isbn=9780123694836|date=  2005}}</ref>

[[File:Paal-Knorr-Furan-Synthesis_mechanism.svg|center|900px|Paal-Knorr furan synthesis mechanism]]

The mechanism of the Paal–Knorr furan synthesis was elucidated in 1995 by V. Amarnath ''et al''.<ref name="Amarnath1"/> Amarnath's work showed that the [[Chemistry:Diastereomer|diastereomer]]s of 3,4-disubstituted-2,5-hexane diones react at different rates. In the commonly accepted mechanism, these diones would go through a common enol intermediate, meaning that the meso and ''d,l''-racemic isomers would cyclize at the same rate as they form from a common intermediate. The implication of different reaction is that cyclization needs to occur in a concerted step with enol formation. Thus the mechanism was proposed to occur via attack of the protonated carbonyl with the forming enol. Amarnath also found that the unreacted dione had not undergone conformational isomerization, which also indicated that an enol was not an intermediate.

===Pyrrole synthesis===
{{Reactionbox
| Name = Paal-Knorr pyrrole synthesis
| | Section3 = {{Reactionbox Identifiers
   | OrganicChemistryNamed = paal-knorr-pyrrole-synthesis
   | RSC_ontology_id = 0000164
 }}
}}
The mechanism for the synthesis of the pyrrole was investigated by V. Amarnath ''et al.'' in 1991.<ref name="Amarnath2"/> His work suggests that the protonated carbonyl is attacked by the amine to form the hemiaminal. The amine attacks the other carbonyl to form a 2,5-dihydroxytetrahydropyrrole derivative which undergoes dehydration to give the corresponding substituted pyrrole.<ref name ="Wollrab">{{citation|surname1=Adalbert Wollrab|title=''Organische Chemie'' |publisher=Springer-Verlag|pages=850|isbn=3-540-43998-6|date=  1999|language=German}}</ref>

[[File:Paal-Knorr-pyrrole-synthesis_mechanism.svg|center|550px|Paal–Knorr pyrrole synthesis mechanism]]

The reaction is typically run under protic or Lewis acidic conditions, with a primary amine. Use of ammonium hydroxide or ammonium acetate (as reported by Paal) gives the N-unsubstituted pyrrole.

===Thiophene synthesis===
{{Reactionbox
| Name = Paal-Knorr thiophene synthesis
| | Section3 = {{Reactionbox Identifiers
   | OrganicChemistryNamed = paal-knorr-thiophene-synthesis
   | RSC_ontology_id = 0000163
 }}
}}
Thiophene synthesis is achieved via a mechanism very similar to the furan synthesis. The initial diketone is converted to a [[Chemistry:Thioketone|thioketone]] with a sulfurizing agent, which then undergoes the same mechanism as the furan synthesis.<ref name=Foye />

[[File:Paal-Knorr-thiophen-synth_mechanism.svg|center|900px|Paal–Knorr thiophene synthesis mechanism]]

Most sulfurization agents are strong dehydrators and drive completion of the reaction. Early postulates toward the mechanism of the Paal-Knorr furan synthesis suggested that the thiophene was achieved by sulfurization of the furan product. Campaigne and Foye showed that treatment of isolated furans from the Paal-Knorr furan synthesis with [[Chemistry:Phosphorus pentasulfide|phosphorus pentasulfide]] gave inconsistent results with the treatment of 1,4-dicarbonyls with phosphorus pentasulfide, which ruled out the sulfurization of a furan mechanism and suggests that the reaction proceeds via sulfurization of a dicarbonyl, producing a [[Chemistry:Thioketone|thioketone]].<ref name=Foye>{{citation |author1=Campaigne, E. |author2=Foye, W. O. | title=The Synthesis of 2,5-Diarylthiophenes| journal=The Journal of Organic Chemistry| year=1952| volume=17| issue=10| pages=1405–1412| doi=10.1021/jo50010a023}}</ref>

==Scope==

[[File:Pyrrole Ring.svg|right|100px|Pyrrole Ring]]

The Paal–Knorr reaction is quite versatile. In all syntheses almost all dicarbonyls can be converted to their corresponding heterocycle. R2 and R5 can be H, aryl or alkyl. R3 and R4 can be H, aryl, alkyl, or an ester. In the pyrrole synthesis (X = N), R1 can be H, aryl, alkyl, amino, or hydroxyl.<ref name="Holman">{{citation | author=Holman, R. W. |title=Strategic Applications of Named Reactions in Organic Synthesis: Background and Detailed Mechanisms (Kürti, László; Czakó, Barbara) |journal=Journal of Chemical Education|year=2005|volume=82|issue=12 |pages=1780|doi=10.1021/ed082p1780.3|bibcode = 2005JChEd..82S1780H |doi-access=free}}</ref>

A variety of conditions can be used to carry out these reactions, most of which are mild. The Paal–Knorr Furan synthesis is normally carried out under aqueous acidic conditions with protic acids such as aqueous sulfuric or [[Chemistry:Hydrochloric acid|hydrochloric acid]], or anhydrous conditions with a Lewis acid or dehydrating agent. Common dehydrating agents include [[Chemistry:Phosphorus pentoxide|phosphorus pentoxide]], anhydrides, or zinc chloride. The pyrrole synthesis requires a primary amine under similar conditions, or ammonia (or ammonia precursors) can be used. Synthesis of a thiophene requires a sulfurizing agent which is typically a sufficient dehydrator, such as [[Chemistry:Phosphorus pentasulfide|phosphorus pentasulfide]], [[Chemistry:Lawesson's reagent|Lawesson's reagent]], or [[Chemistry:Hydrogen sulfide|hydrogen sulfide]].

Traditionally, the Paal–Knorr reaction has been limited in scope by the availability of 1,4-diketones as synthetic precursors. Current chemical methods have greatly expanded the accessibility of these reagents, and variations of the Paal-Knorr now allow for different precursors to be used. The Paal–Knorr was also considered limited by harsh reaction conditions, such as prolonged heating in acid, which may degrade sensitive functionalities in many potential furan precursors. Current methods allow for milder conditions that can avoid heat altogether, including microwave catalyzed cyclizations.

==Variations==

Several 1,4-dicarbonyl surrogates can be used in place of a 1,4-dicarbonyl. While these substitutes have different structures from a 1,4-dicarbonyl, their reactions proceed via mechanisms very similar to that of the Paal-Knorr.

===β-Epoxy carbonyls===

β-Epoxy carbonyls have been known to cyclize to furans. This procedure can use the β-γ-unsaturated carbonyls as starting materials, which can be epoxidized. The resulting epoxycarbonyl can be cyclized to a furan under acidic or basic conditions.<ref name="Cormier">{{citation |author1=Cormier, R. A. |author2=Francis, M. D. |title=The Epoxyketone-Furan Rearrangement |journal=[[Chemistry:Synthetic Communications|Synthetic Communications]]|year=1981|volume=11|number=5 |pages=365 |doi=10.1080/00397918108064300}}</ref>

[[File:PK epoxy carbonyl.svg|center|350px|Epoxy carbonyl synthesis]]

===1,4-Diol-2-ynes===

1,4-diol-2-yne systems have also been used to do Paal–Knorr chemistry. Using palladium, a 1,4-diol-2-yne can be isomerized to the corresponding 1,4-diketone ''in situ'' and then dehydrated to the corresponding furan using a dehydration agent.<ref name="Ji">{{citation |author1=Ji, J. |author2=Lu, X. |title=Facile synthesis of 2,5-disubstituted furans via palladium complex and perfluorinated resinsulfonic acid catalysed isomerization–dehydration of alkynediols |journal=Journal of the Chemical Society, Chemical Communications|year=1993|issue=9|pages=764–765 |doi=10.1039/C39930000764}}</ref>

[[File:PKF dione yne.svg|center|400px|1,4-diol-2-yne Paal-Knorr]]

The significance of this variation is in the fact that it increases the scope of the Paal–Knorr by taking advantage of the wealth of acetylene chemistry that exists, specifically that for the generation of propargyl alcohols.

===Acetals===

[[Chemistry:Acetal|Acetal]]s have also proven useful starting materials for the Paal-Knorr. A ketone with an acetal 3 bonds away from it can be converted under exactly the same conditions as a 1,4-diketone to the corresponding heterocycle.

===Microwave-assisted Paal–Knorr===

Another variation has been the introduction of microwave radiation to enhance the Paal–Knorr. Traditional Paal–Knorr conditions involved prolonged heating of strong acids to drive dehydration which occurred over a period of several hours. Microwave-assisted Paal–Knorr reactions have been demonstrated to occur on time scales measured in minutes and in open flasks at room temperature.<ref name="Minetto1">{{citation |author1=Minetto, G. |author2=Raveglia, L. F. |author3=Taddei, M. |title=Microwave-Assisted Paal−Knorr Reaction. A Rapid Approach to Substituted Pyrroles and Furans |journal=[[Chemistry:Organic Letters|Organic Letters]]|year=2004|volume=6|issue=3 |pages=389–392|doi=10.1021/ol0362820|pmid=14748600 }}</ref>

==Related reactions==

The [[Chemistry:Knorr pyrrole synthesis|Knorr pyrrole synthesis]], reported by Knorr in 1884 is the synthesis of a substituted pyrrole from an amino-ketone and a ketone.<ref name="Knorr2">{{citation | author=Knorr, L. |title=Synthese von Pyrrolderivaten |journal=Berichte der deutschen chemischen Gesellschaft|year=1884|volume=17|issue=2 |pages=1635–1642|doi=10.1002/cber.18840170220|url=https://zenodo.org/record/1425351 }}</ref>

{{Reactionbox
| Name = Knorr pyrazole synthesis
| Type = Ring forming reaction
| NamedAfter = Ludwig Knorr
| Section3 = {{Reactionbox Identifiers
   | RSC_ontology_id = 0000391
 }}
}}
Also reported by Knorr is a synthesis of [[Chemistry:Pyrazole|pyrazole]]s from 1,3-dicarbonyls and [[Chemistry:Hydrazines|hydrazines]], hydrazides, or semibicarbazides. This synthesis occurs via a condensation mechanism similar to the Paal-Knorr, however if a substituted hydrazine is used, it results in a mixture of regioisomers where the substituted heteroatom is either next to the R1 substituent or the R3 substituent.<ref name="Knorr3">{{citation | author=Knorr, L. |title=Einwirkung von Acetessigester auf Phenylhydrazin |journal=Berichte der deutschen chemischen Gesellschaft|year=1883|volume=16|issue=2 |pages=2597–2599|doi=10.1002/cber.188301602194|url=https://zenodo.org/record/1425305 }}</ref>

[[File:Knorr pyrazole.png|center|500px|Knorr pyrazole synthesis]]

==Synthetic applications==

In 2000, B. M. Trost ''et al.'' reported a formal synthesis of the antibiotic roseophilin. Trost's route to the macrocyclic core of roseophilin, like others, relied on a Paal–Knorr Pyrrole synthesis to obtain the fused pyrrole.<ref name="Roseophilin">{{citation |author1=Trost, B. M. |author2=Doherty, G. A. |title=An Asymmetric Synthesis of the Tricyclic Core and a Formal Total Synthesis of Roseophilin via an Enyne Metathesis |journal=[[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]|year=2000|volume=122|issue=16 |pages=3801–3810|doi=10.1021/ja9941781}}</ref> Heating the 1,4-diketone with ammonium acetate in methanol with camphor sulfonic acid and 4 angstrom molecular sieves gave the pyrrole with no N-substitution. This pyrrole was found to be unstable, and as such was treated with [[Chemistry:2-(Trimethylsilyl)ethoxymethyl chloride|trimethylsilyl ethoxy methoxy chloride]] (SEM-Cl) to protect the pyrrole prior to isolation.

[[File:PK roseophilin.png|center|400px|Roseophillin Paal-Knorr]]

In 1982, H. Hart ''et al.'' reported a synthesis of a macrocycle containing fused furan rings using a Paal–Knorr furan synthesis.<ref name="Macrocycle">{{citation |author1=Hart, H. |author2=Takehira, Y. |title=Adducts derived from furan macrocycles and benzyne |journal=The Journal of Organic Chemistry|year=1982|volume=47|issue=22 |pages=4370–4372|doi=10.1021/jo00143a049}}</ref> Refluxing ''para''-toluene sulfonic acid in benzene was found to dehydrate the 1,4-diketones to their respective furans to achieve the challenging macrocyclic fused furans.

[[File:PK furan macrocycle.png|center|400px|Fused Macrocycle Furan]]

==See also==
*[[Chemistry:Hantzsch pyrrole synthesis|Hantzsch pyrrole synthesis]]
*[[Chemistry:Knorr pyrrole synthesis|Knorr pyrrole synthesis]]
*[[Chemistry:Feist–Benary synthesis|Feist–Benary synthesis]]
*[[Chemistry:Volhard–Erdmann cyclization|Volhard–Erdmann cyclization]]
*[[Chemistry:Hantzsch pyridine synthesis|Hantzsch pyridine synthesis]]

==References==
{{Reflist}}

{{DEFAULTSORT:Paal-Knorr synthesis}}
[[Category:Heterocycle forming reactions]]
[[Category:Name reactions]]

{{Sourceattribution|Paal–Knorr synthesis}}