Editing Heck reaction

{{Short description|Coupling reaction}}
{{Reactionbox
| Name = Heck reaction
| Type = Coupling reaction
| NamedAfter = [[Richard F. Heck]]
| Section3 = {{Reactionbox Identifiers
   | OrganicChemistryNamed = heck-reaction
   | RSC_ontology_id = 0000024
 }}
}}
The '''Heck reaction''' (also called the '''Mizoroki–Heck reaction''')<ref>{{cite journal | last=Drahl|first=Carmen | title=In Names, History And Legacy | journal=[[Chem. Eng. News]] | date=May 17, 2010 | volume=88 | issue=22 | pages=31–33 | url=http://pubs.acs.org/cen/science/88/8820sci1.html|access-date=June 4, 2011 | doi=10.1021/cen-v088n020.p031| url-access=subscription }}</ref> is the [[chemical reaction]] of an unsaturated [[halide]] (or [[triflate]]) with an [[alkene]] in the presence of a [[base (chemistry)|base]] and a [[palladium catalyst]]  to form a substituted alkene. It is named after [[Tsutomu Mizoroki]] and [[Richard F. Heck]]. Heck was awarded the 2010 [[Nobel Prize in Chemistry]], which he shared with [[Ei-ichi Negishi]] and [[Akira Suzuki (chemist)|Akira Suzuki]], for the discovery and development of this reaction. This reaction was the first example of a carbon-carbon bond-forming reaction that followed a Pd(0)/Pd(II) catalytic cycle, the same catalytic cycle that is seen in other Pd(0)-catalyzed [[cross-coupling reaction]]s. The Heck reaction is a way to substitute alkenes.<ref>{{cite journal | doi = 10.1002/0471264180.or027.02 | title = Palladium-catalyzed vinylation of organic halides | author = Heck, R. F. | author-link =  Richard F. Heck | journal = [[Org. React.]] | year = 1982 | volume = 27 | pages = 345–390| isbn = 978-0471264187 }}</ref><ref>{{cite journal | title = Fine Feathers Make Fine Birds: The Heck Reaction in Modern Garb | author1 = de Meijere, A. |author2 = Meyer, F. E. | journal = [[Angew. Chem. Int. Ed. Engl.]] | year = 1994 | volume = 33 | pages = 2379–2411 | doi = 10.1002/anie.199423791 | issue = 2324}}</ref><ref>{{cite journal | title = The Heck Reaction as a Sharpening Stone of Palladium Catalysis |author1= Beletskaya, I. P.|author1-link= Irina Beletskaya |author2=Cheprakov, A. V.  | journal = [[Chem. Rev.]] | year = 2000 | volume = 100 | pages = 3009–3066 | doi = 10.1021/cr9903048 | pmid=11749313 | issue = 8 }}</ref><ref>{{cite journal | doi = 10.1039/C1CS15101K | title = The asymmetric Heck and related reactions | year = 2011 | last1 = Mc Cartney | first1 = Dennis | last2 = Guiry | first2 = Patrick J. | journal = [[Chem. Soc. Rev.]] | volume = 40 | issue = 10 | pages = 5122–5150 | pmid = 21677934}}</ref>

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[[File:Heck Reaction Scheme.png|center|300px|The Heck reaction]]
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! The Heck reaction
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==History==
The original reaction by Tsutomu Mizoroki (1971) describes the coupling between [[iodobenzene]] and [[styrene]] in [[methanol]] to form [[stilbene]] at 120&nbsp;°C ([[autoclave]]) with [[potassium acetate]] base and [[palladium chloride]] catalysis. This work was an extension of earlier work by Fujiwara (1967) on the Pd(II)-mediated coupling of arenes (Ar–H) and alkenes<ref>{{cite journal|last=Moritani|first=Ichiro|author2=Fujiwara, Yuzo|title=Aromatic substitution of styrene-palladium chloride complex|journal=[[Tetrahedron Lett.]]|year=1967|volume=8|issue=12|pages=1119–1122|doi=10.1016/S0040-4039(00)90648-8}}</ref><ref>{{cite journal|doi=10.1021/ja01053a047|title=Aromatic substitution of olefins. VI. Arylation of olefins with palladium(II) acetate|year=1969|last1=Fujiwara|first1=Yuzo|last2=Noritani|first2=Ichiro|last3=Danno|first3=Sadao|last4=Asano|first4=Ryuzo|last5=Teranishi|first5=Shiichiro|journal=[[J. Am. Chem. Soc.]]|volume=91|pages=7166–9|issue=25|pmid=27462934}}</ref> and earlier work by Heck (1969) on the coupling of arylmercuric halides (ArHgCl) with alkenes using a stoichiometric amount of a palladium(II) species.<ref>{{cite journal|doi=10.1021/ja01052a029|title=Mechanism of Arylation and Carbomethoxylation of Olefins with Organopalladium Compounds|year=1969|author= Richard F. Heck|author-link=Richard F. Heck|journal=J. Am. Chem. Soc.|volume=91|pages=6707–6714|issue=24}}</ref>

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[[File:Mizoroki 1971 iodobenzene styrene.svg|center|400px|Mizoroki 1971]]
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! Mizoroki 1971
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In 1972 Heck acknowledged the Mizoroki publication and detailed ''independently discovered'' work. Heck's reaction conditions differ in terms of the catalyst (palladium acetate), catalyst loading (0.01 eq.), base (hindered amine), and absence of solvent.<ref>{{cite journal | title = Palladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides | author1 = Heck, R. F.| author1-link = Richard F. Heck | author2 = Nolley, J. P. | journal = [[J. Org. Chem.]] | year = 1972 | volume = 37 | pages = 2320–2322 | doi = 10.1021/jo00979a024 | issue=14 }}</ref><ref>{{cite journal |author1=Mizoroki, T. |author2=Mori, K. |author3=Ozaki, A. | journal = [[Bull. Chem. Soc. Jpn.]] | year = 1971 | volume = 44 | pages = 581 | doi = 10.1246/bcsj.44.581 | title = Arylation of Olefin with Aryl Iodide Catalyzed by Palladium | issue = 2| doi-access =  }}</ref>

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[[File:Heck 1972 iodobenzene styrene.svg|center|400px|Heck 1972]]
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! Heck 1972
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In 1974 Heck showed that phosphine ligands facilitated the reaction.<ref>{{cite journal|doi=10.1021/ja00811a029|title=Organophosphinepalladium complexes as catalysts for vinylic hydrogen substitution reactions|year=1974|last1=Dieck|first1=H. A.|last2=Heck|first2=R. F.|journal=J. Am. Chem. Soc.|volume=96|pages=1133|issue=4}}</ref>
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[[File:Heck Dieck 1974.svg|center|400px|Dieck & Heck 1974]]
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! Heck reaction 1974 phosphines
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==Catalyst and substrates==
The reaction is catalyzed by palladium complexes. Typical catalysts and precatalysts include [[tetrakis(triphenylphosphine)palladium(0)]], [[palladium chloride]], and [[palladium(II) acetate]]. Typical supporting [[ligand]]s are [[triphenylphosphine]], [[phosphinooxazolines|PHOX]], and [[BINAP]]. Typical bases are [[triethylamine]], [[potassium carbonate]], and [[sodium acetate]].

The aryl electrophile can be a halide (Br, Cl) or a triflate as well as [[benzyl]] or [[vinyl group|vinyl]] halides. The alkene must contain at least one sp<sup>2</sup>-C-H bond. Electron-withdrawing substituents enhance the reaction, thus [[acrylate]]s are ideal.<ref>{{OrgSynth | author=Littke, A. F. | author2=Fu, G. C. | year=2005 | title=Heck reactions of aryl chlorides catalyzed by palladium/tri-''tert''-butylphosphine: (''E'')-2-Methyl-3-phenylacryacid butyl ester and (''E'')-4-(2-phenylethenyl)benzonitrile | volume=81 | pages=63 | prep = v81p0063}}</ref>

== Reaction mechanism ==
The mechanism of this [[vinylation]] involves [[organopalladium]] intermediates. The required palladium(0) compound is often generated [[in situ]] from a palladium(II) precursor.<ref>{{cite journal |author1=Ozawa, F. |author2=Kubo, A. |author3=Hayashi, T. | journal = [[Chemistry Letters]] |volume=21 | year = 1992 | pages = 2177–2180 | doi = 10.1246/cl.1992.2177 | title = Generation of Tertiary Phosphine-Coordinated Pd(0) Species from Pd(OAc)<sub>2</sub> in the Catalytic Heck Reaction | issue = 11}}</ref><ref>{{cite journal|last1=Bradshaw|first1=Michael|last2=Zou|first2=Jianli|last3=Byrne|first3=Lindsay|last4=Swaminathan Iyer|first4=K.|last5=Stewart|first5=Scott G.|last6=Raston|first6=Colin L.|author-link6=Colin L. Raston|title=Pd(II) conjugated chitosan nanofibre mats for application in Heck cross-coupling reactions|journal=[[Chem. Commun.]]|year=2011|volume=47|issue=45|pages=12292–12294|doi=10.1039/C1CC14717J|pmid=22011792}}</ref>

For instance, [[palladium(II) acetate]] is reduced by [[triphenylphosphine]] to bis(triphenylphosphine)palladium(0) ('''1''') concomitant with oxidation of triphenylphosphine to [[triphenylphosphine oxide]]. Step '''A''' is an [[oxidative addition]] in which palladium inserts itself in the aryl-bromide bond. The resulting palladium(II) complex then binds alkene ('''3'''). In step '''B''' the alkene inserts into the Pd-C bond in a [[syn addition]] step. Step '''C''' involves a [[beta-hydride elimination]] (here the arrows are showing the opposite) with the formation of a new palladium - alkene π complex ('''5'''). This complex is destroyed in the next step. The Pd(0) complex is regenerated by [[reductive elimination]] of the palladium(II) compound by [[potassium carbonate]] in the final step, '''D'''. In the course of the reaction the carbonate is stoichiometrically consumed and palladium is truly a catalyst and used in catalytic amounts. A similar palladium cycle but with different scenes and actors is observed in the [[Wacker process]].

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[[File:Heck Reaction Mechanism.svg|center|600px|Heck Reaction Mechanism]]
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! Heck Reaction Mechanism
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This cycle is not limited to vinyl compounds, in the [[Sonogashira coupling]] one of the reactants is an [[alkyne]] and in the [[Suzuki coupling]] the alkene is replaced by an aryl [[boronic acid]] and in the [[Stille reaction]] by an aryl [[stannane]]. The cycle also extends to the other [[group 10 element]] [[nickel]] for example in the [[Negishi coupling]] between aryl halides and organozinc compounds. Platinum forms strong bonds with carbon and does not have a catalytic activity in this type of reaction.

==Stereoselectivity==
This [[coupling reaction]] is [[stereoselective]] with a propensity for [[trans isomer|trans]] coupling as the palladium halide group and the bulky organic residue move away from each other in the reaction sequence in a rotation step. The Heck reaction is applied industrially in the production of [[naproxen]] and the [[sunscreen]] component [[octyl methoxycinnamate]].  The naproxen synthesis includes a coupling between a brominated [[naphthalene]] compound with [[ethylene]]:<ref>{{cite journal | doi = 10.1139/cjc-79-5-6-1086 | title = The Heck reaction in the production of fine chemicals | year = 2001 |author1=De Vries |author2=Johannes G. | journal = [[Can. J. Chem.]] | volume = 79 | pages = 1086 | issue = 5–6}}</ref>

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[[File:Heck naproxen.svg|center|400px|The Heck reaction in Naproxen production]]
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! The Heck reaction in Naproxen production
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== Variations ==

===Ionic liquid Heck reaction===
In the presence of an [[ionic liquid]] a Heck reaction proceeds in absence of a phosphorus ligand. In one modification palladium acetate and the ionic liquid [[bmim|(bmim)PF<sub>6</sub>]] are immobilized inside the cavities of reversed-phase [[silica gel]].<ref>{{cite journal | title = Sustainable Mizoroki–Heck reaction in water: remarkably high activity of Pd(OAc)<sub>2</sub> immobilized on reversed phase silica gel with the aid of an ionic liquid | journal = [[Chem. Commun.]] | year = 2005 | issue = 23 | pages = 2942–2944 | doi = 10.1039/b502528a | author = Hagiwara, Hisahiro | last2 = Sugawara | first2 = Yoshitaka | last3 = Hoshi | first3 = Takashi | last4 = Suzuki | first4 = Toshio | pmid = 15957033}}</ref> In this way the reaction proceeds in water and the catalyst is re-usable.
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[[File:Heck siloxane.svg|center|300px|Siloxane application]]
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! Siloxane application
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=== Heck oxyarylation ===
In the '''Heck oxyarylation''' modification the palladium substituent in the syn-addition intermediate is displaced by a hydroxyl group and the reaction product contains a [[dihydrofuran]] ring.<ref>{{cite journal | title = Further insight into the mechanism of Heck oxyarylation in the presence of chiral ligands |author1=Lorand Kiss |author2=Tibor Kurtan |author3=Sandor Antus |author4=Henri Brunner | journal = [[Arkivoc]] | pages= GB–653J | year = 2003 | url = http://www.arkat-usa.org/ark/journal/2003/I05_Bernath/GB-653J/GB-653J.asp }}</ref>
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[[File:Heck oxyarylation.svg|center|500px|Heck oxyarylation]]
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! Heck oxyarylation
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=== Amino-Heck reaction ===
In the '''amino-Heck reaction''' a [[nitrogen]] to [[carbon]] bond is formed. In one example,<ref>{{cite journal | title = Palladium(0)-catalyzed synthesis of pyridines from β-acetoxy-γ,δ-unsaturated ketone oximes |author1=Mitsuru Kitamura |author2=Daisuke Kudo |author3=Koichi Narasaka | journal = [[Arkivoc]] | pages = JC–1563E | year = 2005 | url = http://www.arkat-usa.org/ark/journal/2006/I03_Coxon/1563/1563.asp}}</ref> an [[oxime]] with a strongly electron withdrawing group reacts [[Intramolecular reaction|intramolecular]]ly with the end of a [[diene]] to form a [[pyridine]] compound. The [[catalyst]] is [[tetrakis(triphenylphosphine)palladium(0)]] and the base is [[triethylamine]]. 
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[[File:Heck amino.svg|center|400px|Amino-Heck reaction]]
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! Amino-Heck reaction
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== See also ==
* [[Hiyama coupling]]
* [[Stille reaction]]
* [[Suzuki reaction]]
* [[Sonogashira coupling]]
* [[Intramolecular Heck reaction]]
* [[Negishi coupling|Negishi Coupling]]

== References ==
{{Reflist|2}}

== External links ==
{{Commons category}}
* The Heck reaction at organic-chemistry.org [https://www.organic-chemistry.org/namedreactions/heck-reaction.shtm Article]
{{Organic reactions}}
{{Authority control}}

{{DEFAULTSORT:Heck Reaction}}
[[Category:Carbon-carbon bond forming reactions]]
[[Category:Substitution reactions]]
[[Category:Palladium]]
[[Category:Name reactions]]