| Heck reaction | |
|---|---|
| Named after | Richard F. Heck |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | heck-reaction |
| RSC ontology ID | RXNO:0000024 |
TheHeck reaction (also called theMizoroki–Heck reaction)[1] is thechemical reaction of an unsaturatedhalide (ortriflate) with analkene in the presence of abase and apalladium catalyst to form a substituted alkene. It is named afterTsutomu Mizoroki andRichard F. Heck. Heck was awarded the 2010Nobel Prize in Chemistry, which he shared withEi-ichi Negishi andAkira 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)-catalyzedcross-coupling reactions. The Heck reaction is a way to substitute alkenes.[2][3][4][5]
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| The Heck reaction |
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The original reaction by Tsutomu Mizoroki (1971) describes the coupling betweeniodobenzene andstyrene inmethanol to formstilbene at 120 °C (autoclave) withpotassium acetate base andpalladium 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[6][7] and earlier work by Heck (1969) on the coupling of arylmercuric halides (ArHgCl) with alkenes using a stoichiometric amount of a palladium(II) species.[8]
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| Mizoroki 1971 |
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In 1972 Heck acknowledged the Mizoroki publication and detailedindependently 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.[9][10]
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| Heck 1972 |
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In 1974 Heck showed that phosphine ligands facilitated the reaction.[11]
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| Heck reaction 1974 phosphines |
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The reaction is catalyzed by palladium complexes. Typical catalysts and precatalysts includetetrakis(triphenylphosphine)palladium(0),palladium chloride, andpalladium(II) acetate. Typical supportingligands aretriphenylphosphine,PHOX, andBINAP. Typical bases aretriethylamine,potassium carbonate, andsodium acetate.
The aryl electrophile can be a halide (Br, Cl) or a triflate as well asbenzyl orvinyl halides. The alkene must contain at least one sp2-C-H bond. Electron-withdrawing substituents enhance the reaction, thusacrylates are ideal.[12]
The mechanism of thisvinylation involvesorganopalladium intermediates. The required palladium(0) compound is often generatedin situ from a palladium(II) precursor.[13][14]
For instance,palladium(II) acetate is reduced bytriphenylphosphine to bis(triphenylphosphine)palladium(0) (1) concomitant with oxidation of triphenylphosphine totriphenylphosphine oxide. StepA is anoxidative addition in which palladium inserts itself in the aryl-bromide bond. The resulting palladium(II) complex then binds alkene (3). In stepB the alkene inserts into the Pd-C bond in asyn addition step. StepC involves abeta-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 byreductive elimination of the palladium(II) compound bypotassium 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 theWacker process.
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| Heck Reaction Mechanism |
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This cycle is not limited to vinyl compounds, in theSonogashira coupling one of the reactants is analkyne and in theSuzuki coupling the alkene is replaced by an arylboronic acid and in theStille reaction by an arylstannane. The cycle also extends to the othergroup 10 elementnickel for example in theNegishi 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.
Thiscoupling reaction isstereoselective with a propensity fortrans 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 ofnaproxen and thesunscreen componentoctyl methoxycinnamate. The naproxen synthesis includes a coupling between a brominatednaphthalene compound withethylene:[15]
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| The Heck reaction in Naproxen production |
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In the presence of anionic liquid a Heck reaction proceeds in absence of a phosphorus ligand. In one modification palladium acetate and the ionic liquid(bmim)PF6 are immobilized inside the cavities of reversed-phasesilica gel.[16] In this way the reaction proceeds in water and the catalyst is re-usable.
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| Siloxane application |
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In theHeck oxyarylation modification the palladium substituent in the syn-addition intermediate is displaced by a hydroxyl group and the reaction product contains adihydrofuran ring.[17]
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| Heck oxyarylation |
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In theamino-Heck reaction anitrogen tocarbon bond is formed. In one example,[18] anoxime with a strongly electron withdrawing group reactsintramolecularly with the end of adiene to form apyridine compound. Thecatalyst istetrakis(triphenylphosphine)palladium(0) and the base istriethylamine.
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| Amino-Heck reaction |
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