Heck reaction

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The Heck reaction (also called the Mizoroki-Heck reaction) is the chemical reaction of an unsaturated halide (or triflate) with an alkene and a strong base and palladium catalyst to form a substituted alkene.[1][2] It is named after the American chemist Richard F. Heck.

The Heck reaction

The reaction is performed in the presence of an organopalladium catalyst. The halide or triflate is an aryl, benzyl, or vinyl compound and the alkene contains at least one proton and is often electron-deficient such as acrylate ester or an acrylonitrile.The catalyst can be tetrakis(triphenylphosphine)palladium(0), palladium chloride or palladium(II) acetate. The ligand is triphenylphosphine or BINAP. The base is triethylamine, potassium carbonate or sodium acetate.

Several reviews have been published.[3][4][5]

This coupling reaction is stereoselective with a propensity for 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 involves a coupling between a brominated naphthalene compound with ethylene:

The Heck reaction in Naproxen production

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[edit] Reaction mechanism

The catalytic cycle for the Heck reaction involves a series of transformations around the palladium catalyst. The palladium(0) compound required in this cycle is generally prepared in situ from a palladium(II) precursor.[6]

For instance, palladium(II) acetate is reduced by triphenylphosphine to di(triphenylphosphine)palladium(0) and triphenylphosphine is oxidized to triphenylphosphine oxide in step 1. Step 2 is an oxidative addition in which palladium inserts itself in the aryl to bromide bond. In step 3, palladium forms a π complex with the alkene and in step 4 the alkene inserts itself in the palladium - carbon bond in a syn addition step. Step 5 is a torsional strain relieving rotation and step 6 is a Beta-hydride elimination step with the formation of a new palladium - alkene π complex. This complex is destroyed in step 7. The palladium(0) compound is regenerated by reductive elimination of the palladium(II) compound by potassium carbonate in the final step 8. 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.

The Heck reaction mechanism, ultimate product either cis or trans

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 aryl halide 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.

[edit] Variations

[edit] 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)PF6 are immobilized inside the cavities of reversed-phase silica gel [7]. In this way the reaction proceeds in water and the catalyst is re-usable.

Heck reaction

[edit] 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 tetrahydrofuran ring.[8]

Heck oxyarylation

[edit] Amino-Heck reaction

In the amino-Heck reaction a nitrogen to carbon bond is formed. In one example,[9] an oxime with a strongly electron withdrawing group reacts intramolecularly with the terminal end of a diene to a pyridine compound. The catalyst is tetrakis(triphenylphosphine)palladium(0) and the base is triethylamine.

Amino-Heck modification

[edit] References

  1. ^  Palladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides Richard F. Heck; Nolley, Jr., J. P. J. Org. Chem. 1972, 37(14), 2320-2322. (doi:10.1021/jo00979a024)
  2. ^  Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jap. 1971, 44, 581.
  3. ^  Heck, R. F. Org. React. 1982, 27, 345-390. (Review)
  4. ^  Fine Feathers Make Fine Birds: The Heck Reaction in Modern Garb A. de Meijere, F. E. Meyer, Jr.; Angew. Chem. Int. Ed. Engl. 1994, 33(23-24), 2379–2411. (Review)
  5. ^  Belestskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066. (Review, doi:10.1021/cr9903048)
  6. ^  Ozawa, F.; Kubo, A.; Hayashi, T. Chemistry Lett. 1992, 2177–2180.
  7. ^  Sustainable Mizoroki–Heck reaction in water: remarkably high activity of Pd(OAc)2 immobilized on reversed phase silica gel with the aid of an ionic liquid Chemical Communications, 2005, (23), 2942 - 2944. (Abstract)
  8. ^  Further insight into the mechanism of Heck oxyarylation in the presence of chiral ligands Lorand Kiss, Tibor Kurtan, Sandor Antus, Henri Brunner Arkivoc GB-653J 2003 (Online Article)
  9. ^  Palladium(0)-catalyzed synthesis of pyridines from β-acetoxy-γ,δ-unsaturated ketone oximes Mitsuru Kitamura, Daisuke Kudo, and Koichi Narasaka Arkivoc JC-1563E 2005 (Online article)

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[edit] See also