Heck reaction
The Heck reaction is the chemical reaction of an unsaturated halide with an alkene in the presence of a 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, 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/Pd catalytic cycle, the same catalytic cycle that is seen in other Pd-catalyzed cross-coupling reactions. The Heck reaction is a way to substitute alkenes.
| The Heck reaction |
History
The original reaction by Tsutomu Mizoroki describes the coupling between iodobenzene and styrene in methanol to form stilbene at 120 °C with potassium acetate base and palladium chloride catalysis. This work was an extension of earlier work by Fujiwara on the Pd-mediated coupling of arenes and alkenes and earlier work by Heck on the coupling of arylmercuric halides with alkenes using a stoichiometric amount of a palladium species.| Mizoroki 1971 |
In 1972 Heck acknowledged the Mizoroki publication and detailed independently discovered work. The reaction conditions differ in catalyst used and catalyst loading, base used and lack of solvent.
| Heck 1972 |
In these reactions the active catalyst Pd is formed by Pd coordination to the alkene.
In 1974 Heck introduced phosphine ligands into the equation.
| Heck reaction 1974 phosphines |
Catalyst and substrates
The reaction is catalyzed by palladium salts and complexes. Typical catalysts and precatalysts include tetrakispalladium, palladium chloride, and palladium acetate. Typical supporting ligands are triphenylphosphine, PHOX and BINAP. Typical bases are triethylamine, potassium carbonate, and sodium acetate.The aryl electrophile can be a halide or a triflate as well as benzyl or vinyl halides. The alkene must contain at least one sp2-C-H bond. Electron-withdrawing substituents enhance the reaction, thus acrylates are ideal.
Reaction mechanism
The mechanism involves organopalladium intermediates. The palladium compound required in this cycle is generated in situ from a palladium precursor.For instance, palladium acetate is reduced by triphenylphosphine to bispalladium and triphenylphosphine is oxidized to triphenylphosphine oxide. Step A is an oxidative addition in which palladium inserts itself in the aryl to bromide bond. Palladium then forms a π complex with the alkene and in step B the alkene inserts itself in the palladium - carbon bond in a syn addition step. Then follows a torsional strain relieving rotation to the trans isomer and step C is a beta-hydride elimination step with the formation of a new palladium - alkene π complex. This complex is destroyed in the next step. The palladium compound is regenerated by reductive elimination of the palladium 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.
| Heck Reaction Mechanism |
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 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:| The Heck reaction in Naproxen production |
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 PF6 are immobilized inside the cavities of reversed-phase silica gel. In this way the reaction proceeds in water and the catalyst is re-usable.| Siloxane application |
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.| Heck oxyarylation |
Amino-Heck reaction
In the amino-Heck reaction a nitrogen to carbon bond is formed. In one example, an oxime with a strongly electron withdrawing group reacts intramolecularly with the end of a diene to form a pyridine compound. The catalyst is tetrakispalladium and the base is triethylamine.| Amino-Heck reaction |