Heck reaction
Overview
 
The Heck reaction is the chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...

 of an unsaturated halide
Halide
A halide is a binary compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative than the halogen, to make a fluoride, chloride, bromide, iodide, or astatide compound. Many salts are halides...

 (or triflate
Triflate
Trifluoromethanesulfonate, also known by the trivial name triflate, is a functional group with the formula CF3SO3-. The triflate group is often represented by -OTf, as opposed to -Tf...

) with an alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...

 and a base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

 and palladium catalyst to form a substituted alkene. Together with the other palladium-catalyzed cross-coupling reactions, this reaction is of great importance, as it allows one to do substitution reactions on planar centers. It is named after Tsutomu Mizoroki and Richard F. Heck
Richard F. Heck
Richard Fred Heck is an American chemist noted for the discovery and development of the Heck reaction, which uses palladium to catalyze organic chemical reactions that couple aryl halides with alkenes....

. Heck was awarded the 2010 Nobel Prize in Chemistry
Nobel Prize in Chemistry
The Nobel Prize in Chemistry is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in chemistry, physics, literature,...

 for the discovery and development of this reaction.


The reaction is performed in the presence of an organopalladium
Organopalladium
Organopalladium chemistry is a branch of organometallic chemistry that deals with organic palladium compounds and their reactions. Palladium is often used as a catalyst in the reduction of alkenes and alkynes with hydrogen. This process involves the formation of a palladium-carbon covalent bond...

 catalyst.
Encyclopedia
The Heck reaction is the chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...

 of an unsaturated halide
Halide
A halide is a binary compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative than the halogen, to make a fluoride, chloride, bromide, iodide, or astatide compound. Many salts are halides...

 (or triflate
Triflate
Trifluoromethanesulfonate, also known by the trivial name triflate, is a functional group with the formula CF3SO3-. The triflate group is often represented by -OTf, as opposed to -Tf...

) with an alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...

 and a base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

 and palladium catalyst to form a substituted alkene. Together with the other palladium-catalyzed cross-coupling reactions, this reaction is of great importance, as it allows one to do substitution reactions on planar centers. It is named after Tsutomu Mizoroki and Richard F. Heck
Richard F. Heck
Richard Fred Heck is an American chemist noted for the discovery and development of the Heck reaction, which uses palladium to catalyze organic chemical reactions that couple aryl halides with alkenes....

. Heck was awarded the 2010 Nobel Prize in Chemistry
Nobel Prize in Chemistry
The Nobel Prize in Chemistry is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in chemistry, physics, literature,...

 for the discovery and development of this reaction.

The Heck reaction


The reaction is performed in the presence of an organopalladium
Organopalladium
Organopalladium chemistry is a branch of organometallic chemistry that deals with organic palladium compounds and their reactions. Palladium is often used as a catalyst in the reduction of alkenes and alkynes with hydrogen. This process involves the formation of a palladium-carbon covalent bond...

 catalyst. The halide (Br, Cl) or triflate is an aryl
Aryl
In the context of organic molecules, aryl refers to any functional group or substituent derived from an aromatic ring, be it phenyl, naphthyl, thienyl, indolyl, etc....

, benzyl
Benzyl
In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...

, or vinyl
Vinyl
A vinyl compound is any organic compound that contains a vinyl group ,which are derivatives of ethene, CH2=CH2, with one hydrogen atom replaced with some other group...

 compound and the alkene contains at least one proton
Hydrogen ion
Hydrogen ion is recommended by IUPAC as a general term for all ions of hydrogen and its isotopes.Depending on the charge of the ion, two different classes can be distinguished: positively charged ions and negatively charged ions....

 and is often electron-deficient such as acrylate
Acrylate
The acrylate ion is the ion of acrylic acid.Acrylates are the salts and esters of acrylic acid. They are also known as propenoates ....

 ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

 or an acrylonitrile
Acrylonitrile
Acrylonitrile is the chemical compound with the formula C3H3N. This pungent-smelling colorless liquid often appears yellow due to impurities. It is an important monomer for the manufacture of useful plastics. In terms of its molecular structure, it consists of a vinyl group linked to a nitrile...

.The catalyst can be tetrakis(triphenylphosphine)palladium(0)
Tetrakis(triphenylphosphine)palladium(0)
Tetrakispalladium is the chemical compound Pd[P3]4, often abbreviated Pd4, or even PdP4. It is a bright yellow crystalline solid that becomes brown upon decomposition in air.-Structure and properties:...

, palladium chloride or palladium(II) acetate
Palladium(II) acetate
Palladium acetate is a chemical compound of palladium described by the formula Pd2 or Pd2. It is considered more reactive than the analogous platinum compound...

. The ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

 is triphenylphosphine
Triphenylphosphine
Triphenylphosphine is a common organophosphorus compound with the formula P3 - often abbreviated to PPh3 or Ph3P. It is widely used in the synthesis of organic and organometallic compounds. PPh3 exists as relatively air stable, colorless crystals at room temperature...

 or BINAP
BINAP
BINAP is an abbreviation for the organophosphorus compound 2,2'-bis-1,1'-binaphthyl. This chiral ligand is widely used in asymmetric synthesis. It consists of a pair of 2-diphenylphosphinonaphthyl groups linked at the 1 and 1´ positions. This C2-symmetric framework lacks stereogenic atom, but...

. The base is triethylamine
Triethylamine
Triethylamine is the chemical compound with the formula N3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine, for which TEA is also a common abbreviation....

, potassium carbonate
Potassium carbonate
Potassium carbonate is a white salt, soluble in water , which forms a strongly alkaline solution. It can be made as the product of potassium hydroxide's absorbent reaction with carbon dioxide. It is deliquescent, often appearing a damp or wet solid...

 or sodium acetate
Sodium acetate
Sodium acetate, CH3COONa, also abbreviated NaOAc, also sodium ethanoate, is the sodium salt of acetic acid. This colourless salt has a wide range of uses.-Industrial:...

.

Several reviews have been published.

History

The original reaction by Tsutomu Mizoroki (1971) describes the coupling between iodobenzene
Iodobenzene
Iodobenzene is an organic compound consisting of a benzene ring substitituted with one iodine atom. It is useful as a synthetic intermediate in organic chemistry.-Preparation:...

 and styrene to form stilbene
Stilbene
-Stilbene, is a diarylethene, i.e., a hydrocarbon consisting of a trans ethene double bond substituted with a phenyl group on both carbon atoms of the double bond. The name stilbene is derived from the Greek word stilbos, which means shining....

 in methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...

 at 120°C (autoclave
Autoclave
An autoclave is an instrument used to sterilize equipment and supplies by subjecting them to high pressure saturated steam at 121 °C for around 15–20 minutes depending on the size of the load and the contents. It was invented by Charles Chamberland in 1879, although a precursor known as the...

) with potassium acetate
Potassium acetate
Potassium acetate is the potassium salt of acetic acid.-Preparation:It can be prepared by reacting a potassium-containing base such as potassium hydroxide or potassium carbonate with acetic acid:...

 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 and earlier work by Heck (1969) on the coupling of arylmercuric halides (ArHgCl) with alkenes using a stoichiometric amount of a palladium(II) species.

Mizoroki 1971


The 1972 Heck publication acknowledged the Mizoroki publication and detailed independently discovered work. The reaction conditions differ in catalyst used (palladium acetate), base used (a hindered amine) and lack of solvent.

Heck 1972


In these reactions the active catalyst Pd(0) (see reaction mechanism) is formed by Pd coordination to the alkene.

In 1974 Heck introduced phosphine ligands into the equation.

Heck reaction 1974 phosphines

Reaction mechanism

The catalytic cycle
Catalytic cycle
A catalytic cycle in chemistry is a term for a multistep reaction mechanism that involves a catalyst . The catalytic cycle is the main method for describing the role of catalysts in biochemistry, organometallic chemistry, materials science, etc. Often such cycles show the conversion of a...

 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
In situ
In situ is a Latin phrase which translated literally as 'In position'. It is used in many different contexts.-Aerospace:In the aerospace industry, equipment on board aircraft must be tested in situ, or in place, to confirm everything functions properly as a system. Individually, each piece may...

 from a palladium(II) precursor.

For instance, palladium(II) acetate
Palladium(II) acetate
Palladium acetate is a chemical compound of palladium described by the formula Pd2 or Pd2. It is considered more reactive than the analogous platinum compound...

 is reduced by triphenylphosphine
Triphenylphosphine
Triphenylphosphine is a common organophosphorus compound with the formula P3 - often abbreviated to PPh3 or Ph3P. It is widely used in the synthesis of organic and organometallic compounds. PPh3 exists as relatively air stable, colorless crystals at room temperature...

 to bis(triphenylphosphine)palladium(0) (1) and triphenylphosphine is oxidized to triphenylphosphine oxide. Step A is an oxidative addition
Oxidative addition
Oxidative addition and reductive elimination are two important and related classes of reactions in organometallic chemistry. Oxidative addition is a process that increases both the oxidation state and coordination number of a metal centre...

 in which palladium inserts itself in the aryl to bromide bond. Palladium then forms a π complex with the alkene (3) and in step B the alkene inserts itself in the palladium - carbon bond in a syn addition
Syn addition
In organic chemistry, syn and anti addition are different ways in which two substituents can be added to a double bond or triple bond. This article will use alkenes as examples....

 step. Then follows a torsional strain relieving rotation to the trans isomer (not shown) and step C is a beta-hydride elimination
Beta-hydride elimination
Beta-hydride elimination is a reaction in which an alkyl group bonded to a metal centre is converted into the corresponding metal-bonded hydride and an alkene. The alkyl must have hydrogens on the beta carbon. For instance butyl groups can undergo this reaction but methyl groups cannot...

 step with the formation of a new palladium - alkene π complex (5). This complex is destroyed in the next step. The palladium(0) compound is regenerated by reductive elimination of the palladium(II) compound by potassium carbonate
Potassium carbonate
Potassium carbonate is a white salt, soluble in water , which forms a strongly alkaline solution. It can be made as the product of potassium hydroxide's absorbent reaction with carbon dioxide. It is deliquescent, often appearing a damp or wet solid...

 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
Wacker process
The Wacker process or the Hoechst-Wacker process originally referred to the oxidation of ethylene to acetaldehyde by oxygen in water in the presence of a tetrachloropalladate catalyst...

.

Heck Reaction Mechanism


This cycle is not limited to vinyl compounds, in the Sonogashira coupling
Sonogashira coupling
In organic chemistry, a Sonogashira coupling is a coupling reaction of terminal alkynes with aryl or vinyl halides. This reaction was first reported by Kenkichi Sonogashira and Nobue Hagihara in 1975.-Catalyst:...

 one of the reactants is an alkyne
Alkyne
Alkynes are hydrocarbons that have a triple bond between two carbon atoms, with the formula CnH2n-2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature...

 and in the Suzuki coupling the alkene is replaced by an aryl boronic acid
Boronic acid
A boronic acid is an alkyl or aryl substituted boric acid containing a carbon–boron bond belonging to the larger class of organoboranes. Boronic acids act as Lewis acids. Their unique feature is that they are capable of forming reversible covalent complexes with sugars, amino acids, hydroxamic...

 and in the Stille reaction
Stille reaction
The Stille reaction is a chemical reaction coupling an organotin compound with an sp2-hybridized organic halide catalyzed by palladium. The reaction is widely used in organic synthesis....

 by an aryl stannane
Stannane
Stannane is the hydride of tin. Stannane can be prepared by the reaction of SnCl4 and LiAlH4. Stannane decomposes slowly at room temperature to give metallic tin and hydrogen and ignites on contact with air....

. The cycle also extends to the other group 10 element
Group 10 element
A Group 10 element is one in the series of elements in group 10 in the periodic table, which consists of the transition metals nickel , palladium , platinum , and darmstadtium ....

 nickel
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...

 for example in the Negishi coupling
Negishi coupling
The Negishi coupling is a cross coupling reaction in organic chemistry involving an organozinc compound, an organic halide and a nickel or palladium catalyst creating a new carbon-carbon covalent bond:* The halide X can be chloride, bromine or iodine but also a triflate or acetyloxy group with as...

 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
Coupling reaction
A coupling reaction in organic chemistry is a catch-all term for a variety of reactions where two hydrocarbon fragments are coupled with the aid of a metal catalyst...

 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
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...

 and the sunscreen
Sunscreen
Sunblock is a lotion, spray, gel or other topical product that absorbs or reflects some of the sun's ultraviolet radiation on the skin exposed to sunlight and thus helps protect against sunburn...

 component octyl methoxycinnamate
Octyl methoxycinnamate
Octyl methoxycinnamate or octinoxate , trade names Eusolex 2292 and Uvinul MC80, is an organic compound that is an ingredient in some sunscreens and lip balms. It is an ester formed from methoxycinnamic acid and 2-ethylhexanol...

. The naproxen synthesis includes a coupling between a brominated naphthalene
Naphthalene
Naphthalene is an organic compound with formula . It is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromatic hydrocarbon, naphthalene's structure consists of a fused pair of benzene rings...

 compound with ethylene
Ethylene
Ethylene is a gaseous organic compound with the formula . It is the simplest alkene . Because it contains a carbon-carbon double bond, ethylene is classified as an unsaturated hydrocarbon. Ethylene is widely used in industry and is also a plant hormone...

:

The Heck reaction in Naproxen production

Ionic liquid Heck reaction

In the presence of an ionic liquid
Ionic liquid
An ionic liquid is a salt in the liquid state. In some contexts, the term has been restricted to salts whose melting point is below some arbitrary temperature, such as . While ordinary liquids such as water and gasoline are predominantly made of electrically neutral molecules, ILs are largely made...

 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
Silica gel
Silica gel is a granular, vitreous, porous form of silica made synthetically from sodium silicate. Despite its name, silica gel is a solid. It is a naturally occurring mineral that is purified and processed into either granular or beaded form...

. 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 tetrahydrofuran
Tetrahydrofuran
Tetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...

 ring.

Heck oxyarylation

Amino-Heck reaction

In the amino-Heck reaction a nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

 to carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

 bond is formed. In one example, an oxime
Oxime
An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds...

 with a strongly electron withdrawing group reacts intramolecular
Intramolecular
Intramolecular in chemistry describes a process or characteristic limited within the structure of a single molecule, a property or phenomenon limited to the extent of a single molecule.- Examples :...

ly with the terminal end of a diene
Diene
In organic chemistry a diene or diolefin is a hydrocarbon that contains two carbon double bonds.Conjugated dienes are functional groups, with a general formula of CnH2n-2. Dienes and alkynes are functional isomers...

 to a pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...

 compound. The catalyst is tetrakis(triphenylphosphine)palladium(0)
Tetrakis(triphenylphosphine)palladium(0)
Tetrakispalladium is the chemical compound Pd[P3]4, often abbreviated Pd4, or even PdP4. It is a bright yellow crystalline solid that becomes brown upon decomposition in air.-Structure and properties:...

 and the base is triethylamine
Triethylamine
Triethylamine is the chemical compound with the formula N3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine, for which TEA is also a common abbreviation....

.

Amino-Heck reaction

See also

  • Hiyama coupling
    Hiyama coupling
    In organic chemistry, a Hiyama coupling is a palladium or nickel-catalyzed cross coupling reaction of organosilanes with organic halides or triflates. Hiyama couplings were first reported by Yasuo Hatanaka and Tamejiro Hiyama in 1988....

  • Stille reaction
    Stille reaction
    The Stille reaction is a chemical reaction coupling an organotin compound with an sp2-hybridized organic halide catalyzed by palladium. The reaction is widely used in organic synthesis....

  • Suzuki reaction
    Suzuki reaction
    The Suzuki reaction is the organic reaction of an aryl- or vinyl-boronic acid with an aryl- or vinyl-halide catalyzed by a palladium complex. It is widely used to synthesize poly-olefins, styrenes, and substituted biphenyls, and has been extended to incorporate alkyl bromides...

  • Sonogashira coupling
    Sonogashira coupling
    In organic chemistry, a Sonogashira coupling is a coupling reaction of terminal alkynes with aryl or vinyl halides. This reaction was first reported by Kenkichi Sonogashira and Nobue Hagihara in 1975.-Catalyst:...


External links

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