The Heck reaction (also called the Mizoroki–Heck reaction) is the

chemical reaction A chemical reaction is a process that leads to the chemistry, chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an Gibbs free energy, ...

of an unsaturated

halide In chemistry, a halide (rarely halogenide) is a binary chemical compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative (or more electropositive) than the halogen, to make a fl ...

(or

triflate In organic chemistry, triflate (Preferred IUPAC name, systematic name: trifluoromethanesulfonate), is a functional group with the Chemical formula, formula and Chemical structure, structure . The triflate group is often represented by , as opp ...

) with an

alkene In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins. The Internationa ...

in the presence of a base and a

palladium catalyst Palladium is a chemical element; it has symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1802 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas (formally 2 Pallas), wh ...

to form a substituted alkene. It is named after Tsutomu Mizoroki and

Richard F. Heck Richard Frederick Heck (August 15, 1931 – October 9, 2015) was 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 alken ...

. Heck was awarded the 2010

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 outst ...

, which he shared with

Ei-ichi Negishi was a Japanese chemist who was best known for his discovery of the Negishi coupling. He spent most of his career at Purdue University in the United States, where he was the Herbert C. Brown Distinguished Professor and the director of the Negi ...

and

Akira Suzuki is a Japanese chemist and Nobel Prize Laureate (2010), who first published the Suzuki reaction, the organic reaction of an aryl- or vinyl- boronic acid with an aryl- or vinyl- halide catalyzed by a palladium(0) complex, in 1979. Early life a ...

, 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 In organic chemistry, a cross-coupling reaction is a reaction where two different fragments are joined. Cross-couplings are a subset of the more general coupling reactions. Often cross-coupling reactions require metal catalysts. One important re ...

s. The Heck reaction is a way to substitute alkenes.

History

The original reaction by Tsutomu Mizoroki (1971) describes the coupling between

iodobenzene Iodobenzene is an aryl iodide and the simplest of the iodobenzenes, consisting of a benzene ring substituted with one iodine atom. Its chemical formula is . It is useful as a synthetic intermediate in organic chemistry. It is a volatile colorles ...

and

styrene Styrene is an organic compound with the chemical formula C6H5CH=CH2. Its structure consists of a vinyl group as substituent on benzene. Styrene is a colorless, oily liquid, although aged samples can appear yellowish. The compound evaporates easi ...

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

to form

stilbene Stilbene may refer to one of the two stereoisomers of 1,2-diphenylethene: * (''E'')-Stilbene (''trans'' isomer) * (''Z'')-Stilbene (''cis'' isomer) See also * Stilbenoid Stilbenoids are hydroxylated derivatives of stilbene. They have a C6–C ...

at 120 °C (

autoclave An autoclave is a machine used to carry out industrial and scientific processes requiring elevated temperature and pressure in relation to ambient pressure and/or temperature. Autoclaves are used before surgical procedures to perform steriliza ...

) with

potassium acetate Potassium acetate (also called potassium ethanoate), (CH3COOK) is the potassium salt of acetic acid. It is a hygroscopic solid at room temperature. Preparation It can be prepared by treating a potassium-containing base such as potassium hydroxide ...

base and

palladium chloride Palladium(II) chloride, also known as palladium dichloride and palladous chloride, are the chemical compounds with the formula PdCl2. PdCl2 is a common starting material in palladium chemistry – palladium-based catalysts are of particular value ...

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. 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. In 1974 Heck showed that phosphine ligands facilitated the reaction.

Catalyst and substrates

The reaction is catalyzed by palladium complexes. Typical catalysts and precatalysts include

tetrakis(triphenylphosphine)palladium(0) Tetrakis(triphenylphosphine)palladium(0) (sometimes called quatrotriphenylphosphine palladium) is the chemical compound d(P(C6H5)3)4 often abbreviated Pd( PPh3)4, or rarely PdP4. It is a bright yellow crystalline solid that becomes brown upon d ...

, and

palladium(II) acetate Palladium is a chemical element; it has symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1802 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas (formally 2 Pallas), wh ...

. Typical supporting

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

s are

triphenylphosphine Triphenylphosphine (IUPAC name: triphenylphosphane) is a common organophosphorus compound with the formula P(C6H5)3 and often abbreviated to P Ph3 or Ph3P. It is versatile compound that is widely used as a reagent in organic synthesis and as a l ...

PHOX In automated theorem proving, PhoX is a proof assistant based on higher-order logic which is eXtensible. The user gives PhoX an initial goal and guides it through subgoals and evidence to prove that goal; internally, it constructs natural deduction ...

, and

BINAP BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) is an organophosphorus compound. This Optical isomerism, chiral diphosphines, diphosphine ligand is widely used in chiral synthesis, asymmetric synthesis. It consists of a pair of 2-diphe ...

. Typical bases are

triethylamine Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. Like triethanolamine and the tetraethylammonium ion, it is often abbreviated TEA. It is a colourless volatile liquid with a strong fishy odor remini ...

potassium carbonate Potassium carbonate is the inorganic compound with the formula . It is a white salt, which is soluble in water and forms a strongly alkaline solution. It is deliquescent, often appearing as a damp or wet solid. Potassium carbonate is mainly used ...

, and

sodium acetate Sodium acetate, CH3COONa, also abbreviated Sodium, NaOxygen, OAcetyl, Ac, is the sodium Salt (chemistry), salt of acetic acid. This salt is colorless, deliquescent, and hygroscopy, hygroscopic. Applications Biotechnological Sodium acetate is u ...

. The aryl electrophile can be a halide (Br, Cl) or a triflate as well as

benzyl In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group (). Nomenclature In IUPAC nomenclature, the prefix benzyl refers to a substituent ...

vinyl Vinyl may refer to: Chemistry * Polyvinyl chloride (PVC), a particular vinyl polymer * Vinyl cation, a type of carbocation * Vinyl group, a broad class of organic molecules in chemistry * Vinyl polymer, a group of polymers derived from vinyl ...

halides. The alkene must contain at least one sp²-C-H bond. Electron-withdrawing substituents enhance the reaction, thus

acrylate Acrylates (IUPAC: prop-2-enoates) are the salts, esters, and conjugate bases of acrylic acid. The acrylate ion is the anion . Often, acrylate refers to esters of acrylic acid, the most common member being methyl acrylate. These acrylates contain ...

s are ideal.

Reaction mechanism

The mechanism of this

vinylation In organic chemistry, vinylation is the process of attaching a vinyl group () to a substrate. Many organic compounds contain vinyl groups, so the process has attracted significant interest, especially since the reaction scope includes substituted ...

involves

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 ...

intermediates. The required palladium(0) compound is often generated

in situ is a Latin phrase meaning 'in place' or 'on site', derived from ' ('in') and ' ( ablative of ''situs'', ). The term typically refers to the examination or occurrence of a process within its original context, without relocation. The term is use ...

from a palladium(II) precursor. For instance,

is reduced by

to bis(triphenylphosphine)palladium(0) (1) concomitant with oxidation of triphenylphosphine to

triphenylphosphine oxide Triphenylphosphine oxide (often abbreviated TPPO) is the organophosphorus compound with the formula , also written as or (Ph = ). It is one of the more common phosphine oxides. This colourless crystalline compound is a common but potentially u ...

. Step A is an

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. Oxidat ...

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 In organic chemistry, syn- and anti-addition are different ways in which substituent molecules can be added to an alkene () or alkyne (). The concepts of syn and anti addition are used to characterize the different reactions of organic chemistry ...

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 Reductive elimination is an elementary step in organometallic chemistry in which the oxidation state of the metal center decreases while forming a new covalent bond between two ligands. It is the microscopic reverse of oxidative addition, and is ...

of the palladium(II) compound by

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 The Wacker process or the Hoechst-Wacker process (named after the chemical companies of the same name) is an industrial chemical reaction: the aerobic oxidation of ethylene to acetaldehyde in the presence of catalysis, catalytic, aqueous palladium( ...

. This cycle is not limited to vinyl compounds, in the

Sonogashira coupling The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or vi ...

one of the reactants is an

alkyne \ce \ce Acetylene \ce \ce \ce Propyne \ce \ce \ce \ce 1-Butyne In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and n ...

and in the

Suzuki coupling The Suzuki reaction or Suzuki coupling is an organic reaction that uses a palladium complex catalyst to cross-couple a boronic acid to an organohalide. It was first published in 1979 by Akira Suzuki, and he shared the 2010 Nobel Prize in Chemis ...

the alkene is replaced by an aryl

boronic acid A boronic acid is an organic compound related to boric acid () in which one of the three hydroxyl groups () is replaced by an alkyl or aryl group (represented by R in the general formula ). As a compound containing a carbon–boron bond, memb ...

and in the

Stille reaction The Stille reaction is a chemical reaction widely used in organic synthesis. The reaction involves the coupling of two organic groups, one of which is carried as an organotin chemistry, organotin compound (also known as organostannanes). A variet ...

by an aryl

stannane Stannane or tin hydride is an inorganic compound with the chemical formula Sn H4. It is a colourless gas and the tin analogue of methane. Stannane can be prepared by the reaction of and . : Stannane decomposes slowly at room temperature to ...

. The cycle also extends to the other

group 10 element Group 10, numbered by current IUPAC style, is the group of chemical elements in the periodic table that consists of nickel (Ni), palladium (Pd), platinum (Pt), and darmstadtium (Ds). All are d-block transition metals. All known isotopes o ...

nickel Nickel is a chemical element; it has symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive, but large pieces are slo ...

for example in the

Negishi coupling The Negishi coupling is a widely employed transition metal catalyzed cross-coupling reaction. The reaction couples organic halides or triflates with organozinc compounds, forming carbon–carbon bonds (C–C) in the process. A palladium (0) s ...

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 In organic chemistry, a coupling reaction is a type of reaction in which two reactant molecules are bonded together. Such reactions often require the aid of a metal catalyst. In one important reaction type, a main group organometallic compound o ...

stereoselective In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non- stereospecific creation of a new stereocenter or during a non-stereospecific transformation o ...

with a propensity for

trans Trans- is a Latin prefix meaning "across", "beyond", or "on the other side of". Used alone, trans may refer to: Sociology * Trans, a sociological term which may refer to: ** Transgender, people who identify themselves with a gender that di ...

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, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, and inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It ...

and the

sunscreen Sunscreen, also known as sunblock, sun lotion or sun cream, is a photoprotection, photoprotective topical product for the Human skin, skin that helps protect against sunburn and prevent skin cancer. Sunscreens come as lotions, sprays, gels, fo ...

component

octyl methoxycinnamate Octyl methoxycinnamate or ethylhexyl methoxycinnamate ( INCI) or octinoxate ( USAN), 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 methoxycin ...

. The naproxen synthesis includes a coupling between a brominated

naphthalene Naphthalene is an organic compound with formula . It is the simplest polycyclic aromatic hydrocarbon, and is a white Crystal, crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 Parts-per notation ...

compound with

ethylene Ethylene (IUPAC name: ethene) is a hydrocarbon which has the formula or . It is a colourless, flammable gas with a faint "sweet and musky" odour when pure. It is the simplest alkene (a hydrocarbon with carbon–carbon bond, carbon–carbon doub ...

Variations

Ionic liquid Heck reaction

In the presence of an

ionic liquid An ionic liquid (IL) is a salt (chemistry), salt in the liquid state at ambient conditions. In some contexts, the term has been restricted to salts whose melting point is below a specific temperature, such as . While ordinary liquids such as wate ...

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 is an amorphous and porosity, porous form of silicon dioxide (silica), consisting of an irregular three-dimensional framework of alternating silicon and oxygen atoms with nanometer-scale voids and pores. The voids may contain wate ...

. In this way the reaction proceeds in water and the catalyst is re-usable.

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 Dihydrofuran may refer to: * 2,3-Dihydrofuran *2,5-Dihydrofuran 2,5-Dihydrofuran is an organic compound classified as a monounsaturated derivative of furan Furan is a Heterocyclic compound, heterocyclic organic compound, consisting of a fiv ...

ring.

Amino-Heck reaction

In the amino-Heck reaction a

nitrogen Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...

carbon Carbon () is a chemical element; it has chemical symbol, symbol C and atomic number 6. It is nonmetallic and tetravalence, tetravalent—meaning that its atoms are able to form up to four covalent bonds due to its valence shell exhibiting 4 ...

bond is formed. In one example, an

oxime In organic chemistry, an oxime is an organic compound belonging to the imines, with the general Chemical formula, formula , where R is an organic Side chain, side-chain and R' may be hydrogen, forming an aldoxime, or another organic functional g ...

with a strongly electron withdrawing group reacts intramolecularly with the end of a

diene In organic chemistry, a diene ( ); also diolefin, ) or alkadiene) is a covalent compound that contains two double bonds, usually among carbon atoms. They thus contain two alk''ene'' units, with the standard prefix ''di'' of systematic nome ...

to form a

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom . It is a highly flammable, weak ...

compound. The

catalyst Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

and the base is

References

External links

* The Heck reaction at organic-chemistry.or
Article
{{DEFAULTSORT:Heck Reaction Carbon-carbon bond forming reactions Substitution reactions Palladium Name reactions