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

chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and breaking ...

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 flu ...

(or

triflate In organic chemistry, triflate ( systematic name: trifluoromethanesulfonate), is a functional group with the formula and structure . The triflate group is often represented by , as opposed to −Tf, which is the triflyl group, . For example, ...

) with an

alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic ...

in the presence of a base and a

palladium catalyst Palladium is a chemical element with the symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1803 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas, which was itself nam ...

(or palladium

nanomaterial-based catalyst Nanomaterial-based catalysts are usually heterogeneous catalysts broken up into metal nanoparticles in order to enhance the catalytic process. Metal nanoparticles have high surface area, which can increase catalytic activity. Nanoparticle catalysts ...

) 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 alkenes ...

. Heck was awarded the 2010

Nobel Prize in Chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...

, 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, 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 fragments are joined together with the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M (R = organic fragment, M ...

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 organoiodine compound consisting of a benzene ring substituted with one iodine atom. It is useful as a synthetic intermediate in organic chemistry. It is a volatile colorless liquid, although aged samples appear yellowish. Prepa ...

and

styrene Styrene () is an organic compound with the chemical formula C6H5CH=CH2. This derivative of benzene is a colorless oily liquid, although aged samples can appear yellowish. The compound evaporates easily and has a sweet smell, although high concen ...

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...

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– ...

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 sterilizati ...

) with

potassium acetate Potassium acetate (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 or potassium carbonate with acetic ...

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. The reaction conditions differ in catalyst used (palladium acetate) and catalyst loading (0.01 eq.), base used (a hindered amine) and lack of solvent. 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.

Catalyst and substrates

The reaction is catalyzed by palladium salts and 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 de ...

, and

palladium(II) acetate Palladium(II) acetate is a chemical compound of palladium described by the formula d(O2CCH3)2sub>n, abbreviated d(OAc)2sub>n. It is more reactive than the analogous platinum compound. Depending on the value of n, the compound is soluble in ma ...

. Typical supporting

ligand In coordination chemistry, a ligand is an ion or molecule (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 elect ...

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 widely used in the synthesis of organic and organometallic compounds. PPh3 exists ...

PHOX PHOX was an American six-piece alternative folk / indie pop band from Baraboo, Wisconsin. Active from 2011 until 2017, they released their self-titled debut LP on June 24, 2014. History Prior to the formation of PHOX, many eventual members col ...

and BINAP. Typical bases are

triethylamine Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine or tetraethylammonium, for which TEA ...

potassium carbonate Potassium carbonate is the inorganic compound with the formula K2 CO3. It is a white salt, which is soluble in water. It is deliquescent, often appearing as a damp or wet solid. Potassium carbonate is mainly used in the production of soap and gl ...

, and

sodium acetate Sodium acetate, CH3COONa, also abbreviated Na O Ac, is the sodium salt of acetic acid. This colorless deliquescent salt has a wide range of uses. Applications Biotechnological Sodium acetate is used as the carbon source for culturing bacteria ...

. 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 () group. Nomenclature In IUPAC nomenclature, the prefix benzyl refers to a substi ...

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 C H2=CHC OO−. Often, acrylate refers to esters of acrylic acid, the most common member being methyl acrylate. These acr ...

s are ideal.

Reaction mechanism

The mechanism 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 t ...

intermediates. The palladium(0) compound required in this cycle is generated

in situ ''In situ'' (; often not italicized in English) is a Latin phrase that translates literally to "on site" or "in position." It can mean "locally", "on site", "on the premises", or "in place" to describe where an event takes place and is used in ...

from a palladium(II) precursor. For instance,

is reduced by

to bis(triphenylphosphine)palladium(0) (1) and triphenylphosphine is oxidized to triphenylphosphine oxide. 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. Oxid ...

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 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 by refl ...

step. Then follows a torsional strain relieving rotation to the trans isomer (not shown) and step C is a

beta-hydride elimination β-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 β-carbon. For instance butyl groups can undergo th ...

(here the arrows are showing the opposite) 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 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. 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 is an organic reaction, classified as a cross-coupling reaction, where the coupling partners are a boronic acid and an organohalide and the catalyst is a palladium(0) complex. It was first published in 1979 by Akira Suzuki, ...

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, membe ...

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 compound (also known as organostannanes). A variety of organic electroph ...

by an aryl stannane. The cycle also extends to the other group 10 element

nickel Nickel is a chemical element with 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 slow t ...

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 A coupling reaction in organic chemistry is a general term for a variety of reactions where two fragments are joined together with the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M (R = ...

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 of ...

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: Arts, entertainment, and media * Trans (festival), a former festival in Belfast, Northern Ireland, United Kingdom * ''Trans'' (fil ...

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 is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulat ...

and the

sunscreen Sunscreen, also known as sunblock or sun cream, is a photoprotective topical product for the skin that mainly absorbs, or to a much lesser extent reflects, some of the sun's ultraviolet (UV) radiation and thus helps protect against sunbur ...

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 methoxycinna ...

. 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 crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromat ...

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 double bonds). Ethylene ...

Variations

Ionic liquid Heck reaction

In the presence of an

ionic liquid An ionic liquid (IL) is a salt in the liquid state. 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 water and gasoline are predominantly made of ...

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 porous form of silicon dioxide (silica), consisting of an irregular tridimensional framework of alternating silicon and oxygen atoms with nanometer-scale voids and pores. The voids may contain water or some other l ...

. 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 ring.

Amino-Heck reaction

In the amino-Heck reaction a

nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...

carbon Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon ma ...

bond is formed. In one example, an

oxime In organic chemistry, an oxime is a organic compound belonging to the imines, with the general formula , where R is an organic side-chain and R’ may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted ...

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

diene In organic chemistry a diene ( ) (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 nomenclature. ...

to form a

pyridine Pyridine is a basic 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, weakly alkaline, water-miscible liquid w ...

compound. The

catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

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