organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, ...

, a cross-coupling reaction is a

reaction Reaction may refer to a process or to a response to an action, event, or exposure: Physics and chemistry *Chemical reaction *Nuclear reaction * Reaction (physics), as defined by Newton's third law *Chain reaction (disambiguation). Biology and m ...

where two fragments are joined together with the aid of a metal

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 ...

. In one important reaction type, a main group

organometallic compound Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and s ...

of the type R-M (R = organic fragment, M = main group center) reacts with an organic halide of the type R'-X with formation of a new

carbon–carbon bond A carbon–carbon bond is a covalent bond between two carbon atoms. The most common form is the single bond: a bond composed of two electrons, one from each of the two atoms. The carbon–carbon single bond is a sigma bond and is formed bet ...

in the product R-R'. Cross-coupling reaction are a subset of

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 = ...

s. It is often used in arylations. Richard F. Heck,

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 were 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 ...

for developing

palladium-catalyzed coupling reactions 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 = ...

Mechanism

The

mechanism Mechanism may refer to: * Mechanism (engineering), rigid bodies connected by joints in order to accomplish a desired force and/or motion transmission *Mechanism (biology), explaining how a feature is created *Mechanism (philosophy), a theory that ...

generally involves reductive elimination of the organic substituents R and R' on a metal complex of the type L_nMR(R') (where L is some arbitrary spectator ligand). The crucial intermediate L_nMR(R') is formed in a two step process from a low valence precursor L_n. The

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 ...

of an

organic halide Halocarbon compounds are chemicals in which one or more carbon atoms are linked by covalent bonds with one or more halogen atoms ( fluorine, chlorine, bromine or iodine – ) resulting in the formation of organofluorine compounds, organoch ...

(RX) to L_nM gives L_nMR(X). Subsequently, the second partner undergoes

transmetallation Transmetalation (alt. spelling: transmetallation) is a type of organometallic reaction that involves the transfer of ligands from one metal to another. It has the general form: :M1–R + M2–R′ → M1–R′ + M2–R where R and R′ can be, but ...

with a source of R'⁻. The final step is

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 two coupling fragments to regenerate the catalyst and give the organic product. Unsaturated substrates, such as C(sp)−X and C(sp²)−X bonds, couple more easily, in part because they add readily to the catalyst.

Catalysts

Catalysts are often based on palladium, which is frequently selected due to high

functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the re ...

tolerance.

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 ...

compounds are generally stable towards water and air. Palladium catalysts can be problematic for the pharmaceutical industry, which faces extensive regulation regarding heavy metals. Many pharmaceutical chemists attempt to use coupling reactions early in production to minimize metal traces in the product.

Heterogeneous catalyst In chemistry, heterogeneous catalysis is catalysis where the phase of catalysts differs from that of the reactants or products. The process contrasts with homogeneous catalysis where the reactants, products and catalyst exist in the same phase. P ...

s based on Pd are also well developed. Copper-based catalysts are also common, especially for coupling involving heteroatom-C bonds. Iron-, cobalt-, and nickel-based catalysts have been investigated.

Leaving groups

The

leaving group In chemistry, a leaving group is defined by the IUPAC as an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction. However, in common usage, the term is often limited ...

X in the organic partner is usually a halide, although

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, ...

tosylate In organic chemistry, a toluenesulfonyl group (tosyl group, abbreviated Ts or Tos) is a univalent functional group with the chemical formula –. It consists of a tolyl group, –, joined to a sulfonyl group, ––, with the open valence on s ...

and other

pseudohalide Pseudohalogens are polyatomic analogues of halogens, whose chemistry, resembling that of the true halogens, allows them to substitute for halogens in several classes of chemical compounds. Pseudohalogens occur in pseudohalogen molecules, inorganic ...

have been used. Chloride is an ideal group due to the low cost of organochlorine compounds. Frequently, however, C–Cl bonds are too inert, and

bromide A bromide ion is the negatively charged form (Br−) of the element bromine, a member of the halogens group on the periodic table. Most bromides are colorless. Bromides have many practical roles, being found in anticonvulsants, flame-retardant ...

iodide An iodide ion is the ion I−. Compounds with iodine in formal oxidation state −1 are called iodides. In everyday life, iodide is most commonly encountered as a component of iodized salt, which many governments mandate. Worldwide, iodine de ...

leaving groups are required for acceptable rates. The main group metal in the organometallic partner usually is an electropositive element such as

tin Tin is a chemical element with the symbol Sn (from la, stannum) and atomic number 50. Tin is a silvery-coloured metal. Tin is soft enough to be cut with little force and a bar of tin can be bent by hand with little effort. When bent, t ...

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

, silicon, or boron.

Carbon–carbon cross-coupling

Many cross-couplings entail forming carbon–carbon bonds.

Carbon–heteroatom coupling

Many cross-couplings entail forming carbon–heteroatom bonds (heteroatom = S, N, O). A popular method is the Buchwald–Hartwig reaction:

Miscellaneous reactions

One method for palladium-catalyzed cross-coupling reactions of

aryl halides In organic chemistry, an aryl halide (also known as haloarene) is an aromatic compound in which one or more hydrogen atoms, directly bonded to an aromatic ring are replaced by a halide. The haloarene are different from haloalkanes because they exhi ...

with fluorinated arenes was reported by Keith Fagnou and co-workers. It is unusual in that it involves C–H functionalisation at an electron deficient arene. Fagnou fluoroarene coupling

Applications

Cross-coupling reactions are important for the production of pharmaceuticals, examples being

montelukast Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. It is generally less preferred for this use than inhaled corticosteroids. It is not useful for acute asthma attacks. Ot ...

eletriptan Eletriptan, sold under the brand name Relpax and used in the form of eletriptan hydrobromide, is a second generation triptan medication intended for treatment of migraine headaches. It is used as an abortive medication, blocking a migraine att ...

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 ...

varenicline Varenicline (trade name Chantix and Champix) is a medication used for smoking cessation. Varenicline is also used for the treatment of dry eye disease. The most common side-effects include nausea (feeling sick), insomnia (difficulty sleeping), a ...

, and resveratrol. with Suzuki coupling being most widely used. Some polymers and monomers are also prepared in this way.Hartwig, J. F. Organotransition Metal Chemistry, from Bonding to Catalysis; University Science Books: New York, 2010.

Reviews

* * * * * *

References

{{DEFAULTSORT:Coupling Reaction Organometallic chemistry Carbon-carbon bond forming reactions Catalysis