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 = main group center) reacts with an organic halide of the type R'-X with formation of a new carbon–carbon bond in the product R-R'. Cross-coupling reaction are a subset of coupling reactions. It is often used in arylations.

Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki were awarded the 2010 Nobel Prize in Chemistry for developing palladium-catalyzed coupling reactions.

Mechanism

The mechanism 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 of an organic halide (RX) to L_nM gives L_nMR(X). Subsequently, the second partner undergoes transmetallation with a source of R'⁻. The final step is reductive elimination 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 tolerance. Organopalladium 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 catalysts 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 X in the organic partner is usually a halide, although triflate, tosylate and other pseudohalide 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 or iodide leaving groups are required for acceptable rates. The main group metal in the organometallic partner usually is an electropositive element such as tin, zinc, 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 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.

Applications

Cross-coupling reactions are important for the production of pharmaceuticals, examples being montelukast, eletriptan, naproxen, varenicline, 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

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References

{{DEFAULTSORT:Coupling Reaction

Organometallic chemistry
Carbon-carbon bond forming reactions
Catalysis