Cross-coupling reaction

Mechanism

Many mechanisms exist reflecting the myriad types of cross-couplings, including those that do not require metal catalysts. Often, however, cross-coupling refers to a metal-catalyzed reaction of a nucleophilic partner with an electrophilic partner.

In such cases, the mechanism generally involves reductive elimination of R-R' from LnMR(R') (L = spectator ligand). This intermediate LnMR(R') is formed in a two-step process from a low valence precursor LnM. The oxidative addition of an organic halide (RX) to LnM gives LnMR(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, pivalate esters, and other pseudohalides 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 is usually an electropositive element such as tin, zinc, silicon, or boron.

Carbon–carbon cross-coupling

Many cross-couplings entail forming carbon–carbon bonds.

The restrictions on carbon atom geometry mainly inhibit β-hydride elimination when complexed to the catalyst.

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

Palladium-catalyzes the cross-coupling of aryl halides with fluorinated arene. The process 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, with Suzuki coupling being most widely used. Some polymers and monomers are also prepared in this way.

Reviews

References

References

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