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Cross-coupling reaction

Chemical reaction in which two molecules are joined due to a metal catalyst

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R−M+R′X⟶R−R′+MX
R, R' = organic fragments, usually aryl;
M = main group center such as Li or Mg;
X = halide

These reactions are used to form carbon–carbon bonds but also carbon-heteroatom bonds. Cross-coupling reaction are a subset of coupling reactions.

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

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.

Alternatives to palladium cross-couplings became prevalent in the 2000s, with interest in non-precious and less toxic metals. Copper-based catalysts are especially useful for coupling involving heteroatom-C bonds. Iron- and cobalt-catalysis have also been investigated. The use of nickel-based catalysis has become more widespread.

Leaving groups

The leaving group X in the organic partner is usually a halide, although triflate, tosylate, pivalate esters, carbamates, 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.

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