Coupling

Coupling

The coupling reaction is a 2A-B→A-A type reaction, which is a process in which a certain chemical reaction is carried out by two organic units to obtain an organic molecule, which includes a radical coupling reaction and a transition metal catalyzed coupling reaction. The narrowly defined coupling reaction refers to a carbon-carbon bond forming reaction involving an organometallic catalyst. In conclusion, coupling reactions with multiple reaction pathways are widely used in organic synthesis. Figure 1 is a schematic diagram of the mechanism of the coupling reaction. The first step is the oxidative addition of an organic halide (Ar-Br) to the catalyst. In the second step, the second coupling agent (R-MgBr) is subjected to metal transfer, and the two coupling agents are placed in the same metal center while eliminating the functional groups. The final step is to eliminate the reducibility of the two coupled fragments to regenerate the catalyst and to obtain the desired product.

Figure 1. The schematic diagram of the mechanism of the coupling reaction

Catalysts

The most common catalyst for the coupling reaction is palladium, but more and more reactions use nickel. There are of course other catalysts, including copper, platinum, iron, cobalt and amines. Palladium is a strong catalyst and is often used due to its high functional group tolerance and low sensitivity of organic palladium compounds to water and air. Nickel catalysts are cheaper, easier to remove, and less toxic. And they typically require a high energy matrix or cocatalyst such as a Photoredox catalyst.

Applications

Coupling reactions are mostly used in the pharmaceutical industry and in the preparation of conjugated organic materials.

• Suzuki reaction: This is a transition metal-catalyzed coupling reaction of palladium or nickel, which has been one of the most effective methods for synthesizing aryl-aryl bonds.
• Heck reaction: This is an important synthesis reaction of halogenated aromatic alkenylation and the formation of a new C-C bond, which is a reaction of an unsaturated halogenated hydrocarbon (or triflate) and an olefin to form a substituted olefin under the catalysis of a base and palladium. The catalyst mainly includes palladium chloride, palladium acetate, triphenylphosphine palladium, CuI, etc.; the carrier mainly includes triphenylphosphine, BINAP, etc.; the base used mainly includes triethylamine, potassium carbonate, sodium acetate and the like. The solvent is mainly a polar aprotic solvent such as DMF or NMP.

  Figure 2. The diagram of heck reaction

• Stille coupling reaction: The stille reaction is a cross-coupling reaction of an organotin compound and a halogenated hydrocarbon (or triflate) containing no β-hydrogen under palladium catalysis.
• Negishi coupling reaction: The Negishi reaction is a type of coupling reaction between an organozinc reagent catalyzed by Ni or Pd and a halogenated hydrocarbon, and is suitable for preparing an asymmetric diaryl, diarylmethane, styrene or phenylacetylene type compound. A similar reaction can also be carried out with a halogenated heterocyclic aromatic hydrocarbon. The common types of reactions are shown in Figure 3:

  Figure 3. The diagram of Negishi coupling reaction

References

1. Benny Bogoslavsky. (2012). ‘Do Carbyne Radicals Really Exist in Aqueous Solution?’. Angewandte Chemie International Edition. 51(1): 90-94.
2. Brad M. Rosen. (2011). ‘Nickel-Catalyzed Cross-Couplings Involving Carbon−Oxygen Bonds’. Chem. Rev. 111 (3):1346-1416.
3. Lunxiang Yin. (2007). ‘Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts’. Chem. Rev. 107(1):133-173.