Cross-Coupling Reactions

Cross-coupling reactions use a metal catalyst to combine an aryl halide electrophile and an organometallic nucleophile. Palladium or nickel catalysts are generally used. 

Importance

Cross-coupling reactions are used frequently in synthesis in molecules with many industrial applications. They are used in pharmaceuticals, agrochemicals (pesticides, herbicides), natural products (hormones, vitamins), and materials science (organic semiconductors, conductive polymers).

These reactions are reliable and reproducible and often have high yields. They can be used to form C-C and C-X bonds which is a very useful synthetic method.

There is a large amount of research still being done in this field. 

Drawbacks

• Efficiency
  • Reactions must be optimized for each substrate used
  • Halides, boronic acids, alkynes, etc often needed that could add extra steps
• Harsh Conditions/Toxicity
  • High temp, strong bases, inert atmospheres for reactions not stable in air
  • Heavy metal contamination
  • Toxic coupling reagents, such as tin in Stille coupling
• Cost
  • Metal catalysts can be expensive and hard to scale up for industrial use

Reactions

• Kumada
• Negishi
• Stille
• Suzuki

General Mechanism

     R-X + M-R' → R-R' 

R = Electrophile

R' = Nucleophile

Catalytic Cycle

Every step in the catalytic cycle is important. Many of these steps could be rate limiting steps.