CrossCoupling

Cross-coupling is a class of organic reactions in which two molecular fragments are joined by forming a new bond, most commonly a carbon–carbon bond, under the influence of a transition-metal catalyst. In its classic form, an electrophilic partner bearing a leaving group—such as an aryl or vinyl halide or triflate—couples with a nucleophilic partner that carries a metal substituent, such as organoboron, organotin, organozinc, or organosilicon reagents. The most widely used catalysts are palladium and nickel complexes, often with bulky phosphine or N-heterocyclic carbene ligands, and a base to facilitate transmetallation.

Mechanistically, the catalytic cycle typically involves oxidative addition of the electrophile to the active metal center, followed by transmetallation with the nucleophilic partner, and reductive elimination to forge the new bond and regenerate the active catalyst. The reaction usually occurs under relatively mild conditions and can tolerate a range of functional groups, though substrate selection and catalyst choice strongly influence outcomes.

Major families include Suzuki–Miyaura (boron reagents), Negishi (zinc reagents), Kumada–Tamao–Corriu (Grignard reagents), Stille (tin reagents), Sonogashira (alkynyl reagents, often with copper co-catalysis), and Hiyama (silicon reagents). While many cross-couplings form C–C bonds, the scope has broadened to heteroatom–carbon bonds (C–N, C–O, C–S) and other bond types.

Applications of cross-coupling are widespread, including pharmaceutical and agrochemical synthesis, natural product construction, and materials science. Limitations include the need for suitable leaving groups, sensitivity of some catalysts to air or moisture, and functional-group compatibility concerns. Developments in nickel catalysis and reductive cross-coupling have expanded substrate scope and may reduce cost and environmental impact.