Cross-coupling reaction

A cross-coupling reaction in organic chemistry is a reaction where two fragments are joined together with the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M (R = organic fragment, M = main group center) reacts with an organic halide of the type R'-X with formation of a new carbon-carbon bond in the product R-R'.[1][2][3] Cross-coupling reaction are a subset of coupling reactions. It is often used in arylations.

Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki were awarded the 2010 Nobel Prize in Chemistry for developing palladium-catalyzed cross coupling reactions.[4][5]


The mechanism generally involves reductive elimination of the organic substituents R and R' on a metal complex of the type LnMR(R') (where L is some arbitrary spectator ligand. The crucial intermediate LnMR(R') is formed in a two step process from a low valence precursor Ln. 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 organic groups couple more easily in part because they add readily. The intermediates are also less prone to beta-hydride elimination.[6]


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.[7] Heterogeneous catalysts based on Pd are also well developed.[8]

Copper-based catalysts are also common, especially for coupling involving heteroatom-C bonds.[9][10]

Iron-,[11] cobalt-,[12] and nickel-based nickel.[13] catalysts have been investigated.

Leaving groups

The leaving group X in the organic partner is usually a halide, although triflate, tosylate and other pseudohalide 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, worse, iodide leaving groups are required for acceptable rates. The main group metal in the organometallic partner usually is an electropositive element such as tin, zinc, silicon, or boron.

Carbon-carbon cross-coupling

Many cross-couplings entail forming carbon-carbon bonds.

ReactionYear Reactant A Reactant BCatalystRemark
Cadiot-Chodkiewicz coupling1957RC≡CHspRC≡CXspCurequires base
Castro-Stephens coupling1963RC≡CHspAr-Xsp2Cu
Corey-House synthesis1967R2CuLi or RMgXsp3 R-Xsp2, sp3 Cu Cu-catalyzed version by Kochi, 1971
Kumada coupling1972Ar-MgBrsp2, sp3Ar-Xsp2Pd or Ni or Fe
Heck reaction1972alkenesp2Ar-Xsp2Pd or Nirequires base
Sonogashira coupling1975RC≡CHspR-Xsp3 sp2Pd and Curequires base
Negishi coupling1977R-Zn-Xsp3, sp2, spR-Xsp3 sp2Pd or Ni
Stille cross coupling1978R-SnR3sp3, sp2, spR-Xsp3 sp2Pd
Suzuki reaction1979R-B(OR)2sp2R-Xsp3 sp2Pd or Nirequires base
Murahashi coupling[14] 1979 R-Li sp2, sp3 R-X sp2 Pd or Ru
Hiyama coupling1988R-SiR3sp2R-Xsp3 sp2Pdrequires base
Fukuyama coupling1998R-Zn-Isp3RCO(SEt)sp2Pd or Nisee Liebeskind–Srogl coupling, gives ketones
Liebeskind–Srogl coupling2000R-B(OR)2sp3, sp2RCO(SEt) Ar-SMesp2Pdrequires CuTC, gives ketones

Carbon-heteroatom coupling

Many cross-couplings entail forming carbon-heteroatom bonds (heteroatom = S, N, O). A popular method is the Buchwald–Hartwig reaction:






ReactionYear Reactant A Reactant BCatalystRemark
Ullmann-type reactionArO-MM, ArNH2,RS-M,NC-Msp3Ar-X (X = OAr, N(H)Ar, SR, CN)sp2Cu
Chan-Lam coupling[15]Ar-B(OR)2sp2Ar-NH2sp2Cu
Buchwald-Hartwig reaction[16]1994R2N-Hsp3R-Xsp2PdN-C coupling,
second generation free amine

Miscellaneous reactions

One method for palladium-catalyzed cross-coupling reactions of aryl halides with fluorinated arenes was reported by Keith Fagnou and co-workers. It is unusual in that it involves C-H functionalisation at an electron deficient arene.[17]


Cross-coupling reactions are important for the production of pharmaceuticals[3] and even some polymers.[6]


  • Fortman, George C.; Nolan, Steven P. (2011). "N-Heterocyclic carbene (NHC) ligands and palladium in homogeneous cross-coupling catalysis: a perfect union". Chemical Society Reviews. 40 (10): 5151–69. doi:10.1039/c1cs15088j. PMID 21731956.
  • Yin; Liebscher, Jürgen (2007). "Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts". Chemical Reviews. 107 (1): 133–173. doi:10.1021/cr0505674. PMID 17212474.
  • Jana, Ranjan; Pathak, Tejas P.; Sigman, Matthew S. (2011). "Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-organometallics as Reaction Partners". Chemical Reviews. 111 (3): 1417–1492. doi:10.1021/cr100327p. PMC 3075866. PMID 21319862.
  • Molnár, Árpád (2011). "Efficient, Selective, and Recyclable Palladium Catalysts in Carbon−Carbon Coupling Reactions". Chemical Reviews. 111 (3): 2251–2320. doi:10.1021/cr100355b. PMID 21391571.
  • Miyaura, Norio.; Suzuki, Akira. (1995). "Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds". Chemical Reviews. 95 (7): 2457–2483. CiteSeerX doi:10.1021/cr00039a007.
  • Roglans, Anna; Pla-Quintana, Anna; Moreno-Mañas, Marcial (2006). "Diazonium Salts as Substrates in Palladium-Catalyzed Cross-Coupling Reactions". Chemical Reviews. 106 (11): 4622–4643. doi:10.1021/cr0509861. PMID 17091930.


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