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A coupling reaction in organic chemistry is a general term for a variety of reactions 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]

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]

Broadly speaking, two types of coupling reactions are recognized:

  • Heterocouplings couple two different partners, such as in the Heck reaction of an alkene (RC=CH) and an alkyl halide (R'-X) to give a substituted alkene. Heterocouplings are called cross-couplings.
  • Homocouplings couple two identical partners, as in the Glaser coupling of two acetylides (RC≡CH) to form a dialkyne (RC≡C-C≡CR).

Contents

Mechanism of cross couplingEdit

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]

CatalystsEdit

The most common catalyst is palladium, but an increasing number of reactions use nickel. Other catalysts include copper, platinum, iron, cobalt, and amines.

Palladium is robust catalyst and is frequently used due to high functional group tolerance, and low sensitivity of organopalladium compounds towards water and air. However, palladium is a quite rare and costly noble metal. Additionally palladium catalysts are notoriously difficult to remove. Purification typically involves extensive column chromatography, recrystallization, metal scavengers, distillation, or extraction to name a few techniques. Most methods typically do not completely remove the catalyst. This typically causes issues 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]

Nickel catalysts, while less robust than palladium ones, are cheaper, easier to remove, and less toxic. Nickel catalysts frequently require energetic substrates or co-catalysts such as Photoredox catalysts. Currently, many research groups are trying to create heterogeneous reusable catalysts to minimize cost and reduce purification needs.

Most catalysts use bulky L type ligands such as triphenylphosphine,

In depth-reviews have been written for example on cobalt,[8] palladium [9][10][11][12][13] and nickel [14] mediated reactions and on applications [15][16]

Leaving groupsEdit

The leaving group X in the organic partner is usually a halogen. Chloride is the most ideal group due to their low cost, but frequently have issues with reactivity. The main group metal in the organometallic partner usually is tin, zinc, silates or boron.

Coupling typesEdit

Coupling reactions include (not exhaustive):

Reaction Year Reactant A Reactant B Homo/Cross Catalyst Remark
Wurtz reaction 1855 R-X sp3 R-X sp3 homo Na as reducing agent
Pinacol coupling reaction 1859 R-HC=O or R(C=O)R2 R-HC=O or R(C=O)R2 homo various metals requires proton donor
Glaser coupling 1869 RC≡CH sp RC≡CH sp homo Cu O2 as H-acceptor
Grignard reaction 1900 R-MgBr R-HC=O or R(C=O)R2 cross
Ullmann reaction 1901 Ar-X sp2 Ar-X sp2 homo Cu high temperatures
Gomberg-Bachmann reaction 1924 Ar-H sp2 Ar-N2X sp2 homo requires base
Cadiot-Chodkiewicz coupling 1957 RC≡CH sp RC≡CX sp cross Cu requires base
Castro-Stephens coupling 1963 RC≡CH sp Ar-X sp2 cross Cu
Corey-House synthesis 1967 R2CuLi or RMgX sp3 R-X sp2, sp3 cross Cu Cu-catalyzed version by Kochi, 1971
Cassar reaction 1970 Alkene sp2 R-X sp3 cross Pd requires base
Kumada coupling 1972 Ar-MgBr sp2, sp3 Ar-X sp2 cross Pd or Ni or Fe
Heck reaction 1972 alkene sp2 Ar-X sp2 cross Pd or Ni requires base
Sonogashira coupling 1975 RC≡CH sp R-X sp3 sp2 cross Pd and Cu requires base
Negishi coupling 1977 R-Zn-X sp3, sp2, sp R-X sp3 sp2 cross Pd or Ni
Stille cross coupling 1978 R-SnR3 sp3, sp2, sp R-X sp3 sp2 cross Pd
Suzuki reaction 1979 R-B(OR)2 sp2 R-X sp3 sp2 cross Pd or Ni requires base
Hiyama coupling 1988 R-SiR3 sp2 R-X sp3 sp2 cross Pd requires base
Buchwald-Hartwig reaction 1994 R2N-H sp3 R-X sp2 cross Pd N-C coupling,
second generation free amine
Fukuyama coupling 1998 R-Zn-I sp3 RCO(SEt) sp2 cross Pd or Ni[17]
Liebeskind–Srogl coupling 2000 R-B(OR)2 sp3, sp2 RCO(SEt) Ar-SMe sp2 cross Pd requires CuTC
Coupling reaction overview[18]

Miscellaneous reactionsEdit

In one study, an unusual coupling reaction was described in which an organomolybdenum compound, [Mo3(CCH3)2(OAc)6(H2O)3](CF3SO3)2 not only sat on a shelf for 30 years without any sign of degradation but also decomposed in water to generate 2-butyne, which is the coupling adduct of its two ethylidyne ligands. This, according to the researchers, opens another way for aqueous organometallic chemistry.[19]

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.[20]

ApplicationsEdit

Many coupling reactions have found their way into pharmaceutical industry[3] and into conjugated organic materials and also in production of C-C bond or coupling.[6]

ReferencesEdit

  1. ^ Organic Synthesis using Transition Metals Rod Bates ISBN 978-1-84127-107-1
  2. ^ New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor) 2014 ISBN 978-1-84973-896-5
  3. ^ a b King, A. O.; Yasuda, N. "Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals". Organometallics in Process Chemistry. Heidelberg: Springer. p. 205-245. doi:10.1007/b94551.CS1 maint: Multiple names: authors list (link)
  4. ^ "The Nobel Prize in Chemistry 2010 - Richard F. Heck, Ei-ichi Negishi, Akira Suzuki". NobelPrize.org. 2010-10-06. Retrieved 2010-10-06.
  5. ^ Johansson Seechurn, Carin C. C.; Kitching, Matthew O.; Colacot, Thomas J.; Snieckus, Victor (2012). "Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize". Angewandte Chemie International Edition. 51 (21): 5062–5085. doi:10.1002/anie.201107017. PMID 22573393.
  6. ^ a b Hartwig, J. F. Organotransition Metal Chemistry, from Bonding to Catalysis; University Science Books: New York, 2010. ISBN 1-891389-53-X
  7. ^ Thayer, Ann (2005-09-05). "Removing Impurities". Chemical & Engineering News. Retrieved 2015-12-11.
  8. ^ Cahiez, GéRard; Moyeux, Alban (2010). "Cobalt-Catalyzed Cross-Coupling Reactions". Chemical Reviews. 110 (3): 1435–1462. doi:10.1021/cr9000786. PMID 20148539.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ Miyaura, Norio.; Suzuki, Akira. (1995). "Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds". Chemical Reviews. 95 (7): 2457–2483. CiteSeerX 10.1.1.735.7660. doi:10.1021/cr00039a007.
  13. ^ 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.
  14. ^ Rosen, Brad M.; Quasdorf, Kyle W.; Wilson, Daniella A.; Zhang, Na; Resmerita, Ana-Maria; Garg, Neil K.; Percec, Virgil (2011). "Nickel-Catalyzed Cross-Couplings Involving Carbon−Oxygen Bonds". Chemical Reviews. 111 (3): 1346–1416. doi:10.1021/cr100259t. PMC 3055945. PMID 21133429.
  15. ^ Corbet, Jean-Pierre; Mignani, Gérard (2006). "Selected Patented Cross-Coupling Reaction Technologies". Chemical Reviews. 106 (7): 2651–2710. doi:10.1021/cr0505268. PMID 16836296.
  16. ^ Evano, Gwilherm; Blanchard, Nicolas; Toumi, Mathieu (2008). "Copper-Mediated Coupling Reactions and Their Applications in Natural Products and Designed Biomolecules Synthesis". Chemical Reviews. 108 (8): 3054–3131. doi:10.1021/cr8002505.
  17. ^ Nielsen, Daniel K.; Huang, Chung-Yang (Dennis); Doyle, Abigail G. (2013-08-20). "Directed Nickel-Catalyzed Negishi Cross Coupling of Alkyl Aziridines". Journal of the American Chemical Society. 135 (36): 13605–13609. doi:10.1021/ja4076716. ISSN 0002-7863. PMID 23961769.
  18. ^ For references consult satellite pages
  19. ^ A. Bino; M. Ardon; E. Shirman (2005). "Formation of a Carbon-Carbon Triple Bond by Coupling Reactions In Aqueous Solution". Science. 308 (5719): 234–235. Bibcode:2005Sci...308..234B. doi:10.1126/science.1109965. PMID 15821086.
  20. ^ M. Lafrance; C. N. Rowley; T. K. Woo; K. Fagnou (2006). "Catalytic Intermolecular Direct Arylation of Perfluorobenzenes". J. Am. Chem. Soc. 128 (27): 8754–8756. CiteSeerX 10.1.1.631.607. doi:10.1021/ja062509l. PMID 16819868.