Coupling reaction

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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'. The most common type of coupling reaction is the cross coupling reaction.[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 combine 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).

Homo-coupling types[]

Coupling reactions are illustrated by the famous Ullmann reaction:

Ullmann overview
Reaction Year Reactant A Reactant B Reagent Remark
Wurtz reaction 1855 R-X sp3 R-X sp3 Na as reducing agent
Pinacol coupling reaction 1859 R-HC=O or R2(C=O) R-HC=O or R2(C=O) various metals requires proton donor
Glaser coupling 1869 RC≡CH sp RC≡CH sp Cu O2 as H-acceptor
Ullmann reaction 1901 Ar-X sp2 Ar-X sp2 Cu high temperatures

Cross-coupling types[]

Main article: cross-coupling reaction

An illustrative cross-coupling reaction is the Heck coupling of an alkene and an aryl halide:

The Heck reaction
Reaction Year Reactant A Reactant B Catalyst Remark
Grignard reaction 1900 R-MgBr sp, sp2, sp3 R-HC=O or R(C=O)R2 sp2 not catalytic
Gomberg-Bachmann reaction 1924 Ar-H sp2 Ar'-N2+X− sp2 not catalytic
Cadiot-Chodkiewicz coupling 1957 RC≡CH sp RC≡CX sp Cu requires base
Castro-Stephens coupling 1963 RC≡CH sp Ar-X sp2 Cu
Corey-House synthesis 1967 R2CuLi or RMgX sp3 R-X sp2, sp3 Cu Cu-catalyzed version by Kochi, 1971
1970 Alkene sp2 R-X sp3 Pd requires base
Kumada coupling 1972 Ar-MgBr sp2, sp3 Ar-X sp2 Pd or Ni or Fe
Heck reaction 1972 alkene sp2 Ar-X sp2 Pd or Ni requires base
Sonogashira coupling 1975 RC≡CH sp R-X sp3 sp2 Pd and Cu requires base
Negishi coupling 1977 R-Zn-X sp3, sp2, sp R-X sp3 sp2 Pd or Ni
Stille cross coupling 1978 R-SnR3 sp3, sp2, sp R-X sp3 sp2 Pd
Suzuki reaction 1979 R-B(OR)2 sp2 R-X sp3 sp2 Pd or Ni requires base
Hiyama coupling 1988 R-SiR3 sp2 R-X sp3 sp2 Pd requires base
Buchwald-Hartwig reaction 1994 R2N-H sp3 R-X sp2 Pd N-C coupling,
second generation free amine
Fukuyama coupling 1998 R-Zn-I sp3 RCO(SEt) sp2 Pd or Ni[6]
Liebeskind–Srogl coupling 2000 R-B(OR)2 sp3, sp2 RCO(SEt) Ar-SMe sp2 Pd requires CuTC
(Li) Cross dehydrogenative coupling(CDC) 2004 R-H sp, sp2, sp3 R'-H sp, sp2, sp3 Cu, Fe, Pd etc requires oxidant or dehydrogenation

Applications[]

Coupling reactions are routinely employed in the preparation of pharmaceuticals.[3] Conjugated polymers are prepared using this technology as well.[7]

References[]

  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. ^ Jump up to: a b King, A. O.; Yasuda, N. "Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals". Organometallics in Process Chemistry. Heidelberg: Springer. pp. 205–245. doi:10.1007/b94551.
  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. ^ 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.
  7. ^ Hartwig, J. F. (2010). Organotransition Metal Chemistry, from Bonding to Catalysis. New York: University Science Books. ISBN 1-891389-53-X.
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