In organic chemistry, a coupling reaction is a type of reaction in which two reactant molecules are bonded together. Such reactions often require the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M (where R = organic group, M = main group centre metal atom) 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:

  • Homocouplings joining two identical partners. The product is symmetrical R−R
  • Heterocouplings joining two different partners. These reactions are also called cross-coupling reactions.[6] The product is unsymmetrical, R−R'.

Homo-coupling types

Coupling reactions are illustrated by the Ullmann reaction:

Ullmann overview
Ullmann overview
ReactionYear Reactant A Reactant BReagentRemark
Wurtz reaction1855R-Xsp3R-Xsp3Na as reducing agentdry ether as medium
Pinacol coupling reaction1859R-HC=O or R2(C=O)R-HC=O or R2(C=O)various metalsrequires proton donor
Glaser coupling1869RC≡CHspRC≡CHspCuO2 as H-acceptor
Ullmann reaction1901Ar-Xsp2Ar-Xsp2Cuhigh temperatures
Fittig reaction Ar-X sp2 Ar-X sp2 Na dry ether as medium

Cross-coupling types

The Heck reaction
The Heck reaction
ReactionYear Reactant A Reactant BCatalystRemark
Grignard reaction1900R-MgBrsp, sp2, sp3 R-HC=O or R(C=O)R2sp2not catalytic
Gomberg-Bachmann reaction 1924 Ar-H sp2 Ar'-N2+X sp2 not catalytic
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
Cassar reaction1970Alkenesp2R-Xsp3Pdrequires base
Kumada coupling1972Ar-MgBrsp2, sp3Ar-Xsp2Pd or Ni or Fe
Heck reaction1972alkenesp2Ar-Xsp2Pd or Nirequires base
Sonogashira coupling1975RC≡CHspR-Xsp3 sp2Pd and Curequires base
Murahashi coupling[7] 1975 RLi sp2, sp3 Ar-X sp2 Pd or Ni Pd-catalyzed version by Murahashi, 1979
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
Hiyama coupling1988R-SiR3sp2R-Xsp3 sp2Pdrequires base
Buchwald-Hartwig reaction1994R2N-Hsp3R-Xsp2PdN-C coupling,
second generation free amine
Fukuyama coupling1998R-Zn-Isp3RCO(SEt)sp2Pd or Ni[8]
Liebeskind–Srogl coupling2000R-B(OR)2sp3, sp2RCO(SEt) Ar-SMesp2Pdrequires CuTC
(Li) Cross dehydrogenative coupling(CDC)2004R-Hsp, sp2, sp3R'-Hsp, sp2, sp3Cu, Fe, Pd etcrequires oxidant or dehydrogenation
Wurtz-Fittig reaction R-X sp3 Ar-X sp2 Na dry ether

Applications

Coupling reactions are routinely employed in the preparation of pharmaceuticals.[3] Conjugated polymers are prepared using this technology as well.[9]

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. 1 2 King, A. O.; Yasuda, N. (2004). "Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals". Organometallics in Process Chemistry. Topics in Organometallic Chemistry. Vol. 6. Heidelberg: Springer. pp. 205–245. doi:10.1007/b94551. ISBN 978-3-540-01603-8.
  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. Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 449, ISBN 978-0-471-72091-1
  7. Hazra, Susanta; Johansson Seechurn, Carin C. C.; Handa, Sachin; Colacot, Thomas J. (2021-10-15). "The Resurrection of Murahashi Coupling after Four Decades". ACS Catalysis. 11 (21): 13188–13202. doi:10.1021/acscatal.1c03564. ISSN 2155-5435. S2CID 244613990.
  8. 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.
  9. Hartwig, J. F. (2010). Organotransition Metal Chemistry, from Bonding to Catalysis. New York: University Science Books. ISBN 978-1-891389-53-5.
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