Coupling reaction

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

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Coupling reactions are illustrated by the Ullmann reaction:

Ullmann overview
Ullmann overview
Reaction Year Organic compound Coupler Remark
Wurtz reaction 1855 R-X sp3 Na as reductant dry ether as medium
Pinacol coupling reaction 1859 R-HC=O or R2(C=O) various metals requires proton donor
Glaser coupling 1869 RC≡CH sp Cu O2 as H-acceptor
Ullmann reaction 1901 Ar-X sp2 Cu high temperatures
Fittig reaction Ar-X sp2 Na dry ether as medium
Scholl reaction 1910 ArH sp2 NaAlCl4(l) O2 as H-acceptor; presumably trace Fe3+ catalyst; requires high heat

Cross-coupling types

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Main article: Cross-coupling reaction
The Heck reaction
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
Cassar reaction 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
Murahashi coupling[7] 1975 RLi sp2, sp3 Ar-X sp2 Pd or Ni Pd-catalyzed version by Murahashi, 1979
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[8]
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
Wurtz-Fittig reaction R-X sp3 Ar-X sp2 Na dry ether

Applications

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

References

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  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. (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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