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.
Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki were awarded the 2010 Nobel Prize in Chemistry for developing palladium-catalyzed cross coupling reactions.
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. The product is unsymmetrical, R−R'.
Homo-coupling types
Coupling reactions are illustrated by the Ullmann reaction:
| 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
Main article: Cross-coupling 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 coupling7 | 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 reaction | 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 amination | 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 Ni8 | |
| 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 | 1864 | R-X | sp3 | Ar-X | sp2 | Na | dry ether |
Applications
Coupling reactions are routinely employed in the preparation of pharmaceuticals.9 Conjugated polymers are prepared using this technology as well.10
References
Organic Synthesis using Transition Metals Rod Bates ISBN 978-1-84127-107-1 /wiki/ISBN_(identifier) ↩
New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor) 2014 ISBN 978-1-84973-896-5 /wiki/ISBN_(identifier) ↩
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. 978-3-540-01603-8 ↩
"The Nobel Prize in Chemistry 2010 - Richard F. Heck, Ei-ichi Negishi, Akira Suzuki". NobelPrize.org. 2010-10-06. Retrieved 2010-10-06. http://nobelprize.org/nobel_prizes/pornhemistry/laureates/2010/ ↩
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. /wiki/Doi_(identifier) ↩
Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 449, ISBN 978-0-471-72091-1 978-0-471-72091-1 ↩
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. https://pubs.acs.org/doi/pdf/10.1021/acscatal.1c03564 ↩
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. Bibcode:2013JAChS.13513605N. doi:10.1021/ja4076716. ISSN 0002-7863. PMID 23961769. /wiki/Bibcode_(identifier) ↩
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. 978-3-540-01603-8 ↩
Hartwig, J. F. (2010). Organotransition Metal Chemistry, from Bonding to Catalysis. New York: University Science Books. ISBN 978-1-891389-53-5. 978-1-891389-53-5 ↩