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

Coupling reactions are illustrated by the Ullmann reaction:

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

Main article: Cross-coupling 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

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. 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.