Coupling reaction

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

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
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
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

Applications

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

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References

Organic Synthesis using Transition Metals Rod Bates ISBN 978-1-84127-107-1
New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor) 2014 ISBN 978-1-84973-896-5
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.CS1 maint: multiple names: authors list (link)
"The Nobel Prize in Chemistry 2010 - Richard F. Heck, Ei-ichi Negishi, Akira Suzuki". NobelPrize.org. 2010-10-06. Retrieved 2010-10-06.
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.
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.
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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[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

[Pharma-3] 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.CS1 maint: multiple names: authors list (link)

[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.

[JFH-7] Hartwig, J. F. (2010). Organotransition Metal Chemistry, from Bonding to Catalysis. New York: University Science Books. ISBN 1-891389-53-X.