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.

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
• Heterocouplings joining two different partners. These reactions are also called cross-coupling reactions. The product is unsymmetrical, .

Homo-coupling types

Coupling reactions are illustrated by the Ullmann reaction:

class=skin-invert-image|center|350px|Ullmann overview

{|align="center" class="wikitable"

!Reaction||Year

! colspan="2" align=left |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

class=skin-invert-image|center|300px|The Heck reaction

{|align="center" class="wikitable"

!Reaction||Year

! colspan="2" align=left |Reactant A

! colspan="2" align=left |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||requires base

|-

|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

|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,<br />second generation free amine

|-

|Fukuyama coupling||1998||R-Zn-I||sp³||RCO(SEt)||sp²||Pd or Ni||

|-

|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.

References