In organic chemistry, a cross-coupling reaction is a reaction where two different fragments are joined. Cross-couplings are a subset of the more general coupling reactions. Often cross-coupling reactions require metal . One important reaction type is this:
- R-M + R'X -> R-R' + MX
- :R, R' = organic fragments, usually aryl;
- :M = main group center such as Li or Mg;
- :X = halide
These reactions are used to form carbon–carbon bonds but also carbon-heteroatom bonds.[ New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor) 2014 ]
Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki were awarded the 2010 Nobel Prize in Chemistry for developing palladium-catalyzed coupling reactions.
Mechanism
Many mechanisms exist reflecting the myriad types of cross-couplings, including those that do not require metal catalysts.
Often, however, cross-coupling refers to a metal-catalyzed reaction of a nucleophilic partner with an electrophilic partner.
In such cases, the mechanism generally involves reductive elimination of R-R' from L
nMR(R') (L =
spectator ligand). This intermediate L
nMR(R') is formed in a two-step process from a low valence precursor L
nM. The oxidative addition of an
Halocarbon (RX) to L
nM gives L
nMR(X). Subsequently, the second partner undergoes
transmetallation with a source of R'
−. The final step is reductive elimination of the two coupling fragments to regenerate the catalyst and give the organic product. Unsaturated substrates, such as C(sp)−X and C(sp
2)−X bonds, couple more easily, in part because they add readily to the catalyst.
Catalysts
Catalysts are often based on
palladium, which is frequently selected due to high
functional group tolerance.
Organopalladium compounds are generally stable towards water and air. Palladium catalysts can be problematic for the pharmaceutical industry, which faces extensive regulation regarding heavy metals. Many pharmaceutical chemists attempt to use coupling reactions early in production to minimize metal traces in the product.
Heterogeneous catalysts based on Pd are also well-developed.
Copper-based catalysts are also common, especially for coupling involving heteroatom-C bonds.
Iron-,
Leaving groups
The
leaving group X in the organic partner is usually a
halide, although
triflate,
tosylate, pivalate esters, and other
pseudohalide have been used.
Chloride is an ideal group due to the low cost of organochlorine compounds. Frequently, however, C–Cl bonds are too inert, and
bromide or
iodide leaving groups are required for acceptable rates. The main group metal in the organometallic partner is usually an electropositive element such as
tin,
zinc, silicon, or
boron.
Carbon–carbon cross-coupling
Many cross-couplings entail forming carbon–carbon bonds.
|
| requires base |
| |
| sp3 | sp2, sp3 | Cu | Cu-catalyzed version by Jay Kochi, 1971 |
| |
| requires base |
| requires base |
| |
| |
| requires base |
Murahashi coupling | 1979 | R-Li | sp2, sp3 | R-X | sp2 | Pd or Ru | |
| requires base |
| see Liebeskind–Srogl coupling, gives ketones |
| requires CuTC, gives ketones |
| requires oxidant or dehydrogenation |
| Requires little-to-no base |
The restrictions on carbon atom geometry mainly inhibit beta elimination when complexed to the catalyst.[Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford UP: Oxford, U.K., 2012. pp. 1069-1102.]
Carbon–heteroatom coupling
Many cross-couplings entail forming carbon–heteroatom bonds (heteroatom = S, N, O). A popular method is the Buchwald–Hartwig reaction:
|
| 1905 | |
N-C coupling,
second generation free amine |
| |
|
Miscellaneous reactions
Palladium-catalyzes the cross-coupling of
Halogenoarene with fluorinated arene. The process is unusual in that it involves C–H functionalisation at an electron deficient arene.
Applications
Cross-coupling reactions are important for the production of pharmaceuticals,
[ examples being montelukast, eletriptan, naproxen, varenicline, and resveratrol.][Hartwig, J. F. Organotransition Metal Chemistry, from Bonding to Catalysis; University Science Books: New York, 2010. ]
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