cross-coupling reaction

{{Short description|Chemical reaction in which two molecules are joined due to a metal catalyst}}

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 catalysts. One important reaction type is this:

:{{chem2| R\sM + R'\sX -> R\sR' + MX}} (R, R' = organic fragments, usually aryl; M = main group center such as Li or MgX; X = halide)

These reactions are used to form carbon–carbon bonds but also carbon-heteroatom bonds.{{cite journal |doi=10.1021/acs.chemrev.8b00628 |title=Cross-Coupling of Heteroatomic Electrophiles |date=2019 |last1=Korch |first1=Katerina M. |last2=Watson |first2=Donald A. |journal=Chemical Reviews |volume=119 |issue=13 |pages=8192–8228 |pmid=31184483 |pmc=6620169 }}{{cite journal |doi=10.1021/cr0505268 |title=Selected Patented Cross-Coupling Reaction Technologies |date=2006 |last1=Corbet |first1=Jean-Pierre |last2=Mignani |first2=Gérard |journal=Chemical Reviews |volume=106 |issue=7 |pages=2651–2710 |pmid=16836296 }}New Trends in Cross-Coupling: Theory and Applications Thomas Colacot (Editor) 2014 {{ISBN|978-1-84973-896-5}}{{cite book|author=King, A. O.|author2=Yasuda, N.|title=Organometallics in Process Chemistry|volume=6|pages=205–245 |chapter=Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals|doi=10.1007/b94551|publisher = Springer|location=Heidelberg|series=Topics in Organometallic Chemistry|year=2004|isbn=978-3-540-01603-8}} Cross-coupling reaction are a subset of coupling reactions.

Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki were awarded the 2010 Nobel Prize in Chemistry for developing palladium-catalyzed coupling reactions.{{cite web|url=http://nobelprize.org/nobel_prizes/chemistry/laureates/2010/ |title=The Nobel Prize in Chemistry 2010 - Richard F. Heck, Ei-ichi Negishi, Akira Suzuki |publisher=NobelPrize.org |date=2010-10-06 |accessdate=2010-10-06}}{{cite journal | doi = 10.1002/anie.201107017| pmid = 22573393| title = Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize| journal = Angewandte Chemie International Edition| volume = 51| issue = 21| pages = 5062–5085| year = 2012| last1 = Johansson Seechurn| first1 = Carin C. C.| last2 = Kitching| first2 = Matthew O.| last3 = Colacot| first3 = Thomas J.| last4 = Snieckus| first4 = Victor| s2cid = 20582425}}

Mechanism

Many mechanisms exist reflecting the myriad types of cross-couplings, including those that do not require metal catalysts.{{cite journal |doi=10.1021/cr400274j|title=Transition-Metal-Free Coupling Reactions |year=2014 |last1=Sun |first1=Chang-Liang |last2=Shi |first2=Zhang-Jie |journal=Chemical Reviews |volume=114 |issue=18 |pages=9219–9280 |pmid=25184859 }} Often, however, cross-coupling refers to a metal-catalyzed reaction of a nucleophilic partner with an electrophilic partner.

Image:Katalysezyklus-Kumada-Kupplung.png (L = Ligand, Ar = Aryl).]]

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 organic halide (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(sp²)−X bonds, couple more easily, in part because they add readily to the catalyst.

=Catalysts=

File:Sonogashira coupling mechanism.png.]]

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.{{cite journal |url=https://pubs.acs.org/cen/coverstory/83/8336chiral3.html |title=Removing Impurities |last=Thayer |first=Ann |date=2005-09-05 |journal=Chemical & Engineering News |access-date=2015-12-11 }} Heterogeneous catalysts based on Pd are also well-developed.{{cite journal|author=Yin, L.|author2=Liebscher, J.|s2cid=36974481|title=Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts|journal=Chemical Reviews|year=2007|volume=107|issue=1|pages=133–173|doi=10.1021/cr0505674|pmid=17212474}}

Copper-based catalysts are also common, especially for coupling involving heteroatom-C bonds.{{cite journal | doi = 10.1021/cr0505268| pmid = 16836296| title = Selected Patented Cross-Coupling Reaction Technologies| journal = Chemical Reviews| volume = 106| issue = 7| pages = 2651–2710| year = 2006| last1 = Corbet| first1 = Jean-Pierre| last2 = Mignani| first2 = Gérard}}{{cite journal | doi = 10.1021/cr8002505| pmid = 18698737| title = Copper-Mediated Coupling Reactions and Their Applications in Natural Products and Designed Biomolecules Synthesis| journal = Chemical Reviews| volume = 108| issue = 8| pages = 3054–3131| year = 2008| last1 = Evano| first1 = Gwilherm| last2 = Blanchard| first2 = Nicolas| last3 = Toumi| first3 = Mathieu}}

Iron-,{{cite journal|title=How Low Does Iron Go? Chasing the Active Species in Fe-Catalyzed Cross-Coupling Reactions|author=Robin B. Bedford|journal=Acc. Chem. Res.|year=2015|volume=48|issue=5|pages=1485–1493|doi=10.1021/acs.accounts.5b00042|pmid=25916260}} cobalt-,{{cite journal | doi = 10.1021/cr9000786| pmid = 20148539| title = Cobalt-Catalyzed Cross-Coupling Reactions| journal = Chemical Reviews| volume = 110| issue = 3| pages = 1435–1462| year = 2010| last1 = Cahiez| first1 = GéRard| last2 = Moyeux| first2 = Alban}} and nickel-based{{cite journal | doi = 10.1021/cr100259t| pmid = 21133429| pmc = 3055945| title = Nickel-Catalyzed Cross-Couplings Involving Carbon−Oxygen Bonds| journal = Chemical Reviews| volume = 111| issue = 3| pages = 1346–1416| year = 2011| last1 = Rosen| first1 = Brad M.| last2 = Quasdorf| first2 = Kyle W.| last3 = Wilson| first3 = Daniella A.| last4 = Zhang| first4 = Na| last5 = Resmerita| first5 = Ana-Maria| last6 = Garg| first6 = Neil K.| last7 = Percec| first7 = Virgil}} catalysts have been investigated.

=Leaving groups=

The leaving group X in the organic partner is usually a halide, although triflate, tosylate, pivalate esters, and other pseudohalides have been used.{{March6th|page=792}} 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.

align="center" class="wikitable" !Reaction	Year ! colspan="2" align=left \|Reactant A ! colspan="2" align=left \|Reactant B	Catalyst	Remark
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
Kumada coupling	1972	RMgBr	sp², sp³	R-X	sp²	Pd or Ni or Fe
Heck reaction	1972	alkene	sp²	Ar-X	sp²	Pd or Ni	requires base
Sonogashira coupling	1975	ArC≡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 or Ni
Suzuki reaction	1979	R-B(OR)₂	sp²	R-X	sp³ sp²	Pd or Ni	requires base
Murahashi coupling{{Cite journal\|last1=Murahashi\|first1=Shunichi\|last2=Yamamura\|first2=Masaaki\|last3=Yanagisawa\|first3=Kenichi\|last4=Mita\|first4=Nobuaki\|last5=Kondo\|first5=Kaoru\|date=1979\|title=Stereoselective synthesis of alkenes and alkenyl sulfides from alkenyl halides using palladium and ruthenium catalysts\|journal=The Journal of Organic Chemistry\|language=en\|volume=44\|issue=14\|pages=2408–2417\|doi=10.1021/jo01328a016\|issn=0022-3263}} \|1979 \|R-Li \|sp², sp³ \|R-X \|sp² \|Pd or Ru \|
Hiyama coupling	1988	R-SiR₃	sp²	R-X	sp³ sp²	Pd	requires base
Fukuyama coupling	1998	R-Zn-I	sp³	RCO(SEt)	sp²	Pd or Ni	see Liebeskind–Srogl coupling, gives ketones
Liebeskind–Srogl coupling	2000	R-B(OR)₂	sp³, sp²	RCO(SEt) Ar-SMe	sp²	Pd	requires CuTC, gives ketones
Cross dehydrogenative coupling	2004	R-H	sp, sp², sp³	R'-H	sp, sp², sp³	Cu, Fe, Pd etc.	requires oxidant or dehydrogenation
Decarboxylative cross-coupling	2000s	R-CO₂H	sp²	R'-X	sp, sp²	Cu, Pd	Requires little-to-no base

The restrictions on carbon atom geometry mainly inhibit β-hydride 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:

{{NumBlk|:|File:Buchwaldhartwig.png|{{EquationRef|Eq.1}}}}

align="center" class="wikitable" !Reaction	Year ! colspan="2" align=left \|Reactant A ! colspan="2" align=left \|Reactant B	Catalyst	Remark
Ullmann-type reaction	1905 \|ArO-MM, ArNH₂,RS-M,NC-M	sp³	Ar-X (X = OAr, N(H)Ar, SR, CN)	sp²	Cu
Buchwald–Hartwig reaction{{cite journal\|author=Ruiz-Castillo, P.\|author2=Buchwald, S. L.\|title=Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions \|journal=Chemical Reviews \|year=2016\|volume=116\|issue=19 \|pages=12564–12649\|doi=10.1021/acs.chemrev.6b00512\|pmid=27689804 \|pmc=5070552}}	1994	R₂N-H	sp³	R-X	sp²	Pd	N-C coupling, second generation free amine
Chan–Lam coupling{{cite book\|chapter=Recent Advances in Chan–Lam Coupling Reaction: Copper-Promoted C–Heteroatom Bond Cross-Coupling Reactions with Boronic Acids and Derivatives\|author=Jennifer X. Qiao\|author2=Patrick Y.S. Lam\|title=Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials\|pages=315–361\|editor=Dennis G. Hall\|year=2011\|publisher=Wiley-VCH\|doi=10.1002/9783527639328.ch6\|isbn=9783527639328}}	1998	Ar-B(OR)₂	sp²	Ar-NH₂	sp²	Cu

Miscellaneous reactions

Palladium-catalyzes the cross-coupling of aryl halides with fluorinated arene. The process is unusual in that it involves C–H functionalisation at an electron deficient arene.{{cite journal |author1=M. Lafrance |author2=C. N. Rowley |author3=T. K. Woo |author4=K. Fagnou | title = Catalytic Intermolecular Direct Arylation of Perfluorobenzenes | year = 2006 | journal = J. Am. Chem. Soc. | volume = 128 | issue = 27 | pages = 8754–8756 | doi = 10.1021/ja062509l | pmid = 16819868|citeseerx=10.1.1.631.607 }}

Applications

Cross-coupling reactions are important for the production of pharmaceuticals, examples being montelukast, eletriptan, naproxen, varenicline, and resveratrol.{{cite book|doi=10.1002/9783527651733.ch2|chapter=Hydroformylation|title=Applied Homogeneous Catalysis with Organometallic Compounds|year=2017|last1=Cornils|first1=Boy|last2=Börner|first2=Armin|last3=Franke|first3=Robert|last4=Zhang|first4=Baoxin|last5=Wiebus|first5=Ernst|last6=Schmid|first6=Klaus|pages=23–90|isbn=9783527328970}} with Suzuki coupling being most widely used.{{cite journal |doi=10.1021/jm200187y|title=The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates|year=2011|last1=Roughley|first1=Stephen D.|last2=Jordan|first2=Allan M.|journal=Journal of Medicinal Chemistry|volume=54|issue=10|pages=3451–3479|pmid=21504168}} Some polymers and monomers are also prepared in this way.Hartwig, J. F. Organotransition Metal Chemistry, from Bonding to Catalysis; University Science Books: New York, 2010. {{ISBN|1-891389-53-X}}

Reviews

{{Cite journal|title = N-Heterocyclic carbene (NHC) ligands and palladium in homogeneous cross-coupling catalysis: a perfect union|journal = Chemical Society Reviews|volume = 40|issue = 10|pages = 5151–69|doi = 10.1039/c1cs15088j|pmid = 21731956|language = en|first1 = George C.|last1 = Fortman|first2 = Steven P.|last2 = Nolan|year = 2011}}
{{cite journal | doi = 10.1021/cr0505674| pmid = 17212474| title = Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts| journal = Chemical Reviews| volume = 107| issue = 1| pages = 133–173| year = 2007| last1 = Yin| last2 = Liebscher| first2 = Jürgen| s2cid = 36974481}}
{{cite journal | doi = 10.1021/cr100327p| pmid = 21319862| pmc = 3075866| title = Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-organometallics as Reaction Partners| journal = Chemical Reviews| volume = 111| issue = 3| pages = 1417–1492| year = 2011| last1 = Jana| first1 = Ranjan| last2 = Pathak| first2 = Tejas P.| last3 = Sigman| first3 = Matthew S.}}
{{cite journal | doi = 10.1021/cr100355b| pmid = 21391571| title = Efficient, Selective, and Recyclable Palladium Catalysts in Carbon−Carbon Coupling Reactions| journal = Chemical Reviews| volume = 111| issue = 3| pages = 2251–2320| year = 2011| last1 = Molnár| first1 = Árpád}}
{{cite journal | doi = 10.1021/cr00039a007| title = Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds| journal = Chemical Reviews| volume = 95| issue = 7| pages = 2457–2483| year = 1995|author1-link=Norio Miyaura |author2-link=Akira Suzuki (chemist)| last1 = Miyaura| first1 = Norio| last2 = Suzuki| first2 = Akira| citeseerx = 10.1.1.735.7660}}
{{cite journal | doi = 10.1021/cr0509861| pmid = 17091930| title = Diazonium Salts as Substrates in Palladium-Catalyzed Cross-Coupling Reactions| journal = Chemical Reviews| volume = 106| issue = 11| pages = 4622–4643| year = 2006| last1 = Roglans| first1 = Anna| last2 = Pla-Quintana| first2 = Anna| last3 = Moreno-Mañas| first3 = Marcial| s2cid = 8128630}}
{{cite journal |doi=10.1021/acs.chemrev.8b00628|title=Cross-Coupling of Heteroatomic Electrophiles |year=2019 |last1=Korch |first1=Katerina M. |last2=Watson |first2=Donald A. |journal=Chemical Reviews |volume=119 |issue=13 |pages=8192–8228 |pmid=31184483 |pmc=6620169 }}
{{cite journal |doi=10.1021/cr9000786|title=Cobalt-Catalyzed Cross-Coupling Reactions |year=2010 |last1=Cahiez |first1=Gérard |last2=Moyeux |first2=Alban |journal=Chemical Reviews |volume=110 |issue=3 |pages=1435–1462 |pmid=20148539 }}
{{cite journal |doi=10.1021/acs.chemrev.6b00620|title=Recent Advances in Radical C–H Activation/Radical Cross-Coupling |year=2017 |last1=Yi |first1=Hong |last2=Zhang |first2=Guoting |last3=Wang |first3=Huamin |last4=Huang |first4=Zhiyuan |last5=Wang |first5=Jue |last6=Singh |first6=Atul K. |last7=Lei |first7=Aiwen |journal=Chemical Reviews |volume=117 |issue=13 |pages=9016–9085 |pmid=28639787 }}

References

Category:Organometallic chemistry

Category:Carbon-carbon bond forming reactions

Category:Catalysis