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{{Short description|Coupling reaction of aryl or alkyl groups}} |
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The '''Ullmann reaction''' or '''Ullmann coupling''', named after [[Fritz Ullmann]], couples two aryl or alkyl groups with the help of copper. The reaction was first reported by Ullmann and his student Bielecki in 1901. It has been later shown that palladium and nickel can also be effectively used.<ref>{{Cite journal |last1=Yin |last2=Liebscher |first2=Jürgen |date=2007-01-01 |title=Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts |url=https://pubs.acs.org/doi/10.1021/cr0505674 |journal=Chemical Reviews |language=en |volume=107 |issue=1 |pages=133–173 |doi=10.1021/cr0505674 |issn=0009-2665}}</ref><ref>{{Cite journal |last1=Nelson |first1=Todd D. |last2=Crouch |first2=R. David |date=2004-11-23 |title= |
The '''Ullmann reaction''' or '''Ullmann coupling''', named after [[Fritz Ullmann]], couples two aryl or alkyl groups with the help of copper. The reaction was first reported by Ullmann and his student Bielecki in 1901. It has been later shown that palladium and nickel can also be effectively used.<ref>{{Cite journal |last1=Yin |last2=Liebscher |first2=Jürgen |date=2007-01-01 |title=Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts |url=https://pubs.acs.org/doi/10.1021/cr0505674 |journal=Chemical Reviews |language=en |volume=107 |issue=1 |pages=133–173 |doi=10.1021/cr0505674 |pmid=17212474 |issn=0009-2665}}</ref><ref>{{Cite journal |last1=Nelson |first1=Todd D. |last2=Crouch |first2=R. David |date=2004-11-23 |title=Cu-, Ni-, and Pd-Mediated Homocoupling Reactions in Biaryl Syntheses: The Ullmann Reaction |url=http://dx.doi.org/10.1002/chin.200451250 |journal=ChemInform |volume=35 |issue=51 |doi=10.1002/chin.200451250 |issn=0931-7597}}</ref> |
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[[Image:Ullmann reaction.svg|center|350px|Ullman overview]] |
[[Image:Ullmann reaction.svg|center|350px|Ullman overview]] |
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==Mechanism== |
==Mechanism== |
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The [[reaction mechanism]] of the Ullmann reaction has been extensively studied. [[Electron spin resonance]] rules out a [[radical (chemistry)|radical]] intermediate. This was confirmed in a set of experiments performed in 2008 by Hartwig and |
The [[reaction mechanism]] of the Ullmann reaction has been extensively studied. [[Electron spin resonance]] rules out a [[radical (chemistry)|radical]] intermediate. This was confirmed in a set of experiments performed in 2008 by Hartwig and co-workers.<ref>{{Cite journal |last1=Tye |first1=Jesse W. |last2=Weng |first2=Zhiqiang |last3=Johns |first3=Adam M. |last4=Incarvito |first4=Christopher D. |last5=Hartwig |first5=John F. |date=2008-07-01 |title=Copper Complexes of Anionic Nitrogen Ligands in the Amidation and Imidation of Aryl Halides |url=http://dx.doi.org/10.1021/ja076668w |journal=Journal of the American Chemical Society |volume=130 |issue=30 |pages=9971–9983 |doi=10.1021/ja076668w |pmid=18597458 |issn=0002-7863|pmc=2819338 }}</ref> The [[oxidative addition]] / [[reductive elimination]] sequence observed with [[palladium]] catalysts is unlikely for [[copper]] because copper(III) is rarely observed. The reaction likely involves the formation of an [[organocopper compound]] (RCuX) which reacts with the other aryl reactant in a [[nucleophilic aromatic substitution]]. Alternative mechanisms have been proposed such as [[σ-bond metathesis]].<ref>Derek van Allen, PhD Thesis, [[University of Massachusetts at Amherst]] '''2004'''. [http://www.people.umass.edu/dv/group/pdf/dvathesis.pdf Electronic thesis]</ref><ref>{{Cite journal |last1=Bacon |first1=R. G. R. |last2=Hill |first2=H. A. O. |date=1964 |title=210. Metal ions and complexes in organic reactions. Part I. Substitution reactions between aryl halides and cuprous salts in organic solvents |url=http://dx.doi.org/10.1039/jr9640001097 |journal=Journal of the Chemical Society (Resumed) |pages=1097 |doi=10.1039/jr9640001097 |issn=0368-1769}}</ref><ref>{{Cite journal |last=Weingarten |first=Harold |date=December 1964 |title=Mechanism of the Ullmann Condensation 1 |url=https://pubs.acs.org/doi/abs/10.1021/jo01035a046 |journal=The Journal of Organic Chemistry |language=en |volume=29 |issue=12 |pages=3624–3626 |doi=10.1021/jo01035a046 |issn=0022-3263}}</ref> The simplified mechanism shown below is generally accepted.<ref>{{Cite journal |last1=Sambiagio |first1=Carlo |last2=Marsden |first2=Stephen P. |last3=Blacker |first3=A. John |last4=McGowan |first4=Patrick C. |date=2014-04-22 |title=Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development |url=https://pubs.rsc.org/en/content/articlelanding/2014/cs/c3cs60289c |journal=Chemical Society Reviews |language=en |volume=43 |issue=10 |pages=3525–3550 |doi=10.1039/C3CS60289C |pmid=24585151 |issn=1460-4744}}</ref> |
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[[File:Simplified Mechanism of Ullmann reaction.jpg|frameless|600x600px]] |
[[File:Simplified Mechanism of Ullmann reaction.jpg|frameless|600x600px]] |
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:Modern developments also include the use of heterogeneous copper catalysts and [[Nanoparticle|nanoparticles]]. These are highly desirable as the catalyst can be easily separated from the products, reducing waste and cost. <ref>{{Cite journal | |
:Modern developments also include the use of heterogeneous copper catalysts and [[Nanoparticle|nanoparticles]]. These are highly desirable as the catalyst can be easily separated from the products, reducing waste and cost. <ref>{{Cite journal |last1=Sambiagio |first1=Carlo |last2=Marsden |first2=Stephen P. |last3=Blacker |first3=A. John |last4=McGowan |first4=Patrick C. |date=2014-04-22 |title=Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development |url=https://pubs.rsc.org/en/content/articlelanding/2014/cs/c3cs60289c |journal=Chemical Society Reviews |language=en |volume=43 |issue=10 |pages=3525–3550 |doi=10.1039/C3CS60289C |pmid=24585151 |issn=1460-4744}}</ref> In the case of copper nanoparticles, the catalytic activity depended on its size and the formation of aggregates.{{Clear}} |
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== Bidentate ligands for Ullmann Coupling == |
== Bidentate ligands for Ullmann Coupling == |
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Around the year 2000, various [[Denticity|bidentate]] ligands were found to improve the efficieny of the Ullmann reaction. Bidentate ligands allow for milder reaction conditions and higher functional group tolerance. They included amino acids, [[Hydroxyquinol|oxines]], [[Schiff base|Schiff bases]], and many other O-O or N-N bidentates.<ref>{{Cite journal | |
Around the year 2000, various [[Denticity|bidentate]] ligands were found to improve the efficieny of the Ullmann reaction. Bidentate ligands allow for milder reaction conditions and higher functional group tolerance. They included amino acids, [[Hydroxyquinol|oxines]], [[Schiff base|Schiff bases]], and many other O-O or N-N bidentates.<ref>{{Cite journal |last1=Ma |first1=Dawei |last2=Zhang |first2=Yongda |last3=Yao |first3=Jiangchao |last4=Wu |first4=Shihui |last5=Tao |first5=Fenggang |date=1999-04-27 |title=ChemInform Abstract: Accelerating Effect Induced by the Structure of α-Amino Acid in the Copper-Catalyzed Coupling Reaction of Aryl Halides with α-Amino Acids. Synthesis of Benzolactam-V8. |url=http://dx.doi.org/10.1002/chin.199917212 |journal=ChemInform |volume=30 |issue=17 |doi=10.1002/chin.199917212 |issn=0931-7597}}</ref><ref>{{Cite journal |last1=Cristau |first1=Henri-Jean |last2=Cellier |first2=Pascal P. |last3=Spindler |first3=Jean-Francis |last4=Taillefer |first4=Marc |date=2004-10-29 |title=Highly Efficient and Mild Copper-Catalyzed N- and C-Arylations with Aryl Bromides and Iodides |url=http://dx.doi.org/10.1002/chem.200400582 |journal=Chemistry – A European Journal |volume=10 |issue=22 |pages=5607–5622 |doi=10.1002/chem.200400582 |pmid=15457520 |issn=0947-6539}}</ref><ref>{{Cite journal |last1=Fagan |first1=Paul J. |last2=Hauptman |first2=Elisabeth |last3=Shapiro |first3=Rafael |last4=Casalnuovo |first4=Albert |date=2000-05-01 |title=Using Intelligent/Random Library Screening To Design Focused Libraries for the Optimization of Homogeneous Catalysts: Ullmann Ether Formation |url=http://dx.doi.org/10.1021/ja000094c |journal=Journal of the American Chemical Society |volume=122 |issue=21 |pages=5043–5051 |doi=10.1021/ja000094c |issn=0002-7863}}</ref> These initial bidentate systems elevated the practicality of Ullmann reactions but it still had drawbacks. High loadings of copper and ligand were required and activation of the notoriously difficult aryl-chloride was still not possible. These problems were solved in 2015 with the design of special oxalic diamine ligands, making the Ullmann reaction viable for industrial application.<ref>{{Cite journal |title=Assembly of Primary (Hetero)Arylamines via CuI/Oxalic Diamide-Catalyzed Coupling of Aryl Chlorides and Ammonia |url=http://dx.doi.org/10.1021/acs.orglett.5b03230.s001 |access-date=2023-12-08 |doi=10.1021/acs.orglett.5b03230.s001 }}</ref> |
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[[File:Oxalix_Diamide.jpg|frameless|430x430px]] |
[[File:Oxalix_Diamide.jpg|frameless|430x430px]] |
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== Industrial Applications == |
== Industrial Applications == |
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Aqueous Ullmann reactions have been used on the pilot plant scale.<ref>{{Cite journal |doi=10.1002/adsc.200505158 |title=Industrial-Scale Palladium-Catalyzed Coupling of Aryl Halides and Amines –A Personal Account |date=2006 |last1=Buchwald |first1=Stephen L. |last2=Mauger |first2=Christelle |last3=Mignani |first3=Gerard |last4=Scholz |first4=Ulrich |journal=Advanced Synthesis & Catalysis |volume=348 |issue=1–2 |pages=23–39 |s2cid=55030715 }}</ref> |
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Modern developments has made the Ullmann reaction industrially relevant. Copper is cheaper and more air/water tolerant compared to other catalytic metals. Reactions in water are desirable as the solvent is non-toxic and has lower cost; various examples of aqueous Ullmann reactions are used in pharmaceutics. <ref>{{Cite journal |last=Carril |first=Mónica |last2=SanMartin |first2=Raul |last3=Domínguez |first3=Esther |date=2008 |title=Palladium and copper-catalysed arylation reactions in the presence of water, with a focus on carbon–heteroatom bond formation |url=http://dx.doi.org/10.1039/b709565c |journal=Chemical Society Reviews |volume=37 |issue=4 |pages=639 |doi=10.1039/b709565c |issn=0306-0012}}</ref> |
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==See also== |
==See also== |
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Latest revision as of 19:18, 5 November 2024
| Ullmann reaction | |
|---|---|
| Named after | Fritz Ullmann |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | ullmann-reaction |
| RSC ontology ID | RXNO:0000040 |
The Ullmann reaction or Ullmann coupling, named after Fritz Ullmann, couples two aryl or alkyl groups with the help of copper. The reaction was first reported by Ullmann and his student Bielecki in 1901. It has been later shown that palladium and nickel can also be effectively used.[1][2]
Aryl-Aryl bond formation is a fundamental tool in modern organic synthesis, with applications spanning natural product synthesis, pharmaceuticals, agrochemicals, and the development of commercial dyes and polyaromatics. With over a century of history, the Ullmann reaction has been one of the first to use a transition metal, primarily copper, in its higher oxidation states. Despite the significant implications of biaryl coupling in industries, the Ullmann reaction was plagued by a number of problems in its early development. However, in modern times the Ullmann reaction has revived interest due to several advantages of copper over other catalytic metals.
Mechanism
[edit]The reaction mechanism of the Ullmann reaction has been extensively studied. Electron spin resonance rules out a radical intermediate. This was confirmed in a set of experiments performed in 2008 by Hartwig and co-workers.[3] The oxidative addition / reductive elimination sequence observed with palladium catalysts is unlikely for copper because copper(III) is rarely observed. The reaction likely involves the formation of an organocopper compound (RCuX) which reacts with the other aryl reactant in a nucleophilic aromatic substitution. Alternative mechanisms have been proposed such as σ-bond metathesis.[4][5][6] The simplified mechanism shown below is generally accepted.[7]
Scope
[edit]Fritz Ullmann and his student Bielecki were the first to report the reaction.[8] This groundbreaking result was the first to show that a transition metal could help perform an aryl carbon-carbon bond formation.
A typical example of classic Ullmann biaryl coupling is the conversion of ortho-chloronitrobenzene into 2,2'-dinitrobiphenyl with a copper - bronze alloy.[9][10]
- 2 C6H4(NO2)Cl + 2 Cu → (C6H4(NO2))2 + 2 CuCl
The reaction has been applied to fairly elaborate substrates.
Ullmann reaction
The traditional version of the Ullmann reaction requires stoichimoetric equivalents of copper, harsh reaction conditions, and the reaction has a reputation for erratic yields. The traditional Ullmann reaction thus had poor atom economy and produced toxic CuI. Because of these problems many improvements and alternative procedures have been introduced.[11][12][13]
The classical Ullmann reaction is limited to electron deficient aryl halides (hence the example of 2-nitrophenyl chloride above) and requires harsh reaction conditions. Modern variants of the Ullman reaction employing palladium and nickel have widened the substrate scope of the reaction and rendered reaction conditions more mild. Yields are generally still moderate, however.[14] In organic synthesis this reaction is often replaced by palladium coupling reactions such as the Heck reaction, the Hiyama coupling, and the Sonogashira coupling.
Biphenylenes had been obtained before with reasonable yields using 2,2-diiodobiphenyl or 2,2-diiodobiphenylonium ion as starting material.
Closure of 5-membered rings is more facile, but larger rings have also been made using this approach.
- Modern developments also include the use of heterogeneous copper catalysts and nanoparticles. These are highly desirable as the catalyst can be easily separated from the products, reducing waste and cost. [15] In the case of copper nanoparticles, the catalytic activity depended on its size and the formation of aggregates.
Bidentate ligands for Ullmann Coupling
[edit]Around the year 2000, various bidentate ligands were found to improve the efficieny of the Ullmann reaction. Bidentate ligands allow for milder reaction conditions and higher functional group tolerance. They included amino acids, oxines, Schiff bases, and many other O-O or N-N bidentates.[16][17][18] These initial bidentate systems elevated the practicality of Ullmann reactions but it still had drawbacks. High loadings of copper and ligand were required and activation of the notoriously difficult aryl-chloride was still not possible. These problems were solved in 2015 with the design of special oxalic diamine ligands, making the Ullmann reaction viable for industrial application.[19]
Unsymmetric and asymmetric couplings
[edit]Ullmann synthesis of biaryl compounds can be used to generate chiral products from chiral reactants.[20] Nelson and collaborators worked on the synthesis of asymmetric biaryl compounds and obtained the thermodynamically controlled product.[20]
The diastereomeric ratio of the products is enhanced with bulkier R groups in the auxiliary oxazoline group.
Unsymmetrical Ullmann reactions are rarely pursued but have been achieved when one of the two coupling components is in excess.[12]
Imidazole Ullmann reaction
[edit]The Ullmann reaction is limited to electron-deficient aryl halides and requires harsh reaction conditions. In organic synthesis this reaction is often replaced by palladium coupling reactions such as the Heck reaction, the Hiyama coupling, and the Sonogashira coupling
In a variation of the Ullmann reaction, β-bromostyrene is reacted with imidazole in an ionic liquid such as 1-butyl-3-methylimidazolium tetrafluoroborate to give an N-styrylimidazole.[21] The reaction requires Lproline in addition to copper iodide as catalyst.
Industrial Applications
[edit]Aqueous Ullmann reactions have been used on the pilot plant scale.[22]
See also
[edit]- Ullmann condensation - copper-promoted conversion of aryl halides to ethers, also developed by Fritz Ullmann
- Copper(I) thiophene-2-carboxylate, a copper reagent used in the Ullmann reaction
- Wurtz–Fittig reaction, a similar reaction useful for alkylbenzenes synthesis
References
[edit]- ^ Yin; Liebscher, Jürgen (2007-01-01). "Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts". Chemical Reviews. 107 (1): 133–173. doi:10.1021/cr0505674. ISSN 0009-2665. PMID 17212474.
- ^ Nelson, Todd D.; Crouch, R. David (2004-11-23). "Cu-, Ni-, and Pd-Mediated Homocoupling Reactions in Biaryl Syntheses: The Ullmann Reaction". ChemInform. 35 (51). doi:10.1002/chin.200451250. ISSN 0931-7597.
- ^ Tye, Jesse W.; Weng, Zhiqiang; Johns, Adam M.; Incarvito, Christopher D.; Hartwig, John F. (2008-07-01). "Copper Complexes of Anionic Nitrogen Ligands in the Amidation and Imidation of Aryl Halides". Journal of the American Chemical Society. 130 (30): 9971–9983. doi:10.1021/ja076668w. ISSN 0002-7863. PMC 2819338. PMID 18597458.
- ^ Derek van Allen, PhD Thesis, University of Massachusetts at Amherst 2004. Electronic thesis
- ^ Bacon, R. G. R.; Hill, H. A. O. (1964). "210. Metal ions and complexes in organic reactions. Part I. Substitution reactions between aryl halides and cuprous salts in organic solvents". Journal of the Chemical Society (Resumed): 1097. doi:10.1039/jr9640001097. ISSN 0368-1769.
- ^ Weingarten, Harold (December 1964). "Mechanism of the Ullmann Condensation 1". The Journal of Organic Chemistry. 29 (12): 3624–3626. doi:10.1021/jo01035a046. ISSN 0022-3263.
- ^ Sambiagio, Carlo; Marsden, Stephen P.; Blacker, A. John; McGowan, Patrick C. (2014-04-22). "Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development". Chemical Society Reviews. 43 (10): 3525–3550. doi:10.1039/C3CS60289C. ISSN 1460-4744. PMID 24585151.
- ^ Ullmann, F.; Bielecki, Jean (May 1901). "Ueber Synthesen in der Biphenylreihe". Berichte der Deutschen Chemischen Gesellschaft. 34 (2): 2174–2185. doi:10.1002/cber.190103402141. ISSN 0365-9496.
- ^ Reynold C. Fuson; E. A. Cleveland (1940). "2,2'-Dinitrobiphenyl". Org. Synth. 20: 45. doi:10.15227/orgsyn.020.0045.
- ^ Fanta, P.E. (1974). "The Ullmann Synthesis of Biaryls". Synthesis. 1974: 9–21. doi:10.1055/s-1974-23219. PMID 21016995. S2CID 30018391.
- ^ Beletkaya, I.P.; Cheprakov, A.V. (2004). "Copper in Cross Coupling Reactions: The Post Ullman Chemistry". Coord. Chem. Rev. 248: 2337–2364. doi:10.1016/j.ccr.2004.09.014.
- ^ a b J. Hassan; M. Sevignon; C. Gozzi; E. Schulz; M. Lemaire (2002). "Aryl–Aryl Bond Formation One Century after the Discovery of the Ullmann Reaction". Chemical Reviews. 102 (5): 1359–1470. doi:10.1021/cr000664r. PMID 11996540.
- ^ Sambiagio, Carlo; Marsden, Stephen P.; Blacker, A. John; McGowan, Patrick C. (2014-04-22). "Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development". Chemical Society Reviews. 43 (10): 3525–3550. doi:10.1039/C3CS60289C. ISSN 1460-4744. PMID 24585151.
- ^ Nelson, T. D.; Crouch, R. D. (2004). "Cu, Ni, and Pd Mediated Homocoupling Reactions in Biaryl Syntheses: The Ullmann Reaction". Org. React. 63: 265. doi:10.1002/0471264180.or063.03. ISBN 0-471-26418-0.
- ^ Sambiagio, Carlo; Marsden, Stephen P.; Blacker, A. John; McGowan, Patrick C. (2014-04-22). "Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development". Chemical Society Reviews. 43 (10): 3525–3550. doi:10.1039/C3CS60289C. ISSN 1460-4744. PMID 24585151.
- ^ Ma, Dawei; Zhang, Yongda; Yao, Jiangchao; Wu, Shihui; Tao, Fenggang (1999-04-27). "ChemInform Abstract: Accelerating Effect Induced by the Structure of α-Amino Acid in the Copper-Catalyzed Coupling Reaction of Aryl Halides with α-Amino Acids. Synthesis of Benzolactam-V8". ChemInform. 30 (17). doi:10.1002/chin.199917212. ISSN 0931-7597.
- ^ Cristau, Henri-Jean; Cellier, Pascal P.; Spindler, Jean-Francis; Taillefer, Marc (2004-10-29). "Highly Efficient and Mild Copper-Catalyzed N- and C-Arylations with Aryl Bromides and Iodides". Chemistry – A European Journal. 10 (22): 5607–5622. doi:10.1002/chem.200400582. ISSN 0947-6539. PMID 15457520.
- ^ Fagan, Paul J.; Hauptman, Elisabeth; Shapiro, Rafael; Casalnuovo, Albert (2000-05-01). "Using Intelligent/Random Library Screening To Design Focused Libraries for the Optimization of Homogeneous Catalysts: Ullmann Ether Formation". Journal of the American Chemical Society. 122 (21): 5043–5051. doi:10.1021/ja000094c. ISSN 0002-7863.
- ^ "Assembly of Primary (Hetero)Arylamines via CuI/Oxalic Diamide-Catalyzed Coupling of Aryl Chlorides and Ammonia". doi:10.1021/acs.orglett.5b03230.s001. Retrieved 2023-12-08.
{{cite journal}}: Cite journal requires|journal=(help) - ^ a b Nelson, T.D.; Meyers, A.I. (1994). "The asymmetric Ullman reaction, 2. The synthesis of enantiomerically pure C2-Symmetric Binaphtyls". J. Org. Chem. 59 (9): 2655–2658. doi:10.1021/jo00088a066.
- ^ Zhiming Wang, Weiliang Bao and Yong Jiang, "L-Proline promoted Ullmann-type reaction of vinyl bromides with imidazoles in ionic liquids", Chemical Communications, 2005, 2849-51. doi:10.1039/b501628b
- ^ Buchwald, Stephen L.; Mauger, Christelle; Mignani, Gerard; Scholz, Ulrich (2006). "Industrial-Scale Palladium-Catalyzed Coupling of Aryl Halides and Amines –A Personal Account". Advanced Synthesis & Catalysis. 348 (1–2): 23–39. doi:10.1002/adsc.200505158. S2CID 55030715.