Chemistry:Ullmann reaction

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Short description: Coupling reaction of aryl or alkyl groups
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]

Ullman overview

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

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]

Simplified Mechanism of Ullmann reaction.jpg

Scope

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 C
6H
4(NO
2)Cl + 2 Cu → (C
6H
4(NO
2))
2 + 2 CuCl

The reaction has been applied to fairly elaborate substrates.

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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.

Ullmann byphenylene synthesis

Closure of 5-membered rings is more facile, but larger rings have also been made using this approach.

Ring close sonogashira
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

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]

Oxalix Diamide.jpg

Unsymmetric and asymmetric couplings

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]

Ullman Asymmetric reaction

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

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.

Imidazole Ullmann reaction.

Industrial Applications

Aqueous Ullmann reactions have been used on the pilot plant scale.[22]

See also

References

  1. ↑ Yin; Liebscher, Jürgen (2007-01-01). "Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts" (in en). Chemical Reviews 107 (1): 133–173. doi:10.1021/cr0505674. ISSN 0009-2665. https://pubs.acs.org/doi/10.1021/cr0505674. 
  2. ↑ 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. http://dx.doi.org/10.1002/chin.200451250. 
  3. ↑ 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. http://dx.doi.org/10.1021/ja076668w. 
  4. ↑ Derek van Allen, PhD Thesis, University of Massachusetts at Amherst 2004. Electronic thesis
  5. ↑ 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. http://dx.doi.org/10.1039/jr9640001097. 
  6. ↑ Weingarten, Harold (December 1964). "Mechanism of the Ullmann Condensation 1" (in en). The Journal of Organic Chemistry 29 (12): 3624–3626. doi:10.1021/jo01035a046. ISSN 0022-3263. https://pubs.acs.org/doi/abs/10.1021/jo01035a046. 
  7. ↑ 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" (in en). Chemical Society Reviews 43 (10): 3525–3550. doi:10.1039/C3CS60289C. ISSN 1460-4744. https://pubs.rsc.org/en/content/articlelanding/2014/cs/c3cs60289c. 
  8. ↑ Ullmann, F.; Bielecki, Jean (May 1901). "Ueber Synthesen in der Biphenylreihe" (in en). Berichte der Deutschen Chemischen Gesellschaft 34 (2): 2174–2185. doi:10.1002/cber.190103402141. ISSN 0365-9496. https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cber.190103402141. 
  9. ↑ Reynold C. Fuson; E. A. Cleveland (1940). "2,2'-Dinitrobiphenyl". Org. Synth. 20: 45. doi:10.15227/orgsyn.020.0045. 
  10. ↑ Fanta, P.E. (1974). "The Ullmann Synthesis of Biaryls". Synthesis 1974: 9–21. doi:10.1055/s-1974-23219. PMID 21016995. 
  11. ↑ 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. 
  12. ↑ 12.0 12.1 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. 
  13. ↑ 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" (in en). Chemical Society Reviews 43 (10): 3525–3550. doi:10.1039/C3CS60289C. ISSN 1460-4744. PMID 24585151. https://pubs.rsc.org/en/content/articlelanding/2014/cs/c3cs60289c. 
  14. ↑ 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. 
  15. ↑ 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" (in en). Chemical Society Reviews 43 (10): 3525–3550. doi:10.1039/C3CS60289C. ISSN 1460-4744. https://pubs.rsc.org/en/content/articlelanding/2014/cs/c3cs60289c. 
  16. ↑ 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. http://dx.doi.org/10.1002/chin.199917212. 
  17. ↑ 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. http://dx.doi.org/10.1002/chem.200400582. 
  18. ↑ 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. http://dx.doi.org/10.1021/ja000094c. 
  19. ↑ "Assembly of Primary (Hetero)Arylamines via CuI/Oxalic Diamide-Catalyzed Coupling of Aryl Chlorides and Ammonia". http://dx.doi.org/10.1021/acs.orglett.5b03230.s001. 
  20. ↑ 20.0 20.1 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. 
  21. ↑ 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
  22. ↑ 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. 



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