Ullmann reaction

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. Palladium and nickel can also be effectively used.

Ullman overview
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 was one of the first to use a transition metal, 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 enjoyed revived interest due to the 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. The oxidative addition/reductive elimination sequence observed with palladium catalysts is unlikely with 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. The simplified mechanism shown below is generally accepted.

Scope

Fritz Ullmann and his student Bielecki first reported the reaction. This groundbreaking result was the first to show that a transition metal could facilitate carbon–carbon bond formation between aryl compounds.

A typical example of classic Ullmann biaryl coupling is the conversion of ortho-chloronitrobenzene into 2,2′-dinitrobiphenyl using a copper/bronze alloy.

2 C6H4(NO2)Cl + 2 Cu → (C6H4(NO2))2 + 2 CuCl

The reaction has been applied to fairly elaborate substrates.

Ullmann reaction
Ullmann reaction

The traditional Ullmann reaction requires stoichiometric equivalents of copper, harsh reaction conditions, is limited to electron-deficient aryl halides (hence the 2-nitrophenyl chloride example above), and provides erratic yields. However, many improvements and alternative procedures have been introduced. Modern Ullman reaction variants employing palladium and nickel have widened the reaction substrate scope and used milder reaction conditions. Yields are generally still moderate, however. 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 most 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. In the case of copper nanoparticles, the catalytic activity depends on the particle size and its tendency to form aggregates.

Bidentate ligands for Ullmann Coupling

Around the year 2000, various bidentate ligands were found to improve the efficiency 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.  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 (oxalamide ligands), making the Ullmann reaction viable for industrial application.

Unsymmetric and asymmetric couplings

Ullmann synthesis of biaryl compounds can be used to generate chiral products from chiral reactants. Nelson and collaborators worked on the synthesis of asymmetric biaryl compounds and obtained the thermodynamically controlled product.

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.

Industrial Applications

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

See also

References

  1. ↑ 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.
  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.
  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. Bibcode:2008JAChS.130.9971T. doi:10.1021/ja076668w. ISSN 0002-7863. PMC 2819338. PMID 18597458.
  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.
  6. ↑ 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.
  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". Chemical Society Reviews. 43 (10): 3525–3550. doi:10.1039/C3CS60289C. ISSN 1460-4744. PMID 24585151.
  8. ↑ 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.
  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. S2CID 30018391.
  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. 1 2 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". Chemical Society Reviews. 43 (10): 3525–3550. doi:10.1039/C3CS60289C. ISSN 1460-4744. PMID 24585151.
  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.{{cite journal}}: CS1 maint: periodical has ISBN (link)
  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". Chemical Society Reviews. 43 (10): 3525–3550. doi:10.1039/C3CS60289C. ISSN 1460-4744. PMID 24585151.
  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.
  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. PMID 15457520.
  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. Bibcode:2000JAChS.122.5043F. doi:10.1021/ja000094c. ISSN 0002-7863.
  19. ↑ "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)
  20. 1 2 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. ↑ 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.