Ullmann reaction

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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]

Contents

Ullman overview Ullmann reaction.svg
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 C6H4(NO2)Cl + 2 Cu → (C6H4(NO2))2 + 2 CuCl

The reaction has been applied to fairly elaborate substrates.

Ullmann reaction Ullmann example.svg
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.

Ullmann biphenyl synthesis.svg

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

Ring close sonogashira.jpg
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 Assymetric reaction.jpg

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-bromo styrene is reacted with imidazole in an ionic liquid such as 1-butyl-3-methylimidazolium tetrafluoroborate to give an N-styrylimidazole. [21] The reaction requires L proline in addition to copper iodide as catalyst.

Imidazole Ullmann reaction. Imidazole ullmann reaction.gif
Imidazole Ullmann reaction.

Industrial Applications

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

See also

Related Research Articles

The Heck reaction is the chemical reaction of an unsaturated halide with an alkene in the presence of a base and a palladium catalyst to form a substituted alkene. It is named after Tsutomu Mizoroki and Richard F. Heck. Heck was awarded the 2010 Nobel Prize in Chemistry, which he shared with Ei-ichi Negishi and Akira Suzuki, for the discovery and development of this reaction. This reaction was the first example of a carbon-carbon bond-forming reaction that followed a Pd(0)/Pd(II) catalytic cycle, the same catalytic cycle that is seen in other Pd(0)-catalyzed cross-coupling reactions. The Heck reaction is a way to substitute alkenes.

The Stille reaction is a chemical reaction widely used in organic synthesis. The reaction involves the coupling of two organic groups, one of which is carried as an organotin compound (also known as organostannanes). A variety of organic electrophiles provide the other coupling partner. The Stille reaction is one of many palladium-catalyzed coupling reactions.

The Suzuki reaction or Suzuki coupling is an organic reaction that uses a palladium complex catalyst to cross-couple a boronic acid to an organohalide. It was first published in 1979 by Akira Suzuki, and he shared the 2010 Nobel Prize in Chemistry with Richard F. Heck and Ei-ichi Negishi for their contribution to the discovery and development of noble metal catalysis in organic synthesis. This reaction is sometimes telescoped with the related Miyaura borylation; the combination is the Suzuki–Miyaura reaction. It is widely used to synthesize polyolefins, styrenes, and substituted biphenyls.

The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or vinyl halide.

Organopalladium chemistry is a branch of organometallic chemistry that deals with organic palladium compounds and their reactions. Palladium is often used as a catalyst in the reduction of alkenes and alkynes with hydrogen. This process involves the formation of a palladium-carbon covalent bond. Palladium is also prominent in carbon-carbon coupling reactions, as demonstrated in tandem reactions.

The Sandmeyer reaction is a chemical reaction used to synthesize aryl halides from aryl diazonium salts using copper salts as reagents or catalysts. It is an example of a radical-nucleophilic aromatic substitution. The Sandmeyer reaction provides a method through which one can perform unique transformations on benzene, such as halogenation, cyanation, trifluoromethylation, and hydroxylation.

The Hiyama coupling is a palladium-catalyzed cross-coupling reaction of organosilanes with organic halides used in organic chemistry to form carbon–carbon bonds. This reaction was discovered in 1988 by Tamejiro Hiyama and Yasuo Hatanaka as a method to form carbon-carbon bonds synthetically with chemo- and regioselectivity. The Hiyama coupling has been applied to the synthesis of various natural products.

The Ullmann condensation or Ullmann-type reaction is the copper-promoted conversion of aryl halides to aryl ethers, aryl thioethers, aryl nitriles, and aryl amines. These reactions are examples of cross-coupling reactions.

The Negishi coupling is a widely employed transition metal catalyzed cross-coupling reaction. The reaction couples organic halides or triflates with organozinc compounds, forming carbon-carbon bonds (C-C) in the process. A palladium (0) species is generally utilized as the catalyst, though nickel is sometimes used. A variety of nickel catalysts in either Ni0 or NiII oxidation state can be employed in Negishi cross couplings such as Ni(PPh3)4, Ni(acac)2, Ni(COD)2 etc.

<span class="mw-page-title-main">Organocopper chemistry</span> Compound with carbon to copper bonds

Organocopper chemistry is the study of the physical properties, reactions, and synthesis of organocopper compounds, which are organometallic compounds containing a carbon to copper chemical bond. They are reagents in organic chemistry.

In organic chemistry, the Buchwald–Hartwig amination is a chemical reaction for the synthesis of carbon–nitrogen bonds via the palladium-catalyzed coupling reactions of amines with aryl halides. Although Pd-catalyzed C–N couplings were reported as early as 1983, Stephen L. Buchwald and John F. Hartwig have been credited, whose publications between 1994 and the late 2000s established the scope of the transformation. The reaction's synthetic utility stems primarily from the shortcomings of typical methods for the synthesis of aromatic C−N bonds, with most methods suffering from limited substrate scope and functional group tolerance. The development of the Buchwald–Hartwig reaction allowed for the facile synthesis of aryl amines, replacing to an extent harsher methods while significantly expanding the repertoire of possible C−N bond formations.

In organic chemistry, the Kumada coupling is a type of cross coupling reaction, useful for generating carbon–carbon bonds by the reaction of a Grignard reagent and an organic halide. The procedure uses transition metal catalysts, typically nickel or palladium, to couple a combination of two alkyl, aryl or vinyl groups. The groups of Robert Corriu and Makoto Kumada reported the reaction independently in 1972.

<span class="mw-page-title-main">XPhos</span> Chemical compound

XPhos is a phosphine ligand derived from biphenyl. Its palladium complexes exhibit high activity for Buchwald-Hartwig amination reactions involving aryl chlorides and aryl tosylates. Both palladium and copper complexes of the compound exhibit high activity for the coupling of aryl halides and aryl tosylates with various amides. It is also an efficient ligand for several commonly used C–C bond-forming cross-coupling reactions, including the Negishi, Suzuki, and the copper-free Sonogashira coupling reactions. It is especially efficient and general when employed as a (2-aminobiphenyl)-cyclometalated palladium mesylate precatalyst complex, XPhos-G3-Pd, which is commercially available and stable to bench storage. The ligand itself also has convenient handling characteristics as a crystalline, air-stable solid.

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:

Metal carbon dioxide complexes are coordination complexes that contain carbon dioxide ligands. Aside from the fundamental interest in the coordination chemistry of simple molecules, studies in this field are motivated by the possibility that transition metals might catalyze useful transformations of CO2. This research is relevant both to organic synthesis and to the production of "solar fuels" that would avoid the use of petroleum-based fuels.

<span class="mw-page-title-main">PEPPSI</span> Group of chemical compounds

PEPPSI is an abbreviation for pyridine-enhanced precatalyst preparation stabilization and initiation. It refers to a family of commercially available palladium catalysts developed around 2005 by Prof. Michael G. Organ and co-workers at York University, which can accelerate various carbon-carbon and carbon-heteroatom bond forming cross-coupling reactions. In comparison to many alternative palladium catalysts, Pd-PEPPSI-type complexes are stable to air and moisture and are relatively easy to synthesize and handle.

Decarboxylative cross coupling reactions are chemical reactions in which a carboxylic acid is reacted with an organic halide to form a new carbon-carbon bond, concomitant with loss of CO2. Aryl and alkyl halides participate. Metal catalyst, base, and oxidant are required.

<span class="mw-page-title-main">Palladium–NHC complex</span>

In organometallic chemistry, palladium-NHC complexes are a family of organopalladium compounds in which palladium forms a coordination complex with N-heterocyclic carbenes (NHCs). They have been investigated for applications in homogeneous catalysis, particularly cross-coupling reactions.

Dialkylbiaryl phosphine ligands are phosphine ligands that are used in homogeneous catalysis. They have proved useful in Buchwald-Hartwig amination and etherification reactions as well as Negishi cross-coupling, Suzuki-Miyaura cross-coupling, and related reactions. In addition to these Pd-based processes, their use has also been extended to transformations catalyzed by nickel, gold, silver, copper, rhodium, and ruthenium, among other transition metals.

Heterobimetallic catalysis is an approach to catalysis that employs two different metals to promote a chemical reaction. Included in this definition are cases where: 1) each metal activates a different substrate, 2) both metals interact with the same substrate, and 3) only one metal directly interacts with the substrate(s), while the second metal interacts with the first.

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. 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.
  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. 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. ↑ 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. S2CID   55030715.
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