Ullmann reaction

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.{{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 }} 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.Derek van Allen, PhD Thesis, University of Massachusetts at Amherst 2004. [http://www.people.umass.edu/dv/group/pdf/dvathesis.pdf Electronic thesis]{{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|url-access=subscription }}{{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|url-access=subscription }} The simplified mechanism shown below is generally accepted.{{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|url-access=subscription }}

File:Simplified Mechanism of Ullmann reaction.jpg

Fritz Ullmann and his student Bielecki were the first to report the reaction.{{Cite journal |last1=Ullmann |first1=F. |last2=Bielecki |first2=Jean |date=May 1901 |title=Ueber Synthesen in der Biphenylreihe |url=https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cber.190103402141 |journal=Berichte der Deutschen Chemischen Gesellschaft |language=en |volume=34 |issue=2 |pages=2174–2185 |doi=10.1002/cber.190103402141 |issn=0365-9496}} 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.{{cite journal|title=2,2'-Dinitrobiphenyl

|author=Reynold C. Fuson |author2=E. A. Cleveland

|journal=Org. Synth.|year=1940|volume=20|page=45

|doi=10.15227/orgsyn.020.0045}}{{cite journal | last1 = Fanta | first1 = P.E. | year = 1974 | title = The Ullmann Synthesis of Biaryls | journal = Synthesis | volume = 1974 | pages = 9–21 | doi = 10.1055/s-1974-23219 | pmid = 21016995 | s2cid = 30018391 }}

:{{chem2|2 C6H4(NO2)Cl + 2 Cu -> (C6H4(NO2))2 + 2 CuCl}}

The reaction has been applied to fairly elaborate substrates.

:File:Ullmann example.svg{{Clear}}

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.{{cite journal | last1 = Beletkaya | first1 = I.P. | last2 = Cheprakov | first2 = A.V. | year = 2004 | title = Copper in Cross Coupling Reactions: The Post Ullman Chemistry | journal = Coord. Chem. Rev. | volume = 248 | pages = 2337–2364|doi=10.1016/j.ccr.2004.09.014}}{{cite journal| title = Aryl–Aryl Bond Formation One Century after the Discovery of the Ullmann Reaction|author1=J. Hassan |author2=M. Sevignon |author3=C. Gozzi |author4=E. Schulz |author5=M. Lemaire|journal = Chemical Reviews| volume = 102| issue = 5| pages = 1359–1470| year = 2002| doi =10.1021/cr000664r|pmid=11996540}}{{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|url-access=subscription }}

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.{{cite journal | last1 = Nelson | first1 = T. D. | last2 = Crouch | first2 = R. D. | year = 2004 | title = Cu, Ni, and Pd Mediated Homocoupling Reactions in Biaryl Syntheses: The Ullmann Reaction| journal = Org. React.| volume = 63 | page = 265 | doi = 10.1002/0471264180.or063.03 | isbn = 0-471-26418-0}} 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.

:File:Ullmann biphenyl synthesis.svg{{Clear}}

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

:Ring close sonogashira

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:

: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. {{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|url-access=subscription }} In the case of copper nanoparticles, the catalytic activity depended on its size and the formation of aggregates.{{Clear}}

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.{{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|url-access=subscription }}{{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|url-access=subscription }}{{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|url-access=subscription }}  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.{{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 }}

File:Oxalix_Diamide.jpg

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.{{cite journal | last1 = Nelson | first1 = T.D. | last2 = Meyers | first2 = A.I. | year = 1994 | title = The asymmetric Ullman reaction, 2. The synthesis of enantiomerically pure C₂-Symmetric Binaphtyls | journal = J. Org. Chem. | volume = 59 | issue = 9| pages = 2655–2658 | doi=10.1021/jo00088a066}}

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.

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.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}} The reaction requires Lproline in addition to copper iodide as catalyst.

Image:Imidazole ullmann reaction.gif

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

• 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

{{Reflist}}

Category:Carbon-carbon bond forming reactions

Category:Name reactions