User:Jeongbean/Ullmann reaction

The Ullmann reaction or Ullmann coupling, named after Fritz Ullmann, couples two aryl or alkyl groups via a copper-mediated process. The reaction was first reported by Ullmann and his student Bielecki in 1901. It has been later shown that palladium and nickel are also effective catalysts. Initially, the reaction was applied to couple two aryl groups through an aryl halide intermediate and a stoichiometric equivalent of copper.

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Aryl-Aryl bond formation is a fundamental tool in modern organic synthesis, with applications spanning natural product synthesis, pharmaceuticals, agrochemicals, development of commercial dyes and polyaromatics, and more. 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 aryl-aryl 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.

History and Development

1. Early 20th Century (1901): Fritz Ullmann and his student Bielecki were the first to report the reaction. They found that phenols could be coupled to biphenols through a copper-catalyzed process. This groundbreaking result showed an aryl carbon-carbon bond formation was possible using transition metal substrates. The reaction was stoichiometric in copper leading to poor atom economy and the reaction required harsh conditions (i.e. high temperatures).
3. Mid 20th Century: The original method required stoichiometric amounts of copper and high temperatures, limiting its utility. Over time, various modifications were made to improve the efficiency of the process.
4. Late 20th Century: Scientists began exploring other transition metals as potential catalysts for similar coupling reactions (e.g., palladium, nickel). However, due to its cost-effectiveness and wide availability, copper remained a popular choice for many applications.
5. Modern Adaptations: In recent years there have been several significant developments in the field of aryl-aryl bond formation using transition metal catalysis:
   • Copper has continued to be used in various forms (e.g., copper salts) with different ligands.
   • There's been an increased focus on developing more efficient catalyst systems that allow reactions to proceed at lower temperatures and pressures.
   • Modifications have allowed for cross-coupling reactions where two different aryl groups can be coupled together.
   • The use of chiral nitrogen-containing ligands with copper(II) allows for enantioselective or diastereoselective biaryl synthesis.

Current State: Today, although palladium-based cross-coupling reactions like Suzuki and Stille couplings have gained more attention due their broad scope & robustness under variety conditions; traditional methods like Ullmann coupling continue being relevant especially when dealing with certain substrates/reactions where these modern methods might not work as efficiently or economically viable due factors like stability/reactivity issues with organoboron/organotin reagents etc., showcasing importance of having diverse set tools within synthetic chemist's arsenal for tackling wide range challenges encountered during complex organic synthesis endeavors.

Industrial Applications

Simplified explanation of the mechanism:

1. Formation of the Copper Complex: The reaction begins with the copper catalyst (often copper(I) iodide) reacting with the aryl halide to form a copper complex. This is an oxidative addition step where the copper binds to the aryl group and the halide.
2. Transmetallation: The aryl group is transferred from the copper complex to another equivalent of the aryl halide. This is the key step where the carbon-carbon bond is formed.
3. Reductive Elimination: Finally, the copper is removed from the complex, regenerating the copper(I) catalyst and liberating the coupled biaryl product.

The reaction conditions typically include a strong base and a polar solvent, and the reaction is often carried out at high temperatures. It's worth noting that this reaction, while useful, is not always the most efficient or selective method for forming biaryl bonds. Modern variants of this reaction, such as the Buchwald-Hartwig amination and the Suzuki-Miyaura coupling, often provide better yields and selectivities.

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References

Hassan, Jwanro. "Aryl-aryl bond formation one century after the discovery of the Ullmann reaction." Chemical reviews, vol. 102, no. 5, 05/2002, pp. 1359-1470, , doi:10.1021/cr000664r.

Yamamoto, Y. (2013). Copper‐Mediated Aryl–Aryl bond formation leading to biaryls: A century after the ullmann breakthrough. In G. Evano, & N. Blanchard (Eds.), Copper‐Mediated Cross‐Coupling reactions (pp. 335-399). John Wiley & Sons, Inc. https://doi.org/10.1002/9781118690659.ch10