乌尔曼反应 Ullmann reaction — 定义、原理与由来

定义Definition

乌尔曼反应原指两分子芳基卤化物在铜粉作用下高温偶联生成对称联芳烃；广义上也包括铜催化的芳基卤化物与酚、胺、硫醇形成 C–O、C–N、C–S 键的“乌尔曼型缩合”。

The Ullmann reaction originally meant the copper-promoted high-temperature coupling of two aryl halides to a symmetrical biaryl; more broadly it includes copper-catalysed ‘Ullmann-type condensations’ of aryl halides with phenols, amines and thiols to form C–O, C–N and C–S bonds.

机理Mechanism

经典偶联中铜与芳基卤化物生成芳基铜物种，再与第二分子芳基卤化物经氧化加成/还原消除（Cu(I)/Cu(III)）得联芳烃。缩合反应中 Cu(I) 与亲核试剂形成铜酚盐或铜酰胺，再与芳基卤化物反应。

In the classic coupling copper forms an arylcopper species that reacts with a second aryl halide via oxidative addition/reductive elimination (Cu(I)/Cu(III)). In condensations Cu(I) forms a copper phenoxide or amide that then reacts with the aryl halide.

由来Origin

德国化学家弗里茨·乌尔曼于 1901 年报道联芳烃偶联；1903–1906 年他与伊尔玛·戈德堡发展了 C–N 与 C–O 缩合（戈德堡反应）。

Fritz Ullmann reported the biaryl coupling in 1901; in 1903–1906 he and Irma Goldberg developed the C–N and C–O condensations (Goldberg reaction).

现代改进Modern improvements

经典条件需 200 °C 以上和化学计量的铜。加入二胺、氨基酸（如马大为发展的 L-脯氨酸、N,N-二甲基甘氨酸）、菲咯啉等配体后，催化量 CuI 可在 80–120 °C 进行，成本低于钯催化，工业上用于二芳基醚和芳胺合成。

Classic conditions need >200 °C and stoichiometric copper. Ligands such as diamines, amino acids (L-proline, N,N-dimethylglycine developed by Ma Dawei) and phenanthroline allow catalytic CuI at 80–120 °C, cheaper than palladium and used industrially for diaryl ethers and arylamines.

反应Reactions

2 Ar–X + Cu ⟶ Ar–Ar + CuX₂Ar–X + Ar′OH CuI/配体, 碱⟶ Ar–O–Ar′2 Ar–X + Cu ⟶ Ar–Ar + CuX₂; Ar–X + Ar′OH CuI/Ligand,⟶ Ar–O–Ar′

经典：Cu 粉，约 200 °C；现代：CuI/配体，K₂CO₃ 或 Cs₂CO₃，DMSO 或 DMF，80–120 °C

Classic: copper bronze at ~200 °C; modern: CuI/ligand, K₂CO₃ or Cs₂CO₃, DMSO or DMF, 80–120 °C

Cu(I) 与亲核试剂（或芳基卤）形成有机铜中间体。
Cu(I) forms an organocopper intermediate with the nucleophile (or aryl halide).
芳基卤化物氧化加成到铜上形成 Cu(III)。
The aryl halide oxidatively adds to give Cu(III).
还原消除形成新键。
Reductive elimination forms the new bond.

2 邻硝基氯苯 + Cu ⟶ 2,2′-二硝基联苯2 + Cu ⟶ 2,2′-Biphenyl

乌尔曼最初的联芳烃偶联。

Ullmann's original biaryl coupling.

年表Timeline

1901
乌尔曼报道铜介导联芳烃偶联
Ullmann reports copper-mediated biaryl coupling
1906
戈德堡报道铜催化 C–N 缩合
Goldberg reports copper-catalysed C–N condensation
2003
氨基酸配体促进的温和乌尔曼反应
Amino-acid-ligand-promoted mild Ullmann reactions

乌尔曼反应Ullmann reaction