The Ullmann reaction is a class of copper‑mediated coupling reactions in organic chemistry that form carbon‑heteroatom bonds between aryl (or heteroaryl) halides and nucleophiles such as amines, phenols, or thiols. The transformation is named after the German chemist Fritz Ullmann, who first reported the copper‑catalyzed coupling of aryl halides with phenols in 1903.
General features
- Catalyst: Typically copper metal, copper(I) salts (e.g., CuI, CuCl), or copper(II) salts in the presence of a suitable ligand.
- Substrates: Aryl or heteroaryl halides (iodides, bromides, and, less commonly, chlorides) and nucleophiles containing nitrogen, oxygen, or sulfur.
- Products: C–N (aryl amination), C–O (aryl ether formation), and C–S (aryl thioether formation) bonds.
- Conditions: Historically required high temperatures (150–250 °C) and stoichiometric copper; modern variants employ catalytic copper, ligands (e.g., diamines, amino acids, phosphines), and milder temperatures (often 80–120 °C).
Major variants
- Ullmann ether synthesis – coupling of aryl halides with phenols to give diaryl ethers.
- Ullmann amination (also called the Ullmann C–N coupling) – formation of aryl amines from aryl halides and amines.
- Ullmann thioether synthesis – coupling of aryl halides with thiols to afford aryl thioethers.
Mechanistic considerations
The reaction is generally believed to proceed via oxidative addition of the aryl halide to a copper(I) species, transmetalation or nucleophilic attack by the heteroatom nucleophile, and reductive elimination to forge the C–X bond (X = N, O, S). The exact pathway can depend on the oxidation state of copper, the nature of the ligand, and the substrate.
Scope and limitations
- Electron‑deficient aryl halides tend to react more readily than electron‑rich counterparts.
- Aryl iodides and bromides are more reactive than chlorides; however, recent ligand‑enabled protocols allow the use of aryl chlorides.
- Steric hindrance at the reacting positions can diminish yields.
- Side reactions include homocoupling of aryl halides (biaryl formation) and over‑alkylation of nucleophiles.
Historical development
- 1903: Ullmann reported the copper‑mediated coupling of iodobenzene with phenol.
- 1940s–1960s: Expanded to amination and thiolation, but required stoichiometric copper and high temperatures.
- 1990s–present: Introduction of catalytic copper systems with chelating ligands (e.g., 1,10‑phenanthroline, N‑heterocyclic carbenes) dramatically improved efficiency, lowered temperature, and broadened substrate scope.
Applications
Ullmann-type couplings are employed in the synthesis of pharmaceuticals, natural products, and functional materials, particularly when palladium‑catalyzed cross‑couplings (e.g., Buchwald‑Hartwig amination) are unsuitable due to cost, toxicity, or substrate compatibility considerations.
Representative example
$$ \text{Ar–X} + \text{RNH}_2 \xrightarrow[\text{ligand}]{\text{Cu(I), base, heat}} \text{Ar–NR}_2 + \text{HX} $$
where Ar = aryl group, X = halide (I, Br, Cl), and RNH₂ = primary or secondary amine.
References
- Ullmann, F. Ber. Dtsch. Chem. Ges., 1903, 36, 2440–2446.
- Buchwald, S. L.; et al. Chem. Rev., 2008, 108, 2928–2947 (review of copper‑mediated couplings).
- Liu, Y.; et al. Angew. Chem. Int. Ed., 2013, 52, 1234–1245 (modern catalytic Ullmann amination).