Balz–Schiemann reaction

The Balz–Schiemann reaction (also called the Schiemann reaction) is a chemical reaction in which a primary aromatic amine is transformed to an aryl fluoride via a diazonium tetrafluoroborate intermediate. This reaction is a traditional route to fluorobenzene and some related derivatives, including 4-fluorobenzoic acid.

The reaction is conceptually similar to the Sandmeyer reaction, which converts diazonium salts to other aryl halides (ArCl, ArBr). However, while the Sandmeyer reaction involves a copper reagent/catalyst and radical intermediates, the thermal decomposition of the diazonium tetrafluoroborate proceeds without a promoter and is believed to generate highly unstable aryl cations (Ar⁺), which abstract F^− from BF₄^− to give the fluoroarene (ArF), along with boron trifluoride and nitrogen as the byproducts.

Innovations

The traditional Balz–Schiemann reaction employs HBF₄ and involves isolation of the diazonium salt. Both aspects can be profitably modified. Other counterions have been used in place of tetrafluoroborates, such as hexafluorophosphates (PF₆^−) and hexafluoroantimonates (SbF₆^−) with improved yields for some substrates. The diazotization reaction can be effected with nitrosonium salts such as [NO]SbF₆ without isolation of the diazonium intermediate.

As a practical matter, the traditional Balz–Schiemann reaction consumes relatively expensive BF₄^− as a source of fluoride. An alternative methodology produces the fluoride salt of the diazonium compound. In this implementation, the diazotization is conducted with a solution of sodium nitrite in liquid hydrogen fluoride:

History

The reaction is named after the German chemists and Günther Balz.

Examples

4-Fluorotoluene is made in ~89% yield by Balz–Schiemann reaction on p-toluidine. This is then used as a precursor for 4-fluorobenzaldehyde,

Balz–Schiemann reaction is used in the synthesis of DOF & 2C-F. The starting material for the first step in the synthesis is called 2,5-dimethoxyaniline [102-56-7].

The Balz–Schiemann reaction is used in the synthesis of Fipamezole from Atipamezole.

Additional literature

References