Sandmeyer reaction
The Sandmeyer reaction is a chemical reaction used to synthesize aryl halides from aryl diazonium salts using copper salts as reagents or catalysts.
It is an example of a radical-nucleophilic aromatic substitution. The Sandmeyer reaction provides a method through which one can perform unique transformations on benzene, such as halogenation, cyanation, trifluoromethylation, and hydroxylation.
The reaction was discovered in 1884 by Swiss chemist Traugott Sandmeyer, when he attempted to synthesize phenylacetylene from benzenediazonium chloride and copper acetylide. Instead, the main product he isolated was chlorobenzene. In modern times, the Sandmeyer reaction refers to any method for substitution of an aromatic amino group via preparation of its diazonium salt followed by its displacement with a nucleophile in the presence of catalytic copper salts.
The most commonly employed Sandmeyer reactions are the chlorination, bromination, cyanation, and hydroxylation reactions using CuCl, CuBr, CuCN, and Cu2O, respectively. More recently, trifluoromethylation of diazonium salts has been developed and is referred to as a 'Sandmeyer-type' reaction. Diazonium salts also react with boronates, iodide, thiols, water, hypophosphorous acid and others, and fluorination can be carried out using tetrafluoroborate anions. However, since these processes do not require a metal catalyst, they are not usually referred to as Sandmeyer reactions. In numerous variants that have been developed, other transition metal salts, including copper, iron and cobalt have also been employed. Due to its wide synthetic applicability, the Sandmeyer reaction, along with other transformations of diazonium compounds, is complementary to electrophilic aromatic substitution.
Reaction mechanism
The Sandmeyer reaction is an example of a radical-nucleophilic aromatic substitution. The radical mechanism of the Sandmeyer reaction is supported by the detection of biaryl byproducts. The substitution of the aromatic diazo group with a halogen or pseudohalogen is initiated by a one-electron transfer mechanism catalyzed by copper to form an aryl radical with loss of nitrogen gas. The substituted arene is possibly formed by direct transfer of Cl, Br, CN, or OH from a copper species to the aryl radical to produce the substituted arene and regenerate the copper catalyst. In an alternative proposal, a transient copper intermediate, formed from coupling of the aryl radical with the copper species, undergoes rapid reductive elimination to afford the product and regenerate copper. However, evidence for such an organocopper intermediate is weak and mostly circumstantial, and the exact pathway may depend on the substrate and reaction conditions.Single electron transfer
Synthetic applications
Variations on the Sandmeyer reaction have been developed to fit multiple synthetic applications. These reactions typically proceed through the formation of an aryl diazonium salt followed by a reaction with a copper salt to yield a substituted arene:There are many synthetic applications of the Sandmeyer reaction.
Halogenation
One of the most important uses of the Sandmeyer reaction is the formation of aryl halides. The solvent of choice for the synthesis of iodoarenes is diiodomethane, while for the synthesis of bromoarenes, bromoform is used. For the synthesis of chloroarenes, chloroform is the solvent of choice. The synthesis of -curcuphenol, a bioactive compound that displays antifungal and anticancer activity, employs the Sandmeyer reaction to substitute an amine group by a bromo group.One bromination protocol employs a Cu/Cu mixture with additional amounts of the bidentate ligand phenanthroline and phase-transfer catalyst dibenzo-18-crown-6 to convert an aryl diazonium tetrafluoroborate salt to an aryl bromide.
The Balz–Schiemann reaction uses tetrafluoroborate and delivers the halide-substituted product, fluorobenzene, which is not obtained by the use of copper fluorides. This reaction displays motifs characteristic of the Sandmeyer reaction.
Cyanation
Another use of the Sandmeyer reaction is for cyanation which allows for the formation of benzonitriles, an important class of organic compounds. A key intermediate in the synthesis of the antipsychotic drug Fluanxol is synthesized by a cyanation through the Sandmeyer reaction.The Sandmeyer reaction has also been employed in the synthesis of neoamphimedine, a compound that is suggested to target topoisomerase II as an anti-cancer drug.