|Named after||Traugott Sandmeyer|
|Reaction type||Substitution reaction|
|Organic Chemistry Portal|
|RSC ontology ID|
The Sandmeyer reaction is a chemical reaction used to synthesize aryl halides from aryl diazonium salts. 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 synthesized phenylacetylene from benzenediazonium chloride and cuprous acetylide. The reaction is a method for substitution of an aromatic amino group via preparation of its diazonium salt followed by its displacement with a nucleophile, often catalyzed by copper(I) salts. The nucleophile can include halide anions, cyanide, thiols, water, and others. The reaction does not proceed well with the fluoride anion, but fluorination can be carried out using tetrafluoroborate anions (Balz–Schiemann reaction).
The nitrous acid is typically prepared in situ from sodium nitrite and acid. Following two protonation steps, one equivalent of water is lost to form the nitrosonium ion. The nitrosonium ion then acts as an electrophile in a reaction with an aromatic (or heterocyclic) amine, such as aniline, to form a diazonium salt, proceeding through a nitrosamine intermediate. The substitution of the aromatic diazo group with a halogen or pseudohalogen is initiated by a one-electron transfer mechanism catalyzed by copper(I) to form an aryl radical with loss of nitrogen gas. The substituted arene is formed through a radical mechanism with regeneration of the copper(I) catalyst. This reaction is known as the Sandmeyer reaction and is an example of a radical-nucleophilic aromatic substitution. The radical mechanism of the Sandmeyer reaction was resolved through the detection of biaryl byproducts. It proceeds through the following mechanism.
Formation of the nitrosonium ion
Formation of the benzenediazonium ion
Several improvements have been made to the standard procedures to improve reaction yield such as the utilization of copper(II), iron(III), cobalt(III), or zinc(II) salts.
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(I) salt to yield a substituted arene according to the scheme below.
Some examples of the synthetic applications of the Sandmeyer reaction are provided below.
One of the most important uses of the Sandmeyer reaction is the formation of aryl halides. The solvent of choice for the synthesis of aryl iodides is diiodomethane, while for the synthesis of aryl bromides, bromoform is used. For the synthesis of aryl chlorides, 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(I)/Cu(II) 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.
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 anti-psychotic drug, Fluanxol, is synthesized by a cyanation through the Sandmeyer reaction.
It has been demonstrated that Sandmeyer-type reactions can be used to generate aryl compounds functionalized by trifluoromethyl substituent groups. This process of trifluoromethylation provides unique chemical properties with a wide variety of practical applications. Particularly, pharmaceuticals with CF3 groups have enhanced metabolic stability, lipophilicity, and bioavailability. Sandmeyer-type trifluoromethylation reactions feature mild reaction conditions and greater functional group tolerance relative to earlier methods of trifluoromethylation. An example of a Sandmeyer-type trifluoromethylation reaction is presented below.
The Sandmeyer reaction can also be used to convert aryl amines to phenols proceeding through the formation of an aryl diazonium salt as shown below. According to the Germans, this is called Verkochung.
Due to its wide synthetic applicability, the Sandmeyer reaction is complementary to electrophilic aromatic substitution.
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