The reaction was discovered in 1884 by Swiss chemist Traugott Sandmeyer, when he attempted to synthesize phenylacetylene from benzenediazonium chloride and copper(I) acetylide. Instead, the main product he isolated was chlorobenzene.[5] 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(I) 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,[6] and fluorination can be carried out using tetrafluoroborate anions (Balz–Schiemann reaction). 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(II), iron(III) and cobalt(III) have also been employed.[7] 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 (SRNAr). The radical mechanism of the Sandmeyer reaction is supported by the detection of biaryl byproducts.[8] 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.[9][10][11][8] The substituted arene is possibly formed by direct transfer of Cl, Br, CN, or OH from a copper(II) species to the aryl radical to produce the substituted arene and regenerate the copper(I) catalyst. In an alternative proposal, a transient copper(III) intermediate, formed from coupling of the aryl radical with the copper(II) species, undergoes rapid reductive elimination to afford the product and regenerate copper(I).[12][13][14] However, evidence for such an organocopper intermediate is weak and mostly circumstantial,[15][16] 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(I) 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,[17][18] while for the synthesis of bromoarenes, bromoform is used. For the synthesis of chloroarenes, chloroform is the solvent of choice.[19] 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.[20]
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.[23]
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.[24]
Trifluoromethylation
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.[25][26] An example of a Sandmeyer-type trifluoromethylation reaction is presented below.[27]
Hydroxylation
The Sandmeyer reaction can also be used to convert aryl amines to phenols proceeding through the formation of an aryl diazonium salt. In the presence of copper catalyst, such as copper(I) oxide, and an excess of copper(II) nitrate, this reaction takes place readily at room temperature neutral water.[28] This is in contrast to the classical procedure (known by the German name Verkochung[de]), which calls for boiling the diazonium salt in aqueous acid, a process that is believed to involve the aryl cation instead of radical and is known to generate other nucleophilic addition side products in addition to the desired hydroxylation product.
M. P. Doyle, B. Siegfried and J. F. Dellaria (1977). "Alkyl nitrite-metal halide deamination reactions. 2. Substitutive deamination of arylamines by alkyl nitrites and copper(II) halides. A direct and remarkably efficient conversion of arylamines to aryl halides". J. Org. Chem.42 (14): 2426–2431. doi:10.1021/jo00434a017.
Galli, Carlo (August 1988). "Radical reactions of arenediazonium ions: An easy entry into the chemistry of the aryl radical". Chemical Reviews. 88 (5): 765–792. doi:10.1021/cr00087a004.
Nonhebel, D. C.; Waters, W. A. (8 October 1957). "A Study of the Mechanism of the Sandmeyer Reaction". Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences. 242 (1228): 16–27. Bibcode:1957RSPSA.242...16N. doi:10.1098/rspa.1957.0150. S2CID97536209.
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Timms, Allan W.; Walton, Paul H.; Rowell, Simon C.; Hanson, Peter (2004-06-28). "Promotion of Sandmeyer hydroxylation (homolytic hydroxydediazoniation) and hydrodediazoniation by chelation of the copper catalyst: bidentate ligands". Organic & Biomolecular Chemistry. 2 (13): 1838–1855. doi:10.1039/B404699D. ISSN1477-0539. PMID15227536.
Timms, Allan W.; Walton, Paul H.; Taylor, Alec B.; Rowell, Simon C.; Hanson, Peter (2002-05-22). "Sandmeyer reactions. Part 6. A mechanistic investigation into the reduction and ligand transfer steps of Sandmeyer cyanation". Journal of the Chemical Society, Perkin Transactions 2 (6): 1126–1134. doi:10.1039/B200747A. ISSN1364-5471.
W. B. Smith; O. C. Ho (1990). "Application of the isoamyl nitrite-diiodomethane route to aryl iodides". J. Org. Chem. 55 (8): 2543–2545. doi:10.1021/jo00295a056.
V. Nair; S. G. Richardson (1982). "Modification of Nucleic Acid Bases via Radical Intermediates: Synthesis of Dihalogenated Purine Nucleosides". Synthesis. 1982 (8): 670–672. doi:10.1055/s-1982-29896.
Kim, Sung-Gon; Kim, Jaehak; Jung, Heejung (April 2005). "Efficient total synthesis of (+)-curcuphenol via asymmetric organocatalysis". Tetrahedron Letters. 46 (14): 2437–2439. doi:10.1016/j.tetlet.2005.02.047.
P. Beletskaya; Alexander S. Sigeev; Alexander S. Peregudov; Pavel V. Petrovskii (2007). "Catalytic Sandmeyer Bromination". Synthesis. 2007 (16): 2534–2538. doi:10.1055/s-2007-983784.
Nielsen, Martin Anker; Nielsen, Michael Kim; Pittelkow, Thomas (November 2004). "Scale-Up and Safety Evaluation of a Sandmeyer Reaction". Organic Process Research & Development. 8 (6): 1059–1064. doi:10.1021/op0498823.
Browne, Duncan L. (3 February 2014). "The Trifluoromethylating Sandmeyer Reaction: A Method for Transforming C–N into C–CF". Angewandte Chemie International Edition. 53 (6): 1482–1484. doi:10.1002/anie.201308997. PMID24376150.
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