Sandmeyer reaction

Sandmeyer reaction
Named after Traugott Sandmeyer
Reaction type Substitution reaction
Identifiers
Organic Chemistry Portal sandmeyer-reaction
RSC ontology ID RXNO:0000021

The Sandmeyer reaction is a chemical reaction used to synthesize aryl halides from aryl diazonium salts.[1][2][3] 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.[4] The reaction does not proceed well with the fluoride anion, but fluorination can be carried out using tetrafluoroborate anions (Balz–Schiemann reaction).

Reaction mechanism

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.[4] 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.[5][6][7][8] 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.[8] It proceeds through the following mechanism.

Formation of the nitrosonium ion

Formation of the benzenediazonium ion

Sandmeyer reaction

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.[9]

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 according to the scheme below.

Some examples of the synthetic applications of the Sandmeyer reaction are provided below.

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 aryl iodides is diiodomethane,[10][11] while for the synthesis of aryl bromides, bromoform is used. For the synthesis of aryl chlorides, chloroform is the solvent of choice.[12] 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.[13]

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.[14]

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.[15]

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 anti-psychotic drug, Fluanxol, is synthesized by a cyanation through the Sandmeyer reaction.[16]

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.[17]

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.[18][19] An example of a Sandmeyer-type trifluoromethylation reaction is presented below.[20]

Hydroxylation

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.[21] According to the Germans, this is called Verkochung.

Due to its wide synthetic applicability, the Sandmeyer reaction is complementary to electrophilic aromatic substitution.

References

  1. ↑ Traugott Sandmeyer (1884). "Ueber die Ersetzung der Amidgruppe durch Chlor in den aromatischen Substanzen". Berichte der deutschen chemischen Gesellschaft. 17 (3): 1633–1635. doi:10.1002/cber.18840170219.
  2. ↑ Traugott Sandmeyer (1884). "Ueber die Ersetzung der Amid-gruppe durch Chlor, Brom und Cyan in den aromatischen Substanzen". Berichte der deutschen chemischen Gesellschaft. 17 (4): 2650–2653. doi:10.1002/cber.188401702202.
  3. ↑ Ludwig Gattermann (1890). "Untersuchungen über Diazoverbindungen". Berichte der deutschen chemischen Gesellschaft. 23 (1): 1218–1228. doi:10.1002/cber.189002301199.
  4. 1 2 Wang, Zerong (2010). "Sandmeyer Reaction". Comprehensive Organic Name Reactions and Reagents. John Wiley & Sons, Inc. pp. 2471–2475. ISBN 9780470638859.
  5. ↑ J. K. Kochi (1957). "The Mechanism of the Sandmeyer and Meerwein Reactions". J. Am. Chem. Soc. 79 (11): 2942–2948. doi:10.1021/ja01568a066.
  6. ↑ H. H. Hodgson (1947). "The Sandmeyer Reaction". Chem. Rev. 40 (2): 251–277. doi:10.1021/cr60126a003.
  7. ↑ 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.
  8. 1 2 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ V. Nair; S. G. Richardson (1982). "Modification of Nucleic Acid Bases via Radical Intermediates: Synthesis of Dihalogenated Purine Nucleosides". Synthesis. 1982: 670–672. doi:10.1055/s-1982-29896.
  12. ↑ J. I. G. Cadogan; D. A. Roy; D. M. Smith (1966). "An alternative to the Sandmeyer reaction". J. Chem. Soc.: 1249–1250. doi:10.1039/J39660001249.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Wang, Zerong (2009). Comprehensive organic name reactions and reagents. Hoboken, N.J.: John Wiley. pp. 185–190. ISBN 9780471704508.
  16. ↑ 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.
  17. ↑ LaBarbera, Daniel V.; Bugni, Tim S.; Ireland, Chris M. (October 2007). "The Total Synthesis of Neoamphimedine". The Journal of Organic Chemistry. 72 (22): 8501–8505. doi:10.1021/jo7017813. PMC 2547140.
  18. ↑ 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.
  19. ↑ Dai, Jian-Jun; Fang, Chi; Xiao, Bin; Yi, Jun; Xu, Jun; Liu, Zhao-Jing; Lu, Xi; Liu, Lei; Fu, Yao (12 June 2013). "Copper-Promoted Sandmeyer Trifluoromethylation Reaction". Journal of the American Chemical Society. 135 (23): 8436–8439. doi:10.1021/ja404217t.
  20. ↑ Danoun, Grégory; Bayarmagnai, Bilguun; Grünberg, Matthias F.; Gooßen, Lukas J. (29 July 2013). "Sandmeyer Trifluoromethylation of Arenediazonium Tetrafluoroborates". Angewandte Chemie International Edition. 52 (31): 7972–7975. doi:10.1002/anie.201304276.
  21. ↑ Cohen, Theodore; Dietz, Albert G.; Miser, Jane R. (June 1977). "A simple preparation of phenols from diazonium ions via the generation and oxidation of aryl radicals by copper salts". The Journal of Organic Chemistry. 42 (12): 2053–2058. doi:10.1021/jo00432a003.
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