Sandmeyer reaction

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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 using copper salts as reagents or catalysts. [1] [2] [3] [4] 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.

Contents

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.

Sandmeyer.jpg

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

Sandmeyerbromination.png

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:

Sandmeyer Reactions.svg

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]

Bromination using Sandmeyer.png

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. [21]

Bf4sm.png

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. [22]

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. [23]

CyanationSandmeyer.png

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]

Cyanation using the Sandmeyer reaction.png

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]

Trifluoromethylation using Sandmeyer.png

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.

Hydroxylation using Sandmeyer reaction.png

Related Research Articles

In organic chemistry, an aryl halide is an aromatic compound in which one or more hydrogen atoms, directly bonded to an aromatic ring are replaced by a halide. Haloarenes are different from haloalkanes because they exhibit many differences in methods of preparation and properties. The most important members are the aryl chlorides, but the class of compounds is so broad that there are many derivatives and applications.

The Suzuki reaction or Suzuki coupling is an organic reaction that uses a palladium complex catalyst to cross-couple a boronic acid to an organohalide. It was first published in 1979 by Akira Suzuki, and he shared the 2010 Nobel Prize in Chemistry with Richard F. Heck and Ei-ichi Negishi for their contribution to the discovery and development of noble metal catalysis in organic synthesis. This reaction is sometimes telescoped with the related Miyaura borylation; the combination is the Suzuki–Miyaura reaction. It is widely used to synthesize polyolefins, styrenes, and substituted biphenyls.

The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or vinyl halide.

The Hiyama coupling is a palladium-catalyzed cross-coupling reaction of organosilanes with organic halides used in organic chemistry to form carbon–carbon bonds. This reaction was discovered in 1988 by Tamejiro Hiyama and Yasuo Hatanaka as a method to form carbon-carbon bonds synthetically with chemo- and regioselectivity. The Hiyama coupling has been applied to the synthesis of various natural products.

The Ullmann reaction or Ullmann coupling, named after Fritz Ullmann, couples two aryl or alkyl groups with the help of copper. The reaction was first reported by Ullmann and his student Bielecki in 1901. It has been later shown that palladium and nickel can also be effectively used.

The Ullmann condensation or Ullmann-type reaction is the copper-promoted conversion of aryl halides to aryl ethers, aryl thioethers, aryl nitriles, and aryl amines. These reactions are examples of cross-coupling reactions.

<span class="mw-page-title-main">Nucleophilic aromatic substitution</span> Chemical reaction mechanism

A nucleophilic aromatic substitution (SNAr) is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. Aromatic rings are usually nucleophilic, but some aromatic compounds do undergo nucleophilic substitution. Just as normally nucleophilic alkenes can be made to undergo conjugate substitution if they carry electron-withdrawing substituents, so normally nucleophilic aromatic rings also become electrophilic if they have the right substituents.

<span class="mw-page-title-main">Diazonium compound</span> Group of organonitrogen compounds

Diazonium compounds or diazonium salts are a group of organic compounds sharing a common functional group [R−N+≡N]X− where R can be any organic group, such as an alkyl or an aryl, and X is an inorganic or organic anion, such as a halide. The parent compound where R is hydrogen, is diazenylium.

<span class="mw-page-title-main">Isatin</span> Chemical compound

Isatin, also known as tribulin, is an organic compound derived from indole with formula C8H5NO2. The compound was first obtained by Otto Linné Erdman and Auguste Laurent in 1840 as a product from the oxidation of indigo dye by nitric acid and chromic acids.

<span class="mw-page-title-main">Tetrafluoroborate</span> Anion

Tetrafluoroborate is the anion BF−
4. This tetrahedral species is isoelectronic with tetrafluoroberyllate (BeF2−
4), tetrafluoromethane (CF4), and tetrafluoroammonium (NF+
4) and is valence isoelectronic with many stable and important species including the perchlorate anion, ClO−
4, which is used in similar ways in the laboratory. It arises by the reaction of fluoride salts with the Lewis acid BF3, treatment of tetrafluoroboric acid with base, or by treatment of boric acid with hydrofluoric acid.

<span class="mw-page-title-main">Finkelstein reaction</span> Chemistry

The Finkelstein reaction, named after the German chemist Hans Finkelstein, is a type of SN2 reaction that involves the exchange of one halogen atom for another. It is an equilibrium reaction, but the reaction can be driven to completion by exploiting the differential solubility of various halide salts, or by using a large excess of the desired halide.

<span class="mw-page-title-main">Organocopper chemistry</span> Compound with carbon to copper bonds

Organocopper chemistry is the study of the physical properties, reactions, and synthesis of organocopper compounds, which are organometallic compounds containing a carbon to copper chemical bond. They are reagents in organic chemistry.

The Balz–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 Gomberg–Bachmann reaction, named for the Russian-American chemist Moses Gomberg and the American chemist Werner Emmanuel Bachmann, is an aryl-aryl coupling reaction via a diazonium salt.

<span class="mw-page-title-main">Meerwein arylation</span> Organic reaction

The Meerwein arylation is an organic reaction involving the addition of an aryl diazonium salt (ArN2X) to an electron-poor alkene usually supported by a metal salt. The reaction product is an alkylated arene compound. The reaction is named after Hans Meerwein, one of its inventors who first published it in 1939.

In organic synthesis, cyanation is the attachment or substitution of a cyanide group on various substrates. Such transformations are high-value because they generate C-C bonds. Furthermore nitriles are versatile functional groups.

Metal carbon dioxide complexes are coordination complexes that contain carbon dioxide ligands. Aside from the fundamental interest in the coordination chemistry of simple molecules, studies in this field are motivated by the possibility that transition metals might catalyze useful transformations of CO2. This research is relevant both to organic synthesis and to the production of "solar fuels" that would avoid the use of petroleum-based fuels.

Trifluoromethylation in organic chemistry describes any organic reaction that introduces a trifluoromethyl group in an organic compound. Trifluoromethylated compounds are of some importance in pharmaceutical industry and agrochemicals. Several notable pharmaceutical compounds have a trifluoromethyl group incorporated: fluoxetine, mefloquine, Leflunomide, nulitamide, dutasteride, bicalutamide, aprepitant, celecoxib, fipronil, fluazinam, penthiopyrad, picoxystrobin, fluridone, norflurazon, sorafenib and triflurazin. A relevant agrochemical is trifluralin. The development of synthetic methods for adding trifluoromethyl groups to chemical compounds is actively pursued in academic research.

Decarboxylative cross coupling reactions are chemical reactions in which a carboxylic acid is reacted with an organic halide to form a new carbon-carbon bond, concomitant with loss of CO2. Aryl and alkyl halides participate. Metal catalyst, base, and oxidant are required.

<span class="mw-page-title-main">Organic thiocyanates</span>

Organic thiocyanates are organic compounds containing the functional group RSCN. the organic group is attached to sulfur: R−S−C≡N has a S–C single bond and a C≡N triple bond.

References

  1. ↑ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, pp. 984–985, ISBN   978-0-471-72091-1
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ Ludwig Gattermann (1890). "Untersuchungen über Diazoverbindungen". Berichte der Deutschen Chemischen Gesellschaft. 23 (1): 1218–1228. doi:10.1002/cber.189002301199.
  5. ↑ Hodgson, Herbert H. (1947-04-01). "The Sandmeyer Reaction". Chemical Reviews. 40 (2): 251–277. doi:10.1021/cr60126a003. ISSN   0009-2665. PMID   20291034.
  6. ↑ Wang, Zerong (2010). "Sandmeyer Reaction". Comprehensive Organic Name Reactions and Reagents. John Wiley & Sons, Inc. pp. 2471–2475. ISBN   9780470638859.
  7. ↑ 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.
  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. ↑ J. K. Kochi (1957). "The Mechanism of the Sandmeyer and Meerwein Reactions". J. Am. Chem. Soc. 79 (11): 2942–2948. doi:10.1021/ja01568a066.
  10. ↑ H. H. Hodgson (1947). "The Sandmeyer Reaction". Chem. Rev. 40 (2): 251–277. doi:10.1021/cr60126a003. PMID   20291034.
  11. ↑ 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. S2CID   97536209.
  12. ↑ Anslyn, Eric V. (2006). Modern physical organic chemistry. Dougherty, Dennis A., 1952-. Sausalito, CA: University Science. ISBN   978-1891389313. OCLC   55600610.
  13. ↑ C., Vollhardt, K. Peter (2018-01-29). Organic chemistry : structure and function. Schore, Neil Eric, 1948- (8e ed.). New York. ISBN   9781319079451. OCLC   1007924903.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: multiple names: authors list (link)
  14. ↑ Carey, Francis A. (2007). Advanced organic chemistry. Part B, Reactions and synthesis. Sundberg, Richard J., 1938- (5th ed.). New York, NY: Springer. ISBN   9781601195494. OCLC   223941000.
  15. ↑ 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. ISSN   1477-0539. PMID   15227536.
  16. ↑ 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. ISSN   1364-5471.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ Wang, Zerong (2009). Comprehensive organic name reactions and reagents. Hoboken, N.J.: John Wiley. pp. 185–190. ISBN   9780471704508.
  23. ↑ 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.
  24. ↑ 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 . PMID   17900144.
  25. ↑ 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. PMID   24376150.
  26. ↑ 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. PMID   23718557.
  27. ↑ 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. PMID   23832858.
  28. ↑ Cohen, Theodore; Dietz, Albert G.; Miser, Jane R. (1977-06-01). "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. ISSN   0022-3263.
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