Sandmeyer reaction
{{Short description|Chemical reaction used to synthesize aryl halides from aryl diazonium salts}}
{{Reactionbox
| Name = Sandmeyer reaction
| Type = Substitution reaction
| NamedAfter = Traugott Sandmeyer
| Section3 = {{Reactionbox Identifiers
| OrganicChemistryNamed = sandmeyer-reaction
| RSC_ontology_id = 0000021
}}
}}
The Sandmeyer reaction is a chemical reaction used to synthesize aryl halides from aryl diazonium salts using copper salts as reagents or catalysts.{{March6th|pages=984–985}}{{cite journal | author = Traugott Sandmeyer | author-link = Traugott Sandmeyer | title = Ueber die Ersetzung der Amidgruppe durch Chlor in den aromatischen Substanzen | year = 1884 | journal = Berichte der deutschen chemischen Gesellschaft | volume = 17 | issue = 3 | pages = 1633–1635 | doi = 10.1002/cber.18840170219 | url = http://gallica.bnf.fr/ark:/12148/bpt6k90700r/f56.chemindefer}}
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(I) acetylide. Instead, the main product he isolated was chlorobenzene.{{Cite journal|last=Hodgson|first=Herbert H.|date=1947-04-01|title=The Sandmeyer Reaction|journal=Chemical Reviews|volume=40|issue=2|pages=251–277|doi=10.1021/cr60126a003|pmid=20291034|issn=0009-2665}} 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,{{cite book|last1=Wang|first1=Zerong|title=Comprehensive Organic Name Reactions and Reagents|date=2010|publisher=John Wiley & Sons, Inc.|isbn=9780470638859|pages=2471–2475|language=en|chapter=Sandmeyer Reaction}} 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.{{cite journal|author=M. P. Doyle, B. Siegfried and J. F. Dellaria|year=1977|title=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|journal=J. Org. Chem.|volume=42|issue=14|pages=2426–2431|doi=10.1021/jo00434a017}} 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. 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.{{cite journal | author = J. K. Kochi | title = The Mechanism of the Sandmeyer and Meerwein Reactions | year = 1957 | journal = J. Am. Chem. Soc. | volume = 79 | issue = 11 | pages = 2942–2948 | doi = 10.1021/ja01568a066}}{{cite journal | author = H. H. Hodgson | title = The Sandmeyer Reaction | year = 1947 | journal = Chem. Rev. | volume = 40 | issue = 2 | pages = 251–277 | doi = 10.1021/cr60126a003| pmid = 20291034 }}{{cite journal|last1=Nonhebel|first1=D. C.|last2=Waters|first2=W. A.|title=A Study of the Mechanism of the Sandmeyer Reaction|journal=Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences|date=8 October 1957|volume=242|issue=1228|pages=16–27|doi=10.1098/rspa.1957.0150|bibcode=1957RSPSA.242...16N|s2cid=97536209}}{{cite journal|last1=Galli|first1=Carlo|title=Radical reactions of arenediazonium ions: An easy entry into the chemistry of the aryl radical|journal=Chemical Reviews|date=August 1988|volume=88|issue=5|pages=765–792|doi=10.1021/cr00087a004}} 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).{{Cite book|title=Modern physical organic chemistry|author=Anslyn, Eric V.|date=2006|publisher=University Science|others=Dougherty, Dennis A., 1952-|isbn=978-1891389313|location=Sausalito, CA|oclc=55600610}}{{Cite book|title=Organic chemistry : structure and function|last=C.|first=Vollhardt, K. Peter|others=Schore, Neil Eric, 1948-|isbn=9781319079451|edition= 8e|location=New York|oclc=1007924903|date = 2018-01-29}}{{Cite book|title=Advanced organic chemistry. Part B, Reactions and synthesis|author=Carey, Francis A.|date=2007|publisher=Springer|others=Sundberg, Richard J., 1938-|isbn=9781601195494|edition= 5th|location=New York, NY|oclc=223941000}} However, evidence for such an organocopper intermediate is weak and mostly circumstantial,{{Cite journal|last1=Timms|first1=Allan W.|last2=Walton|first2=Paul H.|last3=Rowell|first3=Simon C.|last4=Hanson|first4=Peter|date=2004-06-28|title=Promotion of Sandmeyer hydroxylation (homolytic hydroxydediazoniation) and hydrodediazoniation by chelation of the copper catalyst: bidentate ligands|journal=Organic & Biomolecular Chemistry|language=en|volume=2|issue=13|pages=1838–1855|doi=10.1039/B404699D|pmid=15227536|issn=1477-0539}}{{Cite journal|last1=Timms|first1=Allan W.|last2=Walton|first2=Paul H.|last3=Taylor|first3=Alec B.|last4=Rowell|first4=Simon C.|last5=Hanson|first5=Peter|date=2002-05-22|title=Sandmeyer reactions. Part 6. A mechanistic investigation into the reduction and ligand transfer steps of Sandmeyer cyanation|journal=Journal of the Chemical Society, Perkin Transactions 2|language=en|issue=6|pages=1126–1134|doi=10.1039/B200747A|issn=1364-5471}} 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,{{cite journal | author1 = W. B. Smith | author2 = O. C. Ho | journal = J. Org. Chem. | year = 1990 | volume = 55 | pages = 2543–2545 | doi = 10.1021/jo00295a056 | title = Application of the isoamyl nitrite-diiodomethane route to aryl iodides | issue = 8}}{{cite journal | author1 = V. Nair | author2 = S. G. Richardson | journal = Synthesis | year = 1982 | pages = 670–672 | doi = 10.1055/s-1982-29896 | volume=1982 | issue = 8 | title=Modification of Nucleic Acid Bases via Radical Intermediates: Synthesis of Dihalogenated Purine Nucleosides}} while for the synthesis of bromoarenes, bromoform is used. For the synthesis of chloroarenes, chloroform is the solvent of choice.{{cite journal | author1 = J. I. G. Cadogan | author2 = D. A. Roy | author3 = D. M. Smith | journal = J. Chem. Soc. | year = 1966 | pages = 1249–1250 | doi = 10.1039/J39660001249 | title = An alternative to the Sandmeyer reaction}} 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.{{cite journal|last1=Kim|first1=Sung-Gon|last2=Kim|first2=Jaehak|last3=Jung|first3=Heejung|title=Efficient total synthesis of (+)-curcuphenol via asymmetric organocatalysis|journal=Tetrahedron Letters|date=April 2005|volume=46|issue=14|pages=2437–2439|doi=10.1016/j.tetlet.2005.02.047}}
File: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.{{cite journal | title = Catalytic Sandmeyer Bromination |author1=P. Beletskaya |author2=Alexander S. Sigeev |author3=Alexander S. Peregudov |author4=Pavel V. Petrovskii | journal = Synthesis | year = 2007 | volume = 2007 | pages = 2534–2538 | doi = 10.1055/s-2007-983784 | issue = 16}}
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.{{cite book|last1=Wang|first1=Zerong|title=Comprehensive organic name reactions and reagents|date=2009|publisher=John Wiley|location=Hoboken, N.J.|isbn=9780471704508|pages=185–190}}
=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.{{cite journal|last1=Nielsen|first1=Martin Anker|last2=Nielsen|first2=Michael Kim|last3=Pittelkow|first3=Thomas|title=Scale-Up and Safety Evaluation of a Sandmeyer Reaction|journal=Organic Process Research & Development|date=November 2004|volume=8|issue=6|pages=1059–1064|doi=10.1021/op0498823}}
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.{{cite journal|last1=LaBarbera|first1=Daniel V.|last2=Bugni|first2=Tim S.|last3=Ireland|first3=Chris M.|title=The Total Synthesis of Neoamphimedine|journal=The Journal of Organic Chemistry|date=October 2007|volume=72|issue=22|pages=8501–8505|doi=10.1021/jo7017813|pmid=17900144|pmc=2547140}}
=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.{{cite journal|last1=Browne|first1=Duncan L.|title=The Trifluoromethylating Sandmeyer Reaction: A Method for Transforming C–N into C–CF|journal=Angewandte Chemie International Edition|date=3 February 2014|volume=53|issue=6|pages=1482–1484|doi=10.1002/anie.201308997|pmid=24376150}}{{cite journal|last1=Dai|first1=Jian-Jun|last2=Fang|first2=Chi|last3=Xiao|first3=Bin|last4=Yi|first4=Jun|last5=Xu|first5=Jun|last6=Liu|first6=Zhao-Jing|last7=Lu|first7=Xi|last8=Liu|first8=Lei|last9=Fu|first9=Yao|title=Copper-Promoted Sandmeyer Trifluoromethylation Reaction|journal=Journal of the American Chemical Society|date=12 June 2013|volume=135|issue=23|pages=8436–8439|doi=10.1021/ja404217t|pmid=23718557}} An example of a Sandmeyer-type trifluoromethylation reaction is presented below.{{cite journal|last1=Danoun|first1=Grégory|last2=Bayarmagnai|first2=Bilguun|last3=Grünberg|first3=Matthias F.|last4=Gooßen|first4=Lukas J.|title=Sandmeyer Trifluoromethylation of Arenediazonium Tetrafluoroborates|journal=Angewandte Chemie International Edition|date=29 July 2013|volume=52|issue=31|pages=7972–7975|doi=10.1002/anie.201304276|pmid=23832858}}
=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.{{Cite journal|last1=Cohen|first1=Theodore|author-link1=Theodore Cohen (chemist)|last2=Dietz|first2=Albert G.|last3=Miser|first3=Jane R.|date=1977-06-01|title=A simple preparation of phenols from diazonium ions via the generation and oxidation of aryl radicals by copper salts|journal=The Journal of Organic Chemistry|volume=42|issue=12|pages=2053–2058|doi=10.1021/jo00432a003|issn=0022-3263}} This is in contrast to the classical procedure (known by the German name {{ill|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.
References
{{Reflist}}
External links
- http://www.name-reaction.com/sandmeyer-reaction
{{DEFAULTSORT:Sandmeyer Reaction}}