The Eschenmoser fragmentation, first published in 1967, is the

chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and break ...

of α,β-epoxy

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...

s (1) with

aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used as ...

sulfonylhydrazines (2) to give

alkyne \ce \ce Acetylene \ce \ce \ce Propyne \ce \ce \ce \ce 1-Butyne In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and no ...

s (3) and

carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containin ...

compounds (4). The reaction is named after the Swiss chemist

Albert Eschenmoser Albert Jakob Eschenmoser (born 5 August 1925) is a Swiss organic chemist, best known for his work on the synthesis of complex heterocyclic natural compounds, most notably vitamin B12. In addition to his significant contributions to the field of ...

, who devised it in collaboration with an industrial research group of Günther Ohloff, and applied it to the production of

muscone Muscone is an organic compound that is the primary contributor to the odor of musk. The chemical structure of muscone was first elucidated by Leopold Ružička. It consists of a 15-membered ring ketone with one methyl substituent in the 3-positi ...

and related

macrocyclic Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry. ...

musk Musk ( Persian: مشک, ''Mushk'') is a class of aromatic substances commonly used as base notes in perfumery. They include glandular secretions from animals such as the musk deer, numerous plants emitting similar fragrances, and artificial s ...

s. The reaction is also sometimes known as the Eschenmoser–Ohloff fragmentation or the Eschenmoser–Tanabe fragmentation as

Masato Tanabe Masato "Mas" Tanabe was a drug researcher at SRI International, where he spent 45 years studying steroid hormones, which are instrumental in combatting breast cancer and prostate cancer. Education Tanabe graduated from the University of San F ...

independently published an article on the reaction the same year. The general formula of the fragmentation using ''p''-toluenesulfonylhydrazide is: :: Eschemoser Fragmentation Scheme

Several examples exist in the literature, and the reaction is also carried out on industrial scale.

Reaction mechanism

The mechanism of the Eschenmoser fragmentation begins with the condensation of an α,β-epoxyketone (1) with an aryl sulfonylhydrazine (2) to afford the intermediate

hydrazone Hydrazones are a class of organic compounds with the structure . They are related to ketones and aldehydes by the replacement of the oxygen =O with the = functional group. They are formed usually by the action of hydrazine on ketones or aldehydes. ...

(3). This hydrazone can either be protonated at the epoxide oxygen or deprotonated at the sulfonamide nitrogen to initiate the fragmentation, and thus the fragmentation is catalyzed by acids or bases. Most common reaction conditions, however, are treatment with

acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main componen ...

dichloromethane Dichloromethane (DCM or methylene chloride, methylene bichloride) is an organochlorine compound with the formula . This colorless, volatile liquid with a chloroform-like, sweet odour is widely used as a solvent. Although it is not miscible wit ...

. The proton transfer leads to intermediate (4), which undergoes the key fragmentation to alkyne (6) and the corresponding carbonyl compound (7). The driving force for the reaction is the formation of highly stable molecular

nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at seve ...

. There is a

radical Radical may refer to: Politics and ideology Politics * Radical politics, the political intent of fundamental societal change *Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe an ...

variant of this α,β-enone to alkynone fragmentation in which no epoxide is required.

1,3-Dibromo-5,5-dimethylhydantoin DBDMH (also known as 1,3-Dibromo-5,5-Dimethylhydantoin) is an organic compound derived from the heterocycle called dimethylhydantoin. This white crystalline compound with a slight bromine odor is widely used as a disinfectant used for drinking w ...

(DBDMH) in ''sec''-butanol with the appropriate ''p''-tolylhydrazone has been used to prepare exaltone (cyclopentadecanone) and

(the 3-methyl

structural analog A structural analog (analogue in modern traditional English; Commonwealth English), also known as a chemical analog or simply an analog, is a compound having a structure similar to that of another compound, but differing from it in respect to a ...

). The α,β-unsaturated hydrazone is brominated by DBDMH in the allylic position (relative to the sulfonamide nitrogen), leading to a captodatively stabilized radical, and the bromide ion becomes the

leaving group In chemistry, a leaving group is defined by the IUPAC as an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction. However, in common usage, the term is often limited ...

in the subsequent nucleophilic attack by an alcoholate ion. This Fehr–Ohloff–Büchi variant of the Eschenmoser–Ohloff fragramentation in which an

epoxidation In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scal ...

step is avoided is suited to sterically-demanding substrates where low yields typically result from classical Eschenmoser fragmentation. A closely related fragmentation has been reported, employing diazirine derivatives of cyclic α,β-epoxyketones.

References

{{reflist, refs= {{cite journal, title = Novel ring fragmentation products via diazirines and its conversion to a-nor steroids, first1 = Paul, last1 = Borrevang, first2 = Jorgen, last2 = Hüort, first3 = Richard T., last3 = Rapala, first4 = Ronnie, last4 = Edie, journal = Tetrahedron Lett., volume = 9, issue = 47, year = 1968, pages = 4905–4907, doi = 10.1016/S0040-4039(00)72789-4 {{cite journal, year = 1979, title = A New α,β-Enone → Alkynone Fragmentation. Syntheses of exaltone and (±)-muscone, journal = Helv. Chim. Acta, volume = 62, issue = 8, pages = 2655–2660, doi = 10.1002/hlca.19790620815, first1 = Charles, last1 = Fehr, first2 = Günther, last2 = Ohloff, authorlink2 = Günther Ohloff, first3 = George, last3 = Büchi, authorlink3 = George Büchi {{OrgSynth, title = Fragmentation of α-β-Epoxyketones to Acetylenic Aldehydes and Ketones: Preparation of 2,3-Epoxycyclohexanone and its fragmentation to 5-Hexynal, first1 = Dorothee, last1 = Felix, first2 = Claude, last2 = Wintner, first3 = Albert, last3 = Eschenmoser, authorlink3 = Albert Eschenmoser, collvol = 6, collvolpages = 679, year = 1976, volume = 55, pages = 52, doi = 10.15227/orgsyn.055.0052, prep = CV6P0679 {{cite journal, first1 = W., last1 = Dai, first2 = J. A., last2 = Katzenellenbogen, title = New approaches to the synthesis of alkyl-substituted enol lactone systems, inhibitors of the serine protease elastase, year = 1993, journal =

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, volume = 58, issue = 7, pages = 1900–1908, doi = 10.1021/jo00059a049 {{cite journal, first1 = J., last1 = Schreiber, first2 = D., last2 = Felix, first3 = A., last3 = Eschenmoser, authorlink3 = Albert Eschenmoser, first4 = M., last4 = Winter, first5 = F., last5 = Gautschi, first6 = K. H., last6 = Schulte-Elte, first7 = E., last7 = Sundt, first8 = G., last8 = Ohloff, authorlink8 = Günther Ohloff, first9 = J., last9 = Kalovoda, first10 = H., last10 = Kaufmann, first11 = P., last11 = Wieland, first12 = G., last12 = Anner, title = Die Synthese von Acetylen-carbonyl-Verbindungen durch Fragmentierung von α-β-Epoxy-ketonen mit ''p''-Toluolsulfonylhydrazin. Vorläufige Mitteilung, year = 1967, journal = Helv. Chim. Acta, language = German, volume = 50, issue = 7, pages = 2101–2108, doi = 10.1002/hlca.19670500747 {{cite journal, title = α,β-Epoxyketon → Alkinon-Fragmentierung II: Pyrolytischer Zerfall der Hydrazone aus α,β-Epoxyketonen und ''N''-Amino-aziridinen. Über synthetische Methoden, 4. Mitteilung, language = German, first1 = Dorothee, last1 = Felix, first2 = Robert K., last2 = Müller, first3 = U., last3 = Horn, first4 = R., last4 = Joos, first5 = J., last5 = Schreiber, first6 = Albert, last6 = Eschenmoser, authorlink6 = Albert Eschenmoser, year = 1972, journal = Helv. Chim. Acta, volume = 55, issue = 4, pages = 1276–1319, doi = 10.1002/hlca.19720550424 {{cite journal, last1 = Ohloff, first1 = G., authorlink1 = Günther Ohloff, last2 = Becker, first2 = J., last3 = Schulte-Elte, first3 = K. H., year = 1967, title = Synthese von Exalton und racemischem Muscon aus Cyclododecanon Vorläufige Mitteilung, journal = Helv. Chim. Acta, volume = 50, issue = 2, pages = 705–708, doi = 10.1002/hlca.19670500231, language = German {{cite journal, first1 = Albert, last1 = Eschenmoser, authorlink1 = Albert Eschenmoser, first2 = Dorothee, last2 = Felix, first3 = Günther, last3 = Ohloff, authorlink3 = Günther Ohloff, title = Eine neuartige Fragmentierung cyclischer α,β-ungesättigter Carbonylsysteme; Synthese von Exalton und ''rac''-Muscon aus Cyclododecanon Vorläufige Mitteilung, year = 1967, journal = Helv. Chim. Acta, volume = 50, issue = 2, pages = 708–713, doi = 10.1002/hlca.19670500232, language = German {{cite journal, first1 = Dorothee, last1 = Felix, first2 = J., last2 = Schreiber, first3 = Günther, last3 = Ohloff, authorlink3 = Günther Ohloff, first4 = Albert, last4 = Eschenmoser, authorlink4 = Albert Eschenmoser, title = α,β-Epoxyketon → Alkinon-Fragmentierung I: Synthese von exalton und ''rac''-muscon aus cyclododecanon über synthetische methoden, 3. Mitteilung, year = 1971, journal = Helv. Chim. Acta, language = German, volume = 54, issue = 8, pages = 2896–2912, doi = 10.1002/hlca.19710540855 {{cite journal, title = The synthesis of secosteroid acetylenic ketones, first1 = Masato, last1 = Tanabe, authorlink1 = Masato Tanabe, first2 = David F., last2 = Crowe, first3 = Robert L., last3 = Dehn, first4 = George, last4 = Detre, journal = Tetrahedron Lett., volume = 8, issue = 38, year = 1967, pages = 3739–3743, doi = 10.1016/S0040-4039(01)89784-7 {{cite journal, first1 = Masato, last1 = Tanabe, authorlink1 = Masato Tanabe, first2 = David F., last2 = Crowe, first3 = Robert L., last3 = Dehn, title = A novel fragmentation reaction of α,β-epoxyketones the synthesis of acetylenic ketones, journal = Tetrahedron Lett., year = 1967, volume = 8, issue = 40, pages = 3943–3946, doi = 10.1016/S0040-4039(01)89757-4 Elimination reactions Name reactions

Reaction mechanism

See also

References