Epoxides from Alkenes and Peroxidic Reagents

The most widely used reagents for conversion of alkenes to epoxides are peroxy-carboxylic acids.m-Chloroperoxybenzoic acid (MCPBA) is a common reagent. 

Organic Peroxides, Vol. II, Wiley-Interscience, New York, 1971, pp. 355—533 B. Plesnicar, in Oxidation in Organic Chemistry, Part C, W. Trahanovsky, ed.. Academic Press, New York, 1978, pp. 211-253. 

The magnesium salt of monoperoxyphthalic acid is an alternative. Peroxyacetic acid, peroxybenzoic acid, and peroxytrifluoroacetic acid also are used frequently for epoxidation. All of the peroxycarboxylic acids are potentially explosive materials and require careful handling. Potassium hydrogen peroxysulfate, which is sold commercially as Oxone , is a convenient reagent for epoxidations that can be done in aqueous solution. 

It has been demonstrated that no ionic intermediates are involved in the epoxidation of alkenes. The reaction rate is not very sensitive to solvent polarity. Stereospecific syn addition is consistently observed. The oxidation is considered to be a concerted process, as represented by the TS shown below. The plane including the peroxide bond is approximately perpendicular to the plane of the developing epoxide ring, so the oxygen being transferred is in a spiro position. 

The rate of epoxidation of alkenes is increased by alkyl groups and other ERG substituents, and the reactivity of the peroxy acids is increased by EWG substituents. These structure-reactivity relationships demonstrate that the peroxy acid acts as an electrophile in the reaction. Low reactivity is exhibited by double bonds that are conjugated with strongly EWG substituents, and very reactive peroxy acids, such as trifluoroperoxyacetic acid, are required for oxidation of such compounds. Strain increases the reactivity of alkenes toward epoxidation. Norbornene is about twice as reactive as cyclopentene toward peroxyacetic acid. trani-Cyclooctene is 90 times more reactive than cyclohexene. Shea and Kim found a good correlation between relief of strain, as determined by MM calculations, and the epoxidation rate. ° There is also a correlation with ionization potentials of the alkenes. Alkenes with aryl substituents are less reactive than unconjugated alkenes because of ground state stabilization and this is consistent with a lack of carbocation character in the TS. 

The stereoselectivity of epoxidation with peroxycarboxylic acids has been well studied. Addition of oxygen occurs preferentially from the less hindered side of the 

SECTION 12.2. ADDITION OF OXYGEN AT CARBON-CARBON DOUBLE BONDS 

The rate of epoxidation of alkenes is increased by alkyl groups and other ERG substituents and the reactivity of the peroxy acids is increased by EWG substituents.72 These structure-reactivity relationships demonstrate that the peroxyacid acts as an electrophile in the reaction. Decreased reactivity is exhibited by double bonds that are conjugated with strongly electron-attracting substituents, and more reactive peroxyacids, such as trifluoroperoxyacetic acid, are required for oxidation of such compounds.73 Electron-poor alkenes can also be epoxidized by alkaline solutions of 

The stereoselectivity of epoxidation with peroxycarboxylic acids has been well studied. Addition of oxygen occurs preferentially from the less hindered side of the molecule. Norbornene, for example, gives a 96 4 exo endo ratio.76 In molecules where two potential modes of approach are not very different, a mixture of products is formed. 

Hydroxy groups exert a directive effect on epoxidation and favor approach from the side of the double bond closest to the hydroxy group.78 Hydrogen bonding between the hydroxy group and the reagent evidently stabilizes the TS. 

Brougham, M. S. Cooper, D. A. Cummerson, H. Heaney, andN. Thompson, Synthesis 1987 1015. 

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Reagents which effect epoxidation of the enol ether unsaturation effect a-hydroxylation comparable to the peracid approach. Thus a combination of molybdenum hexacarbonyl and r-butyl hydroperoxide converts the substrates to a-silyloxy derivatives. The peroxide generate in situ from benzonitrile, potassium carbonate and hydrogen peroxide can also perform the oxidation. Molybdenum-peroxy complexes, including MoOPH, could presumably also effect this transformation. Lastly, dimethyldioxirane has been used to epoxidize alkenes and it is likely that application of this useful, debris free, organic peroxide to these reactions will soon emerge. 

The most widely used and, presumably, the most chemoselective reagents for the epoxidation of nucleophilic C—C double bonds are the peroxycarboxylic acids (see Houben-Weyl, Vol. IV/ 1 a, p 184, Vol. Vl/3, p 385, Vol. E13/2, p 1258). Using chloroform as solvent, epoxidation rates are particularly high79. Reactive or acid/base sensitive epoxides can often be obtained with dimethyldioxirane (see Houben-Weyl, Vol. R13/2, p 1256 and references 15, 16, 87-90), peracid imides (see Houben-Weyl, Vol. IV/1 a, p 205, Vol. VI/3, p 401, Vol. E13/2, p 1276) (prepared in situ from nitriles and hydrogen peroxide), hydroperoxy acetals (see Houben-Weyl, Vol. El3/2, p 1253) or peroxycarbonic acid derivatives (see Houben-Weyl, Vol. IV/la, p 209 and references 17-19) as oxidants. For less reactive alkenes, potassium hydrogen persulfate is a readily available reagent for direct epoxidation20. 

The initial biotransformation in a one-pot process, however, can also be used to prepare in situ an activated reagent which then reacts with an added substrate. Also not exactly fitting into the above-mentioned scheme of a one-pot two-step process, also here more than one synthetic step is carried out without a work-up in between. An elegant example in this area was reported by Novo Nordisk researchers, who converted in a first step acetic acid into acetic peracid through a catalytic reaction with a lipase and hydrogen peroxide, followed by a subsequent epoxidation of alkenes, for example, 46, with the in situ formed peracid [44]. By means of this method, a range of epoxides were prepared with yields up to >99%. A selected example is shown in Scheme 19.16. A related example was reported by Riisch gen. Klaas and Warwel [45], who started from dimethyl carbonate and hydrogen peroxide for in situ preparation of the needed peracid. 

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