Ozonides, reductive cleavage

Addition compounds called ozonides are produced when alkenes react with ozone and reductive cleavage of these compounds is used extensively in preparative and diagnostic organic chemistry. 

Dichloroaluminium hydride in ether or sodium borohydride in TEA can lead to formation of ethers from ozonides by reductive cleavage of the two C—O bonds of the peroxide bridge (Equation (19)) <85JOC275>. 

Substrates suitable for oxidative conversion into carbonyl compounds are alkenes, primary or secondary alcohols, and benzyl halides. Polystyrene-bound alkenes have been converted into aldehydes (with the loss of one carbon atom) by ozonolysis followed by reductive cleavage of the intermediate ozonide (Entry 1, Table 12.3). 

The deoxygenation of epoxides is not of great preparative value since it involves some loss of stereochemical integrity and the alkenes produced are more readily approached in other ways. Reductive cleavage of ozonides, for example, using triphenylphosphine, commonly forms part of the ozonolysis procedure for conversion of alkenes into carbonyl compounds. If a carbonyl compound is treated with an appropriate P(III) reagent then the reverse process may occur—reductive coupling to form a new C=C double bond. This has found a particularly important... 

Other reaction substrate variations that will not be covered in this chapter include the NaBHt/TFA reductive cleavage of 1,4-epoxy-1,4-dihydronaphthalenes25 and benzylic ozonides,26 the tandem solvolysis-reduction of triarylmethyl chlorides,27 the cleavage of ferrocenyl ketone hydrazines,28 and the reduction of benzophenones to diarylmethanols ( ).29... 

Scheme 7 Ozonization of alcohol (79) followed by treatment of the ozonide with Me2S afforded hydroxy ketones (80), whose acetate derivatives was converted to indenone (83). Hydroxy ketone (84), prepared from (83) was converted to compound (85), whose acetate on oxidation gave diol (87). Its transformation to butenolide (88) was easily carried out. This on oxidation and reduction produced hydroxy phytuberin lactone (89), which was converted to its sulfonyl derivative. Reductive removal of the sulfonate group yielded the cyclopropane derivative (91), which on subjection to reductive cleavage with lithium in liq. NH3 yielded phyberin lactone (92) and deacetyl phytuberin lactone (93)...

Aldehydes can be obtained homogeneously from ozonides by reductive cleavage, which can be effected either by zinc in glacial acetic acid or by catalytic hydrogenation of the ozonide118,119 in the presence of a 1 19 palladium-calcium carbonate catalyst.120 Adipdialdehyde has thus been obtained from cyclohexene in 60-70% yield 121... 

As discussed in Section 3.7.B, ozone adds to an alkene to generate a 1,2,3-trioxolane. Addition of ozone to 1-pentene, for example, generated 425. Rearrangement of this initially formed cycloadduct is facile, even at temperatures as low as -78°C, and results in cleavage of the carbon-carbon bond in 425, with formation of a 1,2,4-trioxolane (426). This product is usually called an ozonide and can be either oxidized or reduced to give the carbonyl compounds characteristic of the oxidative or reductive cleavage reactions. 

Oxidative cleavage of an alkene with ozone leads to an ozonide. Reductive workup with dimethyl sulfoxide or zinc and acetic acid gives ketones and/or aldehydes. Oxidative workup with hydrogen peroxide gives ketones and/or carboxylic acids. Oxidative cleavage of 1,2-diols with periodic acid or with lead tetraacetate gives aldehydes or ketones. 

Ozonides are colourless crystalline substances which are best kept in solution in pentane. They can be converted to shorter-chain aldehydes by reductive cleavage using Lindlar catalyst these can then be identified gas chromatographically or thin-layer chromatographically, then usually as derivatives (see also p. 205). This procedure is suitable for determining the structure of unsaturated lipids (cf. p. 408). 

The production of an ozonide does not, in itself, cause the catastrophic changes observed on exposing natural rubber to ozone. This is due to a subsequent hydrolytic or reductive cleavage reaction. 

This cleavage reaction is more often seen in structural analysis than in synthesis The substitution pattern around a dou ble bond is revealed by identifying the carbonyl containing compounds that make up the product Hydrolysis of the ozonide intermediate in the presence of zinc (reductive workup) permits aide hyde products to be isolated without further oxidation... 

One of the most common reactions for the complete cleavage of an exocyclic C-C double bond is ozonolysis. The reaction is typically performed at low temperature in dichloromethane, methanol or a mixture of both, followed by the usual reduction of the ozonide with dimethyl sulfide 15 17 80 82 i48,337 or thiourea83 to give excellent yields of the corresponding cyclobu-tanone. 

The most common procedure is ozonolysis at -78 °C (P.S. Bailey, 1978) in methanol or methylene chloride in the presence of dimethyl sulfide or pyridine, which reduce the intermediate ozonides to aldehydes. Unsubstituted cydohexene derivatives give 1,6-dialdehydes, enol ethers or esters yield carboxylic acid derivatives. Oxygen-substituted C—C bonds in cyclohexene derivatives, which may also be obtained by Birch reduction of alkoxyarenes (see p. 103f.), are often more rapidly oxidized than non-substituted bonds (E.J. Corey, 1968 D G. Stork, 1968 A,B). Catechol derivatives may also be directly cleaved to afford conjugated hexa-dienedioic acid derivatives (R.B. Woodward, 1963). Highly regioselective cleavage of the more electron-rich double bond is achieved in the ozonization of dienes (W. KnOll, 1975). 

For reducing ozonides or sterically hindered peroxides, magnesium and methanol proved to be a better and mild reducing agent <2004JOC2851>. Thus, the bicylic ozonide prepared from 1-phenylcyclopentene, which is prone to base-mediated cleavage, was cleanly reduced by Mg/MeOH to the keto-acid with the ketonic methyl ester as a by-product, whereas reduction with zinc and acetic acid affords mainly the keto-aldehyde with the keto-acid as a by-product (Equation 7). 

On an industrial scale, the traditional method for cleavage of carbon-carbon double bonds is ozonolysis, used for the manufacture of azelaic acid and nonanoic acids from oleic acid, and of butane tetracarboxylic acid from tetrahydrophthalic anhydride. The process is effectively a quantitative and mild process.178 However, it is capital and energy intensive. The intermediate ozonide is worked up either reductively or oxidatively to produce the aldehyde, ketone or carboxylic acid. Hydrogen peroxide is the common oxidizing agent used in the second step.179-181 Oxygen can also be used either alone182 or in combination with zeolites.183 Reviews on ozonolysis are available and the reader is directed to reference 184 for further information. 

Ozonides are rarely isolated [75, 76, 77, 78, 79], These substances tend to decompose, sometimes violently, on heating and must, therefore, be handled with utmost safety precautions (safety goggles or face shield, protective shield, and work in the hood). In most instances, ozonides are worked up in the same solutions in which they have been prepared. Depending on the desired final products, ozonide cleavage is done by reductive or oxidative methods. Reductions of ozonides to aldehydes are performed by catalytic hydrogenation over palladium on carbon or other supports [80, 81, 82, S3], platinum oxide [84], or Raney nickel [S5] and often by reduction with zinc in acetic acid [72, 81, 86, 87], Other reducing agents are tri-phenylphosphine [SS], trimethyl phosphite [89], dimethyl sulfide (DMS) [90, 91, 92], and sodium iodide [93], Lithium aluminum hydride [94, 95] and sodium borohydride [95, 96] convert ozonides into alcohols. 

The oldest and still very common cleavage is the reaction of unsaturated compounds with ozone and the subsequent treatment of the ozonides formed (equations 95 and 96). Reduction by strong reducing agents such as complex hydrides gives alcohols [94. Cycloalkenes yield diols [82]. 

A much more frequently used reaction is the cleavage of unsaturated compounds to aldehydes (equations 98 and 99). Alkenes and cycloalkenes that possess one or two hydrogens at the double bonds are oxidized by ozone to ozonides, which have to be reduced to prevent a subsequent oxidation to acids by the excess oxygen atom. Reductions are carried out, usually without isolation of the ozonides, by catalytic hydrogenation over palladium catalyst [80, 81,1106] or Raney nickel [55] or by treatment with... 

T he reaction of ozone with olefins usually results in cleavage of the double bond and the formation of aldehydes, ketones, and/or carboxylic acids, depending upon the reaction conditions and the structures involved. For aldehydes, the intermediate ozonides are ordinarily treated with a mild reducing agent—for example, hydrogen or zinc—or subjected to neutral hydrolysis. Yields in excess of 70% are exceptional for the reduction methods, while hydrolysis gives considerably lower yields. 

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