Ozone-Silica Gel1

[10028-15-6]  · O3  · Ozone-Silica Gel  · (MW 48.00)

(powerful oxidizing agent; capable of oxidizing carbon-hydrogen bonds2 and a variety of electron-rich functional groups; provides a high effective concentration of ozone2a)

Physical Data: ozone, mp -193 °C; bp -111.9 °C; d (0 °C, gas) 2.14 g L-1.

Solubility: 4.5% ozone by weight is adsorbed on silica gel at -78 °C.2

Preparative Methods: ozone is generated in the laboratory by passing dry air or oxygen through two electrodes connected to an alternating current source of several thousand volts. Silica gel 60 (70-230 mesh, available from several suppliers) usually is dried prior to use and is saturated with ozone at low temperature.

Handling, Storage, and Precautions: ozone is irritating to all mucous membranes and is highly toxic in concentrations greater than 0.1 ppm by volume. It has a characteristic odor which can be detected at levels as low as 0.01 ppm. All operations with ozone should be carried out in an efficient fume hood and scrubbing systems employing thiosulfate solutions can be used to destroy excess ozone. Liquified ozone poses a severe explosion hazard.

General Procedure.

The organic substrate is preadsorbed on silica gel either by direct mixing or by slurrying in an appropriate solvent followed by removal of the solvent under vacuum. A stream of ozone then is passed through the silica gel at low temperature (usually -78 °C) until it is saturated and a deep blue color. The mixture is then warmed slowly to rt and organic material is isolated by elution. Multiple saturation and warming cycles may be necessary to achieve complete consumption of substrate. This dry ozonation procedure complements ozonation carried out in organic solvents. The high ozone concentration which can be achieved on silica gel allows for a more facile oxidation of substrates normally difficult to ozonize, and problems associated with solvent interference are eliminated.

Oxidation of Carbon-Hydrogen Bonds.

Dry ozonation most often has been used for hydroxylation of tertiary centers in saturated cyclic hydrocarbons with stereoselective retention of configuration. Hydrotrioxides have been detected as intermediates in these reactions.3 The yields of tertiary alcohols from dry ozonation typically are higher than those obtained using either Chromic Acid or solution ozonolysis (eq 1).2,4,5

While the method is generally applicable to cyclic hydrocarbons, the use of acyclic substrates often results in the production of significant amounts of ketones due to carbon-carbon bond cleavage (eq 2).6 Eq 2 shows that in dry ozonation, ozone attack is directed at exposed positions remote to the silica gel binding site. This results from molecules being ordered in a close packed array on the solid support with steric effects hindering reactivity at the proximal positions. Bridgehead hydroxylation of polycyclic hydrocarbons,2,7 and derivatization of terpenoids8 and steroidal systems,9 have been accomplished using dry ozonation. Additionally, remote methylene units have been transformed to ketones in cyclic acetates.10

Dry ozonation also can be used to functionalize cyclopropyl hydrocarbons at the a-position, affording cyclopropyl alkyl ketones.11 The method is quite general and reaction a to the cyclopropyl group is preferred over hydroxylation at tertiary positions (eqs 3 and 4).12

Ozonolysis of Alkenes and Alkynes.

Alkene ozonolysis on dry silica gel results in the efficient formation of ozonides, while reaction on nontreated or hydrated silica gel affords mixtures of aldehydes, ketones, or carboxylic acids (eq 5).13-15 Products from these reactions usually are obtained directly upon elution from the silica gel without the need for either a reductive or oxidative workup.

Notably, ozonides of tetrasubstituted alkenes,16 vinyl ethers,17 vinylic esters,18 and a,b-unsaturated ketones19 (which are normally not observed in solution reactions) can be obtained using ozonation on polyethylene as the solid support. It is believed that solid-supported ozonolysis favors ozonide formation due to the proximity of initial cleavage products and the resulting ease of recombination. Also, since cleavage fragments are fixed on the support, combination to form cross ozonides is reduced dramatically.

In addition to providing a route to otherwise inaccessible ozonides, dry ozonation has been used to cleave normally unreactive alkenes directly to carbonyl compounds (eq 6).20 In another example, bulky tetramethylethylene affords acetone in 95% yield upon dry ozonation using untreated or hydrated silica gel.14

An overall hydroxylation of alkenes using the dry ozonation procedure can be accomplished if the more reactive alkene functionality is first converted to a dibromide. After hydroxylation, deblocking liberates the alkene (eq 7).21

Dry ozonation of alkynes generally results in cleavage to carboxylic acids and carbonyl compounds. Only in the case of diphenylacetylene has a diketone been observed.14,15

Oxidation of Primary Amines.

Aliphatic primary amines are efficiently oxidized by ozone on silica gel to the corresponding nitro compounds (eq 8).22 This procedure is an improvement over solution ozonations in which yields are lower due to solvent interaction with partial oxidation products and competing oxidation of the a-carbon atom (see Ozone).

Ozonation of Aromatic Systems.

Phenyl rings are cleaved to carboxylic acids using dry ozonation, although multiple ozone saturation and warming cycles may be required for high conversions (eq 9).23 Compared to oxidations utilizing Ruthenium(VIII) Oxide, yields are significantly higher.24

Alternate Procedure.

A modification of the dry ozonation procedure employs a microwave discharge of a He-O2 or a He-CO2 gas stream to produce ground-state oxygen atoms [O(3p) atoms] which, when passed over silica gel or Florisil preadsorbed with substrate at low temperature, combine with oxygen on the adsorbent to slowly form ozone in low concentration in situ. The ozone then can react with the absorbed organic substrate.25 This is a milder method than conventional dry ozonation, and this procedure can afford regiospecific ozonation of polyunsaturated compounds or partial oxidative cleavage of polycyclic aromatics (eq 10).26 Conventional solvent ozonolyses or standard dry ozonations often result in cleavage of several bonds.

1. (a) Bailey, P. S. Ozonation in Organic Chemistry; Academic: San Diego, CA, 1982; Vol. 2, pp 312-319. (b) Keinan, E.; Varkony, H. T. In The Chemistry of Peroxides; Patai, S.; Ed.; Wiley: New York, 1983; pp 649-983. (c) Clark, J. H.; Kybett, A. P.; Macquarrie, D. J. Supported Reagents; VCH: New York, 1992; pp 44-46.
2. (a) Cohen, Z.; Keinan, E.; Mazur, Y.; Varkony, T. H. JOC 1975, 40, 2141. (b) Cohen, Z.; Varkony, H.; Keinan, E.; Mazur, Y. OSC 1988, 6, 43.
3. Zarth, M.; de Meijere, A. CB 1985, 118, 2429.
4. Durland, J. R.; Adkins, H. JACS 1939, 61, 429.
5. Bingham, R. C.; Schleyer, P. v. R. JOC 1971, 36, 1198.
6. (a) Beckwith, A. L. J.; Bodkin, C. L.; Duong, T. AJC 1977, 30, 2177. (b) Beckwith, A. L. J.; Bodkin, C. L.; Duong, T. CL 1977, 425. (c) Tal, D.; Keinan, E.; Mazur Y. JACS 1979, 101, 502. (d) Beckwith, A. L. J.; Duong, T. CC 1979, 690.
7. (a) Israel, R. J.; Murray, R. K. JOC 1983, 48, 4701. (b) Sosnowski, J. J.; Danaher, E. B.; Murray, R. K. JOC 1985, 50, 2759.
8. (a) Trifilieff, E.; Bang, L.; Ourisson, G. TL 1977, 2991. (b) Trifilieff, E.; Bang, L.; Narula, A. S.; Ourisson, G. JCR(S) 1978, 64. (c) Suokas, E.; Hase, T. ACS(B) 1978, 32, 623. (d) Akiyama, E.; Tada, M.; Tsuyuki, T.; Takahashi, T. CL 1978, 305; Akiyama, E.; Tada, M.; Tsuyuki, T.; Takahashi, T. BCJ 1979, 52, 164.
9. Cohen, Z.; Keinan, E.; Mazur, Y.; Ulman, A. JOC 1976, 41, 2651. (b) Cohen, Z.; Mazur, Y. JOC 1979, 44, 2318. (c) Cohen, Z.; Berman, E.; Mazur, Y. JOC 1979, 44, 3077. (d) Wife, R. L.; Kyle, D.; Mulheirn, L. J.; Volger, H. C. CC 1982, 306.
10. Beckwith, A. L. J.; Duong, T. CC 1978, 413.
11. (a) Proksch, E.; de Meijere, A. TL 1976, 4851. (b) Preuss, T.; Proksch, E.; de Meijere, A. TL 1978, 833.
12. Proksch, E.; de Meijere, A. AG(E) 1976, 15, 761.
13. Den Besten, I. E.; Kinstle, T. H. JACS 1980, 102, 5968.
14. Aronovitch, C.; Tal, D.; Mazur, Y. TL 1982, 23, 3623.
15. Bouas-Laurent, H.; Desvergne, J. P.; LaPouyade, R.; Thomas, J. M. J. Catal. 1977, 51, 126.
16. (a) Griesbaum, K.; Volpp, W.; Greinert, R. JACS 1985, 107, 5309. (b) Griesbaum, K.; Volpp, W. AG(E) 1986, 25, 81. (c) Griesbaum, K.; Volpp, W.; Greinert, R.; Greuning, H.; Schmid, J.; Henke, H. JOC 1989, 54, 383.
17. (a) Griesbaum, K.; Kim, W.; Nakamura, N.; Mori, M.; Nojima, M.; Kusabayashi, S. JOC 1990, 55, 6153. (b) Griesbaum, K.; Kim, W. JOC 1992, 57, 5574.
18. Griesbaum, K.; Volpp, W.; Huh, T. CB 1989, 122, 941.
19. Griesbaum, K.; Greuning, H.; Volpp, W.; Jung, I. CB 1991, 124, 947.
20. Weinreb, S. M. ACR 1988, 21, 313.
21. Keinan, E.; Mazur, Y. S 1976, 523.
22. Keinan, E.; Mazur, Y. JOC 1977, 42, 844.
23. Klein, H.; Steinmetz, A. TL 1975, 4249.
24. Caputo, J. A.; Fuchs, R. TL 1967, 4729.
25. (a) Zadok, E.; Aronovitch, C.; Mazur, Y. NJC 1982, 6, 695. (b) Zadok, E.; Rubinraut, S.; Mazur, Y. Isr. J. Chem. 1983, 23, 457.
26. Zadok, E.; Rubinraut, S.; Mazur, Y. TL 1984, 25, 4175.

Richard A. Berglund

Eli Lilly and Company, Lafayette, IN, USA

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