Chromium(VI) Oxide1


[1333-82-0]  · CrO3  · Chromium(VI) Oxide  · (MW 99.99)

(reagent for oxidizing carbon-hydrogen bonds to alcohols, oxidizing alkylaromatics to ketones and carboxylic acids, converting alkenes to a,b-unsaturated ketones, oxidizing carbon-carbon double bonds, oxidizing arenes to quinones, oxidizing alcohols to aldehydes, ketones, acids, and keto acids)

Alternate Names: chromic anhydride; Chromic Acid in aqueous media.

Physical Data: mp 196 °C; d 2.70 g cm-3.

Solubility: sol ether, H2O, HNO3, H2SO4, DMF, HMPA.

Form Supplied in: red crystals.

Handling, Storage, and Precautions: caution: chromium(VI) oxide is a highly toxic cancer suspect agent. All chromium(VI) reagents must be handled with care. The mutagenicity of CrVI compounds is well documented.7 HMPA is also a highly toxic cancer suspect agent. Special care must always be exercised in adding CrO3 to organic solvents. Add CrO3 in small portions to HMPA in order to avoid a violent decomposition. This reagent must be handled in a fume hood.

Each mol of chromium(VI) oxide has 1.5 equivalents of oxygen. The oxidizing power of the reagent increases with decreasing water content of the solvent medium. The oxidizing medium may be aqueous acetic acid,2,3 anhydrous acetic acid (Fieser reagent),4 or concentrated5 or aqueous6 sulfuric acid.

Oxidation of Carbon-Hydrogen Bonds to Alcohols.

Chromium(VI) oxide in 91% acetic acid oxidizes the methine hydrogen of (+)-3-methylheptane to (+)-3-methyl-3-heptanol with 70-85% retention of configuration.8 3b-Acetoxy-14a-hydroxyandrost-5-en-17-one is obtained by direct introduction of an a-hydroxyl group at C-14 in the dibromide of 3b-acetoxyandrost-5-en-17-one (eq 1).9

Oxidation of Alkylaromatics to Ketones and Carboxylic Acids.

Chromium(VI) oxide in concentrated sulfuric acid oxidizes 3,4-dinitrotoluene to 3,4-dinitrobenzoic acid (89%).5 Under milder conditions, with longer alkyl chains, the benzylic position is converted to carbonyl. Chromium(VI) oxide in acetic acid oxidizes ethylbenzene to acetophenone and benzoic acid. More rigorous oxidizing experimental conditions convert longer chain alkyl groups to carboxyl, thus yielding benzoic acid or its derivatives. Methylene groups between two benzene rings are oxidized to carbonyl derivatives in preference to reaction at alkyl side chains.10 Indans are oxidized to 1-indanones by use of a dilute (10%) solution of chromium(VI) oxide in acetic acid at room temperature (eq 2).11

Allylic Oxidations.

Allylic oxidations may be complicated by carbonyl formation at either one or both allylic positions. Although chromium(VI) oxide appears to be useful for allylic oxidation in steroid chemistry, better results may be obtained in other systems with Di-t-butyl Chromate or Dipyridine Chromium(VI) Oxide (Collins reagent). However, the Chromium(VI) Oxide-3,5-Dimethylpyrazole complex (CrO3.DMP) is useful for allylic oxidations. The complex oxidized the allylic methylene group in (1) to the a,b-unsaturated ketone (2) which was used in the synthesis of the antibacterial helenanolide (+)-carpesiolin (eq 3).12 Chromium(VI) oxide in glacial acetic acid oxidizes 3,21-diacetoxy-4,4,14-trimethyl-D8-5-pregnene to the enetrione (eq 4).13 Complex product mixtures are formed when epoxidation competes with the allylic oxidation.14

Oxidation of Carbon-Carbon Double Bonds.

Chromium(VI) oxide in aqueous sulfuric acid generally cleaves carbon-carbon double bonds. Rearrangements may further complicate the oxidation. In anhydrous acetic acid, chromium(VI) oxide oxidizes tetraphenylethylene to the oxirane (70% yield) and benzophenone (11%).15 The yield is lower and more double bond cleavage occurs in aqueous acetic acid. However, use of acetic anhydride as solvent (see Chromyl Acetate) affords the oxiranes from tri- and tetrasubstituted alkenes in 50-88% yields, along with benzopinacols.16,17 Many steroidal and terpenic cyclic alkenes react with chromium(VI) oxide in acetic acid to give oxiranes, and saturated, a,b-unsaturated, a-hydroxy, and a,b-epoxy ketones which arise from the initially formed oxirane.18,19 A synthetically useful cleavage of double bonds involving chromium(VI) oxide is the Meystre-Miescher-Wettstein degradation20 which shortens the side chain of a carboxylic acid by three atoms at one time. This procedure is a modification of the Barbier-Wieland degradation.21,22

Oxidation of Arenes to Quinones.

In contrast to alkylaromatics, which undergo oxidation at the side chain with some chromium(VI) oxidants, polynuclear aromatic arenes undergo ring oxidation to quinones with chromium(VI) oxide. This chemoselectivity is shown in the chromium(VI) oxide in anhydrous acetic acid (Fieser reagent) oxidation of 2,3-dimethylnaphthalene to 2,3-dimethylnaphthoquinone in quantitative yield (eq 5).23 In some cases, depending on experimental conditions, both benzylic and ring oxidations occur24 or the alkyl groups may be eliminated (eq 6).25 The oxidation of anthracene derivatives is important in the total synthesis of anthracycline antibiotics.26,27

Oxidation of Alcohols to Aldehydes, Ketones, Acids, and Keto Acids.

Chromium(VI) oxide in acetic acid oxidizes primary alcohols to aldehydes and acids, and secondary alcohols to ketones and keto acids (Fieser reagent) (eq 7).28 Chromium(VI) oxide in water or aqueous acetic acid oxidizes primary alcohols to carboxylic acids.29,30 Chromium(VI) oxide-Hexamethylphosphoric Triamide (CrO3.HMPA) selectively oxidized the primary hydroxyl group of strophanthidol (3) to an aldehyde group in the final step in the synthesis of strophanthidin (4) (eq 8).31 The CrO3.HMPA complex oxidizes saturated primary alcohols to aldehydes in about 80% yield.32,33 The yields are lower with secondary alcohols and highest with a,b-unsaturated primary and secondary alcohols. It is possible to selectively oxidize certain allylic and benzylic hydroxyl groups in the presence of other unprotected saturated groups (eq 9; cf eq 8). Chromium(VI) oxide in DMF in the presence of catalytic amounts of sulfuric acid oxidizes steroidal alcohols to ketones.34 Chromium(VI) oxide on graphite selectively oxidizes primary alcohols in the presence of secondary and tertiary alcohols.35

Other Applications.

Chromium(VI) oxide in aqueous acetic acid converts a-chlorohydrindene to a-hydrindanone (50-60%).36 Suitably protected methylene or benzylidene acetals of alditols are cleaved by chromium(VI) oxide in glacial acetic acid to derivatives of ketoses.37 Chromium(VI) oxide in anhydrous acetic acid converts methyl ethers into the corresponding formates, which can be hydrolyzed by base to alcohols (demethylation).38

Related Reagents.

Chromium(VI) Oxide-3,5-Dimethylpyrazole; Chromium(VI) Oxide-Quinoline; Chromium(VI) Oxide-Silica Gel.

1. (a) Wiberg, K. B. Oxidation in Organic Chemistry; Wiberg, K. B., Ed.; Academic: New York, 1965; Part A, pp 131-135. (b) Freeman, F. Organic Synthesis By Oxidation With Metal Compounds; Miijs, W. J.; de Jonge, C. R. H. I., Eds.; Plenum: New York, 1986; Chapter 2. (c) Lee, D. G. The Oxidation of Organic Compounds by Permanganate Ion and Hexavalent Chromium; Open Court: La Salle, IL, 1980. (d) Stewart, R. Oxidation Mechanisms: Applications to Organic Chemistry; Benjamin: New York, 1964. (e) Cainelli, G.; Cardillo, G. Chromium Oxidations in Organic Chemistry; Springer: Berlin, 1984.
2. Schreiber, J.; Eschenmoser, A. HCA 1955, 38, 1529.
3. Braude, E. A.; Fawcett, J. S. OSC 1963, 4, 698.
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10. Stephen, H.; Short, W. F.; Gladding, G. JCS 1920, 117, 510.
11. Harms, W. M.; Eisenbraun, E. J. OPP 1972, 4, 67.
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13. Flatt, S. J.; Fleet, G. W. J.; Taylor, B. J. S 1979, 815.
14. Barton, D. H. R.; Kulkarni, Y. D.; Sammes, P. G. JCS(C) 1971, 1149.
15. Mosher, W. A.; Steffgen, F. W.; Lansbury, P. T. JOC 1961, 26, 670.
16. Hickinbottom, W. J.; Moussa, G. E. M. JCS 1957, 4195.
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18. Birchenough, M. J.; McGhie, J. F. JCS 1950, 1249.
19. Wintersteiner, O.; Moore, M. JACS 1950, 72, 1923.
20. Meystre, C.; Frey, H.; Wettstein, A.; Miescher, K. HCA, 1944, 27, 1815.
21. Barbier, P.; Loquin, R. CR(C) 1913, 156, 1443.
22. Wieland, H.; Schlichting, O.; Jacobi, R. Z. Physiol. Chem. 1926, 161, 80.
23. Smith, L. I.; Webster, I. M. JACS 1937, 59, 662.
24. Il'inskii, M. A.; Kazakova, V. A. JGU 1941, 11, 16 (CA 1941, 35, 5487).
25. Pschorr, R. CB 1906, 39, 3128.
26. Kende, A. S.; Curran, D. P.; Tsay, Y.; Mills, J. E. TL 1977, 3537.
27. Broadhurst, M. J.; Hassall, C. H.; Thomas, G. J. CC 1982, 158.
28. Fieser, L. F.; Szmuszkovicz, J. JACS 1948, 70, 3352.
29. Pattison, F. L. M.; Stothers, J. B.; Woolford, R. G. JACS 1956, 78, 2255.
30. Newman, M. S.; Arkell, A.; Fukunaga, T. JACS 1960, 82, 2498.
31. Crandall, J. K.; Heitmann, W. R. JOC 1979, 44, 3471.
32. Beugelmans, R.; Le Goff, M.-T. BSF 1969 335.
33. Cardillo, G.; Orena, M.; Sandri, S. S 1976, 394.
34. Snatzke, G. CB 1961, 94, 729.
35. Lalancette, J. M.; Rollin, G.; Dumas, P. CJC 1972, 50, 3058.
36. Pacaud, R. A.; Allen, C. F. H. OSC 1947, 2, 336.
37. Angyal, S. J.; Evans, M. E. AJC 1972, 25, 1513.
38. Harrison, I. T.; Harrison, S. CC 1966, 752.

Fillmore Freeman

University of California, Irvine, CA, USA

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