Chromic Acid1

[7738-94-5]  · CrH2O4  · Chromic Acid  · (MW 118)

(reagent for oxidizing secondary alcohols to ketones, primary alcohols to carboxylic acids, and a-hydroxy ketones to a-diketones; for converting tertiary cyclobutanols to 1,4-ketols and 1,4-diketones; for cleaving 1,2-glycols to keto acids)

Alternate Name: Jones reagent.

Solubility: sol acetone and water.

Preparative Methods: the Jones reagent is a solution of chromium(VI) oxide and sulfuric acid in water,2-4 in a typical procedure,4a 67g of CrO3 is dissolved in 125 mL of H2O and 58 mL of conc H2SO4 is then carefully added; the precipitated salts are dissolved by adding an additional (minimal) quantity of water (the total volume of the resultant solution should not exceed 225 mL); alternatively, 23.5 g of CrO3 is dissolved in 21 mL of conc H2sO4 with cooling and then diluted with distilled water to give a total volume of 175 mL.2,4b

Handling, Storage, and Precautions: the mutagenicity of chromium(VI) compounds is well documented;1f handle with great care; use in a fume hood.

Oxidation of Secondary Alcohols to Ketones.

The Jones reagent oxidizes cyclooctanol to cyclooctanone (92-96%) on a fairly large scale.4 Nortricyclanol (1) is oxidized to the highly strained and reactive ketone nortricyclanone (2) (eq 1).5 An epimeric mixture of 3,3-dimethyl-cis-bicyclo[3.2.0]heptan-2-ols is oxidized by Jones reagent to 3,3-dimethyl-cis-bicyclo[3.2.0]heptan-2-one (83-93%).6 Jones reagent oxidizes alcohols (3) and (5) to the acid labile ketones (4) and (6), respectively (eqs 2 and 3).7 A 90% yield of D5-pregnene-3,20-dione is obtained from the Jones oxidation of pregnenolone.8 The Jones reagent, in the presence of oxalic acid, oxidizes 1,2-diphenylethanol and t-butylphenylmethanol to benzyl phenyl ketone and t-butyl phenyl ketone, respectively, in quantitative yield.9 This procedure is also effective for the oxidation of 7-norbornanol to 7-norbornone. Chromic acid in aqueous acetic acid oxidizes t-butylphenylmethanol to t-butyl phenyl ketone, with formation of significant amounts of the cleavage products benzaldehyde and t-butanol.

1,4-Ketols and 1,4-Diketones from tertiary Cyclobutanols.

Jones reagent cleaves tertiary cyclobutanols to 1,4-ketols (eq 4) and 1,4-diketones (eqs 5 and 6).10

Oxidation of a,b-Unsaturated Alcohols.

In general, allylic alcohols are easily converted to the corresponding a,b-unsaturated ketones. Ethyl 3-hydroxy-4-pentenoate (7) is oxidized to the volatile ketone ethyl 3-oxo-4-pentenoate (8) (eq 7),11 which is an intermediate in the preparation of the Nazarov annulation reagent.12 The Jones reagent was superior to Pyridinium Chlorochromate, Pyridinium Dichromate, and Dimethyl Sulfoxide-Oxalyl Chloride (Swern reagent) for the oxidation of this alcohol.

The steroidal lactone (9) and its isomeric allylic alcohol (10) are stereospecifically oxidized to the epoxy ketone (11) by the Jones reagent (eq 8).13 Epoxidation occurs only when the hydroxyl group is axial and epoxidation is faster than oxidation of the hydroxyl group.

Oxidation of 6-hydroxy-2-(4-methoxyphenyl)-2-methyl-2H-pyran-3(6H)-ones (12) (eq 9) with Jones reagent affords diones (13), which are intermediates in the synthesis of 5-substituted 2-pyrrolidinones14 and 1-oxaspiro[5.5]undecane derivatives.15 The pyrrolidinone (g-lactam) skeleton is found in molecules with great value in medicinal chemistry, and spiroacetals are subunits in numerous important natural products.

Jones oxidation of phosphorus-containing tertiary allylic alcohols such as (14) led to formation of the 1,3-carbonyl transposed b-substituted a,b-unsaturated ketones (15) (eq 10), which are useful intermediates for a variety of phosphorus-substituted and nonphosphorus-bearing heterocyclic systems.16

Alkynic ketones are prepared in 40-80% yield via the Jones oxidation of the corresponding secondary alcohols.2 Alkynic glycols are oxidized to the diketones with Jones reagent.2

Cleavage of s,t-1,2-Glycols to Keto Acids.

Jones reagent oxidatively cleaves s,t-1,2-glycol (16) to keto acid (17) (eq 11), and (18) or (19) to (21) (eq 12).17

Oxidation of Benzoins to Benzils.

Benzoins are oxidized to benzils (90-95%) with Jones reagent in acetone.18

Oxidation of Primary Alcohols.

Primary alcohols are rapidly oxidized by the Jones reagent to carboxylic acids. Double bonds and triple bonds are not oxidized.19,20 Jones oxidation of alcohol (22) affords carboxylic acid (23), which is used in the synthesis of the antitumor agent (±)-sarkomycin (eq 13).21

Other Applications.

Although ethers are generally inert toward chromic acid oxidation, the Jones reagent oxidizes benzyl ethers to the benzoic acid, esters, and ketones (eq 14).22 The bicyclic acetoxy ether (24) is oxidized to the acetoxylactone (25) with Jones reagent at room temperature (eq 15).23

Oxidation of the alcohol (26) with Jones reagent gives the d-lactone (27) instead of the ketone (eq 16).24 The p-methoxy group is necessary for this oxidation of a methyl group.

Phenols substituted by at least one alkyl group in the ortho position are oxidized to p-quinones by a two-phase (ether/aqueous CrO3) Jones reagent.25 Chromic acid in 50% aqueous acetic acid, Collins reagent, and Jones reagent oxidatively deoximate ketoximes to the corresponding carbonyl compounds.26 Jones reagent oxidizes 3-trimethylsilyl-3-buten-2-ol to the Michael acceptor 3-methylsilyl-3-buten-2-one.27 A combination of a catalytic amount of Osmium Tetroxide and stoichiometric Jones reagent in acetone at room temperature oxidizes various types of alkenes into acids and/or ketones.28

1. (a) Wiberg, K. B. In Oxidation in Organic Chemistry; Wiberg, K. B., Ed; Academic: New York, 1965; Part A, Chapter 2. (b) Freeman, F. In Organic Synthesis by Oxidation with Metal Compounds; Miijs, W. J.; de Jonge, C. R. H. I., Ed; 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. (f) Cupo, D. Y.; Wetterhahn, K. E. Cancer Res. 1985, 45, 1146 and references cited therein.
2. Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. L. JCS 1946, 39.
3. Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J. JCS 1953, 2548.
4. (a) Eisenbraun, E. J. OSC 1973, 5, 310. (b) Zibuck, R.; Streiber, J. OS 1993, 71, 236.
5. Meinwald, J.; Crandall, J.; Hymans, W. E. OSC 1973, 5, 866.
6. Salomon, R. G.; Ghosh, S. OSC 1990, 7, 177.
7. Church, R. F.; Ireland, R. E. TL 1961, 493.
8. Djerassi, C.; Engle, R. R.; Bowers, A. JOC 1956, 21, 1547.
9. Müller, P.; Blanc, J. HCA 1979, 62, 1980.
10. Liu, H.-J. CJC 1976, 54, 3113.
11. Zibuck, R.; Streiber, J. M. JOC 1989, 54, 4717.
12. Nazarov, I. N.; Zavyalov, S. I. Zh. Obshch. Khim. 1953, 23, 1703; Engl. Transl. 1953, 23, 1793 (CA 1954, 48, 13 667).
13. Glotter, E.; Greenfield, S.; Lavie, D. CC 1968, 1646.
14. Georgiadis, M. P.; Haroutounian, S. A.; Apostolopoulos, C. D. S 1991, 379.
15. Georgiadis, M. P.; Tsekouras, A.; Kotretsou, S. I.; Haroutounian, S. A.; Polissiou, M. G. S 1991, 929.
16. &OOuml;hler, E.; Zbiral, E. S 1991, 357.
17. de A. Epifanio, R.; Camargo, W.; Pinto, A. C. TL 1988, 29, 6403.
18. Ho, T.-L. CI(L) 1972, 807.
19. Rodin, J. O.; Leaffer, M. A.; Silverstein, R. M. JOC 1970, 35, 3152.
20. Cardillo, G.; Contento, M.; Sandri, S.; Panunzio, M. JCS(P1) 1979, 1729.
21. Liu, Z.-Y., Shi, W.; Zhang, L. S 1990, 235.
22. Bal, B. S.; Kochhar, K. S.; Pinnick, H. W. JOC 1981, 46, 1492.
23. Henbest, H. B.; Nicholls, B. JCS 1959, 221.
24. Jones, R. A.; Saville, J. F.; Turner, S. CC 1976, 231.
25. Liotta, D.; Arbiser, J.; Short, J. W.; Saindane, M. JOC 1983, 48, 2932.
26. Araújo, H. C.; Ferreira, G. A. L.; Mahajan, J. R. JCS(P1) 1974, 2257.
27. Boeckman, R. K. Jr.; Blum, D. M.; Ganem, B.; Halvey, N. OSC 1988, 6, 1033.
28. Henry, J. R.; Weinreb, S. M. JOC 1993, 58, 4745.

Fillmore Freeman

University of California, Irvine, CA, USA

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