Iron(II) Sulfate-Oxygen1


[7720-78-7]  · FeO4S  · Iron(II) Sulfate-Oxygen  · (MW 278.06) (O2)

[7782-44-7]  · O2  · Iron(II) Sulfate-Oxygen  · (MW 32.00)

(selective oxidant for 15-hydroxylation of steroids,1 direct hydroxylation of aromatic and aliphatic substrates7,8)

Alternate Name: ferrous sulfate-oxygen.

Preparative Methods: the reagent combination is generated in situ via dropwise addition of an aqueous solution (500 mL) of Iron(II) Sulfate (15 g, 54 mmol) to a stirred buffer (0.1 M Na2HPO4, pH 6.8, 2.5 L) solution of substrate (2.25 mmol) under bubbling oxygen at 70 °C. Room temperature may be adequate for some substrates.

Handling, Storage, and Precautions: is air and moisture sensitive; keep in a tightly closed container; incompatible with strong oxidizing agents; irritant; ingestion may be lethal.

Hydroxylation of Steroids.1

The bile acids deoxycholic (eq 1),1 nordeoxycholic, and taurodeoxycholic acids2 are 15-hydroxylated in aqueous buffer by dropwise addition of iron sulfate under a stream of oxygen at 70 °C. Acetone can be used as a cosolvent to improve solubility of some steroids.3 It has been postulated that a positively charged species [Fe2+-O2] interacting with the carboxyl sidechain is responsible for the regiochemistry observed.4 These transformations are in contrast to that observed with a hydroxylating system developed earlier by Udenfriend5 which mimics the biological transformation of deoxycholic acid to cholic acid (eq 2)6 via 7-hydroxylation with FeSO4-O2-ascorbic acid-EDTA.

Direct Hydroxylation of Aromatic and Aliphatic Substrates.

It should be pointed out that direct hydroxylation of organic substrates, so efficiently accomplished in nature (via metalloenzymes), is very difficult to achieve synthetically. Adamantane carboxylic acids can be oxygenated with FeSO4-O2 in buffer solution at 40 °C (eq 3).7 Aromatic compounds can also be hydroxylated: benzoic acid yields 41% of five products and phenol two products (eq 4).8 Many alternate reagents have been reported for direct aryl hydroxylations, mostly as modifications of either Fenton's reagent (FeSO4-H2O2) or Udenfriend's reagent (FeSO4-O2-ascorbic acid-EDTA).9 Recently, attention has focused on alkane hydroxylations using metalloporphyrins,10 cluster catalysts,11 and the Gif oxidation.12

1. (a) Kimura, M.; Kawata, M.; Tohma, M.; Fujino, A.; Yamazaki, K.; Sawaya, T. CPB 1972, 20, 1883. (b) Kimura, M.; Kawata, M.; Tohma, M.; Fujino, A.; Yamazaki, K. TL 1970, 2021.
2. Kimura, M.; Fujino, A.; Yamazaki, K.; Sawaya, T. CPB 1976, 24, 2301.
3. Sawaya, T.; Kimura, M. CPB 1983, 31, 3515.
4. (a) Sawaya, T.; Kimura, M. CPB 1983, 31, 1207. (b) Baldwin, J. E.; Huff, J. ACS 1973, 95, 5757.
5. Udenfriend, S.; Clark, C. T.; Axelrod, J.; Brodie, B. B. JBC 1954, 208, 731.
6. Matkovics, B.; Penzes, P.; Gondos, Gy. Steroids 1965, 5, 451.
7. Miura, T.; Shibata, K.; Sawaya, T.; Kimura, M. CPB 1982, 30, 67.
8. Miura, T.; Shibata, K.; Adachi, K.; Sawaya, T.; Kimura, M. CPB 1983, 31, 100.
9. (a) Funabiki, T.; Toyoda, T.; Ishida, H.; Motoyoshi, T. Ozawa, S.; Yoshida, S. J. Mol. Catal. 1990, 61, 235. (b) Tamagaki, S.; Suzuki, K.; Tagaki, W. BCJ 1989, 62, 148. (c) Tamagaki, S.; Sasaki, M.; Tagaki, W. BCJ 1989, 62, 159. (d) Reinaud, O.; Capdevielle, P.; Maumy, M. CC 1990, 566.
10. Meunier, B. CRV 1992, 92, 1411.
11. (a) Fontecave, M.; Roy, B.; Lambeaux, C. CC 1991, 939. (b) Leising, R. A.; Brennan, B. A.; Que, L.; Fox, B. G.; Munck, E. JACS 1991, 113, 3988.
12. Barton, D. H. R.; Csuhai, E.; Doller, D.; Ozbalik, N.; Balavoine, G. PNA 1990, 87, 3401.

Andrew D. White

Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA

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