Perchloryl Fluoride1


[7616-94-6]  · ClFO3  · Perchloryl Fluoride  · (MW 102.45)

(electrophilic reagent capable of fluorinating a variety of activated methylene compounds,1-3 steroids,1,4-13 and organometallics;1,14 useful for the formation of covalent aromatic perchlorates1,15)

Alternate Names: chlorine fluoride oxide; chlorine oxyfluoride.

Physical Data: mp -147.7 °C; bp -46.7 °C; d25 1.412 g cm-3 (liq), 0.065 g cm-3 (g).1b,16

Solubility: sol THF, Me2O, MeOH, DMF, MeCN, H2O. Specific solubilities have been measured.17,18

Form Supplied in: colorless gas shipped in cylinders under its own vapor pressure1b (12 atm at 25 °C).

Analysis of Reagent Purity: assessed in the condensed phase using 19F NMR spectroscopy and in the gas phase using vibrational spectroscopy.1f

Preparative Methods: the synthesis of FClO3 involves extremely hazardous materials1f and should not be attempted by inexperienced or untrained personnel.

Handling, Storage, and Precautions: mixtures of FClO3 and organic compounds are potentially hazardous because explosions are always possible. Numerous serious accidents involving FClO3, including those resulting in fatalities, have been documented.1,19 These incidents are normally violent and destructive and occur unexpectedly, e.g. a mixture of FClO3 and THF exploded violently and without warning at room temperature.20 Toxicity, health, and safety information as well as recommendations for selection and use of personal protective equipment can be found in numerous publications.21 Perchloryl fluoride should only be handled by experienced and thoroughly trained personnel and should only be used in a fume hood.

General Considerations.

Safer alternative reagents are commercially available which perform as well and in many cases better than FClO3 in all of its chemistry, e.g. XeF2, (CF3SO2)2NF, N-fluoropyridinium triflate, N-fluoropyridinium pyridine heptafluorodiborate, N-alkyl-N-fluorotoluenesulfonamides, N-fluoroquinuclidinium triflate, and N-fluorodibenzenesulfonamide. A safer, cost-effective, and easily handled reagent, 1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane Bis(tetrafluoroborate) (F-TEDA-BF4), particularly useful for selective fluorination of steroids as well as a wide range of other activated substrates, including methylene and methine carbons,22,23 has recently become available in commercial quantities.

Perchloryl fluoride was one of the first readily available sources of electrophilic fluorine and, as such, gained immense popularity for selective fluorinations of a wide variety of substrates. However, numerous accidents involving FClO3 and the advent in subsequent years of cleaner and safer-to-use electrophilic fluorination reagents have all but abolished perchloryl fluoride from the synthetic chemist's repertoire. Nevertheless, a short summary of the major synthetic transformations which are possible with FClO3 is given below.

Fluorination of Activated Methylenes.

The acidic hydrogen(s) of a methylene group can be substituted by fluorine with FClO3 providing an equimolar amount of a sufficiently strong base is also used. Selectivity in these reactions does vary, depending on the choice of base and solvent. Thus, the fluorination of diethyl malonate in ethanol (eq 1)3 yields four different products, whereas in toluene (eq 2),3 only two products are obtained.

Fluorination of Activated Methines.

Perchloryl fluoride can be used in many cases to substitute the proton of an activated methine carbon with fluorine. While the majority of examples come from the steroid literature, some nonsteroidal examples have also been reported, e.g. the fluorination of cyclohexene enol ether (eq 3)8.

Fluorination of Activated Steroid Enol Ethers and Esters, Enamines, and Enamides.

Perchloryl fluoride can be used for regioselective incorporation of fluorine at a number of positions on activated steroidal substrates. Thus 2-fluoro steroids can be prepared from their corresponding enol ethers, e.g. 3-ethoxy-5a-cholest-2-ene (eq 4),8 enamines, e.g. cholest-2-en-3-one pyrrolidylenamine (eq 5),4 a-hydroxymethylene ketones, e.g. 2,17b-dihydroxyandrostan-3-one (eq 6),6 and from alkoxalyl enolates,24-26 e.g. 2-methoxalylhydrocortisone 20-ethylene acetal (eq 7).25

Perchloryl fluoride and 3-keto steroids conjugated via 3,5-dienes yield different products depending on the functional group at position 3. Thus 21-acetoxy-3-ethoxy-11b-hydroxy-3,5,17(20)-cis-pregnatriene, an enol ether, and the analogous enol acetate of progesterone yield 6-fluoro products (eqs 8 and 9),27,28 respectively, while methyl 11-oxo-3-pyrrolidyl-3,5,17(20)-cis-pregnatrien-21-oate, a dienamine, gives the 4,4-difluoro product (eq 10).27

Incorporation of fluorine at the 16-position of steroids using FClO3 requires highly activated substrates such as 16-formylandrost-5-en-17-one29 and 16-ethoxalylandrost-5-en-17-one.30 In addition, a noteworthy activating group is found in the 17-amino-D16-steroid (enamide) prepared by Beckmann rearrangement of the corresponding 20-keto-D16-steroid.31 Thus treatment of the androstane derivative 3b-acetoxy-17-acetaminoandrosta-5,16-diene, in pyridine, with FClO3 leads to the 16a-fluoro product, 16a-fluoro-3b-acetoxyandrost-5-en-17-one, in 70% yield (eq 11).31 The same transformation can be accomplished in higher yield using either Xenon(II) Fluoride (95% yield) or N-fluoroquinuclidinium triflate (85% yield).

Fluorination of Organometallic Compounds.

Perchloryl fluoride can be used for the fluorination of carbon-metal bonds in ether or THF at low temperature, yielding the monofluoro and, in most cases, protonated derivatives (eqs 12 and 13).14 This type of reaction has also been applied to the fluorination of organolithium heterocycles.32

The fluorinated products in eqs 12 and 13 can be prepared in higher yields under milder conditions using F-TEDA-BF4.23

Perchlorylation of Aromatic Compounds.

A capability unique to perchloryl fluoride is its use for the Friedel-Crafts perchlorylation of activated aromatics (eq 14).15 This type of electrophilic aromatic substitution can be applied to substituted benzene compounds such as toluene, fluorobenzene, and p-xylene, but does not work for deactivated systems such as nitrobenzene. While perchloryl aromatics are resistant to reduction, oxidation, and hydrolysis, they are easily detonated with either heat or shock.15

Other Applications.

Perchloryl fluoride can be used for a number of other applications, including the fluorination of nitro and polynitro hydrocarbons,20,33-36 the fluorination of steroidal-ring phenols,37 the N-fluorination and N-perchlorylation of certain amines,38 and the oxofluorination of certain alkenes.39

Related Reagents.

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane Bis(tetrafluoroborate); N-Fluoro-N-t-butyl-p-toluenesulfonamide; N-Fluoro-N-(phenylsulfonyl)benzenesulfonamide; N-Fluoropyridinium Triflate; Xenon(II) Fluoride.

1. (a) Schmeisser, M.; Brändle, K. In Advances in Inorganic Chemistry and Radiochemistry; Emeléus, H. J.; Sharpe, A. G.; Eds.; Academic: New York, 1963; Vol. 5, pp 41-89. (b) Gall, J. F. In Kirk-Othmer Encyclopedia of Chemical Technology, 2nd ed.; Parolla, E. A., Ed.; Wiley: New York, 1966; Vol. 9, pp 598-610. (c) Sharts, C. M.; Sheppard, W. A. OR 1974, 21, 225. (d) Khutoretskii, V. M.; Okhlobystina, L. V.; Fainzil'berg, A. A. RCR 1967, 36, 145. (e) Sheppard, W. A.; Sharts, C. M. Organic Fluorine Chemistry; Benjamin: New York, 1969. (f) Christe, K. O.; Schack, C. J. Advances in Inorganic Chemistry and Radiochemistry; Emeléus, H. J.; Sharpe, A. G.; Eds.; Academic: New York, 1976; Vol. 18, pp 371-398. (g) Chambers, R. D. Fluorine in Organic Chemistry; Wiley: New York, 1973; pp 41-44.
2. Inman, C. E.; Oesterling, R. E.; Tyczkowski, E. A. JACS 1958, 80, 6533.
3. Gershon, H.; Renwick, J. A. A.; Wynn, W. K.; D'Ascoli, R. JOC 1966, 31, 916.
4. Gabbard, R. B.; Jensen, E. V. JOC 1958, 23, 1406.
5. Kissman, H. M.; Small, A. M.; Weiss, M. J. JACS 1959, 81, 1262.
6. Edwards, J.; Ringold, H. J. JACS 1959, 81, 5262.
7. Nathan, A. H.; Babcock, J. C.; Hogg, J. A. JOC 1959, 24, 1395.
8. Nakanishi, S.; Morita, K.; Jensen, E. V. JACS 1959, 81, 5259.
9. Mills, J. S. JACS 1959, 81, 5515.
10. Robinson, C. H.; Bruce, N. F.; Oliveto, E. P.; Tolksdorf, S.; Steinberg, M.; Perlman, P. L. JACS 1960, 82, 5256.
11. Akhrem, A. A.; Reshetova, I. G.; Titov, Y. A. RCR 1965, 34, 926.
12. Taylor, N. F.; Kent, P. W. Advances in Fluorine Chemistry; Stacey, M.; Tatlow, J. C.; Sharpe, A. G., Eds.; Butterworths: Washington, 1965; Vol. 4, pp 113-141.
13. Nathan, A. H.; Babcock, J. C.; Hogg, J. A. JACS 1960, 82, 1436.
14. Schlosser, M.; Heinz, G. CB 1969, 102, 1944.
15. Inman, C. E.; Oesterling, R. E.; Tyczkowski, E. A. JACS 1958, 80, 5286. WARNING: Aromatic perchlorates detonate violently when initiated by mild heat or shock!
16. Koehler, J. K.; Giauque, W. F. JACS 1958, 80, 2659.
17. Golub, V. B.; Khutoretskii, V. M.; Besprozvannyi, M. A.; Temchenko, V. G.; Antipenko, G. L. Zh. Prikl. Khim. (Leningrad) 1971, 44, 679.
18. Cady, G. H. JFC 1978, 11, 225.
19. Bretherick, L. Bretherick's Handbook of Reactive Chemical Hazards, 4th ed.; Butterworths: London, 1990; pp 938-940.
20. Freeman, J. P.; JACS 1960, 82, 3869.
21. (a) OSHA Regulated Hazardous Substances; Noyes Data Corp.: New Jersey, 1990; Vol. 2, pp 1531-1532. (b) Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 2nd ed.; Noyes: New Jersey, 1985, p 701. (c) Sax's Dangerous Properties of Industrial Materials, 8th ed.; Lewis, R. J., Ed.; Van Nostrand Reinhold: New York, 1992; Vol. 3, pp 2702-2703.
22. Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.; Syvret, R. G. CC 1992, 595.
23. Lal, G. S. JOC 1993, 58, 2791.
24. Nathan, A. H.; Magerlein, B. J.; Hogg, J. A. JOC 1959, 24, 1517.
25. Kissman, H. M.; Small, A. M.; Weiss, M. J. JACS 1960, 82, 2312.
26. Holmlund, C. E.; Feldman, L. I.; Kissman, H. M.; Weiss, M. J. JOC 1962, 27, 2122.
27. Magerlein, B. J.; Pike, J. E.; Jackson, R. W.; Vandenberg, G. E.; Kagan, F. JOC 1964, 29, 2982.
28. Allen, G. R., Jr.; Austin, N. A. JOC 1961, 26, 5245.
29. Robinson, C. H.; Bruce, N. F.; Oliveto, E. P. JOC 1963, 28, 975.
30. Kissman, H. M.; Hoffman, A. S.; Weiss, M. J. JOC 1961, 26, 973.
31. Nakanishi, S.; Jensen, E. V. JOC 1962, 27, 702.
32. Schuetz, R. D.; Taft, D. D.; O'Brien, J. P.; Shea, J. L.; Mork, H. M. JOC 1963, 28, 1420.
33. Khutoretskii, V. M.; Okhlobystina, L. V.; Fainzil'berg, A. A. IZV 1970, 387.
34. Okhlobystina, L. V.; Khutoretskii, V. M.; Fainzil'berg, A. A. IZV 1971, 1487.
35. Erashko. V. I.; Sankov, B. G.; Shevelev, S. A.; Fainzil'berg, A. A. IZV 1973 344.
36. Shechter, H.; Roberson, Jr., E. B. JOC 1960, 25, 175.
37. Mills, J. S.; Barrera, J.; Olivares, E.; García, H. JACS 1960, 82, 5882.
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39. Neeman, M.; Osawa, Y. JACS 1963, 85, 232.

T. Robert G. Syvret

Air Products and Chemicals, Allentown, PA, USA

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