Trifluoromethyl Hypofluorite1

CF3OF

[373-91-1]  · CF4O  · Trifluoromethyl Hypofluorite  · (MW 104.01)

(electrophilic fluorinating agent1b for the preparation of a-fluoro carbonyl compounds,10 2-fluoroaldoses,13 fluoro dienones,17 aryl fluorides,17 5-fluoropyrimidines (and nucleosides),22 N-fluoroamides,18 and N,N-difluoroamines;27 regioselective replacement of tertiary hydrogen by fluorine28)

Alternate Name: fluoroxytrifluoromethane

Physical Data: mp <-215 °C; bp -97 °C; d 1.9 g cm-3 (at -97 °C).

Solubility: slightly sol CFCl3, CF3CO2H, CF3CH2OH; slightly sol (reacts slowly) MeCO2H, MeCN, MeNO2 (solubility in all solvents increases at low temperature).

Form Supplied in: not presently commercially available; has been available as a compressed gas.

Analysis of Reagent Purity: hypofluorite can be estimated by iodometric titration (CF3OF + 2KI + H2O -> I2 + CO2 + 2KF + 2HF). Comparison of the oxidizing capacity with gas volume and/or acid produced during reduction is a reasonable measure of reagent purity. Reaction with stilbene2 has been used to assay identity and purity of hypofluorites.3e

Preparative Methods: continuous flow fluorination of CO by Fluorine over supported Silver3a or Cesium Fluoride3b,c catalyst (latter preferred). Static fluorination of COF2 by F2 over CsF.3d The aggressive nature of both F2 and CF3OF, the extremely exothermic nature of the reactions (DHformation CF3OF = -775 kJ mol-1), and the variable quality of the catalyst render these preparations rather hazardous. Commercial production (ca. 300 g scale) was plagued by explosions of the liquified product obtained in the first procedures and by rupture of safety discs (200 atm) in the batch process.4 Fluorination of COF2 over CsF in an open continuous flow reactor to produce the reagent as needed (without condensation or other accumulation of large amounts of the product) should be considered. A reasonable small-scale alternative may be use of the mixed C1 and C2 hypofluorites obtained by the fluorination of CF3CO2Na3e (a variety of hypofluorites appear to attach a fluorine atom to most substrates in essentially the same way).5

Purification: the reagent as prepared often contains COF2, which may be removed by passing the gas through water.

Handling, Storage, and Precautions: although thermally stable and reported to survive storage for a year in passivated metal cylinders,3c CF3OF is an extremely aggressive oxidant (H2O is oxidized slowly at neutral pH, quite rapidly at higher pH; unpassivated metal tubing can ignite and burn; explosions have resulted when using PVC tubing). It is recommended that apparatus coming in contact with the reagent be made of glass, passivated metal, or fluorocarbon (e.g. Teflon, Kel-F). Solutions of CF3OF in CFCl3 are reported to be quite stable;3e solutions in most other solvents should be considered metastable and potentially explosive; solutions in oxidizable solvents, particularly ethers, may react spontaneously and explosively. Slow addition of the reagent to the substrate (to minimize accumulation of reagent) is recommended. Reactions should be carried out on a small scale and precautions suited to potentially explosive reactions taken. CF3OF is highly toxic (L(ct)50 ~172 ppm, similar to that of OF2 and perfluoroisobutene).4 Daily exposure to 0.1 ppm for 2 h is reported to cause bone damage in rats.6 Laboratory workers anticipating use of CF3OF should first familiarize themselves with handling3c,13a,18 and safety precautions.3a,c,d,e,22b

Preparation of a-Fluoro Carbonyl Compounds.

Electrophilic addition of CF3OF is well illustrated by the fluorination of the vinyl acetate (1) to give adducts (2) and (3) and a-fluoro ketone (4) (eq 1).7

Formation of F2 adducts such as (2) (presumably through decomposition of CF3O- into COF2 and F-) is characteristic of electrophilic reactions of CF3OF1b (inclusion of a mild, insoluble, inorganic base, for example CaO, MgO, or NaHCO3, protects sensitive substrates). Similar chemistry has been used to prepare 6- and 9-fluorinated steroids.8,9

Silyl enol ethers from aldehydes, ketones, esters, and amides react with CF3OF to provide a-fluoro carbonyl compounds in good yield (eq 2). R can vary widely; note the regioselectivity implicit in formation of (5) and (6).10 (A similar fluorination of less complex substrates with F2 has been reported.11 Compare also the fluorination of enolate anions with N-fluoro-N-methyltoluenesulfonamide.) Fluorination of enamides, e.g. (7) -> (8), provides intermediates for branched chain fluoro sugars (eq 3).12

Acetyl D-glucal (9) fluorinates smoothly to give the 2-fluoro glucose (11) and mannose (10) analogs (eq 4).13a

Each of the adducts (X = F or X = OCF3) can be hydrolyzed to the corresponding pyranose in good yield; this reaction has been used for the synthesis of fluorinated pentoses,13b hexoses,13c and disaccharides.13d The fluorination of acetyl glucal by F2 (little stereoselectivity14) and with Acetyl Hypofluorite15 (gluco:manno ca. 20:1) has been reported. 8-Fluoroerythronolides A and B have been prepared by a similar fluorination (90%) of an internal enol ether.16

Direct Fluorination of Aromatic Rings.

CF3OF substitutes F for H ortho or para to good electron-releasing groups in benzene (and condensed benzene) derivatives.3c,17 While intrinsic ortho:para selectivity is not great (ca. 3:1 with anisole and from 2.5:1 to 9:1 in some N-acylanilides3c), the preparation of (12)-(15) by the direct fluorination of the corresponding hydrocarbon illustrates the utility of the method.3c,17a,c,d

AcOF has been also used for direct fluorination, but it is a good deal less reactive.

Hydroxy substituted aromatics with o- or p-alkyl or fluorine substituents tend to undergo ipso fluorination to give a- or g-fluorocyclohexadienones; thus (16)18 and (17)17a were prepared by fluorination of the corresponding phenols, while (18)17a,b was obtained from fluorination of either the acetate or the methyl ether. Enforced ipso fluorination of pentafluorophenol is the key step in a convenient synthesis of perfluorocyclopentadiene.19

CF3OF tends to give addition products (rather than substitution) with deactivated aromatics, the K region of polycyclics20 and heterocyclics (such as N-acylindole and benzofuran).21

5-Fluoropyrimidines (and Nucleosides).

CF3OF in polar solvents converts pyrimidines into addition products, e.g. (19) -> (20) (eq 5) (X = OH, OMe, or other nucleophile derived from the solvent).22 If R3 = H (otherwise the adducts are stable), heating22a or treatment with Triethylamine22b causes elimination of HX leading to a 5-fluoro pyrimidine, (20) -> (21). The latter procedure is favored as it permits the direct preparation of analogs of cytosine (Y = NH)22b as well as those with X = O and allows for the direct fluorination of nucleosides22b (R1 = ribosyl, deoxyribosyl, etc.).

A variety of 5-F pyrimidines (and nucleosides) of biological interest have been so prepared.22c Radiolabeled 5-F compounds are conveniently prepared through direct fluorination of the readily available 5-H compounds.23 Barbituric acid analogs (R2 = OH) are also converted into 5-F compounds.22a (Pyrimidines have been fluorinated by F2,24 and 5-fluorouracil (21) (X = O, R1 = R2 = H) is prepared commercially on a quite large scale with F2).25

N-Fluoro Amides and N,N-Difluoramines.

CF3OF reacts with amides, first producing an N-F amide which may be further fluorinated (and cleaved) in a second step to give a difluoramino compound and an acyl derivative (X = F or OCF3) (eq 6).18

Although the rapidity of the second step impairs the synthesis of N-F carboxamides, fluorination at low conversion leads to acceptable yields (50-70%) of rather complex products26 (i.e. 22). N-F sulfonamides (23) are formed in good yield,18 as are N-F phosphoramides, e.g. (24).26

As amide nitrogen reacts with CF3OF rather more slowly than activated aromatic rings,18 this method is limited to the preparation of N,N-difluoramines bearing more robust substituents. This limitation is circumvented by fluorination of imino ethers (readily prepared by alkylation of amides) (eq 7), e.g. preparation of (24) and (25) from the corresponding imino ethers having R1 = Ph.18

Schiff bases react with CF3OF,27 and if the reaction is carried out in the presence of an alcohol27b the final cleavage is highly regioselective, affording RNF2 (eq 8); in the absence of alcohol the alternative cleavage giving ArCF2NF2 intrudes.

Use of Ar = Ph leads to easy purification of compounds such as (27), while use of Ar = p-NaO2C-C6H4 leads to easy recovery of the neutral compounds, e.g. (28).

Direct Replacement of sp3 H by F.

CF3OF reacts slowly with saturated hydrocarbons in the presence of a radical chain inhibitor (O2, PhNO2, etc., the absence of which leads to nonselective radical fluorination) to selectively replace tertiary hydrogen atoms with F.28 This remarkable electrophilic reaction is quite regioselective (virtually restricted to tertiary H and extremely sensitive to remote electron-withdrawing groups); note (29)-(31), each obtained by fluorination of the corresponding hydrocarbon. The same regioselectivity and comparable (or superior) yield can be obtained with F2.28

Miscellaneous Reactions.

Fluorination of diazo compounds;29a fluorodemetalation of organometallics;29b photoinitiated radical replacement of H by F;29c photoinitiated radical addition to alkenes.29d


1. (a) Inorganic chemistry: Lustig, M.; Shreeve, J. M. Adv. Fluorine Chem. 1973, 7, 175. Use as fluorinating agent: (b) Hesse, R. H. Isr. J. Chem. 1978, 17, 60. (c) Gerstenberger, M. R. C.; Haas, A. AG(E) 1981, 20, 647. (d) Both: Mukhametshin, F. M.; RCR 1980, 49, 668.
2. Barton, D. H. R.; Hesse, R. H.; Jackman, G. P.; Ogunkoya, L.; Pechet, M. M. JCS(P1) 1974, 739.
3. (a) Cady, G. H. Inorg. Synth. 1966, 8, 165. (b) Wechsberg, M.; Cady, G. H. JACS 1969, 91, 4432. (c) Fifolt, M. J.; Olczak, R. T.; Mundhenke, R. F.; Bieron, J. F. JOC 1985, 50, 4576. (d) Lustig, M.; Pitochelli, A. R.; Ruff, J. K. JACS 1967, 89, 2841. (e) Mulholland, G. K.; Ehrenkaufer, R. E. JOC 1986, 51, 1482.
4. DuBoisson, R. Personal communication.
5. Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Tarzia, G.; Toh, H. T.; Westcott, N. D. CC 1972, 122.
6. Zhang, Y.; Zheng, Z.; Yang, C.; Jiang, Y.; Yang, T. Huaxi Yike Daxue Xuebao 1989, 20, 92 (CA 1989, 110, 207 405w).
7. Barton, D. H. R.; Godinho, L. S.; Hesse, R. H.; Pechet, M. M. CC 1968, 804.
8. Barton, D. H. R.; Danks, L. J.; Hesse, R. H.; Pechet, M. M.; Wilshire, C. NJC 1977, 1, 315.
9. Barton, D. H. R.; Hesse, R. H.; Tarzia, G.; Pechet, M. M. CC 1969, 1497.
10. Middleton, W. J.; Bingham, E. M. JACS 1980, 102, 4845.
11. Purrington, S. T.; Lazaridis, N. V.; Bumgardner, C. L. TL 1986, 27, 2715.
12. Bischofberger, K.; Brink, A. J.; Jordaan, A. JCS(P1) 1975, 2457.
13. (a) Adamson, J.; Foster, A. B.; Hall, L. D.; Hesse, R. H. CC 1969, 309. Adamson, J.; Foster, A. B.; Hall, L. D.; Johnson, R. N.; Hesse, R. H. Carbohyd. Res. 1970, 15, 351. (b) Dwek, R. A.; Kent, P. W.; Kirby, P. T.; Harrison, A. S. TL 1970, 2987. Albano, E. L.; Tolman, R. L.; Robins, R. K. Carbohyd. Res. 1971, 19, 63. Butchard, G. C.; Kent, P. W. T 1971, 27, 3457. (c) Adamson, J.; Marcus, D. M. Carbohyd. Res. 1970, 13, 314. Adamson, J.; Foster, A. B.; Westwood, J. H. Carbohyd. Res. 1971, 18, 345. Adamson, J.; Marcus, D. M. Carbohyd. Res. 1972, 22, 257. Butchard, G. C.; Kent, P. W. T 1979, 35, 2439 and 2551. (d) Kent, P. W.; Dimitrijevich, S. D. JFC 1977, 10, 455.
14. Ido, T.; Wan, C. N.; Fowler, J. S.; Wolf, A. P. JOC 1977, 42, 2341.
15. Bida, G. T.; Satyamurthy, N.; Barrio, J. R. J. Nucl. Med. 1984, 25, 1327. VanRijn, C. J. S.; Herschied, J. D. M.; Visser, G. W. M.; Hoekstra, A. Int. J. Appl. Radiat. Isot. 1985, 36, 111 and references therein.
16. Toscano, L.; Fioriello, G.; Silingardi, S.; Inglesi, M. T 1984, 40, 2177.
17. (a) Barton, D. H. R.; Ganguly, A. K.; Hesse, R. H.; Loo, S. N.; Pechet, M. M. CC 1968, 806. Airey, J.; Barton, D. H. R.; Ganguly, A. K.; Hesse, R. H.; Pechet, M. M.; An. Quim. 1974, 70, 871. (b) Chavis, C. Mousseron-Canet, M. BSF 1971, 632. (c) Barton, D. H. R.; Hesse, R. H.; Ogunkoya, L.; Westcott, N. D.; Pechet, M. M. JCS(P1) 1972, 2889. (d) Bélanger, P. C.; Lau, C. K.; Williams, H. W. R.; Dufresne, C.; Scheigetz, J. CJC 1988, 66, 1479.
18. Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Toh, H. T. JCS(P1) 1974, 732.
19. Solech, R. R.; Mauer, G. W.; Lemal, D. M. JOC 1985, 50, 5845.
20. Patrick, T. B.; LeFaivre, M. H.; Koertge, T. E. JOC 1976, 41, 3413. Patrick, T. B.; Cantrell, G. L.; Chang, C.-Y. JACS 1979, 101, 7434.
21. Barton, D. H. R.; Hesse, R. H.; Jackman, G. P.; Pechet, M. M. JCS(P1) 1977, 2604.
22. (a) Barton, D. H. R.; Hesse, R. H.; Toh, H. T.; Pechet, M. M. JOC 1972, 37, 329; Barton, D. H. R.; Bubb, W. A.; Hesse, R. H.; Pechet, M. M. JCS(P1) 1974, 2095. (b) Robins, M. J.; Naik, S. R. JACS 1971, 93, 5277; Robins, M. J.; MacCoss, M.; Naik, S. R.; Ramani, G. JACS 1976, 98, 7381. (c) see end-note 37 of previous reference.
23. Dawson, W. H.; Dunlap, R. B. J. Labelled Compd. Radiopharm. 1979, 16, 335. Silverman, R. B.; Kapili, L. V. J. Labelled Compd. Radiopharm. 1979, 16, 361.
24. Meinert, H.; Cech, D, ZC 1972, 12, 292. Cech, D.; Holy, A. CCC 1976, 41, 3335. Cech, D.; Beerbaum, H.; Holy, A. CCC 1977, 42, 2694. Cech, D.; Herrmann, G.; Holy, A. Nucleic Acid Res. 1977, 4, 3259 and references cited in the last two papers; it is quite possible that the effective reagent in AcOH is AcOF rather than F2.
25. Stump, E. C. Personal communication.
26. (a) Hammer, C. F.; Chandrasegaran, S. JACS 1984, 106, 1543. (b) Zon, G.; Ludeman, S. M.; Ozakan, G.; Chandrasegaran, S.; Hammer, C. F.; Dickerson, R.; Mizuta, K.; Egan, W. J. Pharm. Sci. 1983, 72, 687.
27. (a) Leroy, J.; Dudrage, F.; Adenis, J. C.; Michaud, C. TL 1973, 2771. (b) Barton, D. H. R.; Hesse, R. H.; Klose, T. R.; Pechet, M. M. CC 1975, 97.
28. Barton, D. H. R.; Hesse, R. H.; Markwell, R. E.; Pechet, M. M.; Toh, H. T. JACS 1976, 98, 3034. Barton, D. H. R.; Hesse, R. H.; Markwell, R. E.; Pechet, M. M.; Rozen, S. JACS 1976, 98, 3036. Alker, D.; Barton, D. H. R.; Hesse, R. H.; Lister-James, J.; Markwell, R. E.; Pechet, M. M.; Rozen, S.; Takeshita, T.; Toh, H. T. NJC 1980, 4, 239.
29. (a) Leroy, J.; Wakselman, C. JCS(P1) 1978, 1224. (b) Bryce, M. R.; Chambers, R. D.; Mullins, S. T.; Parkin, A. BSF 1986, 930. (c) Kollonitsch, J.; Barash, L.; Doldouras, G. A. JACS 1970, 92, 7494. (d) Sekiya, A.; Ueda, K. CL 1990, 609.

Robert H. Hesse

Research Institute for Medicine and Chemistry, Cambridge, MA, USA



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