Acetyl Hypofluorite1

[78948-09-1]  · C2H3FO2  · Acetyl Hypofluorite  · (MW 78.04)

(convertion of alkenes into fluorohydrin derivatives;2 aromatic fluorination;3 instrumental in introducing the 18F isotope in sugars and other biologically important compounds for positron emitting tomography studies;4 fluorination on a carbon a to carbonyl;5 activation of pyridine derivatives6)

Physical Data: mp -96 °C; bp approx +53 °C; 19F NMR +168.5 ppm; thermal decomposition to MeF and CO2.7

Analysis of Reagent Purity: AcOF oxidizes iodides to iodine which is then titrated (AcOF + 2KI + H+ -> KF + AcOH + K+ + I2).

Handling, Storage, and Precautions: as with all hypofluorites this reagent should be treated with care. When not in solution, or when very concentrated, it may explode.8 Solutions of up to 0.3 M in CFCl3 at -78 °C or in MeCN at -45 °C are stable for days, but at rt the half-life is around 2-4 h. No data about the toxicity are available, but some hypofluorite derivatives such as CF3OF and F2O are known to be toxic. Use in a fume hood.

Acetyl hypofluorite, prepared in 1981 by reacting F2 with AcONa,9 was the first hypofluorite to possess a hydrogen-containing alkyl group in the vicinity of the O-F bond. The fluorine in this reagent is of electrophilic nature, as can be judged from reactions with enol acetates10 or enolates5b when a-fluoro carbonyl derivatives are produced (eqs 1 and 2). Similar conclusions can be drawn from its reactions with unsymmetrical alkenes. Apart from regioselectivity, the addition of AcOF across double bonds is also stereospecific, resulting from a preferential syn addition10,11 (eq 3), a mode characteristic of all reagents with electrophilic fluorine.

The electrophilic nature of the fluorine was also used for aromatic substitution of activated aromatic rings with predominant ortho fluorination (eq 4).3,12 This procedure was used for direct fluorination of the opiatic peptide dermorphine (eq 5).13

Aromatic fluorination was also achieved via substitution of an Ar-M bond. It seems that the best metals are tin14 and mercury. The latter was used for synthesis of fluorodopa derivatives (eq 6).15

AcOF was used exclusively for introducing the 18F isotope in order to construct compounds suitable for positron emitting tomography (PET). Among numerous examples, we will mention here the synthesis of 2-deoxy-2-[18F]fluoro-D-glucose16 and [18F]fluorodopa,4,17 both used for brain studies, 6-[18F]fluorometaraminol (eq 7) as a heart imaging agent,18 and [18F]fluoro-2-oxoquasepam (eq 8) with a strong affinity to benzodiazepine receptors.19

AcOF was also used for activating the inert pyridine ring. The reaction takes advantage of the electrophilic power of the fluorine which is able to attack the nitrogen atom. As a result, the 2-position becomes very susceptible to nucleophilic attacks by either the remaining acetate or nucleophilic solvents, if present (eq 9). The elimination of HF is a strong driving force for the reaction, explaining the speed at low temperatures.6

1. (a) Rozen, S. ACR 1988, 21, 307. (b) Purrington, S. T.; Kagen, B. S.; Patrick, T. B. CRV 1986, 86, 997. (c) Mann, J. CSR 1987, 16, 381. (d) Haas, A.; Lieb, M. C 1985, 39, 134. (e) Vyplel, H. C 1985, 39, 305.
2. (a) Rozen, S.; Lerman, O.; Kol, M.; Hebel, D. JOC 1985, 50, 4753. (b) Vyplel, H.; Scholz, D.; Loibner, H.; Kern, M.; Bednarik, K.; Schaller, H. TL 1992, 33, 1261. (c) Rozen, S.; Bareket, Y.; Kol, M. JFC 1993, 61, 141.
3. Lerman, O.; Tor, Y.; Hebel, D.; Rozen, S. JOC 1984, 49, 806.
4. (a) Adam, M. J.; Jivan, S. J. Lab. Comp. Radiopharm. 1992, 31, 39. (b) Tada, M.; Matsuzawa, T.; Yamaguchi, K.; Abe, Y.; Fukuda, H.; Itoh, M.; Sugiyama, H.; Ido, T.; Takahashi, T. Carbohydr. Res. 1987, 161, 314.
5. (a) Lerman, O.; Rozen, S. JOC 1983, 48, 724. (b) Rozen, S.; Brand, M. S 1985, 665.
6. (a) Rozen, S.; Hebel, D. H 1989, 28, 249. (b) Hebel, D.; Rozen, S. JOC 1991, 56, 6298.
7. (a) Appelman, E. H.; Mendelsohn, M. H.; Kim, H. JACS 1985, 107, 6515. (b) Hebel, D.; Lerman, O.; Rozen, S. JFC 1985, 30, 141.
8. Adam, M. J. Chem. Eng. News 1985, 63 (7), 2.
9. (a) Rozen, S.; Lerman, O.; Kol, M. CC 1981, 443. (b) Jewett, D. M.; Potocki, J. F.; Ehrenkaufer, R. E. JFC 1984, 24, 477.
10. Rozen, S.; Lerman, O.; Kol, M.; Hebel, D. JOC 1985, 50, 4753.
11. (a) Adam, M. J.; Pate, B. D.; Nesser, J. R.; Hall, L. D. Carbohydr. Res. 1983, 124, 215. (b) Dax, K.; Glanzer, B. I.; Schulz, G.; Vyplel, H. Carbohydr. Res. 1987, 162, 13.
12. Hebel, D.; Lerman, O.; Rozen, S. BSF 1986, 861.
13. Hebel, D.; Kirk, K. L.; Cohen, L. A.; Labroo, V. M. TL 1990, 31, 619.
14. Adam, M. J.; Ruth, T. J.; Jivan, S.; Pate, B. D. JFC 1984, 25, 329.
15. Luxen, A.; Barrio, J. R. TL 1988, 29, 1501.
16. Shiue, C. Y.; Wolf, A. P. JFC 1986, 31, 255.
17. Chirakal, R.; Garnett, E. S.; Schrobilgen, G. J.; Nahmias, C.; Firnau, G. Chem. Br. 1991, 27, 47.
18. Mislankar, S. G.; Gildersleeve, D. L.; Wieland, D. M.; Massin, C. C.; Mulholland, G. K.; Toorongian, S. A. JMC 1988, 31, 362.
19. Duelfer, T.; Johnström, P.; Stone-Elander, S.; Holland, A.; Halldin, C.; Haaparanta, M.; Solin, O.; Bergman, J.; Steinman, M.; Sedvall, G. J. Lab. Comp. Radiopharm. 1991, 29, 1223.

Shlomo Rozen

Tel Aviv University, Israel

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