Perfluoro-N-fluoropiperidine1

[836-77-1]  · C5F11N  · Perfluoro-N-fluoropiperidine  · (MW 283.06)

(liquid, site-selective, mild electrophilic fluorinating agent for stabilized carbanions2)

Physical Data: bp 49.5 °C; d25 1.7043 g cm-3; n20D 1.2752.

Solubility: sol MeOH, EtOH, Me2CO, Et2O, THF, toluene, perfluorocarbons (PFCs); slightly sol CHCl3; insol H2O; unaffected and insol hot (70 °C) 18% aq HCl or 8% aq NaOH; oxidizes ethanol slowly at 100 °C (EtOH -> acetaldehyde, diethyl ether, diethyl hexafluoroglutarate).3

Form Supplied in: colorless liquid (bp 48-50 °C) of ca. 97% purity; inert PFC impurities are n- and i-C5F12, perfluoro(N-methylpyrrolidine).

Analysis of Reagent Purity: 19F NMR, GC, iodimetric titration (treat with KI in warm Me2CO/H2O (9:1 v/v); estimate I2 with thiosulfate, 1 NF &tbond; 1 I2).

Preparative Methods: electrochemical fluorination in anhydrous HF (Simons process) of pyridine (8% yield) or 2-fluoropyridine (13%) in specialized metal equipment.3

Handling, Storage, and Precautions: this toxic, highly volatile, nonflammable liquid should be stored (preferably at 0-5 °C) in tightly stoppered glass vessels (hydrocarbon or silicone greases are not affected) or in sealed ampoules (PTFE/glass stopcocks). Always cool the reagent before transferring it to reaction vessels to avoid losses by evaporation and toxicity hazards. Transfer, in vacuo, from a storage ampule is desirable. Use in a fume-hood. Take standard precautions to avoid breathing vapor, contact of vapor or liquid with eyes, and liquid or its solution with the skin: avoid contamination of clothing. Beware the high toxicity of perfluoro-1-azacyclohexene, produced initially (see below) when using the reagent to effect electrophilic fluorinations. Treatment of mixtures of the reagent and its defluorination product with alkaline aq KI converts them to alkali metal salts of hexafluoroglutaric acid.

Undergoes defluorination to perfluoro-1-azacyclohexene (CF2(CF2)3CF=N) and thence pentafluoropyridine with mild steel at temperatures above 200 °C.3 (Perfluoro-1-azacyclohexene is best prepared by defluorination of the reagent with triphenylphosphine (-> Ph3PF2)).2,4 The N-F bond is broken homolytically by UV light5 or pyrolysis in platinum.3 Stable in Pyrex at rt in Manchester daylight.

Fluorination of Carbanions.

The reagent delivers F+ to carbon centers in highly stabilized carbanions, e.g. sodium salts of nitroalkanes (eq 1),2 substituted malonates (eq 2),2 b-keto esters (eq 3),2 and tris(alkanesulfonyl)methanes (eq 4).6 Yields can be increased by adding an alkali metal fluoride or chloride to reaction mixtures to scavenge perfluoro-1-azacyclohexene produced through fluorine transfer from nitrogen to carbon (eq 5).2 This highly electrophilic imidoyl fluoride competes with the NF reagent for carbanionic species (eq 6),2 a situation which detracts from the use of perfluoro-N-fluoropiperidine with expensive or hard-won substrates; the same situation applies for the analogous NF reagent perfluoro-N-fluoromorpholine7 (noncommercial at present).

Perfluoro-N-fluoropiperidine (and its 2,6-bis(trifluoromethyl) analog) proved unsatisfactory compared with the hazardous gaseous reagent Perchloryl Fluoride as a means for effecting site-selective fluorination of tetraethyl methylenebisphosphonate.8

Fluorination at Nucleophilic Heteroatom Sites.

The reagent has been used to convert piperidine to N-fluoropiperidine (eq 7; exothermic: care!) and triphenylphosphine, -arsine, and -stibine to the corresponding pentavalent difluorides (eq 8).9 The formation of perfluoro-1-azacyclohexene leads to serious consumption of substrates only in the case of piperidine.

Sodium sulfinates smoothly yield sulfonyl fluorides (eqs 9 and 10),6 although restricted choice of solvent can cause loss of product (eq 10).

Fluorination of Electron-Rich Aromatics.

This application has received relatively scant attention (eqs 11 and 12),10,11 the main objective being to probe the mechanism of F+ transfer (see a recent discussion of SN2(F) vs. SET mechanisms for NF and +NF reagents2,12). As with carbanions, the formation of the imidoyl fluoride perfluoro-1-azacyclohexene leads to loss of substrate material.

Utilization.

Although its fluorinating ability was discovered in the early 1960s,13 perfluoro-N-fluoropiperidine has received little attention owing to its low-yield specialized synthesis. The commercial availability of the reagent, coupled with its ease of use and recovery, should lead to far more interest in its applications.


1. (a) Furin, G. G. In New Fluorinating Agents in Organic Syntheses; German, L.; Zemskov, S., Eds.; Springer: Berlin, 1989; pp 34-68. (b) Murtagh, V. Perform. Chem. 1991, 6 (4), 35. (c) Murtagh, V. Perform. Chem. 1992, 7 (4), 27.
2. Banks, R. E.; Murtagh, V.; Tsiliopoulos, E. JFC 1991, 52, 389.
3. Banks, R. E.; Cheng, W. M.; Haszeldine, R. N. JCS 1962, 3407.
4. Banks, R. E.; Mullen, K.; Nicholson, W. J.; Oppenheim, C.; Prakash, A. JCS(P1) 1972, 1098.
5. Banks, R. E.; Mullen, K.; Williamson, G. E. JCS(C) 1968, 2608.
6. Banks, R. E.; Murtagh, V. unpublished results.
7. Banks, R. E.; Burling, E. D. JCS 1965, 6077.
8. Blackburn, G. M.; England, D. A.; Kolkmann, F. CC 1981, 930.
9. Banks, R. E.; Haszeldine, R. N.; Hatton, R. TL 1967, 3993.
10. Polishchuk, V. R.; Medvedev, B. Ya.; Bubnov, N. N.; German, L. S.; Knunyants, I. L. BAU 1972, 21, 2736.
11. Polishchuk, V. R.; German, L. S. TL 1972, 5169.
12. Banks, R. E.; Sharif, I. JFC 1991, 55, 207.
13. Banks, R. E.; Williamson, G. E. CI(L) 1964, 1864.

R. Eric Banks & Vincent Murtagh

University of Manchester Institute of Science and Technology, UK



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