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Org. Synth. 2010, 87, 245

DOI: 10.15227/orgsyn.087.0245

DIRECT FLUORINATION OF THE CARBONYL GROUP OF BENZOPHENONES USING DEOXO-FLUOR^®: PREPARATION OF BIS(4-FLUOROPHENYL)DIFLUOROMETHANE

Submitted by Ying Chang, Hyelee Lee, and Chulsung Bae¹.

Checked by David Hughes

1. Procedure

Caution! Deoxo-Fluor® reacts rapidly and exothermally with water, generating HF. It is volatile and a respiratory hazard and must be handled in a well-ventilated hood.

Bis(4-fluorophenyl)difluoromethane. An oven-dried 50-mL round-bottomed flask equipped with an oval Teflon-coated magnetic stirring bar (2 cm) is charged with 4,4'-difluorobenzophenone (1) (5.11 g, 23.4 mmol, 1.0 equiv) (Note 1). Deoxo-Fluor^® (Note 2) (13 mL, 15.7 g, 71 mmol, 3 equiv) is added via a disposable graduated pipette. The flask is fitted with a reflux condenser equipped with a gas inlet adapter connected to a nitrogen line and a gas bubbler. The reaction solution is stirred in a preheated 90 °C oil bath (Notes 3, 4, and 5) for 24 h under nitrogen to give a dark red mixture with yellow solids. The flask is removed from the oil bath and cooled to room temperature. Dichloromethane (30 mL) is added and the mixture is transferred to a 250-mL separatory funnel, followed by additional dichloromethane (2 × 30 mL) to rinse the flask. The organic solution is washed with water (2 × 50 mL) (Note 6), then saturated aqueous NaHCO₃ solution (50 mL) (caution: Due to the generation of CO₂, the separatory funnel should be shaken carefully and the pressure released frequently). A final wash is carried out with saturated aqueous NaCl solution (50 mL), then the organic layer is vacuum-filtered through a bed of Na₂SO₄ (20 g) in a 150-mL medium-porosity sintered-glass funnel. The cake is washed with dichloromethane (3 × 25 mL) until colorless. The filtrate is concentrated by rotary evaporation (40 °C bath, 100 mmHg initial vacuum, lowered to 20 mmHg) to afford the crude product as a red oil (6.9 g). Purification using column chromatography (Note 7) on SiO₂ affords 4.42-4.87 g of bis(4-fluorophenyl)difluoromethane (2) as a colorless oil (78-86% yield) (Notes 8 and 9).

2. Notes

1. Reagents and solvents were used as received and sourced as follows: 4,4'-difluorobenzophenone (Acros, 99%), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor^®) (Sigma-Aldrich), dichloromethane (Sigma-Aldrich, ACS reagent, 99.5%), silica gel (Sigma-Aldrich, 230-400 mesh, 60 Å), ethyl acetate (Sigma-Aldrich, ACS reagent, >99.5%), hexanes (Sigma-Aldrich, ACS reagent, >98.5%), and sodium sulfate (Fisher Scientific).

2. Deoxo-Fluor^® is volatile and a respiratory hazard and must be handled in a well-ventilated hood. The checker pipetted Deoxo-Fluor^® in the hood and weighed the stoppered flask before and after addition.

3. Deoxo-Fluor^® is known to decompose initiating at 140 °C.² Thus, the oil bath temperature must be kept below 110 °C for safety concerns. A 90 °C oil bath temperature provides efficient fluorination; raising the oil bath temperature to 100 °C does not improve the yield. For substrates with high molecular weight, such as 4,4'-dibromobenzophenone, the stirring may be difficult at the beginning, but this does not affect the reaction yield as the stirring gradually becomes more efficient during the course of the reaction.

4. In a separate experiment, a 2.5 g reaction was carried out in 2-necked, 50-mL flask with a thermocouple thermometer inserted through a septum. The internal temperature was monitored (84 °C) using a J-Kem Gemini digital thermometer with a Teflon-coated T-Type thermocouple probe (12-inch length, 1/8 inch outer diameter, temperature range -200 to +250 °C). This reaction proceeded to 84% conversion with a 78% isolated yield.

5. The reaction was monitored by ¹H NMR as follows. A drop of the reaction mixture was added to 1 mL of CDCl₃ and 1 mL of sat. NaHCO₃. The layers were mixed, then the bottom layer was filtered into an NMR tube through Na₂SO₄ and a cotton plug. Multiplets at 7.20 and 7.85 ppm from the starting material were integrated relative to the product resonances at 7.1 and 7.5 ppm to assess conversion. The reaction proceeded to 84-90% conversion for experiments carried out at the 2.5-5 g scale. Additional reaction time did not result in increased conversion. Addition of one equiv of Deoxo-Fluor^® at the end of the reaction and heating for a further 24 h only increased conversion by 2-3%.

6. Slight foams are produced due to the remaining Deoxo-Fluor^® or its decomposition products.

7. A 5-cm glass column is wet-packed (2.5% hexanes/EtOAc) with SiO₂ (200 g) topped with 0.5 cm sand. The crude reaction product is loaded neat onto the column and eluted as follows: 2.5% EtOAc/hexanes (600), 3% EtOAc/hexanes (750), collecting 50-mL fractions. TLC (UV visualization) is used to follow the chromatography. The R_f value of the title compound is 0.5 (2.5% EtOAc/hexanes), the starting material has an R_fof 0.05. Fractions 8-21 are concentrated by rotary evaporation (40 °C bath, 20 mmHg), then vacuum dried (20 mmHg) at 22 °C for 2 h to constant weight (4.42-4.87 g, 78-86% yield). The product contains <0.1 wt % EtOAc and hexanes by ¹H NMR analysis. Fractions 25-29 are combined and concentrated to afford 0.50-0.8 g (10-16%) of unreacted starting material 1.

8. The checker obtained the following yields from three experiments:

Scale (1)	Isolated product 2 (%)	Unreacted starting material (1) (%)


5.11 g	4.86 g (86%)	0.50 g (10%)
3.88 g	3.56 g (83%)	0.49 (13%)
2.56 g	2.19 g (78%)	0.41 (16%)

9. Bis(4-fluorophenyl)difluoromethane(2) has the following physical and spectroscopic data: ¹H NMR pdf (400 MHz, CDCl₃) δ: 7.09-7.14 (m, 4 H), 7.46-7.51 (m, 4 H); ¹⁹F NMR pdf (376 MHz, CDCl₃) δ: -110.7 (t, ⁶J_FF = 3 Hz, 2 F, Ar-F), -86.3 (t, ⁶J_FF = 3 Hz, 2 F, CF₂); ¹³C NMR pdf (100 MHz, CDCl₃) δ: 115.5 (d, ²J_CF = 22 Hz), 120.1 (t, ¹J_CF = 242 Hz), 128.1 (dt, ³J_CF = 9.0 Hz, ³J_CF = 5.2 Hz), 133.5 (td, ²J_CF = 29 Hz, ⁴J_CF = 3 Hz), 163.6 (dt, ¹J_CF = 249 Hz, ⁵J_CF = 2 Hz); MS (EI) m/z 240 (M⁺, 48), 221 (16), 145 (100), 126 (16), 95 (18), 75 (17). GC/MS (Shimadzu QP2010S equipped with a 30 m × 0.25 mm SHR-XLB GC column and an EI ionization MS detector) indicated product purity >99%. An analytical sample was prepared by dissolving 100 mg of product in 3 mL of hexanes, filtering through a 0.45 micron PTFE syringe filter, and vacuum concentration for 3 h at ambient temperature. Anal. calcd. for C₁₃H₈F₄: C, 65.01; H, 3.36; found: C, 64.77; H, 3.32. Safety and Waste Disposal Information All hazardous materials should be handled and disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.

3. Discussion

Selective fluorination of carbonyl groups to the gem-difluorides is a useful transformation that has been traditionally achieved by the use of gaseous sulfur tetrafluoride³ and diethylaminosulfur trifluoride (DAST)⁴; however, the harsh reaction conditions and the toxicity of sulfur tetrafluoride and the thermal instability of DAST have limited their use in large-scale reactions. Deoxo-Fluor^® is known to be more thermally stable than DAST.²^,⁵

Compared with the well-studied fluorination of the carbonyl group of aldehydes and alkyl ketones, the carbonyl group of diaryl ketones is much less reactive under the general fluorination conditions and requires harsh conditions, which causes safety concerns.⁶ Thus, two-step procedures which involve conversion of the carbonyl group of benzophenones to more reactive thioketones or thiolanes were developed for the gem-difluorination of benzophenones.^6-7 The direct fluorination procedure of benzophenones with Deoxo-Fluor^® described here is a modified procedure of our previously reported method.⁸ In this work, the fluorination reactions are conducted in a flask equipped with a reflux condenser under a nitrogen atmosphere rather than in a closed system, such as a pressure tube and screw-capped vial. The implementation of this more general experimental procedure allows a more convenient, safer, and scalable preparation of gem-difluoride compounds from the corresponding benzophenones.

The fluorination of 4,4'-difluorobenzophenone (1 g scale) with Deoxo-Fluor^® was monitored by GC/MS and the conversion was improved from 56% to 75% by increasing the reaction time from 4 to 24 h. Considering the high cost of Deoxo-Fluor^® and the limited solubility of some of the substrates in Deoxo-Fluor^® under neat conditions, we choose 24 h as the standard reaction time. The effect of the fluorinating reagent ratio on the conversion was investigated using benzophenone (1 g scale) as substrate. When 1.4 equiv of Deoxo-Fluor^® was used, the corresponding gem-difluoride was isolated in 27% yield. Increasing the amount of Deoxo-Fluor^® to 3 equiv improved the yield to 63%. No significant additional improvement was obtained by a further increase of Deoxo-Fluor^® to 4 equiv.

Table 1. Conversion of Diaryl Ketones to Diaryldifluoromethanes^a

The scope of the direct conversion of the carbonyl groups of benzophenones to the gem-difluorides was examined with substrates containing halogen, alkoxy, and nitro substituents on one or both aromatic rings (Table 1). The effect of steric hindrance was observed in the gem-difluorination of 2-chlorobenzophenone, as only a 20% yield was obtained (entry 2). The electronic effect also plays an important role in the reaction yields: substrates bearing an electron-withdrawing group formed the gem-difluorinated products in good to high yields (61-95%, entries 1 and 3-10) while low yields were obtained for benzophenones bearing an electron-donating group such as methoxy (13%, entry 11).

References and Notes

Department of Chemistry and Chemical Biology, New York State Center for Polymer Synthesis, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180.
Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M. Chem. Commun. 1999, 215-216.
(a) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, 2006 (b) Smith, W. C.; Tullock, C. W.; Muetterties, E. L.; Hasek, W. R.; Fawcett, F. S.; Engelhardt, V. A.; Coffman, D. D. J. Am. Chem. Soc. 1959, 81, 3165-3166. (c) Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J. Am. Chem. Soc. 1960, 82, 543-551. (d) Boswell, G. A; Ripka, W. C.; Scribner, R. M.; Tullock, C. W. Org. React. (N. Y.) 1974, 21, 20-30. (e) Gerstenburger, M. R. C.; Haas, A. Angew. Chem., Int. Ed. Engl. 1981, 20, 647-667. (f) Dmowski, W.; Kaminski, M. J. Fluorine Chem. 1983, 23, 219-228.
(a) Messina, P. A.; Mange, K. C.; Middleton, W. J. J. Fluorine Chem. 1989, 42, 137-143. (b) McCarthy, J. R.; Peet, N. P.; LeTourneau, M. E.; Inbasekaran, M. J. Am. Chem. Soc. 1985, 107, 735-737. (c) Manandhar, S.; Singh, R. P.; Eggers, G. V.; Shreeve, J. M. J. Org. Chem. 2002, 67, 6415-6420. (d) Nishizono, N.; Sugo, M.; Machica, M.; Oda, K. Tetrahedron 2007, 63, 11622-11625. (e) Robins, M. J.; Wnuk, S. F. J. Org. Chem. 1993, 58, 3800-3801. (f) Middleton, W. J. J. Org. Chem. 1975, 40, 574-578. (g) Singh, R. P.; Shreeve, J. M. J. Org. Chem. 2003, 68, 6063-6065. (h) Negi, D. S.; Köppling, L.; Lovis, K.; Abdallah, R.; Geisler, J.; Budde, U. Org. Process Res. Dev. 2008, 12, 345-348.
Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J. Org. Chem. 1999, 64, 7048-7054.
Lal, G. S.; Lobach, E.; Evans, A. J. Org. Chem. 2000, 65, 4830-4832.
(a) Sondej, S. C.; Katzenellenbogen, J. A. J. Org. Chem. 1986, 51, 3508-3513. (b) Chambers, R. D.; Sandford, G.; Sparrowhawk, M. E.; Atherton, M. J. J. Chem. Soc., Perkin Trans. 1 1996, 1941-1944. (c) Motherwell, W. B.; Wilkinson, J. A. Synlett 1991, 191-192. (d) Prakash, G. K. S.; Hoole, D.; Reddy, V. P.; Olah, G. A. Synlett 1993, 691-693. (e) Kuroboshi, M.; Hiyama, T. Synlett 1991, 909-910. (f) Reddy, V. P.; Alleti, R.; Perambuduru, M. K.; Welz-Biermann, U.; Buchholz, H.; Prakash, G. K. S. Chem. Commun. 2005, 654-656.
Chang, Y.; Tewari, A.; Adi, A.-I.; Bae, C. Tetrahedron 2008, 64, 9837-9842.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Deoxo-Fluor: Bis(2-methoxyethyl)aminosulfur trifluoride: Ethanamine, 2-ethoxy-N-(2-ethoxyethyl)-N-(trifluorothio)-; (202289-38-1)

Benzophenone: Diphenylmethanone: Benzoylbenzene; (119-61-9)

Bis(4-fluorophenyl) ketone: 4,4'-Difluorobenzophenone ; (345-92-6)

	Chulsung Bae received his B.S. degree from Inha University and M.S. degrees from Pohang University of Science & Technology in Korea and University of Massachusetts Lowell. He received a Ph.D. in chemistry from University of Southern California in 2002 under the guidance of G. K. Surya Prakash and Nobel Laureate George A. Olah. After postdoctoral research at Yale University with John F. Hartwig in 2002-2004, he joined the faculty in the Chemistry Department at University of Nevada Las Vegas. In summer of 2012, he joined Department of Chemistry & Chemical Biology at Rensselaer Polytechnic Institute. His current research interests include organic chemistry, organofluorine chemistry, catalysis, green chemistry, polymer science for renewable energy applications.
	Ying Chang was born in Anhui Province, China in 1981. He obtained his Ph.D. degree in Applied Chemistry from Nanjing University of Science and Technology, China, in 2006 under the supervision of Professor Chun Cai. After carrying out a postdoctoral research work with Professor William R. Dolbier, Jr. at the University of Florida (2006-2007) on synthetic organofluorine chemistry, he joined Professor Chulsung Bae's group at the University of Nevada Las Vegas as a postdoctoral scholar and now works in the fields of synthetic organofluorine chemistry, functional polymers synthesis for renewable energy applications.
	Hyelee Lee was born in Incheon, South Korea in 1984. She received her B.S. degree in Chemistry from the Chung-Ang University in 2008. After working as a research assistant in the Drug Evaluation Department, Korea Food & Drug Administration until summer of 2009, she joined Professor Chulsung Bae's group at University of Nevada Las Vegas as a Ph.D. student. Her current interest is development of new organic synthetic method for the applications in proton exchange membrane fuel cells.

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