2,2,3,3-Tetrafluoropropyl 4-azido-2,3,5,6-Tetrafluorobenzoate

Abstract

Organic azides are traditionally used in organic synthesis to obtain a wide variety of chemical compounds. This prompted us to report the synthesis of a new polyfluorinated aryl azide, 2,2,3,3-tetrafluoropropyl 4-azido-2,3,5,6-tetrafluorobenzoate, which was obtained in two stages starting from pentafluorobenzoic acid.

1. Introduction

The reactivity of organic azides makes them a valuable class of compounds widely used in organic synthesis [1]. Polyfluorinated aryl azides, in particular, serve as precursors for synthesizing amines [2,3], amides [4,5,6,7], azaylides [8], N-heterocyclic compounds [9,10,11,12,13], and other products [8]. They are also extensively used in polymer chemistry, both for modifying polymers via nitrene C-H insertion [14] and as monomers for producing materials such as organic–inorganic polymers [15]. Furthermore, in recent years, polyfluorinated diazides have been actively employed as photo- [16,17] and thermal [18] cross-linking agents.

Azides can be used not only as a tool for obtaining functional materials, but can also be functional materials themselves. For instance, Wang proposed using polymers modified with polyfluoroaryl azides as “phosphine sponges” [19], while Cen et al. suggested using azide-modified corrole phosphorus complexes for photodynamic therapy [20].

In this paper, we report the synthesis and spectroscopic characterization of a novel compound, 2,2,3,3-tetrafluoropropyl 4-azido-2,3,5,6-tetrafluorobenzoate (2, Scheme 1) (please refer to Supplementary Materials).

2. Results and Discussion

The target compound 2 was synthesized from commercially available pentafluorobenzoic acid in a two-step procedure (Scheme 1).

In the first step, the acid was converted to 2,2,3,3-tetrafluoropropyl pentafluorobenzoate (1) via sulfuric acid-catalyzed esterification similarly to [21]. Compound 1 was obtained in 84% yield and was then involved in the reaction with sodium azide under reflux in a 2:1 (v/v) acetone/water mixture. Subsequent purification by column chromatography afforded the target azide 2 in 85% yield. It is worth noting that reported reaction times for nucleophilic aromatic substitution of pentafluorobenzoates with sodium azide vary widely in the literature, ranging from 2 to over 16 h [22,23,24]. In our case, the reaction proceeds quantitatively within just 1 h. Longer reaction times lead to the accumulation of bis-azide derivatives, as sodium azide was used in a 10% excess. We propose that this significantly accelerated reactivity is due to the enhanced electron-withdrawing character of the 2,2,3,3-tetrafluoropropyl group in ester 1 compared to previously described analogues.

3. Materials and Methods

3.1. General Information

¹H and ¹⁹F spectra were recorded on a Bruker Avance 300 (Bruker Corporation, Billerica, MA, USA) instrument (300 MHz ¹H, 282.4 MHz ¹⁹F), and ¹³C NMR spectra were recorded on a Bruker Avance 400 (100.6 MHz) instrument (Bruker Corporation, Billerica, MA, USA). Chemical shifts (δ) are reported in ppm relative to CCl₃F (¹⁹F, upfield-negative) and TMS (¹H, ¹³C); C₆F₆ (δ_F = −162.9 ppm) and CDCl₃ (δ_C = 76.9 ppm) served as internal standards. Coupling constants (J) are reported in Hz. The following abbreviations were used to designate multiplicities: d = doublet, t = triplet, q = quartet, and m = multiplet.

Molecular masses of the compounds were determined by HRMS with a Thermo Electron Corporation DFS (Thermo Fisher Scientific, Waltham, MA, USA) instrument (EI 70 eV). Accurate mass measurements were made relative to the lines of perfluorokerosene used as a standard by the peak matching procedure.

IR and UV-Vis spectra were recorded on Bruker Vector 22 FT-IR spectrometer (Bruker Corporation, Billerica, MA, USA) and Agilent Cary 5000 spectrophotometer (Agilent Technologies, Santa Clara, CA, USA), respectively.

HPLC analysis was carried out using an HPLC-UV system (Agilent 1100, Agilent Technologies Inc., Santa Clara, CA, USA) including degasser (G1322A), binary pump (G1312A), autosampler (G1329A), thermostated column compartment (G1316A) with a Zorbax RX C18 column (150 × 4.6 mm with 5.0 µm particle size; Agilent Technologies Inc., Santa Clara, CA, USA), diode array detector (DAD G1315B). The column was thermostatically controlled at 30 °C. Gradient elution was used: from 30 to 100% (B) for 18 min, from 100 to 30% (B) for 1 min, 30% (B) for 3 min, where solvent (A) was bidistilled water and solvent (B) was 100% acetonitrile (for HPLC, gradient grade, ≥99.9%; Concord Technology, Tianjin, China). The flow rate was 1.0 mL/min. The sample was dissolved in ACN. The elution volume varied depending on the concentration of prepared solution. Peaks were detected using a maximum wavelength of 210 nm. Peaks from solvents were not included in the purity calculations.

3.2. Synthesis

2,2,3,3-Tetrafluoropropyl 2,3,4,5,6-pentafluorobenzoate (1)

Pentafluorobenzoic acid (63.62 g, 300 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (79.25 g, 600 mmol) were charged to a 250 mL flask equipped with a magnetic stir bar. Concentrated H₂SO₄ (20 mL) was added to the mixture with stirring. The reaction mixture was stirred at 120 °C (oil bath temperature) for 15 h. After cooling to room temperature, the mixture was quenched with saturated aqueous NaHCO₃ solution (300 mL). The aqueous phase was extracted with CH₂Cl₂ (2 × 50 mL), and the combined organic extracts were washed with water (2 × 100 mL). The organic phase was dried over MgSO₄, and the solvent was removed by rotary evaporation to afford the crude product as a light-yellow liquid (90.61 g). Vacuum distillation of the crude material yielded the pure product 1 (82.09 g, 84%) as a colorless liquid (bp 94 °C at 5.5 torr).

UV-Vis (EtOH), λₘₐₓ/nm (lg ε): 215 (3.90), 275 (3.14).

FT-IR (film), ν, cm⁻¹: 2979, 1757, 1654, 1527, 1504, 1454, 1425, 1393, 1333, 1242, 1221, 1199, 1109, 1028, 998, 839, 780, 752.

¹H NMR (300 MHz, CDCl₃), δ: 5.94 (tt, 1H, ²J_HF = 52.9 Hz, ³J_HF = 3.7 Hz), 4.74 (t, 2H, ³J_HF = 12.6 Hz).

¹³C{¹H} NMR (100.6 MHz, CDCl₃), δ: 157.9 (s, C=O), 146.1 (dm, ¹J_CF  =  260.1 Hz), 144.2 (dm, ¹J_CF  =  262.5 Hz), 138.1 (dm, ¹J_CF  =  255.3 Hz), 114.0 (tt, ¹J_CF  = 250.2 Hz, ²J_CF  = 28.5 Hz, CF₂), 109.3 (tt, ¹J_CF  = 250.2 Hz, ²J_CF  = 36.4 Hz, CF₂H), 106.6 (dt, ²J_CF  = 14.6 Hz, ⁴J_CF = 3.8 Hz), 61.2 (t, ²J_CF  = 29.7 Hz, CH₂).

¹⁹F NMR (282.4 MHz, CDCl₃), δ: –124.5 (dt, 2F, ³J_HF = 12.6 Hz, ³J_HF = 2.4 Hz, CF₂), –137.9 (m, 2F, F-2,6), −138.4 (d, 2F, ²J_HF = 52.9 Hz, CF₂H), −147.2 (tt, 1F, ³J_FF = 20.3 Hz, ⁴J_FF = 5.3 Hz, F-4), –160.7 (m, 2F, F-3,5).

HRMS: found m/z 325.9982 [M]⁺; calculated for C₁₀H₃F₉O₂ 325.9984.

Elemental analysis calculated for C₁₀H₃F₉O₂ (%): C, 36.83; H, 0.93; F, 52.43; found (%): C, 36.95; H, 1.13; F, 52.12.

2,2,3,3-Tetrafluoropropyl 4-azido-2,3,5,6-tetrafluorobenzoate (2)

1 (1.63 g, 5 mmol) was dissolved in acetone (10 mL), and then 5 mL of water was added. Sodium azide (0.36 g, 5.5 mmol) was added to the solution while stirring. The solution was stirred at 100 °C (oil bath temperature) for 1 h. After cooling to room temperature, the mixture was diluted with water (100 mL). The aqueous phase was extracted with diethyl ether (2 × 50 mL), and the combined organic extracts were washed with water (2 × 50 mL). The organic phase was dried over MgSO₄, and the solvent was removed by rotary evaporation to afford the crude product as a brown liquid (1.73 g). The crude product was purified by column chromatography on silica gel, with Hex/EtOAc (5:1) as eluent, Rf = 0.74. Orange liquid (1.48 g, 85%).

UV-Vis (EtOH), λₘₐₓ/nm (lg ε): 268 (4.31).

FT-IR (film), ν, cm⁻¹: 2979, 2133, 1752, 1648, 1492, 1421, 1330, 1257, 1185, 1112, 1059, 1007, 977, 839, 777.

¹H NMR (400 MHz, CDCl₃), δ: 5.94 (tt, 1H, ²J_HF = 52.9 Hz, ³J_HF = 3.6 Hz), 4.72 (t, 2H, ³J_HF = 12.5 Hz).

¹³C{¹H} NMR (100.6 MHz, CDCl₃), δ: 158.1 (s, C=O), 145.9 (dm, ¹J_CF  =  260.3 Hz), 140.7 (dm, ¹J_CF  =  253.8 Hz), 124.9 (t, ²J_CF  = 11.8), 114.0 (tt, ¹J_CF  = 250.9 Hz, ²J_CF  = 27.2 Hz, CF₂), 109.3 (tt, ¹J_CF  = 250.9, ²J_CF  = 36.2 CF₂H), 105.7 (t, ²J_CF  = 14.2 Hz), 61.0 (t, ²J_CF  = 30.0 Hz, CH₂).

¹⁹F NMR (282.4 MHz, CDCl₃), δ: –124.7 (dt, 2F, ³J_HF = 12.5 Hz, ³J_HF = 3.6 Hz, CF₂), –138.6 (m, 4F, CF₂H, F-2,4), –151.5 (m, 2F, F-3,5).

HRMS: found m/z 349.0089 [M]⁺; calculated for C₁₀H₃F₈O₂N₃ 349.0092.

Elemental analysis calculated for C₁₀H₃F₈O₂N₃ (%): C, 34.40; H, 0.87; F, 43.53; N, 12.04; found (%): C, 34.63; H, 1.25; F, 44.11; N, 12.69.