1,1,1,3,3,3-Hexafluoropropan-2-yl 2,3,5,6-tetrafluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzoate

Abstract

Acyl chloride alcoholysis is a fundamental and typically high-yielding method for ester synthesis. However, competitive side reactions can occur when the acyl chloride possesses multiple electrophilic sites and the alcohol is a strong nucleophile. We report an example of this phenomenon: the reaction of pentafluorobenzoyl chloride with 1,1,1,3,3,3-hexafluoropropan-2-ol yields not only the expected ester but also a significant quantity of the 1,1,1,3,3,3-hexafluoropropan-2-yl 2,3,5,6-tetrafluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzoate. The formation of the latter results from an effective nucleophilic aromatic substitution (S_NAr) at the para-fluorine position of the pentafluorophenyl ring by the hexafluoroisopropoxide anion.

1. Introduction

Acyl halides are extensively employed in chemical synthesis for the preparation of esters [1,2,3,4,5,6], amides [2,7,8,9,10], acid anhydrides [11,12,13], ketones [14,15,16,17], and other derivatives. Depending on the reaction conditions, the target products can be obtained in high yields; however, side reactions may also occur. For instance, the reaction of acyl chlorides with alcohols can lead to the formation of alkyl chlorides in addition to, or sometimes even in place of, the expected esters. In particular, it takes place when the reaction proceeds without the use of a base, so the forming HCl is not neutralized and catalyzes the formation of alkyl chlorides [3]. This paper describes an example of a nucleophilic aromatic substitution reaction observed during the reaction of pentafluorobenzoyl chloride with 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) in the presence of triethylamine, yielding 1,1,1,3,3,3-hexafluoropropan-2-yl 2,3,5,6-tetrafluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzoate (2) as a byproduct.

2. Results and Discussion

With the aim of synthesizing 1,1,1,3,3,3-hexafluoropropan-2-yl 2,3,4,5,6-pentafluorobenzoate (1) (Scheme 1), we performed the reaction of pentafluorobenzoyl chloride with HFIP using triethylamine (1.2 equiv.) as a base. It is worth mentioning that triethylamine (pK_a = 10.75) is basic enough to deprotonate HFIP (pK_a = 9.3 [18]), forming alkoxide ion, which is a stronger nucleophile than HFIP.

A solution of triethylamine and HFIP was added dropwise to pentafluorobenzoyl chloride at 0 °C, forming a turbid mixture. The reaction mixture was allowed to stay at room temperature over a weekend under stirring. After workup with water and 5% aqueous HCl to remove residual triethylamine and acyl chloride, NMR analysis revealed the crude mixture contained 36 mol.% of the 1,1,1,3,3,3-hexafluoropropan-2-yl 2,3,5,6-tetrafluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzoate (2) alongside the target compound 1. Since compound 1 is a major product, we believe that the reaction of pentafluorobenzoyl chloride with HFIP proceeds in a sequential manner: initial esterification forms 1, followed by nucleophilic aromatic substitution at the para-position of the pentafluorophenyl ring in 1 via an S_NAr mechanism. So, an increase in HFIP amount up to a 2-fold excess will lead to compound 2 as a major product. Similar in structure to 2, 2,2,2-trifluoroethyl 2,3,5,6-tetrafluoro-4-(2,2,2-trifluoroethoxy)benzoate, was obtained by Nishida et al. as a major product in the reaction of pentafluorobenzoyl fluoride with trimethylsilyl ether (2 equiv.) [19]. Compound 2 was isolated in pure form by distillation and characterized by spectroscopic methods.

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 DRX 500 (125.7 MHz) instrument. Chemical shifts (δ) are reported in ppm relative to CCl₃F (¹⁹F, upfield negative) and TMS (¹H, ¹³C); C₆F₆ (δF = −162.9 ppm) and CDCl₃ (δC = 76.9 ppm) served as internal standards. Coupling constants (J) are reported in Hz. The following abbreviations are 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 in the peak matching procedure.

IR and UV-Vis spectra were recorded with a Bruker Vector 22 FT-IR spectrometer 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 a 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), and diode array detector (DAD G1315B). The column was thermostatically controlled at 30 °C. Gradient elution was used as follows: from 30 to 100% (B) for 18 min, from 100 to 30% (B) for 1 min, and at 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 city, China). The flow rate was 1.0 mL/min. The sample was dissolved in ACN. The elution volume varied depending on the concentration of the 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 of Pentafluorobenzoyl Chloride

Pentafluorobenzoic acid (63.62 g, 300 mmol) was treated with thionyl chloride (SOCl₂, 42.17 g, 787.5 mmol) and DMF (3 drops) at room temperature. The mixture was heated at 90 °C for 12 h. After cooling to room temperature, excess SOCl₂ was removed by rotary evaporation. The residue was used in the following step.

3.3. Reaction of Pentafluorobenzoyl Chloride with 1,1,1,3,3,3-Hexafluoro-2-propanol

To the pentafluorobenzoyl chloride (69.15 g, 300 mmol) at 0 °C, a mixture of 1,1,1,3,3,3-hexafluoro-2-propanol (50.40 g, 300 mmol) and triethylamine (36.36 g, 360 mmol) was added. The reaction mixture was stirred at room temperature for 65 h, then quenched with water (300 mL). The organic phase was separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 75 mL). The combined organic extracts were washed with 5% aqueous HCl (50 mL) and dried over MgSO₄. After solvent removal by rotary evaporation, a crude mixture of products was obtained (102.4 g).

The target compound was purified by vacuum distillation, yielding three distinct fractions based on boiling point ranges.

Fraction 1 (37–40 °C at 1.3 torr, 44.21 g) was a colorless liquid consisting of 1,1,1,3,3,3-hexafluoropropan-2-yl 2,3,4,5,6-pentafluorobenzoate (1) (91.8 mol%) as the primary product and minor impurities: 1,1,1,3,3,3-hexafluoropropan-2-yl 2,3,5,6-tetrafluorobenzoate (4) (4.3 mol.%), 1,1,1,3,3,3-hexafluoropropan-2-yl 2,3,5,6-tetrafluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzoate (2) (1.7 mol%), and 1,1,1,3,3,3-hexafluoro-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)propane (3) (2.2 mol%) as indicated by ¹H NMR (see Figure S2, Supplementary Material).

1,1,1,3,3,3-Hexafluoropropan-2-yl 2,3,4,5,6-pentafluorobenzoate (1)

¹H NMR (300 MHz, CDCl₃), δ: 5.97 (sept, 1H, ³J_HF = 5.8 Hz).

¹³C{1H} NMR (125.7 MHz, CDCl₃), δ: 156.4 (s, C=O), 146.4 (dm, ¹J_CF = 262.8 Hz), 144.9 (dm, ¹J_CF = 265.1 Hz), 138.1 (dm, ¹J_CF = 255.7 Hz), 120.1 (qm, ¹J_CF = 282.7, CF₃), 104.9 (tm, ²J_CF = 14.1 Hz), 67.7 (sept, ²J_CF = 35.4 Hz, CH).

¹⁹F NMR (282.4 MHz, CDCl₃), δ: −74.1 (d, 6F, ³J_HF = 5.8 Hz, -CO₂CH(CF₃)₂), −136.4 (m, 2F, F-2,6), −145.0 (tt, 1F, ³J_FF = 20.8 Hz, ⁴J_FF = 6.7 Hz, F-4), −160.0 (m, 2F, F-3,5).

HRMS: found m/z 361.9802 [M]⁺; calculated for C₁₀HF₁₁O₂ 361.9795.

Elemental analysis calculated for C₁₀HF₁₁O₂ (%): C, 33.17; H, 0.28; F, 57.71; found (%): C, 33.00; H, 0.33; F, 58.15

Fraction 2 (55–60 °C at 1.3 torr, 23.38 g) was a white solid, consisting mainly of 2 (89 mol.%) and a small amount of 1 (11 mol.%). ¹H NMR spectrum is shown in Figure S14, Supplementary Material.

Fraction 3 (73 °C at 1.3 torr, 8.43 g) was a white solid, pure (≥98%, HPLC) 1,1,1,3,3,3-hexafluoropropan-2-yl 2,3,5,6-tetrafluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzoate (2).

Melting point: 35.7–40.2 °C.

UV-Vis (EtOH), λ_max/nm (lg ε): 235 (4.00), 283 (3.22).

FT-IR (KBr), ν, cm⁻¹: 3435, 2981, 2927, 2855, 1768, 1650, 1504, 1428, 1385, 1363, 1334, 1295, 1238, 1207, 1115, 1076, 1040, 993, 944, 910, 690.

¹H NMR (300 MHz, CDCl₃), δ: 5.97 (sept, 1H, ³J_HF = 5.8 Hz, -CO₂CH(CF₃)₂), 5.02 (sept, 1H, ³J_HF = 5.2 Hz, -OCH(CF₃)₂).

¹³C{1H} NMR (125.7 MHz, CDCl₃), δ: 156.3 (s, C=O), 146.4 (dm, ¹J_CF = 265.1 Hz), 140.8 (dm, ¹J_CF = 253.7 Hz), 138.9 (m), 120.3 (qm, ¹J_CF = 285.3 Hz, CF₃), 120.1 (qm, ¹J_CF = 285.3 Hz, CF₃), 106.0 (t, ²J_CF = 14.0 Hz), 67.7 (sept, ²J_CF = 35.4 Hz, CH).

¹⁹F NMR (282.4 MHz, CDCl₃), δ: −74.2 (d, 6F, ³J_HF = 5.8 Hz, -CO₂CH(CF₃)₂), −74.3 (m, 6F, -OCH(CF₃)₂), −136.2 (m, 2F, F-2,6), −154.4 (m, 2F, F-3,5).

HRMS: found m/z 509.9739 [M]⁺; calculated for C₁₃H₂F₁₆O₃ 509.9743.

Elemental analysis calculated for C₁₃H₂F₁₆O₃ (%): C, 30.61; H, 0.40; F, 59.59; found (%): C, 30.96; H, 0.70; F, 59.97.