How to Produce Triflic Anhydride by Reaction of Triflyl Chloride with Carboxylic Acids or Salts

The reaction of trifluoromethanesulfonyl chloride (CF₃SO₂Cl, triflyl chloride) with carboxylic acids or their salts offers an alternative route to triflic anhydride ((CF₃SO₂)₂O, trifluoromethanesulfonic anhydride), a versatile reagent in organic synthesis for sulfonylation and activation. This method is particularly useful for lab-scale preparation and avoids phosphorus-based dehydrating agents, reducing waste. It proceeds in two steps: (1) formation of a mixed sulfonic-carboxylic anhydride via nucleophilic substitution, and (2) thermal disproportionation of the mixed anhydride, often via reactive distillation, to yield triflic anhydride and a carboxylic anhydride coproduct. The process is described in patent literature as an efficient variant for industrial applications, with carboxylic acids containing 2–8 carbon atoms (e.g., acetic acid, R = CH₃) preferred for volatility and separation ease.

This approach is adaptable to batch or continuous modes and leverages the reactivity of triflyl chloride as an electrophile. Below is a step-by-step breakdown, including equations, mechanisms, conditions, yields, examples, and considerations.

Step 1: Formation of the Mixed Anhydride

This step involves reacting triflyl chloride with a carboxylic acid (RCOOH) or its salt (RCOOM, where M is an alkali metal like Na or K, or preferably Ag for better yields due to insoluble halide precipitation).

Chemical Equations:

• With carboxylic acid salt (preferred for clean reaction): CF₃SO₂Cl + RCOOM → CF₃SO₂OC(O)R + MCl

• Example with silver acetate: CF₃SO₂Cl + CH₃COOAg → CF₃SO₂OC(O)CH₃ + AgCl (acetyl triflate + silver chloride).

• With carboxylic acid (requires base to neutralize HCl): CF₃SO₂Cl + RCOOH → CF₃SO₂OC(O)R + HCl

• Often conducted with a base like pyridine or triethylamine to scavenge HCl and prevent side reactions.

Reaction Mechanism: The reaction is a nucleophilic acyl substitution at the sulfur center. The carboxylate anion (from the salt) attacks the electrophilic sulfur of triflyl chloride, displacing chloride. The CF₃ group enhances electrophilicity, making the reaction rapid. For acids, deprotonation occurs first if a base is present. With silver salts, the insoluble AgCl drives equilibrium forward (metathesis). No catalyst is typically needed, but anhydrous conditions prevent hydrolysis to triflic acid.

Reaction Conditions:

• Temperature: 0–25°C (low to control exothermicity and volatility; ice bath often used).

• Mole Ratio: 1:1 triflyl chloride to carboxylate; slight excess of salt (1.05–1.1 equiv) for complete conversion.

• Solvent: Dry inert solvents like diethyl ether, benzene, acetonitrile, or dichloromethane to dissolve reactants and facilitate filtration.

• Pressure: Ambient.

• Time: 1–2 hours with stirring; monitor by TLC or IR (loss of S-Cl stretch at ~1400 cm⁻¹).

• Workup: Filter off insoluble MCl (e.g., AgCl), then evaporate solvent under reduced pressure. The mixed anhydride is often used without further purification due to sensitivity.

• Safety: Conduct in a fume hood; triflyl chloride is toxic, lachrymatory, and hydrolyzes to HF/HCl. Anhydrous conditions essential to avoid triflic acid formation.

Yields and Purity: 80–95% for the mixed anhydride, with purity >95% after workup. Volatile impurities can be removed by distillation under vacuum (bp ~40–60°C at 10–20 mmHg for acetyl triflate).

Step 2: Disproportionation via Reactive Distillation

The mixed anhydride is thermally disproportionated to triflic anhydride and the corresponding carboxylic anhydride.

Chemical Equation:

• 2 CF₃SO₂OC(O)R → (CF₃SO₂)₂O + (RCO)₂O

• Example: 2 CF₃SO₂OC(O)CH₃ → (CF₃SO₂)₂O + (CH₃CO)₂O (triflic anhydride + acetic anhydride).

Reaction Mechanism: Thermal redistribution involves acyl group exchange between two mixed anhydride molecules, forming symmetric anhydrides. The process is equilibrium-driven, favored by separating the lower-boiling triflic anhydride (bp ~82°C) via distillation. Multiple vapor-liquid equilibrations in the column shift the equilibrium. Optional acidic catalysts (e.g., H₂SO₄ or sulfonic resins) protonate and accelerate exchange.

Reaction Conditions:

• Temperature: Column head: 70–90°C (preferred 75–85°C) at ambient pressure, or 35–75°C (preferred 50–70°C) at reduced pressure; column base: 110–150°C for acetic anhydride (preferred 125–145°C), adjusted for R (higher for larger R).

• Pressure: Ambient or subambient (0.1–0.9 atm) to lower temperatures and minimize decomposition.

• Equipment: Reactive distillation column with 5–20 theoretical stages (plates or packing). Feed mixed anhydride to mid-section; collect triflic anhydride overhead, carboxylic anhydride from base.

• Catalyst: Optional 0.1–5 wt% acidic resin (e.g., Nafion) in base to enhance rates.

• Time/Mode: 1–5 hours residence; continuous preferred for scale-up.

• Purification: Redistill triflic anhydride if needed; purity >99% typical.

Yields and Purity: Overall 80–90%, with triflic anhydride purity >99%. Coproduct (e.g., acetic anhydride) is valuable and recyclable.

Specific Examples

• Batch Mode with Silver Acetate: Stir CF₃SO₂Cl (1 mol) with CH₃COOAg (1.05 mol) in dry ether (500 mL) at 0°C for 1 h, filter AgCl, evaporate to isolate acetyl triflate (yield ~90%). Heat in distillation setup (base 130°C, head 80°C) to collect (CF₃SO₂)₂O (yield 85%).

• Continuous Mode: Feed triflyl chloride and sodium acetate into a reactor, form mixed anhydride, then pump to column for disproportionation (similar yields).

Overall Process Advantages and Drawbacks

• Advantages: Uses commercially available triflyl chloride; phosphorus-free; coproduct value; scalable. Silver salts improve yields but increase cost (recoverable AgCl).

• Drawbacks: HCl or salt byproducts require handling; mixed anhydride is moisture-sensitive and corrosive; silver salts expensive for large scale (use Na/K salts with base instead).

• Comparison: Similar to ketene method but avoids hazardous ketenes; suitable for labs where triflyl chloride is preferred over triflic acid.

This method provides a reliable path to triflic anhydride, with optimization for R group affecting separation efficiency