| HS Code | 843464 |
| Chemical Name | 1,1,1,3,3,3-Hexafluoro-2-propanol |
| Cas Number | 920-66-1 |
| Molecular Formula | C3H2F6O |
| Molecular Weight | 168.04 g/mol |
| Appearance | Colorless liquid |
| Boiling Point | 58.2 °C |
| Melting Point | -4 °C |
| Density | 1.596 g/cm3 at 20 °C |
| Refractive Index | 1.2750 at 20 °C |
| Solubility | Miscible with water and most organic solvents |
| Pka | 9.3 |
| Vapor Pressure | 65 mmHg at 20 °C |
| Viscosity | 1.65 cP at 20 °C |
| Dielectric Constant | 16.7 at 20 °C |
As an accredited Hexafluoroisopropanol factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaged in a 1 L amber glass bottle with PTFE-lined cap, sealed under inert nitrogen, labeled with hazard warnings. |
| Container Loading (20′ FCL) | Load Hexafluoroisopropanol in sealed drums/containers, secure for 20′ FCL, label as hazardous, prevent moisture, and ensure proper ventilation. |
| Shipping | Hexafluoroisopropanol (HFIP) ships as UN 2920, Corrosive liquid, flammable, n.o.s., Class 8 (subsidiary hazard 3), Packing Group II. Transport in leakproof, corrosion-resistant drums, grounded and away from heat/ignition sources. Use corrosive and flammable labels, avoid water, bases, and oxidizers, and provide secondary containment. |
| Storage | Store hexafluoroisopropanol in a tightly sealed, corrosion-resistant container under inert gas. Keep in a cool, dry, well-ventilated area away from heat, ignition sources, strong oxidizers, and incompatible chemicals. Protect containers from physical damage, ensure proper grounding during transfers, and follow all safety guidelines for corrosive, toxic materials. |
| Shelf Life | Shelf life is typically two years when stored tightly sealed under inert gas, protected from light and moisture. |
Medical-grade type I collagen derived from bovine achilles tendon or rat tail tendon is dissolved in hexafluoroisopropanol at 2–16 wt%, with 8 wt% representing the most commonly validated dope concentration for fabricating nonwoven scaffolds by electrospinning. Biocompatibility evaluation for such devices follows ISO 10993-1:2018, quality system requirements are governed by ISO 13485:2016, and scaffold characterization is aligned with ASTM F2150-19. Dissolution is carried out at 4 °C to 25 °C under constant agitation for 12–48 h until a visually homogeneous, bubble-free solution is obtained; because hexafluoroisopropanol has a boiling point of 58–59 °C and a high vapour pressure at ambient temperature, closed PTFE-sealed glass vessels and local exhaust ventilation are required to limit operator exposure. Electrospinning uses a programmable syringe pump delivering the dope at 0.5–2.0 mL/h through a blunt-tip 18–22 G needle to a grounded rotating drum collector positioned 10–20 cm from the needle tip, with applied voltage between 15 kV and 30 kV and chamber relative humidity controlled at 20–40%. At relative humidity above 60%, moisture uptake induces droplet formation at the needle orifice and discontinuous fibre deposition; the spinning chamber is therefore purged with desiccated air or dry nitrogen. Post-spinning crosslinking of collagen mats is executed in glutaraldehyde vapour at 25 °C for 12–24 h or with EDC/NHS in 90% ethanol to resist dissolution in tissue culture medium. Terminal product types include type I collagen nanofibrous wound dressings, soft tissue repair scaffolds and haemostatic membranes with fibre diameters typically within 100–500 nm. Residual hexafluoroisopropanol is quantified by headspace gas chromatography–mass spectrometry before packaging; values above the toxicologically qualified limit require additional vacuum drying at 25–35 °C for 24–48 h.
In polyamide and polyester lot release laboratories, hexafluoroisopropanol replaces cresol-chloroform mixtures as the solvent component of the size-exclusion chromatography mobile phase because it dissolves polyamide 6, polyamide 66, polyethylene terephthalate, polybutylene terephthalate and related copolyesters at ambient temperature without hot-clarification steps. The standard configuration uses a mobile phase of 0.05 M potassium trifluoroacetate in hexafluoroisopropanol, prepared by dissolving the anhydrous salt in the solvent and filtering through a 0.22 µm PTFE membrane; the eluent is degassed by vacuum or inert gas sparging before entering the isocratic pump. Sample preparation follows ISO 16014-2:2019 and comprises dissolving polymer pellets in the same eluent at 1–5 mg/mL with orbital shaking for 12–24 h at room temperature, followed by filtration through 0.45 µm PTFE syringe filters. The filtered solution is injected at 50–100 µL onto a bank of mixed-bed polyester-based columns with 7 µm particle size and dimensions of 300 mm × 8.0 mm ID, preceded by a guard column of identical chemistry; the column oven is held at 35 °C ± 0.5 °C and the flow rate is set to 0.5–1.0 mL/min. Detection is performed with a refractive index detector, and calibration uses narrow-disperse poly(methyl methacrylate) or polyethylene glycol/polyethylene oxide standards whose molar mass range brackets the expected distribution. For polyamide samples, Mark-Houwink constants used to convert retention time to molar mass must be documented according to ISO 16014-2:2019 to avoid reporting errors exceeding 10% on number-average molar mass. The resulting output types include molecular weight distribution certificates, lot conformity data for injection moulding and melt-spinning grades, and technical data sheets for polymer procurement. Equipment is fitted with solvent waste containers sealed with PTFE caps and a closed waste line to a central solvent recovery unit because hexafluoroisopropanol should not be discharged to standard laboratory drains.
| Parameter | Controlled setting | Verification point |
|---|---|---|
| Potassium trifluoroacetate in hexafluoroisopropanol | 0.05 M | Before degassing |
| Sample concentration | 1–5 mg/mL | After dissolution on orbital shaker |
| Injection volume | 50–100 µL | Autosampler sequence |
| Column oven temperature | 35 °C ± 0.5 °C | Oven calibration |
| Mobile phase flow rate | 0.5–1.0 mL/min | Pump calibration |
| Refractive index detector cell temperature | 35 °C | Detector status |
In the production of the inhalation anesthetic sevoflurane, hexafluoroisopropanol enters the process as the fluorinated alcohol substrate, and its conversion to fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether proceeds through O-alkylation followed by fractional purification. The process is performed under ICH Q7 good manufacturing practice for active pharmaceutical ingredients, with the finished substance controlled against Ph. Eur. monograph 2269; because hexafluoroisopropanol is not listed in ICH Q3C R8, its residual content in the drug substance must be justified and controlled by a validated gas chromatography method with a reporting threshold at or below 0.1% weight percentage, consistent with USP <467> for residual solvent verification. Approved batch records indicate that synthesis is conducted in Hastelloy C276 reactors with PTFE-wetted internals because the fluoromethylation medium contains hydrogen fluoride; hexafluoroisopropanol is charged at 1.00 ± 0.02 molar equivalent, the fluoromethylating agent at 1.05–1.20 molar equivalents, and the reaction mass is held at −5 °C to +5 °C during the addition. After aqueous quench with chilled water, the crude organic layer is washed with 5% sodium bicarbonate solution and dried over molecular sieves before fractional distillation in a packed column with 20–40 theoretical plates; the distillate fraction boiling at 58.5–60.0 °C is collected as sevoflurane drug substance. Terminal product types are inhalational anesthetic liquids filled into amber glass bottles for hospital vaporizer use, with release specifications covering related substances, water content, and residual hydrogen fluoride. The process is incompatible with aluminium and zinc equipment because traces of hydrogen fluoride or HFIP-derived acid impurities generate corrosive metal fluoride salts; replacement of distillation column packing with borosilicate glass Raschig rings is required after a validated number of batches, with frequency determined by fluoride ion monitoring in column bottoms.
In multipurpose fine chemical plants that manufacture olefin epoxides, sulfoxides and N-oxides, hexafluoroisopropanol functions as a non-aqueous protic reaction medium that activates aqueous hydrogen peroxide through a hydrogen-bonding network rather than through transition-metal catalysts. The process is governed by REACH Regulation (EC) No 1907/2006 for safe handling and by ICH Q3C R8 when the resulting intermediates enter pharmaceutical supply chains; when hydrogen peroxide concentration exceeds 30 wt%, equipment selection must also consider the explosion protection requirements of ATEX Directive 2014/34/EU. A typical batch charges the alkene substrate at 0.10–0.50 mol/L in hexafluoroisopropanol and then doses 30 wt% hydrogen peroxide at 1.1–2.0 molar equivalents over 2–6 h using a peristaltic pump fitted with PTFE tubing and a check valve, while the jacketed glass-lined reactor is maintained at 0–25 °C by a recirculating chiller capable of removing the exothermic heat flow. Reaction progress is monitored by gas chromatography or HPLC; after substrate conversion reaches the defined endpoint, the batch is quenched with 10 wt% aqueous sodium sulfite at 0–5 °C, then extracted with methylene chloride or ethyl acetate. The organic phase is washed with water and concentrated by rotary evaporation under reduced pressure, and the crude product is purified by silica gel chromatography or fractional distillation. For substrates bearing acid-sensitive functional groups, the hexafluoroisopropanol method avoids aqueous mineral acid co-solvents that cause ring opening of the formed epoxide; this is the main motivation for selecting hexafluoroisopropanol over methanol or tert-butanol when processing terminal epoxides with ester or tertiary alcohol substituents. Terminal product types include chiral and achiral epoxide building blocks, sulfoxide intermediates, pyridine N-oxides, and contracted intermediates for antiviral and anti-inflammatory synthetic routes. Published data for continuous flow variants of this oxidation are more limited than for batch operation, where equipment behaviour under peroxide dosing is better documented.
Poly(lactide-co-glycolide) copolymers with lactide:glycolide molar ratios of 50:50, 65:35 and 75:25 are dissolved in hexafluoroisopropanol to prepare drug-eluting electrospun matrices, because the solvent suppresses premature hydrolytic degradation during processing and evaporates rapidly from the collected fibre mass. The product is developed under ISO 10993-1:2018, and in vitro cytotoxicity is evaluated according to ISO 10993-5:2009; when the fibres are loaded with an antimicrobial agent, the drug product component is also subject to the relevant pharmacopoeial content uniformity test set out in USP <905>. Formulation ranges in published electrospinning studies and pilot-scale runs typically place PLGA at 5–30% w/v in hexafluoroisopropanol, with active pharmaceutical ingredient loadings of 1–10 wt% relative to PLGA; for a 75:25 PLGA loaded with 5 wt% dexamethasone, the resulting fibre diameter shifts from approximately 900 nm at 10% w/v to 1.6 µm at 25% w/v. Processing uses a programmable syringe pump at 1.0–3.0 mL/h, a blunt 21 G needle, a grounded drum collector at 10–15 cm, and a high-voltage DC supply set to 12–20 kV, with chamber relative humidity held at 30–40% to avoid surface pitting. After collection, the nonwoven mats are vacuum dried at 25–35 °C for 24–48 h in a vacuum oven with a cold trap, then sealed in aluminium foil pouches with desiccant. Terminal product types include antibiotic-eluting surgical meshes, lidocaine-eluting wound dressings, and subcutaneous long-acting implant prototypes. Hexafluoroisopropanol is incompatible with certain free-base amine drugs that undergo N-trifluoroacetylation or salt displacement in the acidic fluorinated alcohol medium; for such actives, the salt form is substituted or the solvent is exchanged for a non-fluorinated system after a compatibility screen.
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1,1,1,3,3,3-Hexafluoro-2-propanol (CAS 920-66-1) is a fluorinated secondary alcohol with the condensed formula (CF₃)₂CHOH and a molecular weight of 168.04 g/mol. The compound is supplied as a water-white liquid with a boiling point of 58.2 °C, a density of 1.596 g/mL at 25 °C, and a pKa near 9.3 in aqueous solution. Its flash point is approximately 4 °C in closed-cup testing, placing it in the flammable liquid category and requiring ground/bonded transfer equipment. Two trifluoromethyl groups attached to the central carbon reduce hydroxyl nucleophilicity while increasing hydrogen-bond donor strength; this combination produces a solvent that is simultaneously polar, acidic, and weakly coordinating.
Commercial HFIP is not identified by a single model number. Instead, supplier grade codes distinguish standard assay from low-water and high-purity variants. A standard technical grade typically carries an assay of 99.5% or higher, while pharmaceutical and electronic-polymer grades may be supplied at 99.9% assay with water at or below 100 ppm. The low-water designation is operationally relevant because the hydroxyl group and high polarity make the product hygroscopic; repeated opening of drums in humid air raises water burden quickly.
Esterification and condensation chemistry with HFIP as co-solvent or reactant is controlled mainly by residual water and acidic fluoride species. Water above 100 ppm can hydrolyse activated acid chlorides and shift equilibrium away from ester formation, while acidity as hydrofluoric acid above 0.01 wt% promotes fluoride-mediated side reactions in organometallic process steps. Technical data sheets for high-purity HFIP therefore report the panel below; individual producers may use tighter internal release limits. The relevant test methods are designed for volatile solvents and halogenated intermediates rather than aqueous matrices.
| Parameter | Typical release value | Test method |
|---|---|---|
| Assay as HFIP by GC-FID | ≥ 99.5% | ASTM D6806 |
| Water by coulometric Karl Fischer | ≤ 100 ppm | ASTM E203 |
| Acidity as hydrofluoric acid | ≤ 0.01 wt% | ASTM D1613 |
| Non-volatile residue | ≤ 10 ppm | ASTM D1353 |
| Boiling range | 58.0–59.5 °C | ASTM D1078 |
| Density at 25 °C | 1.594–1.600 g/mL | ASTM D4052 |
| Platinum-cobalt colour | ≤ 10 | ASTM D1209 |
Because the liquid solidifies near -3.3 °C, outdoor storage in cold climates requires heat tracing or indoor hold areas. Closed-loop transfer under dry nitrogen, with molecular sieve breather vents, is used in high-purity installations. Water content is confirmed by coulometric Karl Fischer before acid-sensitive operations; if moisture exceeds 250 ppm, the material is pre-dried with activated 3A molecular sieves or redistilled over calcium hydride. Distillation over sodium metal or sodium-potassium alloy is not used because the weakly acidic hydroxyl group can react with alkali metals and generate hydrogen.
Thermal stability is acceptable in clean, water-free systems. Base contamination, especially alkali-metal hydroxides, alkoxides, or strongly basic amine residues, can promote fluoride release and oligomeric ether formation at distillation temperatures. In recycle loops from peptide coupling or esterification, tertiary amine salts are often present. These salts may not trigger runaway decomposition, but they reduce assay and raise reboiler residue. Recovery columns are operated at reduced temperature and with pH monitoring of the reboiler; published data for continuous high-volume pharmaceutical recovery configurations is limited, and batch recovery remains more commonly documented.
In polyester and polyamide dissolution, HFIP is used as a mobile phase or sample solvent because it suppresses aggregation and allows homogeneous molar mass analysis. Published GPC methods commonly employ 0.5–5.0 mg/mL polymer concentrations to avoid viscosity-induced shear degradation and column pressure rise. Mobile phases containing 0.02–0.05 M sodium trifluoroacetate or tetrabutylammonium acetate are typical for charged polymers; these additives reduce ionic interaction with column packing and improve reproducibility.
For dissolution of poly(ethylene terephthalate), nylon 6, and nylon 6,6, heating above 40 °C is usually unnecessary, but high-solids dissolving can exceed 500 cP under low-shear mixing. Production-scale equipment for such operations is not standardised; glass-lined batch vessels with anchor agitators are used where the lower boiling point allows gentle solvent removal. Published rheological data for high-solids HFIP polymer solutions is limited.
When HFIP replaces 2,2,2-trifluoroethanol (TFE) in ring-opening metathesis polymerisation, its lower boiling point simplifies post-reaction precipitation and solvent recovery, but the increased acidity can protonate amine-based initiators. Published screening data indicate that ruthenium alkylidene catalysts can retain activity in degassed HFIP, while early transition metal Ziegler-Natta systems are generally incompatible with the hydroxyl group. Polymer end-group analysis after methanol precipitation should include fluoride ion measurement to detect alkoxide side products generated by the acidic solvent.
The difference between HFIP and other alcohols is most visible in boiling point, density, and acidity. HFIP boils lower than ethanol and TFE despite a much higher molecular weight because the fluorinated surface reduces intermolecular liquid-phase attraction. Its density is substantially higher than both reference alcohols, which creates phase-separation advantages in extraction and work-up. The lower pKa means HFIP can serve as a weak acid catalyst or activator in hydrogen peroxide oxidations without introduction of mineral acid.
| Property | HFIP | TFE | Ethanol |
|---|---|---|---|
| CAS number | 920-66-1 | 75-89-8 | 64-17-5 |
| Boiling point | 58.2 °C | 77.8 °C | 78.4 °C |
| Density at 25 °C | 1.596 g/mL | 1.393 g/mL | 0.789 g/mL |
| pKa in water | 9.3 | 12.4 | 15.9 |
| Closed-cup flash point | ~4 °C | ~29 °C | ~13 °C |
| Hydrogen-bond donor character | Strong | Moderate | Weak-to-moderate |
Compared with TFE, HFIP is a stronger hydrogen-bond donor and weaker nucleophile. This reduces competitive esterification of hindered carboxylic acids but improves stabilisation of radical and cationic intermediates. The two trifluoromethyl groups also increase solvent density and reduce flammability relative to the flash point of ethanol, although HFIP remains a flammable liquid. Water miscibility is high for HFIP; recovery from aqueous streams requires salting out or cold separation rather than simple phase split.
In catalytic epoxidation, HFIP is typically added at 10–20 vol% to stabilise peroxometal transition states. Selectivity improvements have been reported for titanium silicalite and tungsten-based systems. Above 20 vol%, phase separation and competing ring-opening to diol can become significant. The solvent is more resistant to radical oxidation than ethanol, but prolonged contact with strong peroxides at elevated temperature can generate trifluoroacetic acid and reduce assay.
Halogenation and Friedel-Crafts acylations are carried out with HFIP as a co-solvent at 5–15 vol% because the alcohol weakly coordinates Lewis acids and stabilises ionic intermediates. It is not used as a sole solvent for high-temperature electrophilic processes due to its low boiling point. Acid-sensitive protecting groups, including trityl ethers and acetals, may cleave under prolonged exposure; removal under reduced pressure below 40 °C is common.
Long-term contact with unlined carbon steel is avoided because trace hydrofluoric acid formed during hydrolysis or oxidative stress can etch the surface and generate iron fluoride salts. Glass-lined carbon steel, PTFE, and high-nickel alloys such as Hastelloy C-276 are preferred for storage and transfer. Elastomer selection should not rely on EPDM or nitrile for dynamic seals; FFKM or PTFE-encapsulated seals are used in pumps and valve stems. Published compatibility data for specific elastomers in HFIP service is limited, so dynamic seal testing under process temperature is advised.
Handling in unsealed vessels at relative humidity above 60% leads to measurable water uptake within minutes. For moisture-sensitive esterification, Grignard-type chemistry, and electrolytic applications, pre-drying is therefore mandatory. A nitrogen blanket at 0.1–0.2 bar gauge and drum heaters set below the flash point are common. Water levels above 250 ppm in recycle streams can reduce coupling yields by shifting equilibrium and introducing hydrolysis pathways. Batch records from peptide synthesis campaigns show that rejecting solvent above this threshold improves reproducibility more than extending reaction time.
HFIP is a structural precursor for the fluoromethyl ether anaesthetic sevoflurane, in which the alkoxide oxygen of HFIP is converted to a fluoromethyl ether. The two trifluoromethyl groups remain unchanged in this route. Residual HFIP in the final product is controlled by distillation and water washing; because the product and light ether by-products have similar volatility, separation can be challenging. Published process data is limited mainly to patent examples and batch engineering descriptions rather than continuous production studies.
In difficult peptide couplings, HFIP reduces aggregation of protected intermediates and improves solvation of hydrophobic sequences. It does not replace coupling reagent selection. Solvent removal is conducted under reduced pressure below 40 °C to avoid racemization and by-product formation. The recycle stream from such operations often contains tertiary amine salts, which are removed by aqueous washing before redistillation.
In NMR analysis of synthetic polymers, HFIP is used when DMSO or chloroform fails to dissolve aromatic polyamides or crystalline polyesters. The hydroxyl proton can be exchanged with D2O; its residual solvent peak is separate from most aromatic and aliphatic regions. For chromatographic impurity methods, low non-volatile residue is required to avoid ghost peaks, which is why high-purity grade is specified for analytical release.
In membrane casting and specialty polymer processing, HFIP has been evaluated as a solvent for fluoropolymers and cellulose triacetate, but its low boiling point requires solvent recovery systems with sub-ambient condensing surfaces. The high density and strong hydrogen-bond donating character can alter membrane morphology and increase porosity; however, residual solvent must be reduced to trace levels by water extraction or vacuum drying. Published data for production-scale continuous casting with HFIP is limited.
