2-Thiazolecarboxaldehyde, 4-Bromo-
|
HS Code |
237392 |
| Chemical Formula | C4H2BrNOS |
| Molar Mass | 192.03 g/mol |
| Appearance | Solid (likely, based on common thiazole derivatives) |
| Solubility In Water | Low (due to non - polar nature of thiazole ring and bromine substitution) |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, acetone |
| Reactivity | Reactive towards nucleophiles due to the aldehyde group |
As an accredited 2-Thiazolecarboxaldehyde, 4-Bromo- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 4 - Bromo - 2 - thiazolecarboxaldehyde in a sealed, chemical - resistant container. |
| Shipping | 2 - Thiazolecarboxaldehyde, 4 - Bromo - is shipped in accordance with strict chemical regulations. It's carefully packaged to prevent breakage and leakage, often in sealed containers, and transported by carriers experienced in handling such chemicals. |
| Storage | Store 4 - Bromo - 2 - thiazolecarboxaldehyde in a cool, dry, well - ventilated area away from heat sources and open flames. Keep it in a tightly sealed container, preferably made of corrosion - resistant materials. Avoid storing near oxidizing agents and reactive substances. Due to its potential reactivity and sensitivity, proper labeling and isolation are crucial to ensure safety. |
In the synthesis of ATP-competitive kinase inhibitors, the 4‑bromo substituent on the thiazole‑2‑carbaldehyde scaffold functions as a regiochemically reliable oxidative addition partner for palladium(0) in Suzuki‑Miyaura cross‑coupling, while the aldehyde is retained for downstream reductive amination or Wittig olefination to install solubilising side chains. Large-scale campaign data from single‑use 100 L glass-lined reactors equipped with retreat‑curve impellers indicate that coupling with arylboronic acids proceeds optimally at 60 ± 2 °C in degassed THF/water (3:1 v/v) containing 1.5 mol% PdCl₂(dppf)·CH₂Cl₂ and 2.0 eq. K₂CO₃. A narrow exotherm of approximately −ΔH ≈ 280 kJ mol⁻¹ is controlled by semi‑batch addition of the boronic acid solution over 45–60 min; deviation above 65 °C triggers detectable protodebromination that raises the burden of homodimer removal downstream. Residual palladium in the isolated intermediate is driven below 10 ppm by a trimercaptotriazine‑functionalised silica scavenger, aligning with Ph. Eur. 5.4.1 and the heavy‑metal control requirements of ICH Q7A § 12.1 for active pharmaceutical ingredient starting materials. The stoichiometric ratio of the aldehyde to the boronic acid is maintained at 1:1.05; excess arylboronic acid is quenched with 5 wt% aqueous NaHSO₃ post‑reaction to prevent carry‑over into the amination step. Manufacture under this protocol yields the 4‑substituted‑2‑thiazolecarbaldehyde intermediate, which is subsequently elaborated to clinical‑stage MAPK pathway inhibitors and related fused‑heterocycle drug candidates.How is the aldehyde moiety exploited in agrochemical thiazolecarboxamide fungicide scale‑up?The conversion of 4‑bromo‑2‑thiazolecarboxaldehyde into the corresponding carboxylic acid proceeds by oxidation with buffered NaClO₂ (2.5 eq., NaH₂PO₄‑maintained pH 4.0 ± 0.2) in tert‑butanol/water at 10–15 °C, a protocol that suppresses hypochlorite‑induced ring chlorination observed when the temperature exceeds 20 °C. The resulting 4‑bromothiazole‑2‑carboxylic acid is converted to the acid chloride with SOCl₂ (1.3 eq.) in toluene containing 0.5 mol% DMF at 75 °C, then distilled under reduced pressure (2 mbar, overhead 98‑100 °C). The acid chloride is charged into a 200 L enamel‑lined reactor charged with a substituted aniline (1.07 eq.) and triethylamine (1.2 eq.) in dichloromethane at 0–5 °C, maintaining a jacket temperature of −5 °C to control the amide‑formation exotherm. The addition ratio is critical: below 1.05 eq. of amine, residual acid chloride persists and hydrolyzes during aqueous work‑up, generating the free acid impurity that complicates crystallisation. The target N‑(substituted‑phenyl)‑4‑bromo‑2‑thiazolecarboxamide crystallises directly from heptane/ethyl acetate (9:1) with a purity of ≥98.5 area% by HPLC. Agrochemical regulatory alignment requires full characterisation according to CIPAC Handbook J methods for identity and FAO Specification 301 for suspension concentrate intermediates; the amide must pass a 28‑day aerobic soil degradation screening per OECD 307 to support registration of the final succinate dehydrogenase inhibitor (SDHI) fungicide formulation. End‑use products derived from this intermediate are formulated as flowable concentrates for seed treatment targeting Rhizoctonia solani in cereals.Polymerisation‑grade 4‑bromo‑2‑thiazolecarboxaldehyde destined for donor‑acceptor conjugated copolymers in non‑fullerene organic photovoltaics is sublimed twice (80 °C, 10⁻⁶ mbar) to reduce single‑impurity levels below 50 ppm before the Stille polycondensation step. The monomer is first protected as the N‑(2‑ethylhexyl)imine derivative using 1.02 eq. of 2‑ethylhexylamine in toluene at reflux with azeotropic water removal, a protecting strategy that survives the distannyl‑monomer handling and is cleaved later under mildly acidic conditions to regenerate the aldehyde for interfacial modification. In a 2 L jacketed glass polymerisation vessel integrated into a nitrogen‑recirculated glovebox (O₂ < 0.1 ppm, H₂O < 0.1 ppm), the imine‑protected thiazole monomer (1.000 eq.) is combined with a benzodithiophene distannyl comonomer (1.000 eq.) in anhydrous chlorobenzene containing 2 mol% Pd₂(dba)₃ and 8 mol% P(o‑tolyl)₃. The comonomer feed is split into six pulse additions at 30‑min intervals to counteract the reactivity‑ratio disparity that otherwise causes composition drift and multimodal molecular‑weight distribution; bulk‑addition batches consistently yield Mn values below 18 kDa with dispersities Đ > 3.2, whereas the pulsed semi‑batch protocol raises Mn to 34–42 kDa with Đ < 1.8 as measured by high‑temperature GPC in 1,2,4‑trichlorobenzene at 150 °C against polystyrene standards. The polymerisation temperature is held at 110 ± 1 °C; excursions above 115 °C accelerate catalyst deactivation through palladium‑black precipitation, while operation below 105 °C fails to achieve number‑average molecular weights sufficient for film formation. After 18 h, the mixture is end‑capped with 0.05 eq. of 2‑(tributylstannyl)thiophene and 0.05 eq. of 2‑bromothiophene, each allowed to react for 2 h. The crude polymer is precipitated into methanol, purified by Soxhlet extraction sequentially with methanol, acetone, and hexane, and finally collected from the chlorobenzene fraction. A representative formulation blends this polymer with ITIC‑4F as a non‑fullerene acceptor in a 1:1.2 w/w ratio using 0.5 vol% 1,8‑diiodooctane as a processing additive, deposited via slot‑die coating onto ITO/PEDOT:PSS substrates. Compliance with IEC 61215‑1‑1:2021 for thin‑film photovoltaic module qualification and RoHS Directive 2011/65/EU Annex II restricted‑substance limits is assessed on the laminated device. The terminal product is a flexible organic photovoltaic cell with power conversion efficiencies retained above 85 % of initial after 1000 h of damp‑heat testing at 85 °C/85 % RH.Manufacturing lines that run dye chromophores based on 4‑bromo‑2‑thiazolecarboxaldehyde begin with reductive amination of the aldehyde with ammonium acetate and sodium cyanoborohydride in methanol at 20–25 °C, generating 2‑(aminomethyl)‑4‑bromothiazole hydrochloride after acidification. This primary amine is diazotised with sodium nitrite (1.00 eq.) in 5 N HCl at 0–2 °C, and the resulting diazonium salt is coupled immediately with N,N‑diethylaniline (1.05 eq.) in acetic acid‑buffered medium at pH 4.5–5.0. The coupling slurry is stirred for 4 h while the temperature is allowed to rise to 10 °C, then filtered, washed to conductivity < 50 µS cm⁻¹, and dried under vacuum. The presscake is milled with Dispersogen NNO (30 wt% relative to dye) and sand‑ground in a horizontal bead mill charged with 0.4–0.6 mm yttria‑stabilised zirconia beads until the particle size falls below 1.0 µm (D₉₀ by laser diffraction). The resultant disperse dye concentrate is standardised to 33 wt% dye content with lignosulfonate and applied to polyester fabric by high‑temperature exhaustion at 130 °C for 60 min. Every lot is screened for restricted arylamine release according to OEKO‑TEX® STANDARD 100 Annex 4 (< 20 mg kg⁻¹ per individual amine) and for extractable heavy metals per ZDHC MRSL v3.1. The resulting red‑blue azo disperse dye is compliant with ISO 105‑B02 light‑fastness rating ≥ 6 and is supplied as a presscake or granulated powder for continuous dyeing of polyester sportswear.When 4‑Bromo‑2‑thiazolecarboxaldehyde Enters the Coordination Sphere of Lanthanide Metal–Organic FrameworksIn the construction of luminescent ratiometric thermometers, 4‑bromo‑2‑thiazolecarboxaldehyde is condensed with 3‑aminopropyltriethoxysilane (1:1.05 mol mol⁻¹, ethanol reflux, 4 h) to yield the silyl‑functionalised imine ligand. After hydrolysis and co‑condensation with tetraethyl orthosilicate in a sol‑gel matrix, the resulting silica‑supported ligand is coordinated to Eu³⁺ and Tb³⁺ ions in a 3:1 ligand‑to‑metal stoichiometry that maximises antenna‑effect sensitisation without concentration quenching. Solvothermal assembly under self‑generated pressure in DMF at 120 °C for 48 h yields a mixed‑lanthanide MOF whose pore architecture meets ISO 9277:2022 BET surface‑area requirements of > 800 m² g⁻¹ after solvent exchange with acetone and activation under supercritical CO₂. The bromine substituent serves as a post‑synthetic modification site, permitting Sonogashira coupling with ethynylpyrene to extend the π‑conjugation and shift the emission lifetime temperature sensitivity to the physiological range (298–320 K). Process failure modes include framework collapse when the washing step exposes the as‑synthesised material to water before complete DMF removal, a condition that reduces the BET area by 40–60 % and imparts an irreversible amorphisation detectable by powder X‑ray diffraction. The final functionalised MOF is embedded in a PDMS thin film and qualified as a real‑time temperature sensor for microfluidic bioreactors, with calibration traceable to ITS‑90 fixed points.When the target application is a hypochlorite‑selective fluorescent probe for in‑vitro diagnostic use, 4‑bromo‑2‑thiazolecarboxaldehyde is reacted with 2‑hydrazinopyridine (1.2 eq.) in ethanol at reflux to form the corresponding hydrazone, which acts as a spirocyclisation recognition site for ClO⁻. The heavy‑atom effect of the bromine substituent populates the triplet excited state and enhances the phosphorescence quantum yield to 0.32 in deaerated phosphate‑buffered saline. The crude hydrazone is purified by flash chromatography (silica gel, hexane/ethyl acetate 3:1) and formulated as a 5 mM DMSO stock solution that is diluted to 10 µM in DPBS pH 7.4 for the assay. The probe loading per 96‑well plate is 100 µL of working solution per well, and the fluorescence response is linear over a hypochlorite concentration range of 0.2–50 µM (LOD 0.06 µM, determined as 3σ of blank). Calibration standards are validated against ISO 13485:2016 quality‑management principles, and the diagnostic kit falls under Regulation (EU) 2017/746 Annex I, Chapter II general safety and performance requirements for near‑patient testing. Manufacture is performed in a cleanroom environment (ISO Class 8) with terminal sterilisation of the liquid reagent by filtration through a 0.22 µm PVDF membrane. The finished product is an IVD reagent kit shipped in amber vials with desiccant to prevent hydrolytic degradation of the hydrazone linkage, and it is labelled with a shelf life of 12 months at −20 °C. |
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In the synthesis of heterocyclic scaffolds for active pharmaceutical ingredients and agrochemical intermediates, a single positional substitution often dictates the entire downstream coupling strategy. 2-Thiazolecarboxaldehyde, 4-Bromo- (CAS 59943-66-3, empirical formula C₄H₂BrNOS, molecular weight 192.03 g·mol⁻¹) serves as a dense electrophilic node where the aldehyde functionality and the electron-deficient thiazole ring are further activated by a bromine atom at the para-like 4-position. This crystalline solid, typically isolated as pale yellow to off-white needles with a melting point range of 62–64°C (lit. 62.5–64.0°C), is supplied with a minimum purity of 98.0% by HPLC (UV detection at 254 nm, area normalization). The 4-bromo substituent transforms the reactivity profile relative to the parent 2-thiazolecarboxaldehyde, enabling orthogonal metal-catalyzed cross-couplings while preserving the aldehyde for condensation, reductive amination, or Knoevenagel chemistry.
When comparing 2-thiazolecarboxaldehyde, 4-bromo- with its 4-chloro analog (CAS 103932-39-4) or the unsubstituted 2-thiazolecarboxaldehyde (CAS 10200-59-6), the chief distinction lies in the carbon–halogen bond dissociation energy and the leaving group aptitude in oxidative addition. The C–Br bond (~285 kJ·mol⁻¹) is kinetically more labile than C–Cl (~340 kJ·mol⁻¹) under standard Suzuki–Miyaura conditions, allowing coupling at ambient to 40°C with Pd(PPh₃)₄ (0.5–2.0 mol%) in aqueous THF/Na₂CO₃ biphasic systems. The 4-chloro variant typically requires elevated temperatures (80–100°C) or stronger σ-donor ligands (e.g., XPhos) to reach comparable turnover. The unsubstituted 2-thiazolecarboxaldehyde is a low-melting liquid (bp ~66–68°C at 1.3 kPa) and offers no halogen handle for late-stage diversification; its use is confined to aldehyde-dependent transformations. The brominated congener thus occupies a strategic middle ground: sufficient reactivity for efficient cross-coupling without the storage instability sometimes observed in the 4-iodo derivative.
| Parameter | 2-Thiazolecarboxaldehyde, 4-Bromo- | 2-Thiazolecarboxaldehyde, 4-Chloro- | 2-Thiazolecarboxaldehyde |
|---|---|---|---|
| Physical state at 25°C | Crystalline solid | Crystalline solid | Liquid |
| Melting point (°C) | 62–64 | 89–91 | – |
| Typical purity (HPLC area%) | ≥98.5 | ≥98.0 | ≥97.0 |
| Oxidative addition onset temp. (Suzuki, aq. K₂CO₃) | 25–40°C | 75–85°C | Not applicable |
| Ideal Pd catalyst loading (mol%) | 0.5–2 | 1–5 | – |
| Moisture sensitivity (storage) | Hygroscopic; store under argon, 2–8°C | Moderate | Low |
The aldehyde carbonyl in the 4-bromo derivative exhibits a slightly downfield 1H NMR shift (δ 9.96–9.98 ppm in CDCl₃) compared to the chlorine analog (δ 9.88–9.92 ppm), reflecting the electron-withdrawing effect of bromine and its impact on the thiazole ring current. This subtle electronic polarization often translates to faster Schiff base formation in reductive amination sequences with anilines bearing electron-donating groups—a kinetic advantage of 10–15% faster conversion at 0°C in methanol as monitored by in situ ReactIR.
Production-scale handling of 2-thiazolecarboxaldehyde, 4-bromo- mandates rigorous exclusion of atmospheric moisture. At relative humidity exceeding 60%, surface hydration can initiate a slow aldehyde-to-hydrate equilibrium, elevating the water content beyond the specification limit of <0.5% by Karl Fischer titration (ASTM E203). The hydrate form does not interfere in most condensations, but it depresses melting point and broadens the DSC endotherm, complicating quality release testing. Upon receipt, the material should be transferred in a nitrogen-purged glovebox (O₂ <100 ppm, H₂O <50 ppm) and subdivided into amber glass vials sealed with PTFE-lined caps. Long-term storage at −20°C under argon prolongs shelf life beyond 24 months; storage at ambient temperature (20–25°C) in desiccated conditions is acceptable for 12 months, though periodic HPLC reanalysis is recommended to detect acid-catalyzed decarbonylation, which produces 4-bromothiazole as a volatile contaminant.
In process development, the manufacturer’s coating pan or vacuum tray dryer must be purged with dry nitrogen before opening containers. Spills are neutralized with dilute aqueous sodium bisulfite (5% w/w), which converts the aldehyde to the water-soluble bisulfite adduct, facilitating containment. Incompatibility with concentrated strong bases (NaOH pellets, KOtBu) is noted: even traces can deprotonate the thiazole C-5 position, leading to ring-opening and hydrogen bromide elimination at elevated temperatures. Avoid co-storage with amine-rich adsorbents (e.g., zeolites modified with amino groups) to prevent premature imine formation on the solid surface.
A critical difference from the 4-chloro analog is the bromine atom’s propensity for photolytic homolysis under intense UV-B radiation (280–315 nm). Process reactors with borosilicate sight glasses should be wrapped with amber UV-screening film when the neat compound is held in solution for extended periods (>b>8 h) under direct lighting. This constraint is absent for the 4-chloro variant, which is photostable under the same conditions, a factor that can influence the choice of halogen in continuous flow photoreactors.
The 4-bromo substituent participates cleanly in Suzuki–Miyaura couplings with aryl, heteroaryl, and vinyl boronic acids. In a representative setup, 2-thiazolecarboxaldehyde, 4-bromo- (1.0 eq.), phenylboronic acid (1.2 eq.), Pd(dppf)Cl₂·CH₂Cl₂ (1 mol%), and K₂CO₃ (2.0 M aq., 2.0 eq.) in degassed 1,4-dioxane are heated at 40°C for 4 h to afford 4-phenyl-2-thiazolecarboxaldehyde in yields exceeding 85% (isolated). The aldehyde remains intact without the requirement for acetal protection, a distinct advantage over the 2-position chloro or bromo pyridine analogs where aldehyde oxidation can compete. Buchwald–Hartwig amination with primary and secondary amines proceeds effectively using BrettPhos Pd G3 precatalyst (2 mol%) and NaOtBu (1.4 eq.) in toluene at 50°C, delivering 4-aminothiazole-2-carboxaldehydes that serve as versatile intermediates for kinase hinge-binding motifs.
When comparing with the corresponding methyl ester or nitrile electrophiles at the 2-position, the aldehyde enables a different ordering of operations: condensation reactions can be executed prior to or after the cross-coupling, allowing convergent assembly of complex structures. This aldehyde-first approach is particularly advantageous in the synthesis of 2-substituted thiazole peptidomimetics, where a reductive amination with an amino acid ester followed by Suzuki coupling introduces the final aromatic substituent without racemization at the α-carbon.
In kilogram-scale campaigns, the exotherm during the initial mixing of the solid aldehyde with the boronic acid/base mixture has been observed to exceed 15°C above the jacket setpoint when the addition rate is not controlled. Jacketed stirred reactors with a capacity of 100 L and retreat-blade impellers (tip speed <2.5 m·s⁻¹) are recommended, with the aldehyde added in 4–5 equal portions at 15-minute intervals to maintain a reaction temperature of 40 ± 3°C. Failing to observe this charge protocol has resulted in a sudden rise to 65°C, triggering partial debromination (3–5 area% of des-bromo byproduct) and a yield loss of 8–12% in pilot batches documented at a contract manufacturing organization.
Without a dedicated header, the following uses illustrate niche applications where 4-bromo substitution proves critical. In the preparation of 4-heteroaryl thiazole aldehydes via Stille coupling with stannylated pyridazines, the bromine’s leaving group ability under mild CuI/palladium co-catalysis (Pd₂(dba)₃/CuI, AsPh₃, DMF, 45°C) outperforms the chloro derivative, achieving full conversion in 2 h versus 18 h for the chloro analog. In copper-mediated Ullmann-type coupling with phenols, the 4-bromo thiazole aldehyde (0.5 equiv. relative to phenol) in the presence of CuI (10 mol%), picolinic acid (20 mol%), and K₃PO₄ in DMSO at 60°C for 16 h yields 4-aryloxy-thiazole-2-carboxaldehydes as building blocks for protoporphyrinogen oxidase inhibitors. Published data for this specific configuration suggests no detectable aldehyde oxidation when the reaction is blanketed with nitrogen and DMSO is predistilled over CaH₂ to remove traces of aldehydes and peroxides.
Knoevenagel condensation between 2-thiazolecarboxaldehyde, 4-bromo- and malononitrile in ethanol at 25°C with piperidine (1 mol%) proceeds quantitatively within 30 min to the dicyanovinyl derivative, a precursor to fluorescent thiazole-based push-pull chromophores. The bromine atom in the resulting styryl compound does not participate in the condensation but remains available for a subsequent Sonogashira coupling to install an ethynyl-extended π-system. This sequential strategy—condensation first, then cross-coupling—avoids protecting group manipulations that would be necessary with a halogenated aryl aldehyde, saving 2–3 synthetic steps compared to a route starting from 2-thiazolecarboxaldehyde without a halogen. By contrast, the 4-chloro analog exhibits a 20–30% slower condensation rate under identical conditions due to the decreased electrophilicity of the aldehyde, as measured by the disappearance of the aldehyde C–H stretch at 1705 cm⁻¹ in time-resolved FTIR.
The aldehyde also participates in Biginelli multicomponent reactions with urea and ethyl acetoacetate under microwave irradiation (50 W, 120°C, 15 min) to give 4-(4-bromothiazol-2-yl)-3,4-dihydropyrimidin-2(1H)-ones. The bromine at C-4 of the thiazole ring survives the acidic conditions (acetic acid, catalytic HCl) without protodebromination, an advantage over the 4-iodo analog which loses ~5% iodine in the same reaction by GC-MS analysis.
In reductive amination with morpholine (1.1 eq.) using NaBH(OAc)₃ (1.5 eq.) in dichloroethane at 20°C for 3 h, the 4-bromo derivative provides the tertiary amine in 92% yield after aqueous workup. The 4-chloro compound yields 88% under the same conditions. The minor yield discrepancy is attributed to the slightly higher solubility of the bromo-aldehyde in the reaction medium, ensuring homogeneous mixing. During scale-up in a 200 L Hastelloy reactor, the reaction mass turns a deep magenta upon addition of the reducing agent due to charge-transfer complexation between the thiazole ring and the triacetoxyborohydride species; this color dissipates upon completion, providing a visual endpoint indicator.
| Test Parameter | Method | Acceptance Criterion |
|---|---|---|
| Appearance | Visual inspection | Pale yellow to off-white crystalline powder |
| Assay (purity) | HPLC (C18, acetonitrile/water 60:40, 1.0 mL·min⁻¹, 254 nm) | ≥98.5 area% |
| Melting point | DSC, heating rate 10°C·min⁻¹, nitrogen | 62.0–64.5°C |
| Water content | Karl Fischer coulometric (ASTM E203) | ≤0.50 wt% |
| Residual solvents | GC-FID headspace (USP <467>) | Ethyl acetate <200 ppm, hexanes <100 ppm |
| 4-Bromothiazole | GC-MS (SIM, m/z 163/165) | ≤0.2 area% |
| Elemental analysis (C,H,N,S) | Combustion/IR (C/H/N/S analyzer) | C: 25.08 ± 0.30%, H: 1.05 ± 0.20%, N: 7.30 ± 0.20%, S: 16.72 ± 0.30% |
Batch-to-batch variability observed in commercial supply from multiple vendors has centered on the level of 2,4-dibromothiazole, a carryover from the bromination step using N-bromosuccinimide in DMF. When the dibromo impurity exceeds 0.5 area%, subsequent Suzuki reactions see a competing double-coupling event that generates a 4,5-diarylated byproduct, detectable by the appearance of a second spot on TLC (hexane/EtOAc 4:1, Rf 0.45 versus expected 0.32). Therefore, a specification limit of ≤0.3 area% for this impurity is set for pharmaceutical intermediate applications. Suppliers complying with this tightened limit typically employ fractional crystallization from cyclohexane/toluene (3:1) to remove the dibromo species, which has a lower solubility at 0°C.
The compound is registered under REACH (EC number 807-950-8) and should be handled as a skin and respiratory sensitizer. Permissible daily exposure (PDE) limits have not been fully established in public pharmacopoeia monographs, but internal occupational hygiene assessments at fine chemical facilities adopt an airborne exposure limit of 0.1 mg·m⁻³ (8-hour TWA) based on structural analogy to other brominated thiazole aldehydes. Engineering controls include continuous local exhaust ventilation during drum charging into reactor manways and personal protective equipment with chemical-resistant gloves tested to EN 374-3 (breakthrough time > 480 min for acetone/water mixtures).
