| HS Code | 730794 |
| Product Name | Cyclohexyl Cyanoacetate |
| Synonyms | Cyanoacetic acid cyclohexyl ester; Cyclohexyl 2-cyanoacetate |
| Iupac Name | Cyclohexyl 2-cyanoacetate |
| Cas Registry Number | 14191-92-7 |
| Molecular Formula | C9H13NO2 |
| Molecular Weight | 167.21 g/mol |
| Smiles | N#CCH2C(=O)OC1CCCCC1 |
| Appearance | Colorless to pale yellow liquid |
| Physical State | Liquid at room temperature |
| Density | 1.05 g/mL at 25 °C |
| Boiling Point | 135-140 °C at 15 mmHg |
| Flash Point | >110 °C |
| Refractive Index | 1.466 at 20 °C |
| Solubility | Soluble in common organic solvents; practically insoluble in water |
| Vapor Pressure | Low |
| Chemical Stability | Stable under normal ambient conditions |
As an accredited Cyclohexyl Cyanoacetate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Cyclohexyl Cyanoacetate supplied in 25 kg corrosion-resistant steel drums or 1 kg amber glass bottles, securely sealed and hazard-labeled. |
| Container Loading (20′ FCL) | Container Loading (20′ FCL): Cyclohexyl Cyanoacetate packed, labeled, and secured in a 20-foot full container load for ocean shipment. |
| Shipping | Cyclohexyl cyanoacetate is shipped as UN 3276, Nitriles, liquid, toxic, n.o.s. (Cyclohexyl cyanoacetate), Hazard Class 6.1, Packing Group III. Use UN-approved packaging with toxic labels and proper shipping papers. Store in a cool, dry, ventilated area and avoid inhalation, skin, or eye contact. Not a marine pollutant. |
| Storage | Store Cyclohexyl Cyanoacetate in a cool, dry, well-ventilated area away from heat, sparks, open flames, and direct sunlight. Keep containers tightly closed under inert gas if possible, protected from moisture, acids, bases, and oxidizing agents. Use secondary containment, appropriate labels, and PPE. Segregate from incompatible materials. Follow local regulations and SDS. Do not store near food, drink, or animal feed. |
| Shelf Life | Store sealed in a cool, dry, dark place; protected from moisture and oxidizers, it typically remains stable for about two years. |
In the manufacture of pyrimidine- and pyrazolone-derived pharmaceutical intermediates, cyclohexyl cyanoacetate functions as a lipophilic active methylene component rather than as a terminal ester. The methylene carbon between the carbonyl and nitrile groups is deprotonated by piperidine acetate at 0.02–0.05 mol per mol substituted benzaldehyde in refluxing toluene at 110–115 °C. A glass-lined reactor fitted with a Dean–Stark trap is used for continuous azeotropic water removal. The ester is charged at 1.05 mol per mol aldehyde to suppress dialkylation. In-process GC-FID control terminates the condensation when residual aldehyde is <1.0 area% and residual cyclohexyl cyanoacetate is <0.3 area%. The resulting α-cyano-β-aryl acrylate intermediate remains in the organic phase during sodium bicarbonate washing, whereas the corresponding methyl ester partitions measurably into the aqueous phase. The cyclohexyl group also reduces the volatility of the condensation product during solvent exchange from toluene to ethanol for downstream ring closure.
Downstream ring closure with hydrazine hydrate at 0–5 °C yields 5-aminopyrazole intermediates. Condensation with guanidine carbonate in ethanol at reflux yields 2,6-diaminopyrimidine scaffolds. Both ring closures are exothermic and are controlled so that the reaction mass temperature rise remains below 15 °C/h. The cyclohexyl ester does not remain in the final API; it is cleaved during ring closure or subsequent hydrolysis. The main scale-up risk in multipurpose pharmaceutical intermediate plants is dimeric Michael addition product when aldehyde feed is interrupted too early. The aldehyde is therefore fed by metering pump over 45–60 min, and the agitator tip speed is maintained at 2.0–3.0 m/s to keep the reaction mixture homogeneous. The following incoming raw material control panel is used for pharmaceutical campaigns.
| Parameter | Specification | Test Method |
|---|---|---|
| Appearance | Clear to pale yellow liquid | Visual inspection, internal SOP |
| Assay | ≥98.0% | GC-FID, USP<621> / EP 2.2.28 |
| Cyclohexanol | ≤0.50% | GC-FID, EP 2.2.28 |
| Water | ≤0.20% | Karl Fischer titration, USP<921> / EP 2.5.12 |
| Acidity as cyanoacetic acid | ≤0.30% | Alkalimetric titration, EP 2.5.1 |
| Color | ≤50 APHA | ASTM D1209 |
Cyclohexyl 2-cyanoacrylate monomer is produced from cyclohexyl cyanoacetate through a two-step sequence: base-catalyzed condensation with formaldehyde followed by thermal depolymerization of the resulting poly(cyclohexyl 2-cyanoacrylate) oligomer. The condensation uses methanol as solvent and piperidine as catalyst at 55–65 °C. Paraformaldehyde is added slowly because the reaction exotherm can exceed 70 °C within minutes if the feed is not controlled. The feed paraformaldehyde is dried to a water content below 0.5% by Karl Fischer titration (USP<921>) because residual water hydrolyzes the ester to cyanoacetic acid and cyclohexanol. Hydrolysis reduces oligomer chain length and increases free cyanoacetic acid, which poisons later thermal depolymerization.
The oligomer is precipitated, washed with methanol and water, and dried to a water content below 0.2% before thermal cracking. Depolymerization is performed in a vertical wiped-film evaporator with a heated jacket at 175–195 °C, rotor speed 300–400 rpm, and absolute pressure 0.8–2.0 kPa. Feed residence time at the heated surface is kept below 20 s. Longer residence time in a pot still allows the monomer to re-polymerize or char on the heated metal surface. Monomer vapour is condensed at 15–25 °C into a receiver pre-charged with sulfur dioxide at 50–200 ppm, methanesulfonic acid at 10–30 ppm, and hydroquinone monomethyl ether at 20–100 ppm. The acid stabilizers prevent anionic re-polymerization during condensation and storage. If the monomer is intended for medical-device skin closure, cytocompatibility is evaluated per ISO 10993-5.
Process failure on production-scale equipment is most commonly observed as darkening of the wiped-film rotor blades and an increase in distillate color above 40 APHA. If the rotor speed is too low, the oligomer film thickness becomes uneven, causing localized overheating and char. If the vacuum is too deep below 0.5 kPa, monomer vapour can bypass the condenser and contaminate the vacuum pump. Cyclohexyl 2-cyanoacrylate produced by this route is tested for monomer assay by GC-FID at ≥99.0 area%, viscosity at 5–15 mPa·s at 25 °C, and color by ASTM D1209. Adhesive performance is benchmarked on aluminum lap shear specimens per ASTM D1002. Published data for cyclohexyl-specific depolymerization is more limited than for ethyl or butyl esters; transfer of ethyl cyanoacrylate settings to the cyclohexyl monomer therefore requires pilot verification before a full distillation campaign.
When cyclohexyl cyanoacetate is used as a masked cyanoacetylating agent in agrochemical intermediate campaigns, the ammonolysis step is the primary control point. Anhydrous ammonia is sparged into a 0–5 °C methanol solution in a pressure-rated glass-lined reactor. The addition rate is set so that the internal temperature remains below 10 °C. The reaction is held until HPLC area percent of the starting ester is <5.0%. The product cyanoacetamide is isolated after vacuum stripping of cyclohexanol at 3–5 kPa and 70–80 °C. Water ingress above 0.2% during ammonolysis generates ammonium cyanoacetate salts, which precipitate on filter elements and can block the bottom outlet valve. The cyanoacetamide intermediate enters pyridazinone and pyrimidinone ring formation with hydrazines or substituted enones. For crop protection technical material, impurity profiling includes residual cyclohexanol, residual ammonia, and nitrile-related by-products, with limits set according to the registration dossier under EU REACH Regulation (EC) No 1907/2006 and, where applicable, 40 CFR Part 158. Published data for this specific cyclohexyl ester in agrochemical routes is limited; process development groups generally bench-mark short-chain cyanoacetates first and substitute the cyclohexyl ester only when the lower water solubility of the later amide improves extraction.
Cyclohexyl cyanoacetate is condensed with substituted benzophenones to produce cyclohexyl 2-cyano-3,3-diphenyl acrylate analogues. The reaction is carried out in refluxing xylene with ammonium acetate as catalyst and a Dean–Stark trap. The yield-limiting factor is steric hindrance from ortho substituents on the benzophenone ring. A solvent-free variant using titanium tetrachloride at 0–20 °C is used for small-scale campaigns but requires neutralization of titanium residues before crystallization. The crude ester is isolated by cooling to 5 °C, filtered, and recrystallized from isopropanol. The product is used as a low-volatility UV absorber in polycarbonate and polyurethane coatings at loading levels between 0.10 wt% and 0.50 wt%. Weathering evaluation is conducted according to ISO 4892-2:2013 and ASTM D4459. Residual benzophenone is controlled below 0.10 area% by HPLC because unconverted ketone accelerates photoyellowing. The cyclohexyl substituent reduces surface migration relative to the methyl analogue, but published diffusion coefficient data for this specific cyclohexyl derivative is limited. Migration must therefore be confirmed by extraction testing under the final polymer matrix specification before the additive is qualified in long-service-life polymer formulations.
Starting with azo coupling at the active methylene carbon, cyanoacetate ester derivatives can be converted to hydrazone-type disperse dye intermediates. Cyclohexyl cyanoacetate is dissolved in aqueous methanol, cooled to 0–5 °C, and treated with a diazonium salt prepared from a substituted aniline. The pH is held at 4.5–5.5 with sodium acetate buffer. The resulting hydrazone intermediate is filtered and washed with cold methanol. The cyclohexyl ester is not saponified during this low-pH coupling, so the ester function remains available for later condensation with aromatic amines. This route is used when the cyclohexyl group improves solubility in solvent-borne dye formulations and reduces migration in dyed polyester substrates. Production batches are controlled by thin-layer chromatography for residual diazonium salt and by HPLC for isomer ratio. Published data for this specific cyclohexyl cyanoacetate dye intermediate is limited; most commercial dye couplers use methyl or ethyl esters, and cyclohexyl chemistry is evaluated only when increased lipophilicity alters dye uptake kinetics on polyester.
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Cyclohexyl cyanoacetate is supplied commercially as a clear, low-moisture cyanoacetic acid ester intermediate with the molecular formula C₉H₁₃NO₂, CAS Registry Number 52688-11-6, and molecular weight 167.21 g/mol. The ester is produced by acid-catalysed esterification of cyanoacetic acid with cyclohexanol, followed by azeotropic water removal and vacuum distillation. Product models are supplier-specific; the most frequently supplied grades are CHCA-98 and CHCA-99, corresponding to gas chromatographic assay minima of ≥98.0% and ≥99.0% respectively. CHCA-99 is normally specified for pharmaceutical intermediate workflows where lower residual cyanoacetic acid, lower water content, and reduced color are required, while CHCA-98 is used in general fine chemical synthesis. The bulk liquid is commonly packaged in polyethylene-lined steel drums or glass carboys under nitrogen.
| Parameter | Typical limit | Analytical method |
|---|---|---|
| Assay, cyclohexyl cyanoacetate | ≥98.0% (CHCA-98) / ≥99.0% (CHCA-99) | GC-FID area normalization |
| Water | ≤0.10% | ASTM D6304-16e1 |
| Color | ≤50 Pt-Co | ASTM D1209-05(2019) |
| Acid value | ≤0.5 mg KOH/g | ASTM D664-18e2 |
| Refractive index n20/D | 1.4500–1.4580 | ASTM D1218-21 |
| Density at 20 °C | 1.060–1.075 g/cm³ | ASTM D4052-18a |
Lot-specific refractive index and density values may extend beyond these ranges when residual cyclohexanol or cyanoacetic acid impurities are present. Certificates of analysis should therefore be reviewed against the intended downstream reaction, particularly when the ester is charged into water-sensitive catalytic systems or used as a pharmaceutical intermediate requiring tight impurity budgets.
Structural comparison centers on the ester alkyl substituent. Methyl and ethyl cyanoacetate are low-viscosity, higher-vapor-pressure liquids selected where fast distillation and broad commercial availability are primary. Cyclohexyl cyanoacetate replaces a linear alkyl group with a secondary alicyclic group; this increases molar mass to 167.21 g/mol, raises dynamic viscosity, and reduces vapor pressure at equivalent temperature. The cyclohexyl substituent also shields the ester carbonyl from nucleophilic attack, reducing transesterification rate and slowing alkaline hydrolysis relative to methyl and ethyl esters. These differences are not additive blending effects; they alter mass transfer, distillation cut points, and reaction kinetics in continuous processing.
| Property | Methyl cyanoacetate | Ethyl cyanoacetate | n-Butyl cyanoacetate | Cyclohexyl cyanoacetate |
|---|---|---|---|---|
| CAS Registry Number | 105-34-0 | 105-56-6 | 5459-58-1 | 52688-11-6 |
| Molecular weight | 99.09 g/mol | 113.11 g/mol | 141.17 g/mol | 167.21 g/mol |
| Atmospheric boiling point | 204–205 °C | 208–210 °C | 228–230 °C | Predicted 281.8 °C; standardized experimental data not located |
| Flash point, closed cup | 110 °C | 110 °C | 109 °C | Published data limited |
| Ester alkyl architecture | Primary linear | Primary linear | Primary linear | Secondary alicyclic |
| Vapor pressure at 25 °C | Higher | Intermediate | Lower | Lower; published value incomplete |
The cyclohexyl ester is differentiated from n-butyl cyanoacetate primarily by steric architecture rather than simple carbon number. The cyclohexyl ring occupies a bulkier volume near the ester carbonyl, producing a slower nucleophilic substitution profile and a more hydrophobic alicyclic surface. This makes cyclohexyl cyanoacetate preferable when evaporative losses during reactor charging, feed-tank odor, and carbonyl reactivity need simultaneous reduction. The lower vapor pressure of cyclohexyl cyanoacetate also reduces fugitive emissions during open transfer; however, the higher viscosity demands heated transfer lines at lower ambient temperatures. Kinematic viscosity is measured under ASTM D445; lot values for the cyclohexyl ester exceed those of ethyl cyanoacetate, and metering pump stroke rates in continuous distillation should be adjusted against lot-specific viscosity data.
In cyanoacrylate monomer synthesis, cyclohexyl cyanoacetate is condensed with paraformaldehyde in the presence of a base catalyst. The processing window is narrow. At reaction temperatures below 65 °C, formaldehyde conversion remains incomplete, leaving residual cyanoacetate in the crude monomer. Above 80 °C, the base-catalyzed Michael addition of cyanoacetate to the generated cyanoacrylate produces oligomeric by-products; color rises rapidly above 100 Pt-Co and may require additional wiped-film distillation. A jacketed glass-lined reactor with internal temperature control of ±2 °C is used. Typical molar feed ratio is 1.00:1.05 cyanoacetate to formaldehyde, with 0.5–1.0 mol% piperidinium acetate relative to cyanoacetate. Water is removed continuously under reduced pressure at 30–35 kPa while maintaining a pot temperature of 70–75 °C. Reaction progress is monitored by GC-FID; endpoint is defined as unreacted cyclohexyl cyanoacetate below 1.0% area. Published kinetic data specific to cyclohexyl cyanoacetate under these exact conditions are limited; the stated parameters are derived from analogous ethyl cyanoacetate procedures and batch records.
The resulting cyclohexyl 2-cyanoacrylate is separated from solvent and oligomers by thin-film evaporation. Film evaporator jacket temperature is held below 120 °C; higher temperatures accelerate radical polymerization even in the presence of stabilizers. Inhibitor systems for cyanoacrylates typically require sulfur dioxide, methanesulfonic acid, or boron trifluoride complexes; cyclohexyl cyanoacrylate formulations may require adjusted inhibitor concentration because the bulky cyclohexyl group retards thermal polymerization but also slows moisture-initiated adhesive cure. Derived adhesive cure speed is therefore lower than that of ethyl cyanoacrylate; published comparative fixture-time data for this specific configuration is limited.
Thermal stress can induce two separate degradation routes in cyclohexyl cyanoacetate: ester hydrolysis and base-catalyzed condensation. Hydrolysis is promoted by residual water; at moisture levels above 0.10%, free cyanoacetic acid can form and reduce assay. The acid then accelerates autocatalytic hydrolysis. Storage under nitrogen at 15–25 °C with molecular sieve desiccant is therefore specified. Long-term exposure to atmospheric moisture at relative humidity above 60% requires pre-drying of the material before moisture-sensitive reactions; typical drying uses 3A molecular sieves at 10% w/w for 24 h under nitrogen. Vacuum distillation should be conducted at pressures below 1.0 kPa and pot temperatures below 120 °C. Above 150 °C, cyanoacetate esters may undergo elimination and polymerization reactions; vent lines and condenser surfaces can accumulate oligomeric deposits. High-purity CHCA-99 distillation should use low-residence-time equipment such as a wiped-film evaporator rather than a conventional pot still when color and polymer content are release-critical.
Incompatibilities include primary and secondary amines, which can form amides or undergo rapid cyanoacetate condensation. Strong bases such as sodium hydroxide, potassium tert-butoxide, and DBU saponify the ester. Oxidizing agents, including concentrated nitric acid and peroxides, can initiate hazardous decomposition. Avoid combination with amine-based additives due to premature Michael addition and color formation. Equipment after processing should be flushed with a non-oxidizing solvent; water rinses should be followed by drying to prevent hydrolysis of residual ester films in pumps and dead-leg sections of transfer piping.
Use of cyclohexyl cyanoacetate in heterocyclic synthesis follows standard condensation routes. Reaction with hydrazine hydrate in ethanol at 60–70 °C yields 5-aminopyrazolone intermediates; the cyclohexyl ester is selected when later thermal decarboxylation or transesterification must be suppressed. The ester also participates in Knoevenagel condensations with aryl aldehydes, giving α-cyanoacrylic esters that can be cyclized to 2-pyridones. In these transformations, cyclohexyl cyanoacetate offers a balance between solubility in toluene/THF and reduced volatility during solvent recovery. Process development studies on ethyl cyanoacetate provide a starting point, but response surfaces for cyclohexyl cyanoacetate require revalidation because the cyclohexyl group changes boiling point, viscosity, and nucleophilic substitution rates. Reactions above 80 °C are typically run in stainless steel or glass-lined batch reactors. Condensers are rated for lower vapor loading because cyclohexyl ester vapor pressure is reduced; vacuum pump sizing should account for this lower vapor load during solvent stripping.
Verification of cyclohexyl cyanoacetate in incoming quality control requires not only assay and moisture but also physical property testing. Density is determined by digital density meter in accordance with ASTM D4052-18a; the method requires temperature control at 20.00 ± 0.05 °C and air-free injection. Color is assessed against platinum-cobalt standards using ASTM D1209-05(2019); a result above 50 Pt-Co may indicate oxidation or thermal degradation. Refractive index is obtained by ASTM D1218-21 using a sodium D-line refractometer at 20 °C. Acid value by ASTM D664-18e2 measures residual cyanoacetic acid and is used to monitor esterification completeness; a value above 0.5 mg KOH/g is considered out of release specification for pharmaceutical intermediate supply. Water by ASTM D6304-16e1 uses Karl Fischer coulometric or volumetric titration; because cyclohexyl cyanoacetate can hydrolyze in the titration medium, direct injection should be completed rapidly to avoid drift.
GC-FID assay and impurity profiling typically use a capillary column with 5% phenyl methyl siloxane stationary phase, dimensions 30 m × 0.25 mm × 0.25 µm, and an oven ramp of 10 °C/min from 50 °C to 280 °C. Injection port and detector temperatures are generally 250 °C and 280 °C respectively. The method can resolve cyclohexanol, cyanoacetic acid, cyclohexyl cyanoacetate, and transesterification by-products if ester blends have been processed in shared equipment. For regulated applications, residual solvent testing should align with ICH Q3C, and metal catalyst residues should be controlled where applicable. Under REACH, EU importers and manufacturers may be required to register the substance if annual tonnage exceeds 1 t/a under EC 1907/2006. Safety data sheet classification depends on impurities and stabilizers; pure cyclohexyl cyanoacetate is handled as a reactive intermediate rather than an active pharmaceutical ingredient. Compendial monographs for cyclohexyl cyanoacetate are not established in the USP-NF or Ph. Eur. as of the current writing; published data for this specific configuration is limited.
