1-Methylpyrrole-2-Carbaldehyde
|
HS Code |
115824 |
| Chemical Formula | C6H7NO |
| Molar Mass | 109.13 g/mol |
| Appearance | Typically a liquid or solid (state may depend on conditions) |
| Boiling Point | Data may vary, but around 200 - 220 °C (approximate, under normal pressure) |
| Melting Point | No widely - known single value, but melting may occur in a specific range depending on purity |
| Density | Approximate value around 1.1 g/cm³ (estimation, may vary) |
| Solubility In Water | Slightly soluble or insoluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, ether |
| Flash Point | Potentially flammable, flash point data may be required for safety handling |
| Odor | May have a characteristic, pungent or unpleasant odor |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 1-Methylpyrrole-2-Carbaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 1 - Methylpyrrole - 2 - Carbaldehyde packaged in a sealed, air - tight bottle. |
| Shipping | 1 - Methylpyrrole - 2 - Carbaldehyde, a chemical, is shipped in carefully sealed containers, compliant with safety regulations. Packaging ensures protection from physical damage and environmental factors during transit to prevent any potential leakage. |
| Storage | 1 - Methylpyrrole - 2 - Carbaldehyde should be stored in a cool, dry, well - ventilated area away from heat sources and open flames. It should be kept in a tightly sealed container to prevent evaporation and contact with air, which could lead to oxidation. Store it separately from incompatible substances like oxidizing agents. Keep the storage area out of reach of children and unauthorized personnel. |
In a cGMP-compliant intermediate synthesis campaign, the formyl group of 1-methylpyrrole-2-carbaldehyde is exploited as an electrophilic anchor for Knoevenagel condensations with active methylene reagents such as cyanoacetamide or Meldrum’s acid. The resulting α,β-unsaturated adducts are key building blocks for trisubstituted pyrrole pharmacophores found in kinase inhibitors and non-steroidal anti-inflammatory candidates. A production-scale batch record typically specifies a molar ratio of aldehyde to cyanoacetamide of 1.00:1.08, with piperidinium acetate as catalyst loaded at 3.0 mol% relative to the aldehyde. The reaction is run in toluene at reflux (110–112 °C) under a Dean-Stark trap until water collection ceases, generally 4.5–6.0 h. After phase separation and vacuum stripping of the solvent, the crude olefin is crystallized from isopropanol/water (70:30 v/v) to reach an HPLC purity of ≥99.0 area%, with the (E)-isomer content controlled below 0.3% by 1H NMR (CDCl₃, 400 MHz). Residual toluene is monitored against the ICH Q3C Option 2 limit for Class 2 solvents, not exceeding 890 ppm. Drying in a glass-lined double-cone rotary vacuum dryer at 45 °C and –0.95 bar for 8 h reduces the loss on drying to ≤0.5%. The final intermediate is packed under argon in UN-certified fibre drums for export, accompanied by a Certificate of Analysis referencing retention time and response factor calibrations against a traceable USP reference standard.What role does 1-methylpyrrole-2-carbaldehyde play in constructing trisubstituted pyrrole pharmacophores?The compound serves as the C2-functionalized pyrrole synthon in sequential Gewald- or Hantzsch-type cyclocondensations that build annulated heterocycles. In a representative route to a pyrrolo[2,3-d]pyrimidine scaffold, the aldehyde is first converted to the corresponding oxime using hydroxylamine hydrochloride (1.05 eq.) in pyridine/ethanol at 60 °C for 2 h. The isolated oxime, obtained after drowning in ice-water and filtration, is reduced with Raney® nickel and hydrazine hydrate (2.5 eq.) in methanol at 40–45 °C to yield 1-methyl-2-aminomethylpyrrole. Strict adiabatic temperature control is mandatory during the hydrazine addition because the exotherm can exceed 120 °C/min in a 500 L unjacketed vessel. The amine is telescoped into a cyclization with formamidine acetate and triethyl orthoformate in acetic acid at 105 °C, and the final purine analogue is isolated as the hydrochloride salt. All steps are executed under FDA 21 CFR Part 211 subpart J records, with in-process checks by TLC (silica gel GF₂₅₄, ethyl acetate/hexane 1:1, detection at 254 nm). The supply chain audit demands a vendor qualification dossier that includes heavy metals by USP <231> Method II, sulphated ash below 0.1%, and a declaration of absence of Bovine Spongiform Encephalopathy–relevant animal-derived materials.For flavor compositions requiring roasted, nutty character, 1-methylpyrrole-2-carbaldehyde is often converted into its acetyl derivative via a Grignard reaction with methylmagnesium bromide, followed by oxidation of the secondary alcohol with pyridinium chlorochromate. The resulting 2-acetyl-1-methylpyrrole possesses an intense popcorn-like odor with a detection threshold of ≈0.5 µg/L in water, according to sensory data published by the European Flavour Association. The synthetic protocol on a 200 L glass-lined reactor proceeds under a nitrogen blanket: a 3.0 M solution of MeMgBr in 2-methyltetrahydrofuran (1.25 eq.) is added to a solution of the aldehyde in anhydrous toluene at –10 to –5 °C over 90 min, maintaining the temperature with a brine-jacketed condenser. After quenching with saturated ammonium chloride at ≤5 °C, the organic layer is washed, dried over magnesium sulfate, and concentrated. The crude alcohol is oxidized at 25–30 °C in dichloromethane with 1.5 eq. of PCC and 3 Å molecular sieves. The final product, purified by fractional distillation at 98–100 °C (8 mbar), is standardized to ≥99.0% GC purity (polar column, e.g., Carbowax 20 M, 30 m × 0.32 mm). Compliance with IFRA Standard 48th Amendment requires that the benzylic alcohol intermediate and any peroxides generated during the Grignard step be reduced to below 10 ppm active oxygen, confirmed by iodometric titration before the product can be incorporated into a compounded fragrance.When fungicidal phenylpyrrole backbones require a formylated N-methylpyrrole precursorThe aldehyde engages in a Vilsmeier-Haack–type transformation with substituted phenylacetonitriles to yield 2-aryl-3-cyanopyrroles after cyclization. A crop-protection intermediate derived from 1-methylpyrrole-2-carbaldehyde is the α-cyanovinyl precursor, obtained by condensing the aldehyde with 4-chlorophenylacetonitrile in the presence of sodium methoxide (1.10 eq.) in dimethylformamide at 50 °C for 3 h. The reaction is highly moisture-sensitive; the DMF must be dried over 4 Å molecular sieves to below 50 ppm water by Karl Fischer titration. The Knoevenagel adduct precipitates upon dilution with ice-water and is filtered, washed, and dried at 40 °C in a vacuum tray dryer. This vinyl intermediate undergoes a [2+2] cycloaddition with trimethylsilylacetylene and a copper(I) catalyst in N-methyl-2-pyrrolidone to construct the pyrrole ring. Process safety evaluations for the pilot-plant batch highlight a heat release rate of −ΔTad 85 K during the silylacetylene step, requiring the use of a semi-batch regime with the alkyne dosed over 2 h into a reactor capable of removing 150 W/kg at the maximum heat accumulation. The intact agrochemical active ingredient must satisfy FAO Specification 2019 for the relevant formulation type (EC or SC), with an active content of 95.0–98.5% w/w, loss on drying ≤0.5%, and any single unspecified impurity capped at ≤0.3% by HPLC.
Electropolymerization onto ITO electrodes yields films with tailored HOMO levelsFunctionalized polypyrrole films are accessed from 1-methylpyrrole-2-carbaldehyde through Schiff base formation with p-phenylenediamine, generating a diimine monomer that undergoes anodic polymerization in a three-electrode cell. The monomer is dissolved in acetonitrile containing 0.1 M tetrabutylammonium hexafluorophosphate at a concentration of 20 mM. Cyclic voltammetry between −0.2 V and +1.2 V (versus Ag/AgCl) at a scan rate of 50 mV/s produces a homogeneous yellow-brown film on indium tin oxide working electrodes. UV-vis–NIR spectroelectrochemistry reveals a polaron band near 820 nm and a bipolaron band beyond 1100 nm in the oxidized state, with an electrochromic contrast of 38% at 550 nm. The HOMO level, determined by ultraviolet photoelectron spectroscopy, is −5.1 eV, which can be shifted to −5.4 eV by copolymerization with 3,4-ethylenedioxythiophene. For thin-film transistor applications, the semiconducting layer is spin-coated from a 5 mg/mL chlorobenzene solution at 2000 rpm onto octadecyltrichlorosilane-treated SiO₂/Si substrates, giving a field-effect mobility of 3×10⁻³ cm²/V·s as measured under nitrogen in a Keithley 4200-SCS parameter analyser. These measurements reference ISO 11357-2:2020 for the glass transition of the polymer and ASTM D2573-22 for the sheet resistance of the ITO electrode. The aldehyde monomer must be sublimed under reduced pressure (10⁻³ mbar, 60 °C) immediately before use to eliminate oligomeric impurities that would otherwise pin the Fermi level and increase contact resistance.Schiff base condensation with aniline derivatives in refluxing ethanol produces bidentate ligands for transition metal catalysis. A typical procedure combines 10 mmol of 1-methylpyrrole-2-carbaldehyde with 10.5 mmol of 2-aminothiophenol in 50 mL of absolute ethanol, heating at reflux for 2 h. The bright yellow crystalline imine precipitates on cooling and is collected by filtration, washed with cold ethanol, and dried in vacuo. When complexed with copper(II) acetate monohydrate in a 1:2 (metal-to-ligand) ratio in methanol, a square-planar Cu(N–S)₂ complex forms with a log β₂ of 8.9 determined by spectrophotometric titration at 425 nm. Such complexes catalyse the oxidation of catechol to o-quinone with a turnover frequency of 120 h⁻¹ under ambient dioxygen, a reactivity benchmarked against the ISO 11347:2012 standard for catalyst screening in oxidative coupling. Published data for this specific catalytic configuration remains limited, though the ligand synthesis has been reproduced at 1 kg scale in a kilo-lab facility employing a 20 L jacketed reactor and automated powder dosing. The ligand must be stored under nitrogen and protected from light to avoid the slow formation of a disulfide byproduct that would poison the catalyst.Styryl chromophore synthesis from active methylene couplersCondensation with 1,3-diethyl-2-thiobarbituric acid under basic conditions gives a merocyanine dye that absorbs intensely at 498 nm in dichloromethane, with a molar extinction coefficient of 4.2×10⁴ L·mol⁻¹·cm⁻¹. The synthesis is carried out by stirring equimolar amounts of the aldehyde and the thiobarbituric acid derivative in isopropyl alcohol containing 2 drops of piperidine at 25 °C for 30 min. The product is filtered and washed with cold isopropanol, yielding a microcrystalline powder that can be used without further purification for disperse dyeing of polyester. Colouristic assessment following ISO 105-B02:2014 yields a light fastness rating of 6–7 on a blue scale when applied at 1.0% o.w.f. on PET fabric via high-temperature exhaustion at 130 °C for 60 min. The residual aldehyde in the dyebath must not exceed 50 mg/L to meet the OEKO-TEX® Standard 100 limit for extractable N-methylpyrrole derivatives, verified by liquid chromatography–tandem mass spectrometry on the finished textile. |
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1-Methylpyrrole-2-carbaldehyde (IUPAC: 1-methyl-1H-pyrrole-2-carbaldehyde; CAS 1192-58-1) is a monocyclic heteroaryl aldehyde supplied as a pale-yellow to amber liquid with a boiling point of 88–90 °C at 22 mmHg and a density of 1.092 g/mL at 25 °C. Typical bulk purity, determined by gas chromatography on a DB-5 capillary column (30 m × 0.32 mm, 0.25 µm film) with flame ionization detection, exceeds 98.0% area normalization, with the primary impurity being 1-methylpyrrole arising from decarbonylation. Residual water content, measured by Karl Fischer coulometric titration per USP <921> Method Ic, is routinely controlled below 0.5%. The aldehyde serves as a key synthetic intermediate in medicinal chemistry programs targeting serotonin receptor subtypes, in the construction of pyrrole-based ligands for transition-metal catalysis, and in fragrance ingredient manufacturing where its N-methyl substituent confers differentiated olfactory properties versus the parent pyrrole-2-carbaldehyde.
The presence of the N-methyl group eliminates the acidic pyrrolic N–H proton (pKa of pyrrole-2-carbaldehyde is approximately 15.1 in DMSO), thereby suppressing deprotonation-driven side reactions during base-mediated condensations. In the unsubstituted aldehyde, pyrrole NH participation can generate imine-type oligomers under Knoevenagel conditions employing piperidine acetate; with the methyl-blocked analog, the α,β-unsaturated ester yield improves by 12–18 absolute percent when piperidine loading is held at 5 mol%. The steric bulk of the methyl group in the N-position also retards electrophilic substitution at the α′-carbon (C-5), enabling regioselective functionalization at the β-positions via Vilsmeier–Haack formylation without requiring low-temperature kinetic control below −20 °C. Table 1 captures the comparative physical and performance attributes.
| Parameter | 1-Methylpyrrole-2-Carbaldehyde | Pyrrole-2-Carbaldehyde |
|---|---|---|
| CAS Registry Number | 1192-58-1 | 1003-29-8 |
| Physical state at 25 °C | Liquid | Low-melting solid (mp 40–43 °C) |
| Boiling point | 88–90 °C at 22 mmHg | 217–219 °C at 760 mmHg |
| Refractive index (nD20) | 1.5620 | 1.5690 (supercooled liquid) |
| Typical GC purity (commercial grade) | ≥98.0% | ≥97.5% |
| Susceptibility to air oxidation | Moderate; δ-lactam formation ≤0.8% after 48 h exposure to ambient air at 22 °C | High; insoluble brown polymer generated within 8 h under identical conditions |
| Primary synthetic advantage | Controlled N-protection avoids NH-side reactions | Direct NH functionalization possible without deprotection |
When 1-methylpyrrole-2-carbaldehyde is processed in a PFA coiled-tube reactor with 1.0 mm internal diameter and residence time of 12 min at 60 °C, condensation with nitromethane under basic alumina (58 µm particle size, packed bed) gives the corresponding nitrovinyl adduct with 94% conversion and 88% isolated yield after crystallization from isopropanol/water. This flow configuration avoids the formation of the bis-addition byproduct that limits batch-mode conversion to approximately 78%. The aldehyde has also been evaluated in visible-light photoredox systems: using 4CzIPN as the photocatalyst (0.5 mol%) and N-Boc-proline as the organocatalyst, α-alkylation with bromoacetonitrile proceeds with a quantum yield of 0.12 at 440 nm, though published data for this specific configuration is limited to lab-scale runs of 2 mmol.
Prolonged contact with atmospheric oxygen causes slow conversion of the aldehyde to 1-methyl-5-hydroxy-1-H-pyrrol-2(5H)-one, a cyclic lactol, which subsequently dimerizes. In a warehouse stability study conducted at 25 °C/60% RH, headspace purged with nitrogen reduced lactol content to below 0.15% after 24 months, whereas containers closed under ambient air reached 2.1% degradation over the same period. Storage in amber glass bottles at 2–8 °C under a nitrogen blanket is therefore prescribed for long-term holding of pharmaceutical intermediate grades. Freeze–thaw cycling beyond three cycles increases the red hue (APHA color shift from 50 to 220 at a 10% w/w solution in ethanol) due to chromophoric oligomers, although the aldehyde titre remains above 97.8%.
The N-methyl substituent steers Vilsmeier–Haack formylation predominantly to the β-position, furnishing 1-methylpyrrole-2,4-dicarbaldehyde in 55% yield when 3.0 equivalents of DMF/POCl3 complex are applied in 1,2-dichloroethane at 80 °C over 4 h. Such regiocontrol is critical in the synthesis of pyrrolo[2,3-d]pyrimidine scaffolds for kinase inhibitors, where the 4-formyl substitution pattern must be secured before cyclization with guanidine hydrochloride under microwave irradiation at 150 W power. Contrasting this, pyrrole-2-carbaldehyde under the same conditions yields a mixture of 4- and 5-formyl isomers in a 1.3:1 ratio, necessitating preparative HPLC purification with acetonitrile/50 mM ammonium formate buffer (pH 3.5) and extending the production timeline by approximately 2.5 shifts in pilot-plant campaigns.
Control of residual 1-methylpyrrole-2-carbaldehyde in the final active pharmaceutical ingredient is accomplished via a liquid chromatography method validated according to ICH Q2(R1). Chromatographic separation on a C18 column (150 × 4.6 mm, 3.5 µm) with gradient elution using mobile phase A (0.1% trifluoroacetic acid in water) and mobile phase B (acetonitrile) at 1.0 mL/min achieves a limit of quantification of 10 ng/mL at 254 nm detection. Recovery from spiked placebo matrices ranged between 95.2% and 101.7% across three concentration levels. The aldehyde is resolved from structurally related process impurities—1-methylpyrrole, the corresponding carboxylic acid, and the dimethyl acetal formed during methanolic work-up—with a minimum resolution factor of 2.3.
Hydrazone condensation with 4-fluorophenylhydrazine hydrochloride in ethanol requires water content below 200 ppm to prevent hydrolysis of the Schiff base intermediate and subsequent generation of the parent aldehyde, which co-crystallizes with the product in the final tert-butyl methyl ether recrystallization. Introduction of 3 Å molecular sieves in powder form (5 wt% relative to solvent mass) and a 4 h pre-drying period at reflux prior to hydrazine addition reduced the aldehyde carryover in isolated crystal batches from 1.8% w/w to 0.12% w/w, as measured by quantitative 1H NMR using 1,3,5-trimethoxybenzene as an internal standard. This operation is standard when the downstream step involves lithium aluminum hydride reduction at 0 °C, where free aldehyde would consume reductant and increase the heat release rate beyond the cooling capacity of a 100-L glass-lined reactor equipped with a −25 °C brine jacket.
1-Methylpyrrole-2-carbaldehyde undergoes acid-catalyzed acetalization with glycerol formal (a mixture of 5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane) in the presence of 2 wt% montmorillonite K-10 clay at 50 °C to deliver a marine-ozonic acetal used in fabric softener microcapsule formulations. The N-methyl moiety shifts the odor detection threshold to 12 ng/L in air, versus 45 ng/L for the analogous pyrrole-2-carbaldehyde acetal, as determined by gas chromatography–olfactometry according to ASTM E679-04. The difference permits a lower dosage in fragrance oils—typically 0.15% w/w versus 0.45% w/w—thereby reducing raw material cost per finished tonne while maintaining equal headspace impact above the fragrance substantivity limit of 0.8% on cotton fabric.
| Specification Parameter | Technical Grade (≥ 97.0%) | Pharmaceutical Intermediate Grade (≥ 99.0%) | Test Method |
|---|---|---|---|
| Purity (GC, area%) | ≥97.0% | ≥99.0% | GC-FID, DB-5 30 m column |
| Single largest impurity | ≤1.5% | ≤0.3% | Same method, relative retention time window 1.15–1.35 |
| Water content | ≤0.5% | ≤0.2% | USP <921> Method Ic |
| Color (APHA, neat) | ≤100 | ≤50 | ASTM D1209 |
| Heavy metals (as Pb) | ≤20 ppm | ≤5 ppm | USP <231> / ICP-MS |
| Residual solvents | 1-Methylpyrrole ≤ 0.8% | 1-Methylpyrrole ≤ 0.15%; Methanol ≤ 500 ppm | HS-GC-MS, USP <467> |
The aldehyde has been incorporated into a telescoped reductive amination–cyclization sequence toward a tricyclic histamine H3 receptor antagonist, running at 8.7 kg scale in a facility compliant with 21 CFR Part 211. After charging the aldehyde and 2-(piperidin-4-yl)ethanamine in tetrahydrofuran at −5 °C, sodium triacetoxyborohydride (1.4 eq) was added portion-wise while maintaining the internal temperature below 8 °C. The resulting secondary amine was not isolated; instead, 6 N hydrochloric acid was introduced to initiate the Pictet–Spengler cyclization at 60 °C, yielding the desired tricyclic core in 72% overall yield after crystallization. No observable racemization occurred when monitored by chiral HPLC on Chiralpak AD-H with hexane/isopropanol/diethylamine (80:20:0.1). Handling precautions include avoidance of contact with strong oxidizers such as 70% nitric acid, which triggers exothermic decomposition beyond 120 °C with a heat evolution rate exceeding 400 W/kg in an adiabatic calorimeter, and incompatibility with primary amine accelerators used in epoxy curing because the aldehyde reacts exothermically at ambient temperature to form imine adducts that plasticize the cured network.
