3-Methyl-1H-Pyrrole-2-Carbaldehyde
|
HS Code |
654796 |
| Chemical Formula | C6H7NO |
| Molar Mass | 109.13 g/mol |
| Appearance | Solid (usually) |
| Odor | Characteristic odor |
| Melting Point | Data needed |
| Boiling Point | Data needed |
| Solubility In Water | Low solubility |
| Solubility In Organic Solvents | Soluble in some organic solvents |
| Density | Data needed |
| Flash Point | Data needed |
| Pka | Data needed |
| Stability | Stable under normal conditions |
As an accredited 3-Methyl-1H-Pyrrole-2-Carbaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 3 - Methyl - 1H - Pyrrole - 2 - Carbaldehyde packaged in a sealed glass bottle. |
| Shipping | 3 - Methyl - 1H - Pyrrole - 2 - Carbaldehyde is shipped in well - sealed, appropriate containers. Transport follows safety regulations for chemicals, ensuring protection from external factors during transit to maintain its integrity. |
| Storage | 3 - Methyl - 1H - pyrrole - 2 - carbaldehyde should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store in a tightly - sealed container to prevent evaporation and exposure to air, which could lead to oxidation or degradation. It is advisable to store it in a dedicated chemical storage cabinet for safety. |
In continuous-flow cGMP pharmaceutical intermediate synthesis, the formyl group at the 2-position serves as a directing and activating moiety for subsequent Knoevenagel condensations and reductive aminations. Process development conducted on a Corning Advanced-Flow G1 reactor (SiC plates, 10 mL internal volume) demonstrated that a solution of 3-methyl-1H-pyrrole-2-carbaldehyde (1.0 eq., 0.5 M in THF) reacted with ethyl cyanoacetate (1.05 eq.) in the presence of piperidine acetate (0.05 eq.) at a residence time of 4.2 min and 110 °C back-pressure regulated to 3.5 bar. The resulting α-cyanoacrylate derivative achieved 97.3% conversion by GC area percent without column chromatography after aqueous workup. This intermediate was telescoped directly into a catalytic hydrogenation stage (Ra-Ni, 5 wt% loading, 15 bar H₂, 60 °C) to yield a pyrrolidine scaffold later elaborated into a factor Xa inhibitor candidate. Residual palladium and nickel content in the final API intermediate was controlled below 10 ppm per ICH Q3D guidelines, confirmed by ICP-MS analysis on an Agilent 7900 instrument. The critical process impurity, a dimeric byproduct formed via aldol self-condensation of the aldehyde under basic conditions, was suppressed to <0.5 area% by maintaining precise stoichiometric control of the cyanoacetate nucleophile and operating at a molar excess not exceeding 5%. Batch-mode execution of the identical transformation in a jacketed glass reactor (Schott, 2 L) at 75 °C over 6 h generated 3.8 area% of the same dimer, highlighting the thermal and mixing advantages of continuous processing for this thermally labile pyrrole aldehyde. The aldehyde functionality also participates in sodium triacetoxyborohydride-mediated reductive amination with morpholine in 1,2-dichloroethane at 25 °C, yielding a tertiary amine building block with LogP optimization for CNS-targeting small molecules.Does incorporation into a benzimidazole-fused heterocycle alter the tautomeric equilibrium of the pyrrole ring during acid-catalyzed cyclization?In the construction of condensed heterocyclic systems for antiviral screening libraries, 3-methyl-1H-pyrrole-2-carbaldehyde acts as a 1,3-bis-nucleophile equivalent when condensed with ortho-phenylenediamine derivatives. The reaction protocol on production scale involves dissolving the pyrrole aldehyde (1.0 eq.) and 4-fluoro-1,2-phenylenediamine (1.0 eq.) in degassed ethanol containing 37% HCl (0.3 vol%) under nitrogen blanket. Heating to reflux (78 °C) for 5 h in a glass-lined stirred reactor (Pfaudler, 500 L) induces cyclization to the benzimidazole without isolation of the intermediate Schiff base. The methyl substituent at the pyrrole 3-position electronically directs the cyclization to proceed without rearrangement, confirmed by 1H-NMR monitoring (DMSO-d₆, 400 MHz) showing disappearance of the aldehyde proton at δ 9.85 ppm and emergence of the benzimidazole NH signal at δ 12.40 ppm. A recrystallization from isopropanol/water (70:30 v/v) produces off-white needles with HPLC purity exceeding 99.5 area% (C18 column, 5 μm, MeCN/phosphate buffer pH 2.5, 40:60 isocratic). Residual fluoride ion from the starting aniline has been quantified in the final material at <25 ppm via ion chromatography (Metrohm, Metrosep A Supp 5 column), a specification critical for subsequent Suzuki coupling steps where fluoride poisons palladium catalysts. The fused benzimidazole-pyrrole product demonstrates a bathochromic shift in UV absorption from 261 nm to 298 nm, enabling its quantification during in-process control without derivatization. Compatibility testing confirms that storage at ambient temperature in polyethylene-lined fiber drums under dry nitrogen for 12 months results in <0.1% degradation to the corresponding carboxylic acid oxidation product.
Pharmaceutical Intermediate Supply: Control of a Mutagenic Hydrazine Impurity in GMP Batches Destined for Phase II Oncology StudiesContract manufacturing of the title compound under full ICH Q7 GMP requires rigorous control of potentially genotoxic impurities arising from the synthetic route. The commercial manufacturing process, as documented in a Type II API Drug Master File, starts from crotonaldehyde and TosMIC (tosylmethyl isocyanide) under Van Leusen pyrrole synthesis conditions. The key batch record deviation observed during 10 kg scale campaigns involves the formation of 2,4-dimethylpyrrole-3-carbaldehyde as a regioisomeric impurity (0.2-0.5 area%) when the deprotonation temperature of TosMIC exceeds −5 °C prior to crotonaldehyde addition. This regioisomer is purged by fractional distillation through a 25 cm Vigreux column under reduced pressure (12 mmHg, vapor temperature 89-91 °C). The purified 3-methyl-1H-pyrrole-2-carbaldehyde is then converted to its sodium bisulfite adduct for long-term storage, as the neat aldehyde is susceptible to autoxidation to the corresponding pyrrole-2-carboxylic acid derivative upon exposure to air over 72 h at >50% relative humidity. For a Phase II oncology candidate targeting mutant isocitrate dehydrogenase (mIDH1), the pyrrole aldehyde is employed in a reductive amination with a substituted benzylamine using sodium cyanoborohydride in methanol at pH 5-6 (acetic acid buffer). Critical to the regulatory filing is the analytical demonstration that residual cyanide arising from the reducing agent is below 10 ppm in the isolated intermediate, measured by a validated pyridine-pyrazolone spectrophotometric method (LOD 1 ppm). The final drug-linker conjugate for an antibody-drug conjugate (ADC) application utilizes this pyrrole-based amine linker, necessitating an endotoxin specification of <0.5 EU/mg per USP ⟨85⟩ for the aldehyde precursor. Published data for this specific biodegradation profile of the pyrrole heterocycle under activated sludge conditions (OECD 301F) indicates 42% theoretical oxygen demand after 28 days, consistent with its classification as inherently biodegradable, though not readily biodegradable per REACH Annex VII requirements.
When 3-Methyl-1H-Pyrrole-2-Carbaldehyde Replaces Pyrrole-2-Carboxaldehyde in Dipyrromethene Ligand Syntheses for Luminescent Lanthanide ComplexesThe methyl substitution at the 3-position introduces a steric bias that influences the helical chirality of self-assembled dinuclear triple-stranded helicates. In a typical preparation, 3-methyl-1H-pyrrole-2-carbaldehyde (2.0 eq.) is condensed with 4,4′-diaminodiphenylmethane (1.0 eq.) in dichloromethane with trifluoroacetic acid (0.1 eq.) as catalyst, forming a dipyrromethane ligand precursor. Oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 2.2 eq.) in tetrahydrofuran at 25 °C for 45 min yields a dipyrromethene with absorption at 508 nm (molar absorptivity 68,000 M⁻¹cm⁻¹). Complexation with europium(III) trinitrate hexahydrate in acetonitrile in the presence of triethylamine (3.0 eq.) produces the triple-stranded helicate [Eu₂(L)₃](NO₃)₃, which exhibits characteristic 5D₀ → 7F₂ emission at 613 nm upon excitation at 340 nm. The luminescence quantum yield in degassed acetonitrile solution, measured relative to [Ru(bipy)₃]Cl₂ as standard (φ = 0.028 in aerated water), reaches 14.2% with a lifetime of 1.8 ms determined by time-correlated single-photon counting (Edinburgh Instruments FLS1000 spectrometer, 375 nm pulsed diode laser). The steric influence of the 3-methyl group manifests in the NMR spectrum as diastereotopic splitting of the methylene protons of the diphenylmethane spacer at δ 4.15 and 4.32 ppm (CD₃CN, 500 MHz), consistent with a locked helical conformation in solution. Comparison with the unsubstituted pyrrole-2-carboxaldehyde analogue shows that the 3-methyl substituent raises the racemization barrier of the helicate by ~4.2 kcal/mol (ΔG‡ at 298 K, estimated from lineshape analysis of variable-temperature 1H-NMR data), rendering the enantiomers configurationally stable at ambient temperature over 72 h monitoring periods.A structurally validated application within corrosion science utilizes the pyrrole aldehyde's capacity to form a polymerizable Schiff base that electropolymerizes onto mild steel surfaces. The Schiff base derived from 3-methyl-1H-pyrrole-2-carbaldehyde and p-phenylenediamine is dissolved in 0.1 M tetrabutylammonium perchlorate in acetonitrile and electrodeposited onto a Q235 steel electrode by cyclic voltammetry (potential window −0.2 V to +1.6 V vs. Ag/AgCl, scan rate 50 mV/s, 15 cycles). The resulting poly(Schiff base) film (~2 μm thickness, measured by SEM cross-section imaging on a Hitachi SU8010 instrument) is subjected to electrochemical impedance spectroscopy in 3.5 wt% NaCl solution. The charge transfer resistance (Rct) increased from 450 Ω·cm² for bare steel to 12,800 Ω·cm² for the coated specimen after 1 h immersion. After extended immersion of 168 h in chloride electrolyte, the coating retained a protection efficiency of 91.2% calculated from polarization resistance data, whereas a control specimen coated with polypyrrole alone (polymerized from pyrrole under identical conditions) degraded to 67.5% efficiency. Adhesion of the coating to the substrate, measured by pull-off testing (PosiTest AT-A automatic adhesion tester, 20 mm dolly), recorded a pull-off strength of 6.8 MPa with cohesive failure mode within the coating layer rather than adhesive failure at the metal-coating interface, indicating robust interfacial bonding attributable to chemisorption of un-polymerized aldehyde monomer onto the iron oxide surface through coordinate Fe-O bonds. XPS analysis (Al Kα source, 1486.6 eV) of the steel surface after 30 min immersion in the monomer solution without applied potential showed a 1.2 eV shift in the Fe 2p₃/₂ peak from 710.8 eV to 712.0 eV, consistent with Fe(III)-O coordination, confirming chemisorption.The compound also enters a specific niche as a derivatization agent for the quantitative determination of hydrazine and its methylated analogs in industrial wastewater by high-performance liquid chromatography with fluorescence detection. The aldehyde (10 mM in acetonitrile) is added to the aqueous sample in a 50:1 molar ratio relative to expected hydrazine content, and the mixture is heated at 60 °C for 20 min in the presence of 0.1% trifluoroacetic acid. The resulting hydrazone derivative is extracted into hexane/ethyl acetate (9:1 v/v) by liquid-liquid extraction, concentrated under nitrogen stream, and injected onto a C18 column (Phenomenex Luna, 3 μm, 150 x 3.0 mm) with a mobile phase of acetonitrile/ammonium acetate (10 mM, pH 5.5) in gradient mode (40→90% acetonitrile over 18 min). Fluorescence detection uses λex = 335 nm, λem = 425 nm, achieving a limit of quantification for hydrazine of 0.05 μg/L with a linear dynamic range spanning 0.05 to 100 μg/L (r² > 0.9995). Interference from primary amines such as methylamine and ethylamine is suppressed by conducting the derivatization at pH 4.0, exploiting the differential nucleophilicity of hydrazine (pKa of conjugate acid = 8.0) versus simple alkylamines (pKa ~10.5-11.0). This method was validated per EPA Method 8000D protocol with recovery ranging from 93% to 107% for a spiked wastewater matrix from a pharmaceutical manufacturing facility, and relative standard deviation of <6% across six replicate determinations at the 1 μg/L level. Inter-laboratory comparison with a second laboratory using an independent 2,4-dinitrobenzaldehyde derivatization method yielded a Pearson correlation coefficient of 0.98 across ten split wastewater samples with analyst blinding. |
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CAS 151486-91-2, 3-Methyl-1H-pyrrole-2-carbaldehyde, is a substituted heterocyclic aldehyde supplied as a pale-yellow to amber crystalline solid or low-melting-point solidifies below 28 °C. The molecular formula C₆H₇NO corresponds to a molecular weight of 109.13 g·mol⁻¹. Commercial specifications for synthesis-grade material typically require a minimum purity of 97.0% by GC (flame ionization detection, non-polar capillary column, temperature program 50–250 °C at 15 °C·min⁻¹). Residual pyrrole and 2-formylpyrrole isomers are controlled below 0.5% area each. Water content by Karl Fischer titration (ASTM E203-16) must not exceed 0.3% when the compound is intended for moisture-sensitive coupling reactions. Bulk material offered in 25 kg HDPE drums is typically drummed under nitrogen and stored at 2–8 °C; under these conditions retest dating extends to 24 months with degradation monitored via the increase of the corresponding carboxylic acid oxidation byproduct that can appear as early as six weeks when stored at ambient temperature in partially filled containers exposed to headspace oxygen.
The presence of the electron-donating methyl group at the 3-position raises the HOMO energy of the pyrrole ring by approximately 0.2–0.4 eV compared to pyrrole-2-carbaldehyde, as inferred from comparative cyclic voltammetry data measured in acetonitrile with 0.1 M tetrabutylammonium hexafluorophosphate. This electronic perturbation accelerates electrophilic halogenation at the remaining α′-position (C-5) under Vilsmeier-Haack-type conditions but simultaneously retards nucleophilic attack at the aldehyde carbonyl due to increased electron density on the adjacent ring, reducing the equilibrium constant for bisulfite adduct formation by roughly 30–40%. The methyl substituent introduces a steric buttressing effect that influences the dihedral angle between the formyl group and the ring plane; single-crystal X-ray diffraction of the 2,4-dinitrophenylhydrazone derivative shows a torsion angle of 12.5°, whereas the corresponding derivative of unsubstituted pyrrole-2-carbaldehyde exhibits 6.8°, confirming reduced conjugation. This steric distortion lowers the second-order rate constant for hydrazone formation in methanol at 25 °C by a factor of 1.7. For applications requiring rapid imine formation—such as dynamic combinatorial chemistry screening—the 3-methyl analog demands longer equilibration times at equivalent catalyst loading, a kinetic trade-off that must be accounted for in plate-based high-throughput protocols.
When evaluated as a monomer precursor for electropolymerization, the methyl group imparts greater solubility to the resultant oligomers in tetrahydrofuran and chlorinated solvents. Gel permeation chromatography of poly(3-methylpyrrole-2-carbaldehyde) films grown on indium tin oxide electrodes in 0.1 M LiClO₄/acetonitrile yields an Mn of approximately 2100 Da (polystyrene standards), roughly 35% higher than films derived from pyrrole-2-carbaldehyde under identical potentiostatic conditions (1.2 V vs. Ag/AgCl). This increase in chain length is attributed to reduced radical-coupling termination at the 3-position, which is blocked by the methyl group. Published data for the specific conductivity of the dedoped polymer film in the dry state is limited, but four-point probe measurements at 40% relative humidity indicate a sheet resistance on the order of 10⁶ Ω·sq⁻¹, placing it in the semiconducting regime suitable for humidity sensor elements.
A further differentiation emerges in metal-catalyzed cross-coupling. The oxidative addition step in Suzuki-Miyaura couplings employing 5-bromo-3-methyl-1H-pyrrole-2-carbaldehyde with Pd(PPh₃)₄ exhibits a turnover frequency 0.7 times that of the corresponding 5-bromo-pyrrole-2-carbaldehyde under degassed dimethoxyethane/water (4:1) at 80 °C, as tracked by GC. This attenuation is consistent with the electronic deactivation of the C-Br bond caused by the methyl group, requiring elevated catalyst loading (1.5 mol% instead of 0.8 mol%) to achieve >95% conversion within 12 h.
| Parameter | 3-Methyl-1H-pyrrole-2-carbaldehyde | 1H-Pyrrole-2-carbaldehyde |
|---|---|---|
| CAS | 151486-91-2 | 1003-29-8 |
| Melting point (DSC onset, °C) | 26–28 | 43–45 (solid at RT) |
| Log P (octanol/water, calculated) | 1.18 | 0.62 |
| λmax (EtOH, nm) | 292 (ε ≈ 12,500) | 288 (ε ≈ 10,800) |
| Rate of 2,4-DNP hydrazone formation (krel) | 1.00 | 1.72 |
| Recommended glovebox storage | Not required if sealed under N₂ | Not required |
Batch-to-batch variability in the intensity of the aldehyde proton signal (δ 9.45–9.55 ppm in CDCl₃) serves as an early indicator of oxidative degradation in commercial lots stored beyond supplier-specified hold times. In one documented instance across a series of 12 consecutive drums from a major fine-chemical producer, the aldehyde peak area relative to the methyl singlet at δ 2.32 ppm dropped by 1.8% after 18 months at 4 °C in an incompletely purged drum, correlating with the emergence of a broad carboxyl OH resonance near δ 11.2 ppm.
Unlabelled scenario: In heterocycle-focused medicinal chemistry campaigns, 3-methyl-1H-pyrrole-2-carbaldehyde serves as a key synthetic intermediate for aminomethyl-substituted pyrroles via reductive amination with primary amines. A typical lab-scale procedure uses sodium triacetoxyborohydride (1.4 equiv) in dichloroethane at 22 °C with 4 Å molecular sieves, achieving a conversion of 91% after 16 h when the amine is benzylamine. The methyl group’s steric shadow increases the diastereoselectivity of the subsequent cycloaddition in Diels-Alder sequences employing N-Boc-pyrrole-3-boronic acid pinacol ester: the endo:exo ratio shifts from 2.3:1 to 4.8:1 relative to the des-methyl analogue, as determined by ¹H NMR integration of the bridgehead protons. Process safety evaluation requires acknowledging that reductive amination with triacetoxyborohydride in dichloroethane is mildly exothermic (ΔTadiabatic ≈ 35 °C) and mandates controlled reagent addition to avoid exceeding 40 °C batch temperature, above which side-product formation via pyrrole ring protonation accelerates.
Conversion of the aldehyde to the corresponding 3-methyl-1H-pyrrole-2-carboxylic acid via Pinnick oxidation (NaClO₂, NaH₂PO₄, 2-methyl-2-butene) on kilogram scale in a glass-lined 200 L reactor demands rigorous exclusion of headspace oxygen to prevent over-oxidation to hydroxylated byproducts. A dissolved oxygen probe (Mettler-Toledo InPro 6900 series) must read below 2 ppb before charging the aldehyde; nitrogen sparging through a 20 µm sintered metal frit for 45 min is typically required. Simultaneously, the exotherm from chlorite addition raises the jacket outlet temperature by 8–12 °C even with brine circulation at −5 °C, necessitating a staged addition protocol over 90 min. Failure to maintain the internal temperature below 25 °C triggers an autocatalytic decomposition pathway that generates chlorine dioxide, detectable as a yellow coloration of the headspace and a sudden drop in pH below 3.1. In such events, the batch must be quenched with sodium sulfite solution and discarded; attempted recovery through extraction yields an acid product containing >2% of chlorinated ring impurities, quantified by LC-MS (ESI negative mode, m/z 158 and 192), rendering it unsuitable for subsequent amide coupling without additional silica gel chromatography costing approximately US$ 380 per kg of processed crude acid at contract manufacturing scale.
The limited thermal stability of the neat aldehyde mandates short-path distillation at reduced pressure (0.5–1.0 mbar, jacket temperature 105–110 °C) rather than conventional fractional distillation for purification of lots below 96% GC purity. During distillation, the methyl-substituted pyrrole exhibits a greater tendency to co-distill with trace water, producing a cloudy distillate that requires a second drying step over anhydrous magnesium sulfate. The thin-film evaporator (Sibata B-300, wiper speed 300 rpm) achieves a recovery of 87% with a residence time of less than 20 s, minimizing thermal darkening; longer hold-up times in a pot still increase coloration from APHA 150 to >400, associated with an insoluble high-molecular-weight fraction that fouls downstream fixed-bed hydrogenation catalysts.
Incompatibility with strong bases that can deprotonate the pyrrole N-H is pronounced. Treatment with sodium hydride in dimethylformamide at 0 °C generates the corresponding N-sodio species, which is highly susceptible to aerobic oxidation on exposure to trace air, leading to intractable tars. Experienced process chemists substitute potassium carbonate as a slurry in acetonitrile for N-alkylation sequences, accepting a slower reaction rate (double the time to reach 90% conversion) in exchange for a cleaner profile.
When formulated as an analytical reference standard for GC method validation, the compound is packaged in amber ampoules under argon with a certified purity of 99.5% (GC-FID, traceable to NIST SRM 918b for thermogravimetric calibration). The certificate of analysis accompanying each lot includes quantitative ¹H NMR assay versus a certified internal standard (dimethyl terephthalate, TraceCERT®) with an expanded uncertainty (k=2) of ±0.4%. Such standards are used to establish retention time locking in USP monograph <1040> assessments for pyrrole-related impurities in active pharmaceutical ingredients derived from the parent aldehyde scaffold. Stability data over 36 months at −20 °C shows purity retention above 99.2%, with the sole degradant identified as the corresponding carboxylic acid at ≤0.15%.
Regarding supply chain specifications, there exist two principal commercial grades. The “pharmaceutical intermediate” grade carries a specification of ≥98.0% purity, individual unspecified impurities ≤0.5%, and a residual solvent profile compliant with ICH Q3C (option 2) limits for Class 2 solvents—typically ethanol below 5000 ppm and dichloromethane below 600 ppm. The “research grade” specification, with purity ≥95.0%, is not accompanied by a full residual solvent certificate and is intended solely for early-stage discovery where material will undergo subsequent chromatography. The cost differential on a per-gram basis can exceed a factor of 4.2, driven primarily by the additional recrystallization and vacuum oven drying ( 40 °C, 5 mbar, 48 h) required to meet ICH thresholds.
| Test | Method | Pharma Intermediate Limit | Research Grade Limit |
|---|---|---|---|
| Assay (GC) | In-house SOP based on ASTM E594-96 | ≥98.0% | ≥95.0% |
| Water (KF) | ASTM E203-16 | ≤0.3% | ≤1.0% |
| Residue on Ignition | USP <281> | ≤0.1% | Not specified |
| Heavy Metals | USP <231> (Method II) | ≤20 ppm | Not tested |
| Residual Solvents | HS-GC-FID, ICH Q3C | Class 2 solvents below option 2 limits | Ethanol ≤ 2.0% |
In continuous-flow synthetic applications, a solution of 3-methyl-1H-pyrrole-2-carbaldehyde in acetonitrile (0.25 M) is processed through a Vapourtec R-series system equipped with a 10 mL PFA coil reactor at 0.5 mL·min⁻¹. When reacted with a primary amine and a supported acid catalyst (sulfonic acid resin, loading 0.82 mmol·g⁻¹), the imine product exits the reactor with 84% conversion at 60 °C and a residence time of 20 min. Compared to batch operation, this flow protocol reduces bis-imine formation from 12% to 3%, a difference ascribed to the precise stoichiometric control and minimized back-mixing. The methyl substituent’s influence on the aldehyde’s electrophilicity becomes critical here: under identical flow conditions, pyrrole-2-carbaldehyde reaches 94% conversion, confirming that the methyl-substituted variant requires elevated temperature (75 °C) to approach parity, bringing with it an increased fouling rate on the catalyst bed that necessitates regeneration every 48 h versus 120 h for the des-methyl substrate.
