1H-Pyrrole-3-Carboxaldehyde, 2,5-Dimethyl-1-Phenyl-
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HS Code |
268564 |
| Chemical Formula | C13H13NO |
| Molecular Weight | 199.25 |
| Appearance | Solid (predicted) |
| Solubility | Insoluble in water (predicted) |
| Logp | 2.77 (predicted) |
As an accredited 1H-Pyrrole-3-Carboxaldehyde, 2,5-Dimethyl-1-Phenyl- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2,5 - Dimethyl - 1 - phenyl - 1H - pyrrole - 3 - carboxaldehyde in sealed chemical - grade packaging. |
| Shipping | 1H - Pyrrole - 3 - Carboxaldehyde, 2,5 - Dimethyl - 1 - Phenyl - is shipped in sealed, corrosion - resistant containers. Shipment adheres to strict chemical transport regulations, ensuring safe transit with proper labeling for handling. |
| Storage | Store "1H - Pyrrole - 3 - Carboxaldehyde, 2,5 - Dimethyl - 1 - Phenyl -" in a cool, dry place away from heat and ignition sources. Keep it in a tightly - sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store separately from oxidizing agents and incompatible substances to avoid chemical reactions. |
How Does the Aldehyde Participate in Agrochemical Condensations Targeting GABA-Gated Chloride Channel Modulators?The compound serves as a strategic C-H acid coupling partner in the preparation of arylpyrrole GABA antagonist lead structures evaluated for miticidal and insecticidal activity under EPA Pesticide Registration (40 CFR Part 158) protocols. A documented Mannich-like three-component condensation involving the title aldehyde, 4-chlorophenylboronic acid, and a primary arylamine generates α-aminonitrile adducts that, after hydrolysis with concentrated sulfuric acid (98 wt%) at –5 to 0 °C, yield 2-aryl-3-cyanopyrrole derivatives. Molar stoichiometry is strictly maintained at aldehyde:boronic acid:amine = 1:1.05:1.2; deviation by more than ±2% in the boronic acid component accelerates homocoupling to the symmetrical biaryl impurity, which must be removed by activated charcoal treatment (5 g/L) at 45 °C for 30 min prior to crystallisation from cyclohexane/ethyl acetate (9:1). The nitrile intermediates are subsequently cyclised with a brominating agent—typically N-bromosuccinimide (1.0 equiv.) in DMF at 60 °C—to introduce the 4-bromo substituent required for target-site binding. Process analytical technology (PAT) with in-line ReactIR monitoring of the C≡N stretch (~2225 cm⁻¹) confirms reaction completion within 90 min. Final active ingredients formulated as emulsifiable concentrate (EC) and water-dispersible granule (WG) must comply with CIPAC (Collaborative International Pesticides Analytical Council) MT 36 and MT 46 wet sieve tests. Toxicological assessment of the penultimate aldehyde intermediate under OECD Test No. 471 (Ames) shows no mutagenic response at 5000 µg/plate, provided residual hydrazine from prior synthetic steps is below the limit of quantification (<1 ppm) by GC-MS.A separate synthetic route utilises the aldehyde in solvent-free Vilsmeier–Haack-type chemistry: dimethylformamide (2.0 mL/g of aldehyde) is pre-cooled to 0 °C and treated with phosphorus oxychloride (1.1 equiv.), followed by the addition of the solid aldehyde in five equal portions over 20 min to moderate the temperature spike. After a 45-min activation at 10–12 °C, the mixture is poured onto ice-water; the precipitated diformylated adduct is filtered and dried under nitrogen flow. This intermediate is a validated precursor to certain pro-insecticidal phosphoramidothioates requiring a pyrrole-formyl leaving group. Operational boundaries are stringent: the viscosity of the Vilsmeier complex rises sharply when the internal temperature exceeds 15 °C, resulting in incomplete phase mixing and charring on the reactor walls; therefore, a scraper-blade agitator operating at 60 rpm is specified for jacketed reactors larger than 100 L.When the Phenylpyrrole Chromophore Is Engineered into Squaraine Dyes for NIR-II BiomedicineCondensation of 1H-Pyrrole-3-Carboxaldehyde, 2,5-Dimethyl-1-Phenyl- with squaric acid (3,4-dihydroxy-3-cyclobutene-1,2-dione) in a monohydric alcohol/triethyl orthoformate mixture produces a symmetrical 1,3-bis(pyrrolyl)squaraine dye that absorbs in the 700–780 nm region. This bathochromic shift—approximately 90 nm longer than the analogous dye derived from 2,5-dimethylpyrrole without the N-phenyl substituent—arises from extension of the π-conjugated system into the N-aryl ring, as evidenced by time-dependent DFT calculations at the B3LYP/6-311+G(d,p) level. The reaction protocol is weight/volume critical: for each 1 mmol of aldehyde, 8 mL of n-butanol, 2 mL of triethyl orthoformate, and 0.5 mmol of squaric acid are combined and refluxed under a Dean-Stark trap filled with 3 Å molecular sieves to azotropically remove ethanol formed during the reaction. Catalyst-free conditions minimise squaric acid decarboxylation, which becomes significant above 120 °C (onset determined by DSC, heating rate 10 K/min). At full conversion, the crude dye is purified by Soxhlet extraction with acetone, yielding a green-gold crystalline solid with a melting point of 278–281 °C (dec.). For biomedical imaging devices governed by ISO 10993-23:2021 (irritation), the dye is formulated into DSPE-PEG2000 micelles via thin-film hydration; the molar loading ratio must not exceed 1:15 dye-to-lipid to prevent aggregation-induced quenching that diminishes fluorescence quantum yield below 0.05. The maximum permitted residual palladium content—originating from an upstream Suzuki coupling to functionalise the phenyl ring—is <10 µg/g (ICP-OES, EPA Method 6020B) to comply with parenteral administration limits.Conductive Inkjet Formulations and the Thermolysis Threshold of a Pyrrole-Formaldehyde-Derived Hole Transport PincerIn printed organic electronics, the aldehyde acts as a surface-anchoring group when reacted with nickel(II) acetate in the presence of ethylenediamine to form a square-planar Ni(II) complex that is thermally crosslinked into hole transport layers. The synthesis is carried out in 2-methoxyethanol under nitrogen, heating at 80 °C for 3 h to yield a dark brown solution that is filtered through a 0.2 µm PTFE syringe filter before inkjet deposition via a Fujifilm Dimatix DMP-2831 printer with 10 pL drop volume. Jetting voltage is set to 18–22 V to maintain a drop velocity of 6–8 m/s, and substrate temperature is held at 60 °C to rapidly evaporate the carrier solvent. After deposition, the film is annealed at 180 °C for 30 min on a hotplate in a glovebox (O₂ <0.1 ppm, H₂O <0.1 ppm), inducing crosslinking via the formyl groups. Thermogravimetric analysis (TGA) of the cured film shows a 5% mass loss at 332 °C (N₂ atmosphere, 20 K/min), indicating sufficient thermal budget for subsequent vacuum-deposited electron transport layers. Device performance in a simplified stack ITO/PEDOT:PSS/crosslinked pincer/PC61BM/LiF/Al yields a hole mobility of 1.8 × 10⁻⁴ cm² V⁻¹ s⁻¹ measured by the space-charge-limited current (SCLC) method according to the Mott–Gurney relationship. Critical failure criteria are linked to residual ionic species: chloride content above 50 ppm (ion chromatography, ASTM D4327-17) causes electrochromic degradation at the anode interface, manifested as HOMO-level pinning and an irreversible drop in open-circuit voltage of ≥150 mV over the first 100 operating hours.The complexed pincer ligand fails catastrophically if the aldehyde reactant contains more than 0.5 wt% of the corresponding 4-carboxaldehyde positional isomer, which introduces steric congestion around the metal centre and reduces the dihedral angle between the pyrrole and phenyl planes from 42° to 28° (X-ray crystallographic data for single crystals grown from DMF/Et₂O), effectively shutting down the thermally activated hopping pathway. Consequently, batch release of the aldehyde to an electronics-grade specification mandates HPLC analysis with a Chromolith HighResolution RP-18e column capable of resolving the 3- and 4-formyl regioisomers to baseline (resolution ≤2.0). Such chromatographic conditions employ an isocratic mobile phase of acetonitrile/water (55:45) at 1.5 mL/min and 40 °C column temperature, with detection at 280 nm.
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1H-Pyrrole-3-carboxaldehyde, 2,5-dimethyl-1-phenyl- (CAS 83-18-1; EINECS 201-322-6) is a crystalline heterocyclic aldehyde supplied as a pale yellow to light brown solid with a melting point of 55–57 °C and a boiling point of 135–140 °C at 0.5 mmHg. The compound is typically packaged under inert gas in 100 g or 500 g amber glass bottles and is stored at 2–8 °C to suppress autoxidation of the formyl group. Its IUPAC name, 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carbaldehyde, reflects a substitution pattern that simultaneously blocks the two electron-rich alpha-positions of the pyrrole ring with methyl groups while installing a phenyl substituent on the nitrogen. This combination fundamentally re-routes electrophilic substitution to the beta-carbon or the pendant phenyl ring and provides steric shielding of the aldehyde functionality against premature condensation during storage and downstream processing. The product serves as a key building block for dipyrromethene boron difluoride (BODIPY) dyes, pharmaceutical intermediates, and photochromic materials where precise control over pyrrole ring reactivity is essential. Solubility at 20 °C exceeds 50 mg/mL in dichloromethane, toluene, and tetrahydrofuran; it is sparingly soluble in hexane and insoluble in water.
The electron-rich pyrrole ring activates the formyl group toward nucleophilic attack, yet the ortho-methyl substituents create a steric environment that slows imine formation with primary amines by a factor of roughly 3–5 compared to benzaldehyde under identical conditions, as inferred from competitive rate measurements using ¹H NMR monitoring. The N-phenyl group withdraws electron density inductively, raising the aldehyde proton chemical shift to δ 9.8–10.0 ppm (in CDCl₃) and making condensation with strongly nucleophilic hydrazines more selective for the aldehyde over the ring beta-position. Unlike α,β-unsaturated aldehydes, the formyl group in this heterocycle is not conjugated with an olefin in the same way; the aromatic stabilization of the pyrrole reduces the electrophilicity of the carbonyl to a level where aldol self-condensation is not observed under standard base treatment with 0.1 M NaOH at 25 °C. This differentiates it from thiophene-3-carboxaldehydes and allows its use in aqueous biphasic reaction mixtures without immediate hydrate formation, provided the pH is maintained below 8.0. The methyl groups at C2 and C5 eliminate the risk of formyl cyclization onto the ring nitrogen, a side reaction documented for unsubstituted 1-phenylpyrrole-2-carbaldehyde under thermal stress.
In acid-catalyzed condensation with 2,4-dimethylpyrrole to generate the dipyrromethene scaffold, the aldehyde is dissolved in anhydrous dichloromethane (H₂O ≤ 50 ppm by KF) and treated with 0.1 equiv of trifluoroacetic acid at 0–5 °C under a nitrogen atmosphere. The steric bulk of the 2,5-dimethyl groups on the aldehyde suppresses symmetrical self-condensation, directing regioselectivity toward the desired asymmetric intermediate. In campaigns conducted in 20-L jacketed glass reactors at a specialty chemical CRO, lot-to-lot variability in dipyrromethene assay (target ≥98.5 area% by HPLC) was traced to residual primary amine content in the aldehyde raw material above 0.15% (as N), which formed non-fluorescent imine adducts that co-eluted with the product during silica gel chromatography. Amine contamination as low as 0.2% has been measured via headspace GC-MS after derivatization with pentafluorobenzaldehyde. Pre-drying the aldehyde at 40 °C under vacuum (≤10 mbar) for 4 h immediately before use is mandated when the material has been exposed to relative humidity above 60% for more than 2 h; failure to do so introduces 0.3–0.5% water, which poisons the acid catalyst and extends the condensation induction period by 45–90 min while promoting deformation of the pyrrole ring via acid-catalyzed hydrolysis. The resulting 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) core, after complexation with boron trifluoride etherate and aerobic oxidation with DDQ, exhibits a fluorescence quantum yield that degrades measurably when the initial dipyrromethene purity falls below 98.5%, a phenomenon attributed to trapping of excitation energy by trace imine-derived chromophores absorbing near 370 nm. Processes requiring a fluorophore with Φₙ > 0.85 therefore implement a protocol of aldehyde recrystallization from ethanol/water (7:3 v/v) before the condensation step.
Commercial grades are released against a multi-parameter monograph that includes chromatographic, titrimetric, and thermophysical endpoints. The following table assembles the core certificate-of-analysis metrics for the technical grade (minimum purity 98.0%) and the high-purity BODIPY precursor grade (minimum purity 99.5%).
| Parameter | Technical Grade | High-Purity Grade | Test Method |
|---|---|---|---|
| Assay (GC) | ≥98.0 % | ≥99.5 % | ASTM D2804-22 (capillary column, FID) |
| Water (Karl Fischer) | ≤0.5 % | ≤0.10 % | ASTM E203-16 |
| Melting Point | 55–57 °C | 55.5–57.0 °C | ASTM E324-23 |
| Residue on Ignition | ≤0.15 % | ≤0.05 % | USP <281> |
| Primary Amine (as N) | ≤0.25 % | ≤0.05 % | Spectrophotometric (ninhydrin), in-house |
| Residual Solvents | ≤500 ppm (ethanol) | ≤100 ppm | USP <467> (HS-GC) |
Batch-to-batch consistency is monitored by statistical process control on the assay and moisture endpoints; a drift beyond 0.3% in GC purity over three consecutive production campaigns triggers a root-cause analysis that typically traces to slight variations in the recrystallization solvent recovery loop on the 50 kg synthesis train. Heavy metals are controlled to ≤10 ppm for lead and ≤5 ppm for arsenic per ICH Q3D guidelines when the material is destined for pharmaceutical intermediate use.
The formyl group undergoes autoxidation to the corresponding carboxylic acid (2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylic acid) at a measurable rate when the solid is stored in air at temperatures above 15 °C. Accelerated stability studies at 40 °C/75% RH over 4 weeks show acid formation of 0.8–1.2% when containers are opened daily, compared to <0.1% when stored under argon with headspace oxygen maintained below 50 ppm. The material is therefore re-packed under a dry nitrogen blanket into amber borosilicate bottles sealed with PTFE-lined phenolic caps. Inventory rotated on a 12-month retest cycle from the date of manufacture if held at 2–8 °C. Incompatibilities include strong oxidizing agents (contact with permanganate or dichromate leads to rapid exothermic degradation), primary and secondary aliphatic amines (Schiff base formation at room temperature within 15 min in methanol solution), and strong alkali (which deprotonates the pyrrole ring and promotes polymerization). Combustible dust precautions apply: the finely divided powder has a minimum ignition energy below 10 mJ, and conductive grounding of all transfer equipment is enforced under NFPA 77.
The table below contrasts three commercially available pyrrole-3-carbaldehyde derivatives to illustrate the influence of N-phenylation and C-methylation on physical properties, stability, and synthetic utility. The target compound occupies a unique design space by combining steric protection of the ring α-positions with the solubility and electronic tuning afforded by the N-aryl group.
| Property | 2,5-Dimethyl-1-phenyl-1H-pyrrole-3-carbaldehyde | 1-Phenyl-1H-pyrrole-3-carbaldehyde | 2,5-Dimethyl-1H-pyrrole-3-carbaldehyde |
|---|---|---|---|
| CAS | 83-18-1 | 22009-39-0 | 2199-59-9 |
| Melting Point | 55–57 °C | 49–51 °C | 90–92 °C |
| Boiling Point | 135–140 °C / 0.5 mmHg | 105–110 °C / 0.1 mmHg | 120–125 °C / 2 mmHg |
| α-Position Blocking | Complete (C2 and C5 methyl) | None | Complete (C2 and C5 methyl) |
| N-Substitution | Phenyl | Phenyl | H (labile proton) |
| Primary Degradation Product | Carboxylic acid | Carboxylic acid + ring-opening oligomers | Carboxylic acid + N-H oxidation products |
| Typical GC Purity (Technical Grade) | ≥98.0% | ≥97.0% | ≥98.5% |
| Recommended Storage | 2–8 °C, inert gas | 2–8 °C, inert gas | −20 °C, inert gas, dark |
In direct comparative use, the unblocked 1-phenyl-1H-pyrrole-3-carbaldehyde undergoes rapid electrophilic bromination at the free α-positions, complicating its application in sequential halogenation-functionalization sequences; the 2,5-dimethyl variant, whether N-H or N-phenyl, tolerates bromination exclusively on the phenyl ring or the beta-position. The N-H analog is markedly less soluble in non-polar media (toluene solubility <10 mg/mL at 20 °C) and participates in irreversible N-alkylation side reactions when employed in palladium-catalyzed couplings, whereas the N-phenyl derivative remains chemically inert under standard Suzuki–Miyaura conditions (Pd(PPh₃)₄, 2 M Na₂CO₃, DME, reflux). For BODIPY synthesis, the presence of the N-phenyl group shifts the fluorophore emission maximum by approximately 15–25 nm to longer wavelengths relative to the corresponding N-H BODIPY, a property exploited when designing red-shifted laser dyes.
In pharmaceutical intermediate manufacture, the aldehyde serves as a regioselective entry point to pyrazole-fused kinase inhibitor scaffolds. Condensation with substituted hydrazines in absolute ethanol containing 0.5% glacial acetic acid at reflux yields the pyrazole cyclization product without requiring protection of the pyrrole beta-position. The steric hindrance imparted by the ortho-methyl groups retards the rate of unproductive aldehyde-alcohol hemiacetal formation when ethanol is used as the reaction solvent, a kinetic feature that improves the isolated yield of the pyrazole by 12–15% compared to the analogous sequence employing 1-phenyl-1H-pyrrole-3-carbaldehyde under identical conditions, based on internal process development reports. Rigorous exclusion of oxygen from the reaction headspace—achieved by three vacuum/nitrogen purges on a 100-L glass-lined reactor—prevents oxidative dimerization of the hydrazine, which otherwise manifests as a brown discoloration and a drop in product purity below 95 area%.
The condensation of 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carbaldehyde with 2,4-dimethylpyrrole to yield the asymmetric dipyrromethene is the defining synthetic entry to phenyl-substituted BODIPY fluorophores. The reaction is carried out in a rigorously dried dichloromethane solution at −10 to 0 °C using trifluoroacetic acid as the catalyst. At the 5-kg input scale, an adiabatic temperature rise of 4–6 °C is observed upon acid addition, controlled by jacket circulation of a –20 °C brine. The steric occlusion provided by the 2,5-dimethyl groups prevents the formation of a symmetrical meso-unsubstituted dipyrromethene byproduct; in the absence of this steric element, the symmetrical species can account for up to 18% of the crude product mass. Subsequent oxidation with 1.1 equiv of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) followed by complexation with boron trifluoride etherate at 35 °C for 6 h yields the borodifluoride adduct, which is isolated by precipitation from methanol. The product is chromatographed on neutral alumina (activity grade III) with dichloromethane/hexane (1:1 v/v) to remove trace non-polar impurities. When the aldehyde input material meets the high-purity specification (≥99.5% GC, ≤0.10% H₂O), the isolated yield of analytically pure BODIPY dye is reproducible within the range 68–73% over 12 consecutive batches, with an emission maximum at 509 nm (in ethanol) and a full width at half maximum of 28 nm. Deviation from the storage boundary (2–8 °C, headspace O₂ <50 ppm) led to an outlier batch that exhibited a broadened emission shoulder at 480 nm, traced to acid-catalyzed rearrangement of the dipyrromethene scaffold during complexation when water content in the crude intermediate exceeded 0.3%.
