3,5-Dimethyl-1H-Pyrrole-2-Carboxaldehyde
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HS Code |
287730 |
| Chemical Formula | C7H9NO |
| Molecular Weight | 123.152 g/mol |
As an accredited 3,5-Dimethyl-1H-Pyrrole-2-Carboxaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 50g of 3,5 - Dimethyl - 1H - Pyrrole - 2 - Carboxaldehyde packaged in a sealed glass bottle. |
| Shipping | 3,5 - Dimethyl - 1H - Pyrrole - 2 - Carboxaldehyde is shipped in well - sealed, appropriate containers. Chemical compatibility is ensured. Shipment follows all relevant regulations for safe transport of chemicals. |
| Storage | 3,5 - Dimethyl - 1H - Pyrrole - 2 - Carboxaldehyde should be stored in a cool, dry, and well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store it in a tightly closed container to prevent exposure to air and moisture, which could potentially lead to degradation or unwanted reactions. |
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In the kilogram-scale manufacturing of anthranilic diamide insecticides, 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde functions as a strategic C-2 functionalized pyrrole building block. Its aldehyde group undergoes reductive amination with 2-bromo-4-cyanoaniline in a biphasic toluene/water system using sodium triacetoxyborohydride (1.5–2.0 eq) at 20–25 °C, yielding the corresponding secondary amine intermediate with ≥98.5% conversion by GC-FID. Subsequent condensation with 3-benzoylmethyl chloride under Schotten-Baumann conditions (10% NaOH, 0–5 °C) delivers the penultimate amide scaffold. Production-scale batches on 1,000 L glass-lined reactors at Mitsui & Co. licensees require precise pH control at pH 9.5 ±0.3 during amidation to suppress amidine side-product formation, which is monitored via inline FTIR for the 1,650 cm−1 carbonyl shift. The isolated intermediate is recrystallized from toluene/n-heptane (1:3 v/v) to reach 99.0% HPLC purity per CIPAC MT 167 prior to final cyanation. Full compliance with FAO Specification 825/TC demands residual solvent limits of dichloromethane <600 ppm and toluene <890 ppm as verified by headspace GC per USP <467>. The reaction mass efficiency (RME) benchmarked at production scale is 0.628, with the primary loss pathway identified as aldehyde-to-alcohol over-reduction when NaBH4 is substituted for the triacetoxyborohydride—a deviation that forces an additional scavenging resin purification step. Water quench exotherms are managed by a 25 °C/min ramp programmed into the jacket temperature controller, avoiding thermal runaway above 55 °C that triggers aldol self-condensation of the free aldehyde. What Are the Critical Stoichiometric Parameters for BODIPY Core Assembly Using 3,5-Dimethylpyrrole-2-carbaldehyde?The acid-catalyzed condensation between 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (1.0 eq) and an aromatic aldehyde (0.45–0.50 eq) in anhydrous dichloromethane (3.0 L/mol substrate) constitutes the foundational dipyrromethene assembly. The pyrrolic aldehyde serves as the α-unsubstituted donor ring component, while the electrophilic aromatic aldehyde—commonly 4-formylbenzoic acid methyl ester, 2,4-dimethylbenzaldehyde, or 4-cyanobenzaldehyde—dictates the meso-substituent identity. Trifluoroacetic acid (0.08–0.12 eq relative to total pyrrole) is added dropwise over 45–60 min at 0 °C under a nitrogen blanket; the solution turns deep red, and in-process TLC (silica gel 60 F254, hexane:ethyl acetate 7:3) monitors disappearance of the limiting aromatic aldehyde. After 18–24 h at ambient temperature, the dipyrromethane intermediate is oxidized in situ with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.05 eq) at 25 °C for 4 h, converting the methylene bridge to the fully conjugated dipyrromethene. The reaction mixture is then treated with triethylamine (8.0–10.0 eq) followed by boron trifluoride diethyl etherate (10.0–12.0 eq) at 0 °C, stirring for an additional 12 h. The BF2-chelated BODIPY product precipitates upon hexane addition and is collected by vacuum filtration through a sintered glass funnel (porosity 3). Crude yield ranges from 55–78%, with major impurity identified as the half-condensed monopyrrole-BF2 adduct that partitions into the hexane mother liquor. Purification on silica gel (particle size 40–63 µm) with gradient elution from 0–30% ethyl acetate in hexane yields analytically pure dye with MFD (minimum fluorescence decay) confirmed by time-resolved single-photon counting. Process robustness at 20 L pilot scale requires anhydrous solvent handling: dichloromethane is dried over activated 4 Å molecular sieves to water content <50 ppm (Karl Fischer titration, ASTM E1064-18a), as moisture levels exceeding 120 ppm shift the condensation equilibrium toward pyrrole regeneration and drop the dipyrromethane yield below 40%. Boron complexation efficiency is critically sensitive to triethylamine/boron trifluoride stoichiometry—sub-stoichiometric BF3·Et2O (<9.5 eq) leaves unchelated dipyrromethene that absorbs at 525 nm and degrades within weeks, while excess beyond 13 eq promotes demethylation at the 3,5-positions under prolonged stirring. Post-reaction solvent recovery via rotary evaporation (40 °C, 100 mbar) recycles 85% of the dichloromethane; the residual fraction is incinerated due to chlorinated waste handling mandates under EU Directive 2010/75/EU. Aqueous wash fractions containing TFA salts are neutralized with 30% NaOH to pH 7.0 before discharge, with biotoxicity monitoring via the OECD 209 activated sludge respiration inhibition test.
a Measured on a Shimadzu UV-2600i spectrophotometer, bandwidth 1 nm; b Horiba Fluorolog-3, excitation at 470 nm, emission slit 2 nm; c Absolute quantum yield determined with a Hamamatsu Quantaurus-QY 11347-01 integrating sphere, referenced to sulforhodamine 101 in ethanol (ΦF = 0.95) per IUPAC Technical Report 2018; d Molar extinction coefficient at absorption maximum. Terminal-use BODIPY conjugates for flow cytometry (CD4, CD8, CD19 antibody labelling kits) must satisfy ISO 13485:2016 design transfer validation when intended for in-vitro diagnostic devices. Residual non-chelated dye is quantified by reverse-phase UPLC at 254 nm with a C18 column (2.1 × 50 mm, 1.7 µm) and must remain below 0.15 area%. The final fluorescent conjugate exhibits a Stoke shift of 10–12 nm, and its photostability under 488 nm argon-ion laser irradiation (5 mW, continuous wave) is assessed by 105-cycle illumination; acceptable fading is less than 8% signal loss according to CLSI EP25-A. Formulated as a 10 mM stock in DMSO, the dye is stored under argon at −20 °C to prevent BF2 hydrolysis; accelerated stability studies at 40 °C/75% RH for 30 days show ≤2.2% degradation. In the synthesis of pyrrole-imine post-metallocene catalysts, 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde is condensed with 2,6-diisopropylaniline (1.05 eq) in refluxing toluene (200 mL/mol) containing a catalytic p-toluenesulfonic acid monohydrate (0.5 mol%). Water is removed azeotropically via a Dean-Stark trap over 6–8 h. The resulting Schiff base ligand, N-(2,6-diisopropylphenyl)-1-(3,5-dimethyl-1H-pyrrol-2-yl)methanimine, crystallizes from hot methanol as pale yellow needles in 85–92% yield, melting point 138–140 °C. Single-crystal X-ray diffraction confirms an E configuration with a dihedral angle of 48.3° between the pyrrole and aryl rings. The ligand (1.0 eq) is then reacted with TiCl4 (1.0 eq in anhydrous toluene) at −78 °C under argon, allowed to warm to 25 °C over 12 h, yielding the dichlorido titanium(IV) complex as a dark brown microcrystalline solid after hexane trituration. Elemental analysis (C, H, N) consistently falls within ±0.4% of calculated values for C19H25Cl2N2Ti. Activation with methylaluminoxane (MAO, 30 wt% in toluene, Al/Ti molar ratio 1,000:1) in a 1 L Büchi glass autoclave charged with 400 mL dried toluene, ethylene pressure 1.0 bar (g), and polymerization temperature 30 °C for 30 min yields linear polyethylene. The activity profiles exhibit a rapid initial uptake reaching 95% of peak rate within 2.5 min, followed by constant-rate propagation that suggests a single-site nature. The activity at Al/Ti 1,000 is reported as 1,240 kg PE/(mol Ti·h·atm) for analogous pyrrole-aldimine systems measured under identical conditions, while the 3,5-dimethyl-substituted variant typically delivers 800–1,150 kg PE/(mol Ti·h·atm) depending on alkylaluminum scavenger purity; trace oxygen (>0.5 ppm in the ethylene feed) depresses activity by 30–40% due to irreversible oxidation of the Ti(III) active species. The resulting polymer is characterized by gel permeation chromatography (Polymer Laboratories PL-GPC 220, 1,2,4-trichlorobenzene at 160 °C, polystyrene standards) with weight-average molecular weight Mw 280,000 and molecular weight distribution Ɖ = 2.1, indicative of minor chain-transfer to aluminum. Differential scanning calorimetry per ASTM D3418-21 (heating rate 10 K/min) determines a peak melting temperature Tm = 135.4 °C and crystallinity 62% based on the 293 J/g enthalpy of fusion for 100% crystalline PE. Melt flow index at 190 °C/2.16 kg (ASTM D1238-20) is 0.45 g/10 min, consistent with a high-density polyethylene grade suitable for blown film extrusion. The ligand framework exhibits a practical limit: exposure to protic solvents during complexation irreversibly hydrolyzes the Ti–Cl bonds, forming inactive oxo-bridged dimers. Therefore, all manipulations of the titanium complex must be conducted in a glovebox with O2 < 0.1 ppm and H2O < 0.1 ppm. When This Pyrrolic Aldehyde Competes with Aromatic Aldehydes in Porphyrinogen CondensationMixed-aldehyde Rothemund-type condensation of 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (1.0 eq), benzaldehyde (3.0 eq), and pyrrole (4.0 eq) in refluxing propionic acid (0.5 L/mol total aldehyde) under aerobic conditions generates a statistical mixture of meso-substituted porphyrins, whereby the pyrrolic aldehyde inserts at one or two meso positions. The crude tar is evaporated, neutralized with aqueous ammonia, and extracted with chloroform. The 5-(3,5-dimethylpyrrol-2-yl)-10,15,20-triphenylporphyrin is isolated after two consecutive silica gel columns (CHCl3/hexane gradient) in 6–9% yield, requiring 72 h of chromatographic labor per gram of purified product. Zinc insertion (Zn(OAc)2·2H2O in CHCl3/MeOH, reflux 2 h) provides the metalloporphyrin with a Soret band at 420 nm. This mixed porphyrin has been examined as a sensitizer for photodynamic therapy (PDT) in vitro, with singlet oxygen quantum yield (ΦΔ) of 0.55 in D2O determined by the 1,3-diphenylisobenzofuran bleaching method relative to Rose Bengal (ΦΔ = 0.76). Scale-up is constrained by the low statistical selectivity; process intensification using a continuous-flow microreactor (Uniqsis FlowSyn, PFA tubing ID 1.0 mm, residence time 15 min at 140 °C) improves the proportion of the mono-pyrryl porphyrin to 14% by suppressing polypyrrolic side products. No regulated pharmacopoeial monograph exists for this compound; all biological studies are limited to experimental protocols reviewed under institutional animal care guidelines equivalent to NIH Publication No. 85-23. During a Maillard model reaction comprising D-glucose and L-lysine heated at 140 °C for 30 min at pH 6.5, headspace SPME-GC-MS analysis (divinylbenzene/Carboxen/PDMS fibre, 50/30 µm) identifies 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde as a trace-level volatile (0.12–0.35 µg/L model system) contributing to roasted-nutty sensory notes. Its odor threshold in water is estimated at 45 µg/L (orthonasal, ASTM E679-04 forced-choice triangle test), falling below the 0.5 µg/kg flavor use level exempt from FEMA GRAS listing. Because the aldehyde is generated in situ rather than added as an isolated flavoring substance, it falls outside the scope of EU Regulation 1334/2008/EC for intentionally added flavorings, but any concentrated isolate intended for flavor house compounding would require FGE.407 panel evaluation. Data regarding its stability in acidic beverages (pH 2.8–3.5) indicate rapid hydration of the aldehyde to the gem-diol, which attenuates aroma release and limits commercial relevance to dry-mix formulations. |
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Among pyrrole carboxaldehydes employed as condensation-active building blocks, 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (synonym: 2-formyl-3,5-dimethylpyrrole), CAS 2199-58-8, occupies a distinct operational niche defined by its substitution-driven steric profile. The compound, offered under model code P2C-3502 in bulk and research-grade formats, carries molecular formula C7H9NO and a molecular weight of 123.15 g/mol. Typical physical form is a pale‑yellow to light‑brown crystalline powder with a melting point of 92–95 °C (determined by capillary method per ASTM E324-16). Assay specification by GC area percent and HPLC at 254 nm commonly exceeds 97%, with the balance comprising positional isomers and trace oxidation by‑products. Solubility profiles reflect the molecule’s moderate polarity: freely soluble in dichloromethane, tetrahydrofuran, and ethyl acetate, sparingly soluble in hexane, and insoluble in water at neutral pH. The compound serves as a primary entry point en route to meso‑substituted dipyrromethanes, dipyrromethenes, BODIPY fluorophores, and coordination ligands for transition metals. Its substitution pattern—methyl groups at the 3‑ and 5‑positions, flanking the pyrrolic nitrogen but leaving the 4‑position unsubstituted—differentiates it sharply from regioisomers such as 3,4‑dimethyl‑1H‑pyrrole‑2‑carboxaldehyde and from the parent 1H‑pyrrole‑2‑carboxaldehyde; the consequence is a reproducible, sterically governed reactivity that reduces unwanted side‑reactions during acid‑catalysed oligomerization.
Pyrrole‑aldehyde condensation proceeds through an electrophilic aromatic substitution mechanism wherein the formyl‑bearing pyrrole acts as the electrophile and the free α‑position of a second pyrrole unit serves as the nucleophile. In 3,5‑dimethyl‑1H‑pyrrole‑2‑carboxaldehyde, the aldehyde group at C‑2 experiences steric compression from only one adjacent methyl substituent (C‑3 methyl), in contrast to the 3,4‑dimethyl isomer where the aldehyde is flanked by methyl groups at both C‑3 and C‑4. Molecular mechanics calculations and published kinetic data indicate a reduction in the enthalpy of activation for condensation of the 3,5‑dimethyl isomer relative to the 3,4‑dimethyl analogue by approximately 8–12 kJ·mol⁻¹ when using pyrrole in the presence of 0.1 eq trifluoroacetic acid in dichloromethane at 23 °C. This translates into synthetic practice: under Lindsey‑type conditions (1.0 eq aldehyde, 25 eq pyrrole, 0.1 eq BF3·OEt2, RT), the 3,5‑dimethyl derivative affords dipyrromethane yields consistently within 85–92%. The 3,4‑dimethyl isomer, by comparison, yields 55–70% under identical conditions due to steric deceleration at the formyl‑bearing α‑carbon and increased competitive oligomerization. Electronic contributions are also significant: the electron‑donating effect of the two methyl groups raises the HOMO energy of the pyrrole ring, facilitating the initial protonation and dehydration steps without inducing ring oxidation. The parent 1H‑pyrrole‑2‑carboxaldehyde, lacking any methyl protection, polymerises rapidly in the presence of acid and is rarely isolated in high purity; its use is confined to strictly anhydrous, low‑temperature protocols. Consequently, the 3,5‑dimethyl configuration delivers a favourable balance of steric protection and electronic activation, making it the preferred aldehyde for iterative porphyrinogen construction where regiospecific meso‑substitution is required.
Handling precautions reflect the compound’s sensitivity to oxidative environments. Storage under argon at 2–8 °C with desiccant is standard; exposure to ambient light and humidity for periods exceeding 72 h leads to discernible darkening and an increase in oxidation impurities above 0.5%. For moisture‑sensitive applications, pre‑drying at 40 °C under vacuum (≤10 mbar) for 4 h prior to use is mandatory. Incompatibility with strong mineral acids at elevated temperature and with amines in the absence of solvent must be observed to prevent exothermic resinification.
In the synthesis of trans‑A2B2 porphyrins and related tetrapyrroles, acid‑catalysed scrambling at the meso‑carbon is a well‑documented failure mode that erodes regioisomeric purity and necessitates tedious chromatographic separation. The 3,5‑dimethyl substitution pattern directly suppresses this pathway by imposing a kinetic barrier to the acid‑promoted cleavage of the dipyrromethane bridge. When the methyl group occupies the 3‑position, the adjacent meso‑carbon becomes sterically shielded from protonation by the α‑pyrrole carbon; deuteration experiments monitored by 1H NMR show a half‑life for scrambling in CDCl3/TFA at 0.5% v/v exceeding 48 h for the 3,5‑dimethyl‑derived dipyrromethane, versus <4 h for the 3,4‑dimethyl analogue. This kinetic stability translates directly into process reliability on multigram scale: condensation of 3,5‑dimethyl‑1H‑pyrrole‑2‑carboxaldehyde with p‑tolualdehyde in a 20 L reactor fitted with a nitrogen‑purged condenser and a jacketed addition funnel routinely yields the corresponding meso‑(p‑tolyl)dipyrromethane at 88–91% isolated yield after a single recrystallisation from ethanol/water. The absence of scrambling also simplifies the preparation of asymmetric porphyrins by enabling sequential condensation without intermediate protection of the meso‑position. Batch‑to‑batch variance in colour (APHA value) is typically controlled within ±10% when the condensation is run at a strict internal temperature of 25 ± 1 °C and quenched with triethylamine within 20 min of aldehyde consumption. Published data for the corresponding 3,4‑dimethyl‑based dipyrromethane under the same reactor configuration indicate yields below 65% and a scrambling half‑life of less than 6 h, limiting its utility in convergent porphyrin assembly.
| Isomer | Substituent Adjacent to CHO | Dipyrromethane Yielda | Scrambling Half‑Life (0.5% TFA/CDCl₃) | Typical Purification Method |
|---|---|---|---|---|
| 3,5‑Dimethyl (present product) | One methyl (C‑3) | 85–92% | >48 h | Single recrystallisation |
| 3,4‑Dimethyl | Two methyls (C‑3, C‑4) | 55–70% | <6 h | Column chromatography (SiO₂, hexane/EtOAc) |
| 1H‑Pyrrole‑2‑carboxaldehyde (no methyl) | None | 30–45%b | <1 h | Rapid cold‑trapping; low storage stability |
a Conditions: 1.0 eq aldehyde, 25 eq pyrrole, 0.1 eq BF₃·OEt₂, DCM, 23 °C, 20 min, literature‑compiled range. b Yield from freshly purified material; decreases rapidly upon storage.
Analytical quality control of each production lot relies on reversed‑phase HPLC (C18 column, 150 × 4.6 mm, acetonitrile/water 60:40 v/v, 1.0 mL/min, detection at 254 nm) with retention time of the main peak at 8.7 ± 0.2 min; identity is confirmed by 1H NMR against a certified reference spectrum. Water content is determined by Karl Fischer coulometry per ASTM E203-16 and is routinely controlled below 0.3 wt%. Residual solvent levels—chiefly toluene or ethyl acetate from recrystallisation—are monitored by headspace GC‑MS according to in‑house procedures aligned with ISO 17025 guidelines and are limited to <500 ppm sum. These quality metrics ensure batch‑to‑batch consistency for demanding photonic and pharmaceutical intermediate applications.
BODIPY (4,4‑difluoro‑4‑bora‑3a,4a‑diaza‑s‑indacene) fluorophores constructed from 3,5‑dimethyl‑1H‑pyrrole‑2‑carboxaldehyde retain a vacant 4‑and 8‑position on the indacene core (corresponding to the pyrrole 4‑carbon), a structural feature that decisively influences aggregation‑caused quenching (ACQ) and Stokes shift. Because the 4‑position lacks a methyl group, the planar BODIPY core undergoes face‑to‑face π‑stacking more readily than the tetramethyl‑substituted (e.g., BODIPY 493/503) analogues; however, this same openness permits facile post‑synthetic functionalization via electrophilic substitution at the 4‑and 8‑positions with iodine or formyl groups to install heavy‑atom handles for triplet sensitization. Photophysical characterization of a representative BODIPY made from 3,5‑dimethyl‑1H‑pyrrole‑2‑carboxaldehyde and benzaldehyde shows absorption maximum at 505 nm in ethanol, fluorescence quantum yield (ΦF) of 0.85 (rhodamine 6G standard), and a Stokes shift of 15 nm. In comparison, the corresponding dye derived from 3,4‑dimethyl isomer exhibits a hypsochromic shift of 12 nm and a reduced ΦF of 0.62, a difference attributed to enhanced non‑radiative decay arising from intramolecular steric interactions that distort the B–N chelate ring. These distinctions are critical when designing red‑shifted probes for in‑cell imaging, where the 3,5‑dimethyl scaffold’s brightness compares favourably with nitrobenzoxadiazole (NBD) dyes and where its narrower emission band facilitates multiplex detection.
Condensation of 3,5‑dimethyl‑1H‑pyrrole‑2‑carboxaldehyde with primary amines yields Schiff base ligands that coordinate iron, copper, and zinc centres in geometries relevant to homogeneous catalysis and corrosion inhibitor formulations. When the aldehyde is reacted with p‑anisidine and the resulting bidentate ligand is adsorbed onto mild steel (API 5L X52) in 1.0 M HCl at 30 °C, potentiodynamic polarization measurements per ASTM G59-97(2020) show a shift in corrosion potential of less than 85 mV, classifying the inhibitor as mixed‑type. Weight‑loss data acquired according to ASTM G31-72(2004) for immersion periods of 24 h yield inhibition efficiencies of 92% at a ligand concentration of 100 ppm and 97% at 200 ppm. The adsorption free energy (ΔG°ads) calculated from the Langmuir isotherm is −38 kJ·mol⁻¹, indicating a combination of physisorption and chemisorption consistent with the pyrrolic nitrogen and the azomethine nitrogen acting as donor sites. By comparison, the Schiff base derived from 3,4‑dimethyl‑1H‑pyrrole‑2‑carboxaldehyde requires concentrations above 400 ppm to reach 90% efficiency under the same test conditions, a performance gap linked to the steric hindrance of the methyl group at the 4‑position which restricts planarity and thus the surface coverage density. This measurable difference highlights the practical advantage of the 3,5‑dimethyl configuration in applications requiring dose‑efficient surface protection.
| Parameter | Specification | Test Method |
|---|---|---|
| Assay (GC, area %) | ≥ 97.0% | In‑house GC‑FID, DB‑5 column |
| Melting range | 92–95 °C | ASTM E324-16 |
| Water content | ≤ 0.3% | ASTM E203-16 (KF coulometry) |
| Residual solvents (sum) | ≤ 500 ppm | HS‑GC‑MS, ISO 17025‑aligned |
| Solubility in DCM | Clear solution at 10% w/v | Visual inspection |
| Appearance | Pale‑yellow to light‑brown crystalline powder | Visual, D65 illuminant |
