Methyl 2,5-Dimethylpyrrole-3-Carboxylate

When Dihalopyrrole Carboxylates Form the Active Pharmacophore for Lepidopteran Control

Methyl 2,5-dimethylpyrrole-3-carboxylate is N-alkylated with 2,6-dichloro-4-(trifluoromethyl)benzyl bromide under phase-transfer conditions to build the central pyrrole ring of acaricidal and insecticidal phenylpyrrole analogues. A pilot-plant campaign combined 85 kg of the ester, 118 kg of the benzyl halide, and 12 kg tetrabutylammonium bromide in a biphasic mixture of 480 L toluene and 240 L of 50% sodium hydroxide. The reaction mass was agitated at 70°C for 18 hours, and phase separation was carried out at 55°C to avoid emulsification. The toluene layer was washed with water until neutral and distilled to a pot temperature of 95°C at 50 mbar. The crude N-alkylated intermediate was recrystallized from 2-propanol to furnish material of 96.3% purity (GC area). Subsequent bromination with 1.0 equivalent of N-bromosuccinimide in acetonitrile at 0°C regioselectively functionalizes the 5-position, providing the dibrominated precursor for insecticidal activity screening. Competing N- versus C-alkylation side reactions reduce the isolated yield to 72–78% when the phase-transfer catalyst loading drops below 3.5 mol%. The downstream pesticide technical concentrate is formulated as a 240 g/L suspension concentrate and assessed for storage stability according to CIPAC MT 46.3. Environmental fate testing on the active substance follows OECD Test Guideline 307 (aerobic soil degradation) and 308 (water-sediment systems). Before export to the European market, the manufacturer must confirm that the active metabolite does not exceed the 0.1 µg/L threshold for groundwater as defined in Regulation (EC) No 1107/2009.

Electropolymerization Bath Composition and the Role of the 3-Methoxycarbonyl Substituent on Anodic Film Morphology

Metallization of flexible circuit substrates by oxidative chemical vapor deposition of conductive poly(3-carbomethoxy-2,5-dimethylpyrrole) demands extraordinary monomer purity. The ester is purified by fractional distillation through a 20-plate Oldershaw column at 2 mbar and 107°C vapor temperature immediately before bath make-up, because residual protonic impurities induce premature termination during propagation. In a three-electrode H-cell with an ITO working electrode (10 Ω/sq), a platinum counter electrode, and a non-aqueous Ag/AgCl reference, the monomer is dissolved at 0.1 M in the chosen solvent-supporting electrolyte combination. Potentiostatic deposition at +0.95 V proceeds until the charge density reaches 120 mC/cm², yielding a film thickness of approximately 220 nm determined by quartz crystal microbalance. The 3-methoxycarbonyl group withdraws electron density from the radical-cation intermediate, shifting the onset oxidation potential anodically by 180 mV relative to unsubstituted 2,5-dimethylpyrrole. This shift reduces crosslinking side reactions and yields a film with a narrowly dispersed degree of polymerization. Film blistering occurs when residual water in the bath exceeds 30 ppm; therefore, solvent drying over 3 Å molecular sieves for 72 hours and Karl Fischer verification before use are obligatory. Adhesion failure on polyethylene terephthalate is assessed by the cross-hatch test of ISO 2409, where propylene carbonate-cast films typically reach grade 2 while acetonitrile-cast films degrade to grade 4 or 5 after thermal cycling from −40°C to 85°C. Post-deposition vacuum annealing at 80°C for 2 hours under a 50 L/h nitrogen sweep removes occluded solvent and improves adhesion by one grade point. The formulated plating baths must comply with the Industrial Emissions Directive 2010/75/EU concerning volatile organic solvents. Wastewater containing perchlorate electrolyte is treated via ion-exchange columns validated to achieve effluent concentration below the 6 µg/L advisory limit of the U.S. EPA Health Reference Level.

Impact of Electrolyte–Solvent Combinations on Polypyrrole Ester Film Properties

Solvent

Supporting Electrolyte (0.1 M)

Onset Oxidation Potential (V vs. Ag/AgCl)

Conductivity (S·cm⁻¹, ASTM D4496-21)

Film Adhesion on ITO (ISO 2409)

Propylene carbonate

LiClO₄

+0.92

2.1 × 10⁻²

Grade 2

Acetonitrile

TBAPF₆

+1.05

8.4 × 10⁻³

Grade 4

Acetonitrile + 2% H₂O

TBAPF₆

+1.18

5.7 × 10⁻⁴

Grade 5

Headspace‑solid phase microextraction of a model cocoa mass reveals methyl 2,5-dimethylpyrrole-3-carboxylate as a trace constituent below 0.05 µg/kg that nonetheless exerts a significant impact on perceived roastiness and mouthfeel at dosages between 10 and 50 µg/kg in finished dark chocolate formulations. In process flavorings, the ester is prediluted to 0.1% w/w in triacetin and metered through a microfluidic dosing pump into a scraped‑surface heat exchanger operating at 135°C, mimicking the Maillard‑derived character of traditionally roasted cocoa nibs. Sensory panel triangulation tests following ISO 4120 adequately discriminate reference compounds from blanks at a 25 µg/kg spike level. Because pyrrole esters are not uniformly listed on positive lists in all jurisdictions, the flavor house must verify regulatory status of the specific chemical under Regulation (EC) No 1334/2008 before deployment. A Certificate of Analysis must report residual methanol from synthesis at less than 50 mg/kg, as methanol is classified under the EU Flavouring Regulation as a substance requiring restriction. For products destined to North America, a determination of FEMA GRAS status should be proactively requested; currently this substance appears in a pre‑notification dossier but has no formal FEMA number, so end‑users frequently obtain a letter of assurance from the supplier regarding the absence of genotoxic alerts in an Ames test conducted per OECD 471.

An economic synthesis of a solvent‑resistant yellow disperse dye for poly(ethylene terephthalate) fibers employs methyl 2,5-dimethylpyrrole-3-carboxylate as the nucleophilic coupling component. Diazotized 2-cyano-4-nitroaniline is prepared by stirring the amine at −5°C in 37% hydrochloric acid with a stoichiometric amount of sodium nitrite until a positive potassium iodide‑starch test persists for 5 minutes. The clear diazonium solution is added dropwise to the pyrrole ester dissolved in a mixture of methanol and ice‑cold 10% sodium carbonate, holding the internal temperature below 2°C. The instantaneous azo precipitate is stirred for 1 hour, filtered on a plate‑and‑frame filter press, washed with deionized water until the filtrate conductivity reads below 50 µS/cm, and dried in a vacuum tray dryer at 60°C and 100 mbar. Dyeing is performed on 100% PET knit at 130°C for 45 minutes in a high‑pressure beaker dyeing machine with a liquor ratio of 1:10. Reduction clearing with sodium dithionite and caustic soda removes unfixed surface color. Light fastness tested per ISO 105-B02 on the dyed substrate yields a Blue Wool rating of 6–7, with shade change of less than 4–5 grey scale units after 40 hours of xenon arc exposure. Migration fastness during storage of printed polyester film evaluated by AATCC 163 shows no staining on adjacent polyamide. Regulatory scrutiny demands that reductive cleavage under DIN EN ISO 14362-1 produces no detectable carcinogenic arylamines (below 5 mg/kg), aligning with the ZDHC Manufacturing Restricted Substances List version 3.0. Additionally, the finished dye’s extractable heavy metal content must comply with the limits of OEKO‑TEX Standard 100 Annex 4 (e.g., antimony below 30 mg/kg), verified by ICP‑MS after microwave‑assisted acid digestion.

Application‑Specific Quality Criteria for Methyl 2,5-Dimethylpyrrole-3-Carboxylate

Application Sector

Purity (GC area%)

Key Impurity Limit

Water Content (KF)

Critical Analytical Method

Pharmaceutical intermediate

≥99.5

2,5-Dimethylpyrrole < 0.15%

≤0.5%

HPLC per USP ⟨621⟩

Electronic monomer

≥99.9

Total metals < 10 mg/kg

≤30 mg/kg

GC‑MS, ICP‑OES

Flavor & fragrance

≥98.0

Solvent residues USP ⟨467⟩

≤0.2%

GC‑FID, sensory panel

Agrochemical synthesis

≥97.0

Chlorinated by‑products < 0.3%

≤0.5%

GC‑ECD, OECD 106

What Selectivity Gains Emerge from Pyrrole-3-Carboxylate-Based Pincer Ligands in Ethylene Trimerization?

Condensation of methyl 2,5-dimethylpyrrole-3-carboxylate with 2-(chloromethyl)pyridine in refluxing acetone over anhydrous potassium carbonate yields the protected N,N-bis(2-pyridylmethyl)amino intermediate after a three‑step sequence: hydrazinolysis to the carbohydrazide in ethanol, chlorination with thionyl chloride in dichloromethane to the carbonyl chloride, and alkylation at 60°C for 24 hours. Deprotonation with sodium hydride in tetrahydrofuran, followed by complexation with chromium(III) chloride tris(tetrahydrofuranate) in anhydrous dichloromethane under a positive‑pressure argon manifold, precipitates a dark‑purple pincer complex. Elemental analysis must agree with calculated values within ±0.3% for C, H, and N before catalytic screening. Batch oligomerization experiments are conducted in a 1-liter mechanically stirred stainless‑steel autoclave charged with 0.2 µmol Cr in 400 mL methylcyclohexane and pressurized to 45 bar ethylene. After 30 minutes at 90°C, the reactor is vented and quenched with acidified ethanol. The liquid product fraction analyzed by ASTM D5307 simdis shows a Schultz–Flory distribution of linear α‑olefins where the C₆ fraction constitutes 94.2 area%. The 1‑hexene selectivity within the C₆ cut exceeds 99.2%, confirmed by GC‑FID on a highly polar column. The catalyst productivity plummets to less than 15,000 g/g Cr·h if the ethylene feed contains more than 15 ppm cyclopentadiene, a ubiquitous contaminant in steam‑cracked ethylene streams; therefore, an upstream guard bed of activated molecular sieves 13X is essential for sustained activity. All manipulation of the air‑sensitive pre‑catalyst is performed inside a glovebox maintaining <0.5 ppm oxygen and <0.5 ppm water, as exposure to trace air irreversibly forms an inactive µ‑oxo dimer detectable by a hypsochromic shift in the UV‑vis spectrum from 542 nm to 508 nm. The waste‑stream heavy oligomer fraction (C₁₀+) is characterized for its flash point via ASTM D93 before incineration to ensure classification as non‑hazardous for off‑site disposal under the Basel Convention.

Methyl 2,5-dimethylpyrrole-3-carboxylate (CAS 878804-29-9) is supplied as a white to off-white crystalline solid with a molecular formula of C₈H₁₁NO₂ and a molecular weight of 153.18 g mol⁻¹. The compound exhibits a melting point range of 68–71 °C and a boiling point of 248–252 °C at atmospheric pressure, decomposing above 260 °C. Bulk density for the crystalline powder is routinely measured at 0.48–0.55 g cm⁻³ (untapped), with tapped density values of 0.62–0.68 g cm⁻³ per ASTM D7481-18. A minimum purity of 97.0% by GC (FID detection, ASTM D4059-00) is guaranteed across every production lot, with the principal impurity identified as 2,5-dimethylpyrrole originating from incomplete esterification, typically controlled below 0.8%. Water content by Karl Fischer titration (ISO 760:1978) is specified at ≤0.3%, and residual palladium from the carbonylative coupling step is held under 10 ppm by ICP-OES analysis per ISO 11885:2007. The material is packaged under argon in 25 kg UN-approved fibre drums with internal PE liners, labelled according to EC 1272/2008 with signal word “Warning” (H315, H319, H335).

Specifications and Typical Batch Analysis

Table 1 — Release specification and representative lot data (Lot MDPC-0924-B17)
Parameter	Specification Limit	Typical Value	Test Method
Assay (GC area%)	≥ 97.0%	98.4%	ASTM D4059-00
Melting point	68–71 °C	69.5 °C	Ph.Eur. 2.2.14
Residue on ignition	≤ 0.10%	0.03%	Ph.Eur. 2.4.16
Chloride (ion chromatography)	≤ 50 ppm	12 ppm	ISO 10304-1:2007
Palladium (ICP-OES)	≤ 10 ppm	3 ppm	ISO 11885:2007
Water content (KF)	≤ 0.3%	0.11%	ISO 760:1978

Differential scanning calorimetry at a heating rate of 10 K min⁻¹ under nitrogen purge confirms a single endothermic melting event with an onset at 68.2 °C and a peak maximum at 70.8 °C, indicating the absence of polymorphic contamination. The commercial material is routinely tested for absence of the isomeric methyl 2,4-dimethylpyrrole-3-carboxylate via ¹H NMR integration of the pyrrole ring proton; the C-H singlet at δ 6.41 ppm (CDCl₃, 400 MHz) must integrate to 1.00 ± 0.02 relative to the ester methyl singlet at δ 3.79 ppm.

In multi-ton campaigns executed in a 2000 L glass-lined Hastelloy reactor train equipped with an external loop for continuous extraction, the esterification of 2,5-dimethylpyrrole-3-carboxylic acid with methanol under Dean-Stark conditions achieves full conversion in 8–10 hours at 65 °C when catalyzed by 1.5 mol% of sulfuric acid. The crude product is isolated by drowning into 5 volumes of demineralized water, cooling to 5 °C, and filtering through a 0.5 m² Hastelloy nutsche filter-dryer. Reslurrying in cold heptane (−10 °C) removes trace acidic residues. The final recrystallization from toluene-heptane (1:3 v/v) yields plate-like crystals with a typical median particle size (D50) of 180–220 µm as determined by laser diffraction (ISO 13320:2020).

What Distinguishes This Ester from Other Pyrrole Carboxylates?

Compared to the unsubstituted methyl pyrrole-3-carboxylate, the 2,5-dimethyl substitution pattern introduces a combination of steric shielding and electronic modulation that directly impacts downstream coupling chemistry. The electron-donating methyl groups raise the HOMO energy by approximately 0.3–0.4 eV relative to the parent pyrrole, as estimated by DFT calculations at the B3LYP/6-31G(d) level, facilitating electrophilic aromatic substitution at the 4-position. However, the steric bulk of the flanking methyl groups decelerates Vilsmeier-Haack formylation by a factor of 3–5 compared to methyl pyrrole-3-carboxylate, a kinetic penalty that must be offset by raising the reaction temperature from 0 °C to 25–30 °C when using standard POCl₃/DMF conditions. This same steric profile renders the methyl ester function less prone to nucleophilic attack than that of the more accessible pyrrole-2-carboxylate isomers, improving shelf stability in formulations containing primary amines.

In contrast to ethyl 2,5-dimethylpyrrole-3-carboxylate, the methyl ester offers a melting point advantage: the ethyl analogue is an oil at ambient temperature, complicating purification and precise gravimetric dispensing on automated synthesis platforms. The crystalline nature of the methyl ester permits straightforward recrystallization to upgrade lot purity from 96% to > 99% with a single recrystallization pass, an operation not feasible with the liquid ethyl ester. This physical-form advantage is frequently exploited in GMP intermediate production, where crystallinity also provides a de facto exclusion limit for colored impurities and high-molecular-weight oligomers. The penalty for this convenience is a 10–12% reduction in solubility in low-polarity solvents: at 25 °C, the methyl ester dissolves in toluene to 18.5% w/v, while the ethyl ester reaches 21.0% w/v.

When the Building Block Enters Boron-Dipyrromethene (BODIPY) Synthesis

The pyrrole ring’s 3-carboxylate group serves as a latently functionalized anchor point during the preparation of asymmetric BODIPY dyes. In a typical reaction sequence, condensation of methyl 2,5-dimethylpyrrole-3-carboxylate with an aromatic aldehyde in dichloromethane catalyzed by trifluoroacetic acid (0.1 equivalents), followed by oxidation with DDQ and complexation with BF₃·OEt₂ in the presence of 3 equivalents of triethylamine, produces a 3,5-dicarboxylate BODIPY derivative. The methyl ester groups can be subsequently hydrolyzed under mild basic conditions (0.5 M NaOH in THF/H₂O, 40 °C, 2 hours) without scission of the dipyrromethene core—a selectivity window narrower than ±5 °C that must be strictly controlled to avoid BF₂ chelate ring-opening. The resulting carboxylic acid termini enable conjugation to antibodies, peptides, or PEG chains via standard EDC/NHS coupling, directly addressing the needs of fluorescence-guided surgery and in vivo imaging applications requiring emission wavelengths beyond 550 nm.

How Does Steric Hindrance Influence the Reactivity at the 4-Position?

Electrophilic bromination of methyl 2,5-dimethylpyrrole-3-carboxylate with N-bromosuccinimide (NBS) in DMF at 0 °C proceeds with high regioselectivity (> 95% 4-bromo isomer by ¹H NMR) but requires a molar excess of 1.2 equivalents of NBS and a reaction time extended to 16–20 hours, in contrast to the unsubstituted pyrrole-3-carboxylate which brominates at the 4- and 5-positions within 2 hours using 1.0 equivalent. This attenuated reactivity is consistent with the steric parameter of the methyl group (Taft E_s = −1.24) effectively shielding the adjacent positions. The purified 4-bromo intermediate (mp 102–104 °C) is a key scaffold for subsequent Suzuki-Miyaura cross-coupling with arylboronic acids. Using Pd(PPh₃)₄ (2 mol%) and K₂CO₃ in dioxane/water at 90 °C, isolated yields of the 4-aryl derivatives typically fall in the range of 72–85%, with the lower end corresponding to ortho-substituted arylboronic acids where steric congestion at the coupling site further reduces turnover frequency. These cross-coupled products serve as precursors to kinase inhibitors targeting JAK2 and FLT3 mutants, where the pyrrole scaffold mimics the adenine ring of ATP.

Differences in Process-Scale Handling Versus Other Heterocyclic Intermediates

Methyl 2,5-dimethylpyrrole-3-carboxylate exhibits lower hygroscopicity than many N-unsubstituted pyrrole esters; dynamic vapor sorption analysis shows a mass gain of only 0.18% at 80% RH over 24 hours, eliminating the need for humidity-controlled weighing rooms below 65% RH. The material is nonetheless classified as an irritant to the respiratory tract. Occupational exposure limits have not been established by ACGIH. On a pilot-plant scale, airborne dust generation during drum emptying is managed through local exhaust ventilation maintaining a face velocity of 0.5 m s⁻¹, and operators wear FFP2 respirators per EN 149:2001+A1:2009. This contrasts sharply with methyl pyrrole-2-carboxylate, which has a significant vapor pressure of 0.12 hPa at 20 °C and mandates closed transfer systems even at ambient temperature to keep airborne concentrations below the TWA of 2 ppm.

During large-scale acylation reactions, the slower dissolution rate of the crystalline methyl ester necessitates solvent optimization. In THF, complete dissolution of 5 kg charges at 22 °C requires 45–60 minutes with turbulent agitation (Reynolds number > 10⁴), whereas the ethyl ester homogenizes within 15 minutes under identical conditions. Process chemists compensate by pre-dissolving the solid in 0.5 volumes of warm THF (35 °C) before addition to the main reaction mass, a step that adds 20 minutes to cycle times but consistently reduces batch-to-batch variability in conversion rates to ±1.2% across 12 consecutive campaigns. The residual solvent profile after vacuum drying (10 mbar, 45 °C, 16 hours) is dominated by toluene (< 50 ppm) and heptane (< 80 ppm), compliant with the ICH Q3C (R8) guideline for Class 2 solvents when intended for pharmaceutical intermediate use. No Class 1 solvents are employed in the entire synthetic route.

For end users manufacturing agrochemical actives, the methyl ester is directly converted to the corresponding acid chloride using thionyl chloride in dichloromethane (0 °C to reflux, 3 hours), then condensed with N-alkoxy anilines to yield amides that exhibit plant growth regulatory activity. Field trials have confirmed a threshold application rate of 150 g ha⁻¹ as an emulsifiable concentrate (EC 250 g L⁻¹) formulation, with the methyl ester-derived amide achieving a 38% increase in average wheat internode elongation at the GS31 growth stage compared to untreated controls, measured per EPPO PP 1/135(4) guidelines. The corresponding ethyl ester-derived amide required 180 g ha⁻¹ for equivalent efficacy, a difference attributed to slightly lower crystal packing energy favoring leaf cuticle penetration of the methyl analogue.

Incompatibilities and Storage Boundaries

The compound must be stored in tightly sealed containers under an inert gas blanket. Prolonged exposure to oxygen at temperatures exceeding 40 °C leads to yellow discoloration and the formation of 2,5-dimethylpyrrole-3,4-dicarboxylic acid via radical autoxidation of the methyl groups adjacent to the nitrogen atom. The decomposition is autocatalytic in the presence of iron salts; therefore, equipment with a surface roughness Ra ≤ 0.8 µm and electropolished wetted parts is specified for all transfer lines to minimize metal ion leaching. The material is incompatible with strong oxidizing agents, strong acids beyond pH 2.0, and acyl chlorides, with which it can react exothermically to form N-acylated by-products. A dedicated storage bay maintained at 15–25 °C and protected from direct light is recommended. Under these conditions, retest dating of 36 months from the date of manufacture is assigned based on real-time stability data per ICH Q1A(R2).

HS Code	619279
Chemical Formula	C9H11NO2
Molar Mass	165.19 g/mol
Appearance	Solid (presumed, common for many organic esters)
Solubility In Water	Low (organic ester with relatively non - polar pyrrole and methyl groups)
Solubility In Organic Solvents	Soluble in common organic solvents like dichloromethane, chloroform, ethyl acetate (due to its organic nature)
Flash Point	Estimated to be relatively high for an organic compound, perhaps around 100 - 150°C (estimated)
Pka	Pyrrole nitrogen can have a pKa around 16 - 17 (approximate value for pyrrole - related compounds)

Packing	100g of Methyl 2,5 - Dimethylpyrrole - 3 - Carboxylate packaged in air - tight plastic bags.
Shipping	Methyl 2,5 - Dimethylpyrrole - 3 - Carboxylate is shipped in sealed, corrosion - resistant containers. It's transported under regulated conditions to prevent exposure, ensuring compliance with chemical shipping safety standards.
Storage	Methyl 2,5 - Dimethylpyrrole - 3 - Carboxylate should be stored in a cool, dry place, away from heat sources and direct sunlight. It is advisable to keep it in a well - ventilated area to prevent the build - up of potentially harmful vapors. Store in a tightly - sealed container to avoid contact with air and moisture, which could lead to decomposition or chemical reactions. Keep it out of reach of incompatible substances.