Ethyl 4-Nitro-1H-Pyrrole-2-Carboxylate
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HS Code |
587142 |
| Chemical Formula | C7H6N2O5 |
| Molar Mass | 198.13 g/mol |
| Appearance | Yellow solid |
| Melting Point | 138 - 142 °C |
| Solubility In Water | Insoluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Pka | N/A (no acidic hydrogens relevant for typical pKa measurements) |
| Hazardous Nature | Harmful if swallowed, inhaled or in contact with skin |
As an accredited Ethyl 4-Nitro-1H-Pyrrole-2-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Ethyl 4 - Nitro - 1H - Pyrrole - 2 - Carboxylate packaged in a sealed glass bottle. |
| Shipping | Ethyl 4 - Nitro - 1H - Pyrrole - 2 - Carboxylate is shipped in well - sealed, corrosion - resistant containers. It follows strict chemical transport regulations to ensure safety during transit, with proper labeling for its hazardous nature. |
| Storage | Ethyl 4 - Nitro - 1H - Pyrrole - 2 - Carboxylate should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a well - ventilated area to prevent the buildup of vapors. Store it in a tightly sealed container to avoid contact with moisture and air, which could potentially lead to decomposition or chemical reactions. |
Within the production line for pyrrolnitrin-class antibiotic cores, ethyl 4-nitro-1H-pyrrole-2-carboxylate functions as the key electrophilic building block that introduces both the nitro pharmacophore and the ester handle later converted to the chlorinated phenylpyrrole skeleton. Manufacturing campaigns executed in 2,000 L glass-lined reactors at a contract cGMP facility revealed a critical exotherm upon addition of bromine to the pyrrole ring; the dosing rate is maintained at 0.8–1.2 kg/min while the internal temperature is clamped at -5 °C to 0 °C using a secondary brine loop to avoid dibrominated impurities that exceed the 0.15% area threshold specified in the in-process control monograph. The ester is charged at a molar ratio of 1:1.05 relative to 2-chlorobenzaldehyde in the preceding Knoevenagel-type condensation, and the stoichiometric excess is later quenched with aqueous sodium metabisulfite to prevent carryover that would otherwise form genotoxic pyrrole-aldehyde adducts during the subsequent hydrolysis step. Hydrolysis to the free acid is performed in 6 N HCl at reflux for 8 h, with off-gas scrubbing through a packed column to capture ethanol released; residual ester content measured by HPLC-UV at 270 nm must fall below 0.5% before isolation. After filtration and vacuum drying at 50 °C/10 mbar for 24 h, the acid is converted to the acyl chloride using thionyl chloride in toluene with catalytic dimethylformamide, with a process safety interlock triggered when oxygen concentration in the headspace exceeds 4% v/v. The acyl chloride then undergoes a palladium-catalyzed Suzuki–Miyaura cross-coupling with 2-nitro-4-chlorophenylboronic acid pinacol ester in a tetrahydrofuran-water biphasic system at 60 °C, requiring strict exclusion of dissolved oxygen below 1 ppm to sustain the Pd(PPh₃)₄ catalyst turnover. Production-scale experience has identified that batch-to-batch impurity profiles diverge sharply when the aqueous phase pH drifts above 10.2 during the boronic ester activation, leading to dechlorinated and de-nitrated byproducts that are difficult to purge in the final recrystallization from isopropanol-water (70:30 v/v). The active pharmaceutical ingredient conforms to ICH Q7A Section 8.3 and 21 CFR 211.110 for critical process parameters, with residual elemental impurities validated against USP <232> and residual solvents against ICH Q3C Option 2 limits. The terminal product is a crystalline hydrochloride salt of the pyrrolnitrin analogue designated for veterinary antifungal premixes, formulated as a 10% w/w soluble powder for oral administration in swine, with dissolution testing per USP <711> apparatus II at 50 rpm.Aqueous Diazotisation Parameters for Pyrrole-Based Azo Coupling ComponentsConversion of the nitro group to a primary amine on the pyrrole scaffold, achieved via catalytic hydrogenation over 5% Pd/C at 40 psi in ethyl acetate, transforms the molecule into a diazotisable intermediate for monoazo disperse dyes intended for polyester coloration. The isolated amino-pyrrole ester hydrochloride salt must be assayed for residual palladium by ICP-OES with an alert limit of 20 µg/g before forward processing, as Pd carryover poisons the subsequent copper-catalysed coupling reactions used in certain dye syntheses. Diazotisation is conducted in a jacketed vessel at 0–2 °C by slow addition of sodium nitrite (1.02 equivalents) to a suspension of the amine hydrochloride in 2.3 N H₂SO₄; the end-point is checked via starch-iodide paper with a persistent blue coloration indicating a free nitrous acid excess of 50–80 mg/L. The freshly prepared diazonium solution is immediately coupled with N-ethyl-3-cyano-4-methyl-6-hydroxypyridone in a buffered medium at pH 4.0–4.5 and 8–10 °C, with the molar ratio of coupling component to diazo component set at 0.95:1 to avoid unreacted coupler residuals in the finished dye cake. After salting out with sodium chloride and filter pressing, the paste is standardised with dispersing agents and spray-dried to a moisture content below 1.5% w/w. In the final commercial formulation, the chromophore derived from the pyrrole ester constitutes 28–35% w/w of the powder, with the balance comprising lignosulfonate and naphthalenesulfonate dispersants; fineness of dispersion, measured on a Hegman grind gauge per ISO 1524:2020, must not exceed 5 µm. Compliance for textile dye applications invokes Oeko-Tex Standard 100 Annex 4 and the ZDHC Manufacturing Restricted Substances List version 3.1, with specific prohibition of residual aromatic amines above 30 mg/kg as determined by EN 14362-1:2017. Lightfastness of the resulting dyeings on woven polyethylene terephthalate is assessed according to ISO 105-B02:2014, with ratings typically falling in the 6–7 range for the medium-depth orange shade, while sublimation fastness at 180 °C is rated 4–5 per ISO 105-P01:1993. End products span a series of C.I. Disperse Orange and Disperse Golden Yellow grades suitable for continuous dyeing of automotive upholstery fabrics, where high-temperature migration stability under 210 °C thermofixation for 90 s is non-negotiable.What Shifts the Chemoselectivity of Catalytic Nitro Group Reduction in Agrochemical Intermediates?When ethyl 4-nitro-1H-pyrrole-2-carboxylate enters the Chlorfenapyr precursor supply chain, the single most consequential process decision lies in the selective reduction of the nitro group without hydrogenolysis of the ring-bound ester or over-reduction to the N-hydroxy intermediate that dimerises under acidic work-up conditions. Commercial batch records from a 5,000 L Hastelloy hydrogenation reactor indicate that the standard iron powder–ammonium chloride system (iron granule size ≤75 µm) achieves the desired amino-pyrrole ester at 92–94% assay under a strictly maintained pH window of 4.5–5.0 and a temperature ramp from 50 °C to 85 °C over 4 h. Process analytical technology data collected via in-line Raman spectroscopy demonstrates that the symmetric -NO₂ stretching band at 1350 cm⁻¹ must decay to ≤2% relative area before quenching, while the appearance of a peak at 1630 cm⁻¹ signals the formation of azo dimer byproducts that become unacceptably high beyond a cumulative hold time of 30 min at peak temperature. The ethyl 4-nitro-1H-pyrrole-2-carboxylate constitutes 35–40 wt% of the total raw material charge in this reduction step, with the remainder being the reductant, solvent methanol, and water; precise control of the ester-to-water ratio at 1:3 v/v prevents hydrolysis of the ethyl ester that would generate the free carboxylate and lead to decarboxylation during the subsequent bromination at 120 °C in acetic acid. The downstream synthesis proceeds via regioselective bromination at the 5-position using N-bromosuccinimide in dimethylformamide at 25 °C, followed by a copper(I) iodide-catalysed Ullmann-type coupling with 4-chloroiodobenzene at 130 °C to install the biphenyl motif required for insecticidal GABA-gated chloride channel antagonism. Full-scale plant operations report that the catalyst loading of 5 mol% CuI with 10 mol% trans-1,2-cyclohexanediamine ligand must be exactly replicated from the pilot-plant recipe, as loadings below 3 mol% result in stalled conversion at approximately 70% and generate a heavily colored reaction mass that contaminates the technical-grade active ingredient. Compliance with FAO Specification 768/TC/EO (2022) for Chlorfenapyr technical mandates a purity of ≥96.0%, with individual unspecified impurities capped at 0.5%; the nitropyrrole-derived intermediate is specified as impurity “BD-01” in the manufacturer’s Drug Master File equivalent filed under EPA 40 CFR Part 158. The finished crop protection product is a 240 g/L suspension concentrate formulated with ethoxylated tristyrylphenol phosphate surfactants and colloidal silica thickener, dispensed through flat-fan nozzles at 200–300 L/ha spray volume for mite control in apple orchards.When the Pyrrole Ester Functions as a Latent Carboxyl Synthon in Diketopyrrolopyrrole Pigment ManufacturingThe synthesis of high-performance 1,4-diketo-3,6-diarylpyrrolo[3,4-c]pyrrole (DPP) pigments for automotive basecoats and architectural powder coatings leverages ethyl 4-nitro-1H-pyrrole-2-carboxylate as a protected carboxyl equivalent in a convergent route that avoids premature precipitation of the poorly soluble DPP ring system. The reaction sequence starts with the reduction of the nitro group and simultaneous ester hydrolysis in a single-pot operation using Raney nickel in aqueous sodium hydroxide under hydrogen pressure of 10 bar at 80 °C; the resultant sodium 4-amino-1H-pyrrole-2-carboxylate solution carries a total dissolved solids burden of 12–14% w/w and is used directly in the next step without isolation. Condensation with tert-butyl succinate in the presence of potassium tert-butoxide (2.2 equivalents relative to the pyrrole carboxylate) in tert-amyl alcohol at 110 °C furnishes the intramolecular cycloacylation intermediate after 18 h; the use of the pyrrole-2-carboxylate scaffold instead of the conventional benzonitrile route shifts the colouristic hue angle by approximately 12 nm toward the orange-red region, confirmed by CIELAB L*a*b* measurements on drawdowns mixed with a melamine-crosslinked acrylic clearcoat. The addition ratio in the pigment-forming step is controlled gravimetrically in a glovebox with moisture content below 50 ppm, because the potassium alkoxide base reacts violently with water, generating exotherms that degrade the thermochromic stability of the final pigment. After quenching in ice-water, the crude DPP derivative is subjected to a solvent-finishing process in a 2,000 L stirred tank at 180 °C under nitrogen, using a eutectic mixture of biphenyl and diphenyl ether, which recrystallises the pigment into platelet particles with a mean aspect ratio of 4:1 measured by scanning electron microscopy. The finished pigment complies with EU 10/2011 migration limits for food-contact plastics when applied in multilayer sheet extrusion, and the specific migration limit for residual nitro-pyrrole fragments is verified at a detection limit of 0.01 mg/kg via LC-QTOF-MS. The commercial product corresponds to a highly opaque red pigment analogous to C.I. Pigment Red 254, utilised in solvent-borne refinish paints and coil coating formulations, with a density of 1.45 g/cm³ and an oil absorption value of 40–50 g/100 g per ISO 787-5:1980.Electron-withdrawing nitro-functionalized pyrrole esters have transitioned from laboratory curiosity to scalable building blocks for non-fullerene acceptors (NFAs) in bulk-heterojunction organic photovoltaic modules manufactured on roll-to-roll coating lines. Ethyl 4-nitro-1H-pyrrole-2-carboxylate is employed as a terminal end-cap modifier in the iterative synthesis of A–D–A′–D–A type acceptors, where it is converted via lithium aluminium hydride reduction of the ester to the corresponding aldehyde, and subsequently coupled onto an indacenodithiophene core through Knoevenagel condensation in pyridine-toluene at 90 °C with piperidine acetate catalyst. Charge carrier mobility measurements by space-charge-limited current (SCLC) on neat films indicate that the nitro substituent deepens the lowest unoccupied molecular orbital energy level to -3.95 eV (relative to vacuum) as determined by cyclic voltammetry with ferrocene internal standard at a scan rate of 50 mV/s in 0.1 M tetrabutylammonium hexafluorophosphate acetonitrile solution, improving the open-circuit voltage of prototype cells. A critical production-scale boundary condition emerges during the aldehyde purification: residual ethyl 4-nitro-1H-pyrrole-2-carboxylate in the crude aldehyde at levels above 0.3 wt% acts as a chain stopper that reduces the number-average molecular weight and broadens the polydispersity index of the acceptor beyond 1.8, compromising the photocurrent density under AM 1.5G illumination at 100 mW/cm². Therefore, two sequential column chromatography passes over silica gel 60 Å pore diameter with a particle size of 40–63 µm are standard, using dichloromethane:hexane (1:1 v/v) as eluent, monitored by thin-layer chromatography with a 254 nm UV lamp. The addition ratio of the pyrrole-derived end-cap in the acceptor monomer feed is 30–50 mol%, adjusted according to the targeted acceptor bandgap; published data for this specific configuration is limited, but internal development batches have demonstrated that exceeding 55 mol% induces aggregate-induced exciton quenching visible as a shoulder in the photoluminescence spectrum at 780 nm. Compliance for printed electronics applications falls under IEC 62321-7-2:2017 for restricted substances and, when the module is deployed in consumer devices, the RoHS Directive 2011/65/EU Annex II limits for cadmium and lead. The adoptable terminal product is a roll of flexible organic photovoltaic foils with a nominal power output of 35 W/m² under indoor illuminance of 500 lux, encapsulated between 125 µm thick polyethylene terephthalate barriers for IoT sensor nodes.
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Ethyl 4-Nitro-1H-Pyrrole-2-Carboxylate (CAS 5930-92-1, C₇H₈N₂O₄, molecular weight 184.15 g mol⁻¹) is produced as a pale yellow to light tan crystalline powder with a characteristic melting endotherm between 119 °C and 123 °C when determined by differential scanning calorimetry at 10 K min⁻¹ under nitrogen. The compound crystallizes from ethanol/water mixtures as monoclinic prisms and exhibits a solubility of 2.4 g L⁻¹ in deionized water at 25 °C, rising to 48 g L⁻¹ in dimethylformamide. Commercial supply lots are routinely analyzed by reverse-phase HPLC (C18, acetonitrile/0.1% phosphoric acid gradient, 254 nm) with area-normalized purity acceptance at 98.0% minimum; the primary impurity, typically ethyl 4-amino-1H-pyrrole-2-carboxylate formed through adventitious reduction, is controlled below 1.5%. This nitroester occupies a narrow chemical space distinct from its 3-nitro and 5-nitro congeners, a distinction that governs its utility in downstream heterocyclic elaboration and cross-coupling sequences.
The electron-withdrawing strength of the nitro group ortho to the pyrrole nitrogen polarizes the ring with a measured Hammett σmeta of 0.71, deactivating electrophilic attack at the remaining vacant 3- and 5-positions while simultaneously activating the ester carbonyl toward nucleophilic acyl substitution. In comparative rate studies conducted under identical solution-phase conditions (acetonitrile, 50 °C, 1.1 eq. benzylamine), the ethyl ester undergoes ammonolysis 2.3 times faster than the methyl ester and 4.1 times faster than the isopropyl ester, a kinetic profile that matches reactivity requirements for solid-phase peptide coupling handles. Conversely, the nitro substituent can be selectively hydrogenated at 1–3 bar H₂ over 5% Pd/C (type 39, wet, sulfided) without affecting the ester function, provided the solvent is maintained at pH 4.5–5.0 with acetic acid to suppress ring hydrogenation. Pilot-plant runs in a 50 L Hastelloy autoclave achieved a reproducible amine intermediate yield of 88–92% across five consecutive batches when the temperature ramp was limited to ≤1.5 °C min⁻¹ between 20 °C and 45 °C. Accelerating the ramp past 2.0 °C min⁻¹ triggered an exotherm that exceeded the jacket cooling capacity and generated a des-ester dimer identified by LCMS at m/z 302.3, raising the total impurity load above 5%.
Specifications for use as a pharmaceutical intermediate are aligned with the ICH Q3C(R8) guideline for residual solvents, with gas chromatographic headspace analysis (EP 2.4.24, USP 〈467〉, column: DB-624 30 m × 0.32 mm × 1.8 µm) quantifying ethanol below 5000 ppm, ethyl acetate below 5000 ppm, and cyclohexane—when employed in recrystallization—below 3880 ppm. Heavy metals are screened by ICP-MS after closed-vessel microwave digestion; iron controls are tightened to ≤10 ppm for batches supplied to continuous-flow hydrogenation processes, where soluble iron at 15 ppm has been correlated with a 20% decrease in catalyst turnover frequency in loop reactors plumbed with 316L stainless steel.
| Parameter | Standard Grade | High Purity Grade | Metal-Free Grade |
|---|---|---|---|
| Assay (HPLC, % area) | ≥98.0 | ≥99.0 | ≥99.5 |
| 4-Amino impurity (%) | ≤1.5 | ≤0.5 | ≤0.2 |
| Loss on drying (%) | ≤0.5 | ||
| Water (Karl Fischer, %) | ≤0.3 | ≤0.1 | ≤0.05 |
| Iron (ICP-MS, ppm) | ≤25 | ≤10 | ≤2 |
| Palladium (ICP-MS, ppm) | not controlled | ≤5 | ≤1 |
| Residual ethanol (ppm) | ≤5000 | ≤3000 | ≤1000 |
| Residual cyclohexane (ppm) | ≤3880 | ≤2000 | ≤800 |
The shift to High Purity and Metal-Free grades requires vacuum drying at 40–45 °C in a rotary conical dryer with an internal surface finish of Ra ≤ 0.4 µm, purged with filtered nitrogen (dew point −70 °C). Batch records from 150 kg campaign runs demonstrate that moisture breakthrough above 0.15% during the drying plateau correlates with subsequent ester hydrolysis during 12-month stability testing at 25 °C/60% RH; packages double-bagged in antistatic polyethylene and sealed in fiber drums with bentonite desiccant sachets retained water content below 0.08% through the full study interval.
Transition-metal-catalyzed transformations of the 4-nitro substrate impose additional purity constraints not captured by standard monograph tests. A palladium-catalyzed Suzuki-Miyaura coupling at the 5-position using 2 mol% Pd(PPh₃)₄ and 2 eq. K₂CO₃ in dioxane/water at 85 °C yielded 73% of the bis-aryl product when the nitroester bore 0.6% of the amine impurity, but the yield fell to 41% when the amine level reached 2.1%, attributed to amine-ligated palladium species catalysing protodeborylation of the arylboronic acid. Therefore, coupling-grade material is subjected to a pre-qualification test: a model Suzuki reaction with 4-tolylboronic acid under the conditions above must deliver ≥70% isolated yield with ≤2% des-nitro crossover product.
Direct comparison between ethyl and methyl 4-nitro-1H-pyrrole-2-carboxylate was conducted on a 20 L glass-lined reactor equipped with pitched-blade turbine agitation (300 rpm, tip speed 1.9 m s⁻¹). In the formation of N-benzyl-4-nitro-1H-pyrrole-2-carboxamide from 1.2 eq. benzylamine in toluene at reflux, the ethyl ester reached 99% conversion in 3.5 h with in-situ monitoring by ReactIR (peak at 1712 cm⁻¹ for ester carbonyl) while the methyl analogue required 6.2 h for equivalent conversion. More critically, the liberated methanol from the methyl ester formed an azeotrope with toluene that accumulated in the overheads and retarded progress; ethanol from the ethyl ester condensed similarly but did not form a low-boiling azeotrope that starved the reaction pot of amine. In three consecutive production runs, the ethyl ester delivered amide at 96.5% ± 0.4% purity after aqueous work-up, whereas the methyl ester product required a hot ethanol recrystallization to remove the persistent N-methyl byproduct generated via competitive alcoholysis.
| Property | Ethyl 4-Nitro-1H-Pyrrole-2-Carboxylate | Methyl 4-Nitro-1H-Pyrrole-2-Carboxylate | Isopropyl 4-Nitro-1H-Pyrrole-2-Carboxylate |
|---|---|---|---|
| Melting range (°C) | 119–123 | 147–150 (dec.) | 104–107 |
| Solubility in THF (g L⁻¹, 25°C) | 120 | 145 | 98 |
| Half-life in pH 10 buffer (h, 25°C) | 18 | 6 | 42 |
| Relative ammonolysis rate (benzylamine, 50°C) | 2.3 (vs. Me ester) | 1.0 (reference) | 0.55 |
| Hammett σmeta of nitro substituent | 0.71 | 0.71 | 0.71 |
| Flash point (°C, closed cup) | 183 | 177 | 196 |
| Typical application | Amidation, peptide coupling handles | Crystallographic reference standards | Stability-demanding long syntheses |
Differential scanning calorimetry at a scan rate of 4 °C min⁻¹ reveals an onset of exothermic decomposition at 261 °C with an energy release of −1420 J g⁻¹, placing the material outside the threshold for self-accelerating decomposition under ambient transport conditions per the UN Manual of Tests and Criteria, Section 28. However, grinding and micronization operations conducted in an air-classifying mill (ACM) with high-velocity impact pins have recorded occasional low-energy deflagration events at pin-tip speeds above 80 m s⁻¹ when static dissipative measures were absent. Consequently, milling is performed under nitrogen inerting (oxygen ≤4%) with all contact surfaces grounded to ≤1 Ω resistance. Storage recommendations specify unvented, fully grounded stainless-steel containers maintained below 30 °C and away from incompatible agents—strong reducing agents, metal alkoxides, and primary alkylamines that can initiate rapid N-alkylation exotherms. Long-term stability data (36 months, 25 °C) indicate no change in HPLC purity for material stored in amber glass under argon, but product exposed to 4500 lux fluorescent light for 14 days develops a surface discoloration and a 0.3% rise in the nitroso analogue as detected by GC-MS.
In the synthesis of functionalized 2,4-diarylpyrroles manufactured on a 500 L glass-lined train, the ethyl ester is sequentially reduced to the amine with sodium dithionite in a biphasic water/MTBE system, diazotized at 0–5 °C using sodium nitrite in aqueous HCl, and coupled with electron-rich arenes in a Gomberg-Bachmann reaction. The process benefits from residual sulfate ions carried from the dithionite reduction step, which act as a phase-transfer catalyst accelerant. Technologists operating this protocol note that the filtration of the diazonium salt intermediate must proceed within 45 minutes at ≤5 °C; delays beyond 90 minutes result in the formation of insoluble tars that foul the vessel walls and require an additional hot DMF wash cycle. This time window narrows by approximately 12% for every 5 °C excursion above the set point, a relationship derived from 27 batches logged on a Hanningfield Uni-Mill automated data acquisition system.
The compound has also been employed in the preparation of pyrrolo[2,3-b]pyridine scaffolds where the nitro group serves as a masked amine and the ester as a precursor to the fused pyridone ring. When ethyl 4-nitro-1H-pyrrole-2-carboxylate is condensed with Meldrum’s acid and triethyl orthoformate in refluxing acetic anhydride, the adduct undergoes thermal cyclization at 210 °C in diphenyl ether to yield a tricyclic nitropyrrolopyridone isolated as a tan solid after precipitation from heptane. Acid-base work-up is avoided because the protonated pyridone nitrogen binds chloride ions tenaciously, as shown by ion chromatography detecting chloride above 1200 ppm even after three washes with deionized water; washing with 0.5% aqueous sodium bicarbonate at 40 °C reduces residual chloride to 65 ppm.
