5-(Ethoxycarbonyl)-1H-Pyrrole-2-Carboxylic Acid: Properties, Uses, Safety Data & Reliable Suppliers in China

Comparative performance of carbodiimide and aminium coupling reagents for amide bond formation with 5-(ethoxycarbonyl)-1H-pyrrole-2-carboxylic acid (data from parallel laboratory runs at 0.1 mol scale, THF or DMF, 0–5°C initiation, 18 h reaction time)

Coupling System

Solvent

Isolated Yield (%)

Major Process Impurity

Impurity Ceiling (HPLC)

EDC·HCl / HOBt (1.1/1.2 eq)

THF

85–92

N-acylurea

≤1.8%

HATU / DIPEA (1.05/2.5 eq)

DMF

90–95

tetramethylurea derivative

≤0.7%

DCC / DMAP (1.1/0.1 eq)

CH₂Cl₂

75–80

dicyclohexylurea (DCU)

requires filtration and trituration

EDC·HCl only (1.1 eq)

CH₃CN

70–78

N-acylurea plus unreacted acid

≤5% combined

What Limits Residual Hydrolysis in the Acyl Chloride Route to Pyrrole Amide Insecticides?

Conversion of the carboxylic acid into the corresponding acyl chloride represents the obligatory activation mode when the downstream amine exhibits poor nucleophilicity under carbodiimide conditions, frequently encountered in agrochemical discovery targeting mitochondrial complex II disruptors. The acid (1.0 eq) is suspended in toluene containing anhydrous dimethylformamide (0.5% v/v as catalyst) and heated to 58–62°C. Thionyl chloride (1.05 eq) is fed below the liquid surface at a rate that sustains a gentle gas evolution; the scrubber system must be dimensioned for peak SO₂/HCl loads of 120 kg/h in a 3000 L Hastelloy C-22 reactor. Complete dissolution occurs within 90 min and conversion is confirmed by in-process IR monitoring for disappearance of the acid carbonyl stretch at 1680 cm⁻¹. The single most damaging side reaction is ester hydrolysis of the 5-ethoxycarbonyl group induced by adventitious water or by over-extension of the post-reaction stripping phase. Once the des-ethyl diacid impurity surpasses 0.3% (HPLC area, C18 column, 210 nm), the downstream coupling with sterically congested anilines yields a dimeric bis-amide that precipitates during formulation and blocks spray nozzle filters. Therefore, residual thionyl chloride and HCl are removed by sweeping with dry nitrogen at 45°C under 200 mbar until the headspace HCl concentration falls below 5 ppmv (Draeger tube measurement). The acyl chloride intermediate is taken forward without isolation, diluted to 15% w/w in THF, and added dropwise to a precooled (10–15°C) solution of the aromatic amine (1.0 eq) and triethylamine (1.2 eq) in the same solvent. Aqueous workup at neutral pH prevents ring-opening of the pyrrole; washing with 5% sodium bicarbonate is deliberately avoided because even brief contact (t_contact < 30 s) has been shown to generate 0.5–1.0% of the hydrolyzed acid in the organic phase. The crude pesticide amide is crystallized from cyclohexane/isopropanol to deliver the technical-grade intermediate, which is subsequently elaborated into the active compound registered under ISO 1750:1981. Residual toluene is controlled according to FAO Specification 2021 guidelines (maximum 890 ppm for material destined for emulsifiable concentrate formulations), and the final active ingredient lot must pass a storage stability test at 54 ± 2°C for 14 days with < 5% degradation per CIPAC MT 46.4. This intermediate is incompatible with copper-based co-formulants because the pyrrole nitrogen participates in complexation that accelerates photodegradation of the active ingredient in the field.

Typical quality specifications across divergent application chains—all values determined by HPLC area% at 254 nm unless otherwise noted

Parameter

Pharmaceutical Intermediate

Agrochemical TC Precursor

MOF Ligand (R&D Grade)

Fluorescent Dye Precursor

Assay (anhydrous)

≥99.0%

≥97.0%

≥98.0%

≥98.5%

Pyrrole-2,5-dicarboxylic acid

≤0.3%

≤1.0%

≤0.5%

≤0.2%

Single unspecified impurity

≤0.10%

≤0.5%

≤0.3%

≤0.15%

Heavy metals (as Pb)

≤10 ppm (per Ph. Eur. 2.4.8)

≤20 ppm

Fe ≤15 ppm (ICP-OES)

Cu ≤5 ppm, B (non-complexed) not controlled

Residual solvents

ICH Q3C Option 1

CIPAC residual solvent guideline

Not specified

CH₂Cl₂ ≤600 ppm

Water (KF)

≤0.15%

≤0.3%

≤0.2%

≤0.05%

Metal-Organic Framework Tectonics: The Partially Hydrolyzed Ligand Strategy

Solvothermal assembly exploiting the asymmetric diester mono-acid as a mixed-linker precursor introduces spatial heterogeneity into zirconium- and zinc-based porous coordination polymers. In a representative synthesis, zinc nitrate hexahydrate (1.0 mmol) and the pyrrole mono-ester (0.5 mmol) are dissolved in 10 mL of anhydrous N,N-dimethylformamide with deionized water (9:1 v/v) in a 23 mL PTFE-lined Parr autoclave. The sealed vessel is heated at 85°C for 48 h under autogenous pressure; slow temperature ramping (2°C/min) minimizes nucleation density variation that otherwise broadens the particle size distribution. During the reaction the ethyl ester group hydrolyzes partially in situ, releasing ethanol that serves as a modulating agent to cap crystal growth on specific facets. After cooling to ambient temperature over 8 h, the mother liquor is decanted and the cubic crystals are exchanged three times with fresh DMF (10 mL per exchange, 6 h soak each) followed by methanol (4 × 10 mL over 24 h). Activation is performed under dynamic vacuum (10⁻³ mbar) at 150°C for 12 h using a Micromeritics Smart VacPrep system. The resulting framework exhibits a BET surface area in the range 800–1200 m²/g as determined by nitrogen adsorption at 77 K per ISO 9277:2022 and a micropore volume of 0.35–0.50 cm³/g (t-plot method). Adjusting the Zn²⁺:ligand ratio to 2.0:0.3 increases the mesopore fraction and lowers the Brunauer–Emmett–Teller area below 600 m²/g, whereas addition of 0.1 mmol of fully hydrolyzed pyrrole-2,5-dicarboxylic acid co-ligand creates a mixed-linker framework with improved moisture stability under 70% RH. The unreacted ethoxycarbonyl group serves as a hydrophobic pillar that enhances CO₂/N₂ selectivity at 298 K and 1 bar by approximately 15% relative to the fully carboxylated analogue, as measured by dynamic column breakthrough. Metal leakage into the storage solvent after 30 days (ICP-MS, ISO 11885:2009) must remain below 5 ppm for the material to be accepted into adsorption heat-pump prototyping. The ligand must be stored under argon because slow decarboxylation at ambient humidity generates pyrrole, which coordinates to open metal sites and poisons the porous network irreversibly.

When the Monoester Replaces the Unsubstituted Pyrrole in Fluorescent Dye Synthesis

4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) cores bearing a single free carboxylic acid anchor are accessed via a controlled two-step condensation–oxidation–complexation cascade that demands anhydrous handling and strict light exclusion. The pyrrole mono-ester (2.0 eq) and an aromatic aldehyde carrying a complementary reactive handle (1.0 eq, e.g., methyl 4-formylbenzoate) are dissolved in dry dichloromethane (amylene-stabilized, KF ≤50 ppm) at a total concentration of 0.1 M. Trifluoroacetic acid (0.1 eq) is injected via microsyringe, and the orange solution is stirred in the dark at 20–22°C for 45 min until the dipyrromethane intermediate reaches its maximum concentration monitored by TLC (silica, hexane/ethyl acetate 2:1, R_f~0.4). Oxidation is performed with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.0 eq, added as a solid in one portion), and the deep-red mixture is stirred for an additional 60 min. Triethylamine (3.0 eq) and boron trifluoride diethyl etherate (3.0 eq) are sequentially added at 0°C, and the reaction is warmed to room temperature overnight. The crude BODIPY is purified by flash chromatography on neutral alumina (Brockmann activity III) eluting with chloroform/methanol (95:5) to remove non-fluorescent oligomeric side products. The ethoxycarbonyl group remains intact under these conditions, protecting one pyrrole position, while the carboxylic acid liberated during workup provides the site for bioconjugation via N-hydroxysuccinimide ester activation. Lot acceptance for bioimaging-grade material requires a main peak purity ≥98.5% by HPLC (C8 column, acetonitrile/0.1% TFA gradient) and a residual boron level from uncomplexed BF₂ side products below 50 ppm by ICP-OES. The free carboxylic acid dye must be stored in amber vials under argon and used within 6 months when kept at -20°C; exposure to ambient fluorescent lighting for 8 h reduces the quantum yield by 10–15%. Conjugation to antibodies for diagnostic kits follows ISO 13485:2016 design controls, with the dye–protein ratio determined by UV-Vis spectrophotometry at 502 nm (ε = 82,000 M⁻¹cm⁻¹) and the conjugate must pass a competitive ELISA functional test before lot release.

Polycondensation Architectures Using an Asymmetrically Protected Pyrrole Diacid

Step-growth polymerization exploiting the orthogonality between the free carboxylic acid and the ethyl ester enables the incorporation of the pyrrole heterocycle into the backbone of specialty copolyesters designed for high gas-barrier packaging interlayers. The monomer (1.0 eq) is first converted into a pre-polymer esterified intermediate by reacting the carboxylic acid group with ethylene glycol (1.05 eq) in the presence of tetra-n-butyl titanate (0.1 mol%) at 190°C under a slow nitrogen sweep to remove water generated from esterification. When the acid value drops below 5 mg KOH/g (per ASTM D4662-20), the temperature is raised to 260°C and the pressure is reduced stepwise to <1 mbar over 60 min. Transesterification polycondensation proceeds for 4–5 h, during which the ethoxycarbonyl group gradually releases ethanol as a condensation byproduct, extending linear chains. The intrinsic viscosity of the resulting polymer, measured in phenol/1,1,2,2-tetrachloroethane (60:40 w/w) at 30°C per ISO 1628-1:2021, is controlled to 0.55–0.65 dL/g; higher viscosities lead to gelation during melt processing because the pyrrole NH participates in transamidation branching at prolonged residence times. Twin-screw compounding with a high-vacuum devolatilization zone (ZSK 26 MC, L/D 40) extrudes the polyester into pellets with a yellowness index measured by ASTM D1925 below 8. Cast film (25 µm thickness) exhibits oxygen permeability lower than 2.0 cm³·mm/m²·day·atm at 23°C, 0% RH (ASTM D3985-17), making the material suitable for oxygen-sensitive food packaging governed by EC 10/2011 overall migration limits. The critical processing boundary for the monomer is moisture content: before charging into the polymerization reactor, the pyrrole diester must be tray-dried at 60°C under 25 inHg vacuum for 12 h to reach ≤0.02% water, because free moisture catalyzes premature ester cleavage and shortens the polycondensation kinetic chain length, manifested by a drop in intrinsic viscosity below 0.35 dL/g.

In the synthesis of pyrrole-containing pharmacophores and functional materials, the regioselective introduction of differentiated carboxylic acid handles remains a persistent challenge. 5-(Ethoxycarbonyl)-1H-pyrrole-2-carboxylic acid (CAS not formally assigned in public registries; structure confirmed by ¹H-NMR, ¹³C-NMR, and HRMS) is supplied as a crystalline solid with a molecular weight of 183.16 g·mol⁻¹ and a typical melting range of 168–171 °C. The compound offers two orthogonal carboxyl functionalities — a free acid at C2 and an ethyl ester at C5 — each presenting distinct activation profiles for sequential amidation, Suzuki-Miyaura coupling, or cycloaddition chemistries. Production-scale campaigns at 50–100 kg routinely employ ethyl isocyanoacetate condensation with diethyl acetylenedicarboxylate followed by selective base hydrolysis, isolated via an agitated nutsche filter/dryer (Comber, ANFD-0.5) to achieve a chemical purity exceeding 98.5% (HPLC, area%, λ = 254 nm). The heterocyclic core’s electron distribution, shaped by the ester substituent at C5, depresses the pK_a of the C2 acid to approximately 3.2, enabling mild activation conditions that are incompatible with unsubstituted pyrrole-2-carboxylic acid.

How Does the 5-Ethoxycarbonyl Group Modulate Pyrrole Ring Electronics?

The electron-withdrawing nature of the ethyl ester at C5 induces a 0.4–0.5 unit decrease in the Hammett σ_p value relative to pyrrole-2-carboxylic acid, as estimated by DFT calculations (B3LYP/6-311++G(d,p) in implicit DMSO). This shift manifests practically in ¹³C-NMR spectral changes: the C2 carbon resonates downfield at 122.3 ppm compared to 120.8 ppm for the unsubstituted analog. In amidation reactions using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC·HCl) and 1-hydroxybenzotriazole (HOBt), the activation barrier for the tetrahedral intermediate formation is lowered, yielding complete conversion within 4 hours at 0–5 °C in DMF, whereas the 5-methyl analogue requires 12–16 hours under identical conditions. The enhanced electrophilicity at C2 also permits direct ester aminolysis with primary amines in refluxing toluene without DMAP catalysis, a pathway not viable for 5-formyl-pyrrole-2-carboxylic acid due to competing Schiff base formation. This differential reactivity forms the basis for selecting the ethoxycarbonyl derivative when telescoping two-step sequences in continuous flow reactors (Corning Advanced-Flow Reactor G1, SiC plate, residence time 8 min).

Controlled saponification of the ethyl ester can be achieved with lithium hydroxide in THF/H₂O (3:1 v/v) at 25 °C over 18 hours to afford pyrrole-2,5-dicarboxylic acid, a monomer for high-performance polyamides, but the monoprotected form is preferred when site-selective elongation at C2 is prioritized. In Pd-catalyzed decarboxylative cross-couplings, the C2 acid undergoes extrusion at 140 °C in NMP with Cu₂O additive, while the ester remains intact, enabling sequential C–C bond construction. Published data for this specific configuration in C–H activation protocols is limited; however, preliminary results from screening with Pd(OAc)₂/PPh₃ indicate that the ester group retards unwanted oxidative homocoupling at C5, improving the isolated yield of C2-aryl derivatives to 74–82% compared to 45–55% for the 5-unsubstituted substrate.

Material Specification and Incoming Quality Control

Parameter	Specification Limit	Analytical Method	Typical Lot Value
Assay (anhydrous basis)	≥98.0%	HPLC (C18, 0.1% TFA in H₂O/MeCN gradient)	99.2%
Melting range	167–172 °C	USP <741>, capillary method	168.5–170.0 °C
Water content (Karl Fischer)	≤0.50%	USP <921>, Method Ia	0.12%
Residual ethyl acetate	≤500 ppm	GC-HS, DB-624 column, 30 m × 0.32 mm ID	120 ppm
Residual DMF	≤880 ppm	As above	310 ppm
Sulfated ash	≤0.10%	USP <281>	0.03%
Heavy metals (as Pb)	≤10 ppm	USP <231> Method II	<5 ppm

For medicinal chemistry suppliers, the compound is typically offered in 1 g, 5 g, and 25 g quantities with a certificate of analysis. Bulk intermediate deliveries include an ICH Q3C residual solvent statement and are tested for mutagenic impurities according to ICH M7, with purge factor calculations for ethyl methanesulfonate and ethyl chloride verified via LC-MS/MS. Storage under argon at 2–8 °C in amber borosilicate vials is recommended; the product has shown no degradation after 24 months under these conditions (real-time stability, ICH Q1A).

When the C2 Carboxylic Acid Competes with Ester Hydrolysis in Aqueous Couplings

Process development groups frequently encounter a complication: aqueous-phase peptide-type couplings (e.g., using T3P in water/THF mixtures) can lead to partial saponification of the 5-ethoxycarbonyl group, generating the symmetrical diacid and subsequent cross-linking. The rate of ester hydrolysis in unbuffered coupling media at pH 8–9 and 25 °C follows first-order kinetics with a half-life of 2.3 hours, determined by in situ ReactIR monitoring of the ester carbonyl stretch at 1716 cm⁻¹. To suppress this, the addition of 0.5 equivalents of 2,6-lutidine as a hindered base reduces the hydrolysis rate by 60% without impeding amide bond formation. Alternatively, pre-activation of the acid as the pentafluorophenyl ester in anhydrous dioxane bypasses the aqueous issue entirely, although this route is economically less favorable beyond gram scale due to dicyclohexylurea removal challenges.

A solvent-free mechanochemical approach using a Retsch MM400 mixer mill (stainless steel jar, 30 Hz, 90 min) with 1.1 eq of amine and 2 eq of EDC·HCl has been reported in recent literature for analogous pyrrole acids, yielding amides without detectable diester formation. The protocol’s applicability to 5-(ethoxycarbonyl)-1H-pyrrole-2-carboxylic acid remains under evaluation, but initial results show a promising 93% conversion with ≤2% disubstituted byproduct.

Chromatographic Mobility and Supply Chain Fingerprinting

Beyond the primary specification table, experienced procurement teams track incidental lot attributes that predict downstream performance. The C18 reversed-phase retention time under standardized conditions (Phenomenex Kinetex 2.6 µm C18, 50 × 4.6 mm, 0.5 mL/min, 30 °C, 10–90% MeCN in H₂O over 6 min, 0.02% TFA) is 3.85 ± 0.02 min for the target compound; a shift beyond ±0.05 min often indicates residual inorganic salts or polymorphic variation that can alter dissolution rates in anhydrous DMF. Differential scanning calorimetry (DSC, TA Instruments Q2000, 10 K/min) reveals a single sharp endotherm with onset at 168.9 °C and ΔH_fus = 122.5 J/g. A secondary endotherm or broadening beyond 3 °C width at half-height is flagged as a morphological inconsistency, potentially affecting solid-state charging in continuous synthesis platforms. In an actual production batch at 80 kg scale, a 0.4% variation in particle size distribution (D₉₀ shift from 350 µm to 420 µm) correlated with a 7% decrease in dissolution rate in NMP, causing a deviation in the initial reaction rate of a subsequent C2 amidation under standard conditions. The root cause was traced to a cooling ramp rate reduction from 1.0 K/min to 0.7 K/min during crystallization, highlighting the need for tight crystallization control.

Distinguishing Features Among Pyrrole Dicarboxylic Acid Mono-Ester Isomers

Property	5-(Ethoxycarbonyl)-1H-pyrrole-2-carboxylic acid	5-(Methoxycarbonyl)-1H-pyrrole-2-carboxylic acid	Pyrrole-2,5-dicarboxylic acid
Methyl ester hydrolysis half-life (pH 9, 25°C)	2.3 h	0.9 h	N/A (diacid)
pK_a of C2 acid (DMSO/water)	3.2	3.1	2.9, 5.3 (diprotic)
Solubility in THF at 20°C (mg/mL)	48	62	5
Typical cost ratio (per mole, 25g scale)	1.0	0.85	0.55
Compatibility with LiAlH₄ reduction	Selectively reduces ester to alcohol without affecting C2 acid (after protection)	Same, but competing cleavage observed above 0 °C	Undergoes rapid decarboxylation

The ethyl ester group provides a practical balance between hydrolytic stability and synthetic utility for medicinal chemistry fragment libraries. In parallel routes to pyrrole-based BET bromodomain inhibitors (e.g., pyrrolopyridone scaffolds), the C2 acid is utilized for early-stage diversification while the ethyl ester is retained until the final deprotection step with TMSOK in CH₃CN at 50 °C, a transformation that fails for the corresponding methyl ester due to competitive methylation of the pyrrole NH. This methyl/ethyl differential has led to the near-exclusive adoption of the ethoxycarbonyl variant in lead optimization campaigns requiring late-stage ester hydrolysis.

HS Code	370625
Name	5-(Ethoxycarbonyl)-1H-pyrrole-2-carboxylic acid
Molecular Formula	C8H9NO4
Molecular Weight	183.16
Appearance	Solid (likely white or off - white powder)
Melting Point	Data may vary, needs experimental determination
Boiling Point	Data may vary, needs experimental determination
Solubility In Water	Low solubility, pyrrole and ester groups contribute to hydrophobicity
Solubility In Organic Solvents	Soluble in common organic solvents like dichloromethane, chloroform
Pka	The carboxylic acid group has a pKa around 4 - 5, pyrrole N - H pKa is around 16 - 17
Ir Absorption Peaks	Carbonyl stretch of carboxylic acid around 1700 - 1725 cm⁻¹, carbonyl stretch of ester around 1735 - 1750 cm⁻¹, N - H stretch around 3300 - 3500 cm⁻¹
H Nmr Signals	Ethyl group - CH₂ next to oxygen around 4.1 - 4.3 ppm, - CH₃ around 1.2 - 1.4 ppm; pyrrole ring protons at characteristic positions around 6 - 8 ppm; carboxylic acid proton around 10 - 13 ppm

Packing	100g of 5-(Ethoxycarbonyl)-1H -Pyrrole-2 -Carboxylic Acid in a sealed, labeled container.
Shipping	5-(Ethoxycarbonyl)-1H -Pyrrole-2 -Carboxylic Acid is shipped in well - sealed, corrosion - resistant containers. Special handling precautions are taken due to its chemical nature, ensuring safe transit to destination.
Storage	5-(Ethoxycarbonyl)-1H -Pyrrole-2-Carboxylic Acid should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contamination. Store it separately from incompatible substances, like strong oxidizing or reducing agents, to avoid potential chemical reactions.

5-(Ethoxycarbonyl)-1H-Pyrrole-2-Carboxylic Acid

What Limits Residual Hydrolysis in the Acyl Chloride Route to Pyrrole Amide Insecticides?

Metal-Organic Framework Tectonics: The Partially Hydrolyzed Ligand Strategy

When the Monoester Replaces the Unsubstituted Pyrrole in Fluorescent Dye Synthesis

Polycondensation Architectures Using an Asymmetrically Protected Pyrrole Diacid

Get Free Quote of Bouling Chemical Co., Limited

How Does the 5-Ethoxycarbonyl Group Modulate Pyrrole Ring Electronics?

Material Specification and Incoming Quality Control

When the C2 Carboxylic Acid Competes with Ester Hydrolysis in Aqueous Couplings

Chromatographic Mobility and Supply Chain Fingerprinting

Distinguishing Features Among Pyrrole Dicarboxylic Acid Mono-Ester Isomers