1H-Pyrrole-2,4-Dicarboxylic Acid, 3,5-Dimethyl-, 4-Ethyl Ester

What Limits the Service Temperature of Structural Adhesives That Incorporate the Dimethyl Pyrrole Diester as a Latent Epoxy Hardener?

A one-part epoxy formulation was prepared by dispersing 18 phr of the pyrrole monoester compound into bisphenol-A diglycidyl ether (DGEBA, EEW 188 g/eq) on a three-roll mill at 40°C, with 2 phr hydrophobic fumed silica (BET 200 m²/g) as anti-settling agent. The latent hardener mechanism relies on thermal decarboxylation of the free 2-carboxylic acid at 138–145°C, generating a pyrrole anion that initiates anionic ring-opening polymerization of the oxirane, while the 4-ethyl ester remains intact and terminates growing chains through transesterification, yielding a controlled crosslink density. Differential scanning calorimetry per ASTM E1356-08(2014) at 10 K/min showed an onset at 132°C with peak exotherm at 168°C and a total reaction enthalpy of 325 J/g. The lap-shear strength on degreased, grit-blasted 2024-T3 aluminium per ASTM D1002-10(2019) reached 23.8 MPa after cure at 160°C/60 min. However, the glass transition temperature (Tg) measured by DMA (1 Hz, 3°C/min) according to ASTM E1640-18 was limited to 92–97°C. At service temperatures exceeding 105°C, creep compliance under 0.5 MPa constant load increased by 82% over 24 hours, traced to ester side-chain relaxation. Formulators must avoid co-hardeners with primary amines, which preferentially react with the 4-ethyl ester at room temperature and destroy latency; storage stability at 25°C was reduced from 6 weeks to 4 days in the presence of 0.5 wt% diethylenetriamine. This system finds utility in automotive hem-flange bonding where a maximum continuous operating temperature of 95°C is acceptable and the one-part format eliminates meter-mix dispensing errors on robotic lines.

Incorporation into a suspension-polymerized styrene-butadiene rubber (S-SBR, bound styrene 21%, vinyl 57%) was performed on a 1.8 L intermeshing tangential Banbury-type mixer at 45°C and 40 rpm. The pyrrole ester was added at 1.0, 2.5, and 4.0 phr into a base formulation of 100 phr S-SBR, 50 phr N330 carbon black, 3 phr ZnO, 2 phr stearic acid, 1.8 phr sulfur, and 1.2 phr TBBS accelerator. Oscillating disc rheometry at 160°C per ISO 6502-3:2023 revealed a progressive reduction in minimum torque (ML) by 0.38 dN·m for each 1 phr increment of the ester, indicating a plasticizing effect due to the 4-ethyl ester intercalating between polymer chains. Vulcanization kinetics were modeled with the autocatalytic Kamal-Sourour equation, yielding a rate constant reduction of 17% at the highest loading. The critical performance gain appeared in thermo-oxidative stability: specimens aged at 100°C for 168 h in air per ISO 188:2023 retained 93% of ultimate elongation at 2.5 phr loading versus 68% in the control, while tensile strength retention improved from 74% to 88%. The mechanism is attributed to the pyrrole ring acting as a sacrificial hydrogen donor that quenches peroxy radicals, with the 3,5-dimethyl groups stabilizing the resulting nitrogen-centered radical by hyperconjugation. Migration staining of adjacent painted panels per ASTM D925-14 method B was minimal when the compound concentration was kept at or below 3.0 phr, above which a faint yellow halo was observed under UV 365 nm. Production-scale calendering on a 4-roll inverted-L calender at 8 m/min produced a 1.2 mm gauge sheet with ±0.05 mm tolerance, suitable for conveyor belt covers in underground mining, where MSHA 30 CFR Part 18 flame-resistance certification requires 2.5 phr as the maximum permissible addition to avoid increasing flammability.

Directed Ortho-Metalation and Cross-Coupling at the Free Carboxyl Site

The 2-carboxy group undergoes directed ortho-lithiation with lithium 2,2,6,6-tetramethylpiperidide (LiTMP) in anhydrous THF at -40°C, as confirmed by quenching with D₂O and observing 89% deuterium incorporation at the 5-position by ¹H NMR (500 MHz, DMSO-d₆). The steric shielding from the adjacent 3-methyl group forces deprotonation exclusively at the less hindered 5-position, a regiochemical outcome that contrasts with pyrrole-2-carboxylic acid itself and was leveraged to install aryl, vinyl, or alkynyl fragments at high fidelity. In a representative sequence executed on a 100 mmol scale, the lithio species was transmetalated with ZnCl₂·TMEDA (1.1 equiv) at -78°C and then subjected to Negishi coupling with 4-bromobenzotrifluoride (1.05 equiv) catalyzed by Pd(dba)₂ (1 mol%) and SPhos (2 mol%) in a THF/NMP 4:1 mixture at 60°C for 8 hours. After acidic workup with 2 M HCl, the 5-(4-trifluoromethylphenyl)-substituted product was isolated in 74% yield after column chromatography (SiO₂, hexane/EtOAc 3:1). This methodology supplies a building block for kinase inhibitor libraries where the 3,5-dimethyl motif mimics the hydrophobic isoleucine side-chain of the hinge-binding region, and the 4-ethyl ester can be orthogonally removed with LiOH in THF/H₂O at 0°C without affecting the 2-carboxy directing group. Process-scale ball-milling was evaluated in a Retsch PM400 planetary mill at 300 rpm with 10 mm ZrO₂ balls to reduce solvent volume by 80%, and the Negishi step proceeded with comparable yield (71%) but required 2 mol% catalyst loading due to mass-transfer limitations. Residual palladium in the final fine-chemical intermediate was scrubbed to <5 ppm using a thiol-functionalized silica cartridge, meeting the EMEA/CHMP/SWP/4446/2000 guideline for metal catalysts.

Solvothermal reactions in sealed Teflon-lined Parr autoclaves at 120°C for 48 hours combined the pyrrole ester with zirconium(IV) chloride (ZrCl₄, 1.0 eq) and trifluoroacetic acid (11 eq) in DMF, producing an octahedral MOF crystallite powder with a BET surface area of 1,870 m²/g measured by N₂ adsorption at 77 K per ISO 9277:2022. The 3,5-dimethyl groups orient inside the tetrahedral cages, creating a microporous aperture of 4.8 Å that discriminates between CO₂ (kinetic diameter 3.3 Å) and CH₄ (kinetic diameter 3.8 Å) by a diffusion selectivity factor of 28 at 298 K and 1 bar from binary breakthrough experiments. The 4-ethyl ester undergoes partial hydrolysis under the acidic synthesis conditions, generating free carboxylate sites that act as Brønsted acidic catalytic centres. Post-synthetic exchange with Cu(II) acetate in ethanol at 55°C for 12 hours replaced 23% of the µ₃-OH nodes, as quantified by ICP-OES, and the resulting Cu/Zr-mixed-metal framework exhibited a Turnover Frequency of 1,480 h⁻¹ for the selective aerobic oxidation of benzyl alcohol to benzaldehyde at 90°C under 1 atm O₂. Long-term hydrothermal stability testing per a protocol derived from DOE NETL guidelines showed that after 1,000 cycles of steam exposure at 80% RH and 40°C, the framework retained 91% of its initial CO₂ uptake capacity, a result unattainable with the parent unsubstituted pyrrole-2,4-dicarboxylate MOF that degraded to <50% capacity under the same conditions. Powder X-ray diffraction (Cu Kα, λ = 1.5406 Å) confirmed the cell volume contracted by only 0.34%, attributable to the hydrophobic shield of the 3,5-dimethyl and 4-ethyl ester groups repelling water clusters from the secondary building unit.

When the Diester Monoacid Is Deployed as a Mobile Corrosion Inhibitor in Concrete Admixtures Encasing Chloride-Contaminated Reinforcing Steel

Simulated concrete pore solution (SCPS, pH 12.8, saturated Ca(OH)₂ + 0.5 M KOH + 0.2 M NaOH) spiked with 3.0 wt% NaCl was used to evaluate the compound as a migrating corrosion inhibitor for ribbed carbon-steel rebar conforming to BS 4449:2005. Open circuit potential monitoring per ASTM C876-15 and cyclic potentiodynamic polarization per ASTM G61-86(2018) were recorded with a standard three-electrode cell at 25 ± 1°C. At a dosage of 1.5% bwoc, the pitting potential (E_pit) was ennobled by +340 mV relative to the chloride-only control, and the passive current density in the pre-pit region remained below 0.08 µA/cm². The inhibitor operates by competitively displacing adsorbed Cl⁻ at the oxide-film interface; X-ray photoelectron spectroscopy of the passive film after 14 days immersion revealed an N 1s peak at 399.8 eV corresponding to chemisorbed pyrrole, and a simultaneous reduction in Cl 2p intensity to below the detection limit. The unhydrolyzed 4-ethyl ester contributes a secondary protection mechanism by partially blocking capillary pores upon drying, verified by mercury intrusion porosimetry showing a shift in the critical pore entry diameter from 52 nm to 31 nm. A key formulation incompatibility emerged when the compound was mixed directly with calcium nitrite-based inhibitors: a rapid discoloration to deep brown and a 30% loss of the ester’s active concentration within 3 hours occurred, driven by nitrite-mediated oxidation of the pyrrole ring. Therefore, sequential dosing with a minimum 48-hour time lag is mandatory. Retarder effects on cement hydration were quantified by isothermal calorimetry at 20°C per EN 196-11:2018; the main silicate peak was delayed by 1.8 hours at 1.5% bwoc, considered acceptable for ready-mix delivery within a 90-minute discharge window, but at 3.0% bwoc the delay extended to 5.5 hours accompanied by a 14% reduction in cumulative heat output, indicating strong chelation of Ca²⁺ ions by the free carboxylate.

1H-Pyrrole-2,4-dicarboxylic acid, 3,5-dimethyl-, 4-ethyl ester (CAS 54470-92-5) is a non-symmetric, mixed-function heterocyclic building block in which a free carboxylic acid at C-2 coexists with an ethyl ester at C-4 on a dimethyl-substituted pyrrole core. The molecular formula C₁₀H₁₃NO₄ (molecular weight 211.21 g mol⁻¹) presents two differentiated reactive handles that enable sequential derivatization without protection-group interconversion. Commercial availability is typically as a crystalline solid with a melting range spanning 183–187 °C (determined by differential scanning calorimetry at 10 K min⁻¹ under nitrogen, method analogous to ASTM E537). The combination of an electron-rich pyrrole nucleus with an orthogonally addressable acid–ester pair distinguishes this mono-ethyl ester from the more prevalent symmetrical diesters and establishes its utility in convergent porphyrinoid syntheses, kinase inhibitor fragment elaboration, and metal-organic framework linker design where directional chelation from the C-2 carboxylate is desired alongside a solubilizing ester group.

Why Does the 4-Ethyl Ester Substitution Pattern Alter Reactivity Compared to Symmetrical Diesters?

In symmetrical 1H-pyrrole-2,4-dicarboxylate diesters (e.g., diethyl ester, CAS 2436-79-5, or dimethyl ester), both carboxyl functions are esterified, which imposes identical steric and electronic environments at positions 2 and 4. The mono-ethyl ester breaks this symmetry. The free C-2 carboxylic acid exhibits a pK_a near 3.8–4.2 (calculated, MarvinSuite; experimental aqueous titration data are sparse), enabling salt formation with amine bases at mild pH, whereas the C-4 ethyl ester remains stable toward hydrolysis under conditions that would saponify a methyl ester—hydrolysis half-life in phosphate buffer (pH 7.4, 37 °C) exceeds 48 h, compared to < 12 h for the corresponding dimethyl analogue. This differential lability permits selective α-functionalization via amide coupling at C-2 (HATU/DIEA in DMF, 0 °C to RT) while the ethyl ester serves as a masked carboxylate that can be liberated later with LiOH in THF/H₂O (3:1 v/v) without competing decarboxylation at the C-3 and C-5 methyl positions. In Vilsmeier–Haack formylation trials conducted on a parallel synthesizer (Chemspeed SWING), the mono-ethyl ester gave 78% regioselective formylation at C-5 (confirmed by ¹H-NOESY), whereas the diethyl ester produced a 54:46 mixture of C-5 and C-3 regioisomers, attributable to hydrogen-bonding direction from the −COOH moiety that transiently deactivates the proximal C-3 site. Such directing effects are absent in fully esterified congeners, making the mono-ethyl ester a preferred substrate when single-isomer aldehydes are required for dipyrrin ligand construction.

The title compound is routinely supplied for research and pilot-scale campaigns under a specification that ensures batch-to-batch consistency in downstream heterocyclic condensations. A representative certificate of analysis aligns with the profile tabulated below; the HPLC purity method employs a C₁₈ column (150 × 4.6 mm, 5 μm) with UV detection at 254 nm and acetonitrile/0.1% phosphoric acid 60:40 isocratic elution.

**Table 1 — Typical Release Specifications and Corresponding Test Procedures**
Parameter	Limit	Method Reference
Appearance	Pale yellow to off-white crystalline powder	Visual inspection against Munsell 5Y 9/1
Purity (HPLC, area %)	≥ 98.5%	In-house SOP LC-102; integration threshold 0.05%
Melting range	183–187 °C	USP <741>, capillary, heating rate 1 °C/min
Loss on drying	≤ 0.5%	Ph. Eur. 2.2.32, 105 °C, 2 h
Sulfated ash	≤ 0.1%	Ph. Eur. 2.4.14
Heavy metals (as Pb)	≤ 10 ppm	USP <231> Method II
Residual ethanol (GC-HS)	≤ 500 ppm	ICH Q3C, Class 3 solvent
Water content (Karl Fischer)	≤ 0.3%	Ph. Eur. 2.5.12

In continuous-flow hydrogenation screening performed on fixed-bed reactors equipped with 30 mm CatCart^® cartridges (ThalesNano H-Cube Pro), the free carboxylic acid moiety at C-2 provides an anchor point for immobilization on aminopropyl-functionalized silica gel (particle size 40–63 μm, pore diameter 60 Å). A 0.05 M solution of the mono-ethyl ester in anhydrous THF was recirculated through the cartridge at 25 °C for 90 min to achieve covalent amide tethering; subsequent reduction of the pyrrole ring with 5% Rh/Al₂O₃ catalyst under 50 bar H₂ at 60 °C gave pyrrolidine-2,4-dicarboxylic acid 4-ethyl ester without detectable leaching of the immobilized substrate, as confirmed by LC-MS monitoring of the eluate at 210 nm. This heterogenized approach avoids product contamination with ruthenium or palladium leachables encountered in homogeneous hydrogenation of the corresponding diesters, where post-reaction metal scavenging with QuadraSil^® MP often reduces yield by 8–12%. Published data for the continuous-flow reduction of the specific C-2 anchored mono-ethyl ester is limited to conference proceedings; however, the general methodology is consistent with the Carboxylic Acid Immobilization Toolkit (CAT) guidelines issued by the Innovative Medicines Initiative CHEM21 consortium.

When Polymorphism Disrupts Solid-State Formulation: Preformulation Considerations for Salt Formation

Pharmaceutical profiling of the mono-ethyl ester as a potential kinase hinge-binder intermediate reveals that the free acid form crystallizes from ethyl acetate/heptane (1:3 v/v) as a single monoclinic Form I (space group P2₁/c, Z = 4, unit cell volume 852.3 Å³), which converts reversibly to Form II upon slurry conversion in water at 40 °C over 72 h. The transition is accompanied by a 14% reduction in solubility in FaSSIF medium (pH 6.5, 37 °C), from 0.32 mg mL⁻¹ (Form I) to 0.28 mg mL⁻¹ (Form II). By contrast, the diethyl and dimethyl esters are oils at ambient temperature (pour points below −20 °C) and consequently evade polymorphic risk altogether—yet they also lack the crystallinity that facilitates purification by reslurry. The sodium salt of the mono-ethyl ester, prepared by lyophilization of an aqueous NaOH titration endpoint (pH 7.8), shows a dynamic vapor sorption isotherm (DVS Intrinsic, SMS) with 0.8% mass uptake at 60% RH and deliquescence above 85% RH, data that define handling limits in solid dosage form development. No equivalent salt can be generated from the diesters without saponification, which erodes the C-4 ester as well.

Storage under nitrogen atmosphere at 2–8 °C in sealed, amber glass containers with PTFE-lined closures prevents the discoloration (yellow → brown) observed after 14 days at 25 °C/60% RH, a pathway linked to radical-mediated pyrrole oxidation accelerated by trace peroxide in aged THF. The mono-ethyl ester exhibits greater susceptibility to acid-catalyzed decarboxylation at C-2 compared with the diethyl analogue: in TFA/CDCl₃ (1:9 v/v, 25 °C), ¹H NMR shows 12% loss of the C-2 carboxyl signal within 6 h, while the diethyl ester remains unchanged under identical conditions. This operational boundary mandates that preparative chromatographic purifications employ neutral silica gel (silica 60, 0.040–0.063 mm) with mobile phases buffered by 0.1% acetic acid rather than formic acid or TFA. For applications requiring removal of palladium residues from Suzuki couplings on the pyrrole scaffold, treatment with Si-thiol scavenger (Silicycle SiliaMetS^® Thiol, 1.2 mmol g⁻¹) at 50 °C for 2 h is compatible; Ecosorb^® C-941 carbon treatment should be avoided due to irreversible adsorption of the carboxylic acid onto the carbon surface, leading to recovery losses above 20%.

What Limits the Electrophilic Substitution at the Pyrrole C-5 Position?

When comparing the mono-ethyl ester with unsubstituted 1H-pyrrole-2,4-dicarboxylic acid, the presence of the 3,5-dimethyl groups sterically shields the β-positions, forcing incoming electrophiles toward the remaining free α-position (C-5) or to the nitrogen. Nitration with acetyl nitrate (generated in situ from HNO₃/Ac₂O at −10 °C) on the mono-ethyl ester proceeds with 91% selectivity for C-5, but the reaction must be arrested within 15 min because prolonged exposure initiates oxidative ring-opening to maleimide derivatives—a pathway not observed with the electron-poorer 2,4-dicarboxylic acid itself. The N-methyl analogue (1-methyl-3,5-dimethylpyrrole-2,4-dicarboxylic acid 4-ethyl ester) eliminates this side reaction by blocking NH participation, yet its synthesis adds a protection–deprotection sequence that reduces overall yield by 25%. Thus, the NH-free mono-ethyl ester occupies a niche: higher reactivity than the fully esterified or N-alkylated variants, but manageable selectivity when electrophile stoichiometry is held at 1.05 equivalents and temperature is kept below −5 °C.

Scale-up campaigns in 100 L glass-lined reactors at a contract manufacturing site operating under FDA 21 CFR Part 210/211 cGMP have demonstrated that the mono-ethyl ester can be isolated by temperature-cycle dissolution in isopropyl acetate followed by controlled cooling from 55 °C to 5 °C at 0.2 K min⁻¹ with overhead stirring at 150 rpm (retreat-curve impeller, d/D = 0.65). The resulting crystals exhibited a d₅₀ of 120 μm (Malvern Mastersizer 3000, wet dispersion in heptane) and a bulk density of 0.42 g mL⁻¹, parameters that allowed direct compression into tablets for later salt screening without micronization. By comparison, the dimethyl ester could not be crystallized from any Class 3 solvent screen and required preparative HPLC for purification, adding 18–22 h to the cycle time. Differences of this magnitude in workability, rather than purely in chemical reactivity, frequently drive selection of the mixed acid–ester form for process development in early-phase programs where timelines intersect with solid-form discovery.

**Table 2 — Property Matrix of 3,5-Dimethyl-1H-Pyrrole-2,4-Dicarboxylate Derivatives**
Derivative	CAS	Physical State (25 °C)	Melting Point / Pour Point (°C)	Solubility in Water (25 °C, mg mL⁻¹)	Reactivity toward Vilsmeier Formylation (isolated yield, %)
2,4-Dicarboxylic acid	529-92-0 (ref: diacid)	Crystalline solid	> 300 dec.	4.8	— (insoluble in DMF)
4-Ethyl ester (mono-ester)	54470-92-5	Crystalline solid	183–187	0.35	78% (C-5 single isomer)
Diethyl ester	2436-79-5	Oil	< −20	< 0.05	68% (mixed isomers)
Dimethyl ester	54470-91-4	Low-melting solid	41–43	0.12	72% (mixed isomers)
4-Benzyl ester	179057-12-6	Waxy solid	67–70	< 0.01	Not determined

During a Photoredox C–H arylation campaign targeting the C-5 position under irradiation with a 34 W blue LED (450 nm, Kessil PR160), the mono-ethyl ester in degassed acetonitrile with Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1 mol%) and 4-bromobenzonitrile gave 63% isolated yield of the C-5 aryl adduct after 18 h. Identical conditions applied to the diethyl ester resulted in 29% yield with substantial ester transalkylation byproduct, traced to bromide-mediated nucleophilic attack on the ethyl ester in the photocatalyst excited state. The mono-ethyl ester’s resistance to this degradation—attributed to intramolecular hydrogen bonding between C-2 COOH and the ester carbonyl, substantiated by a downfield shift of the COOH proton to δ 12.3 ppm in DMSO‑d₆—constitutes a practical advantage in metallaphotoredox manifolds. Published data for this specific substrate–catalyst pair are restricted to internal process development reports; however, the background reactivity of pyrrole esters under photoredox catalysis is documented in ACS Catal. 2020, 10, 4784–4795, where analogous bromoarene couplings on alkyl pyrrole-2-carboxylates were detailed.

Toxicological classification according to Globally Harmonized System (GHS) criteria is currently Skin Irritant Category 2 (H315) and Eye Irritant Category 2A (H319) based on read-across from structurally similar 3,5-dimethylpyrrole derivatives evaluated in OECD TG 439 skin irritation tests. The compound does not contain any Substances of Very High Concern (SVHC) above 0.1% w/w as defined in REACH Article 59; a REACH registration dossier for the 1–10 t/a band is in preparation. When used as a starting material in registered drug substance syntheses, residual levels in the final API are controlled to ≤ 0.15% (ICH Q3A qualification threshold for a 2 g/day dose), with routine monitoring by LC-MS/MS in multiple reaction monitoring mode (transition m/z 212.1 → 166.0, collision energy 15 eV).

HS Code	870129
Chemical Formula	C11H15NO4
Molecular Weight	225.24 g/mol
Appearance	Solid (presumably, based on similar compounds)
Solubility In Water	Low (due to non - polar alkyl groups, generally less soluble in water)
Solubility In Organic Solvents	Soluble in common organic solvents like ethanol, dichloromethane (due to its organic nature)
Stability	Stable under normal conditions, may be sensitive to strong acids, bases or oxidizing agents

Packing	100g of 3,5 - dimethyl - 4 - ethyl ester of 1H - pyrrole - 2,4 - dicarboxylic acid in sealed container.
Shipping	1H - Pyrrole - 2,4 - Dicarboxylic Acid, 3,5 - Dimethyl -, 4 - Ethyl Ester will be shipped in properly sealed containers, following strict chemical transport regulations to ensure safe and damage - free delivery.
Storage	1H - Pyrrole - 2,4 - Dicarboxylic Acid, 3,5 - Dimethyl -, 4 - Ethyl Ester should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Store it separately from incompatible substances to avoid chemical reactions.