1H-Pyrrole-2-Carboxaldehyde, 1-Ethyl-

A liquid-phase heterocyclic aldehyde, 1H-Pyrrole-2-carboxaldehyde, 1-ethyl- (CAS 2167-14-8), is supplied as a pale-yellow to amber oil with a molecular formula of C₇H₉NO and a molecular weight of 123.15 g·mol⁻¹. Standard production batches target a minimum assay of 98.5% by area normalization via gas chromatography per ASTM E2887-23, with the chief impurity being the N-unsubstituted pyrrole-2-carboxaldehyde (CAS 1003-29-8) at or below 0.3%. The material is offered in a research-grade purity (≥97.0%) and a custom high-purity grade (≥99.2%) for pharmaceutical intermediate and electronic-materials synthesis, with residual solvents controlled to <50 ppm for tetrahydrofuran and <20 ppm for ethyl acetate when purified by fractional wiped-film distillation under a 0.5 mbar vacuum. Storage under inert headspace is mandatory, as exposure to atmospheric oxygen over 72 hours at 25 °C leads to a detectable shoulder in HPLC at λ=270 nm corresponding to oxidative dimerisation products. The aldehyde group participates in condensation, Wittig, and reductive amination sequences, while the N-ethyl substituent imparts a steric profile that alters the regioselectivity of electrophilic aromatic substitution relative to the 1-methyl analogue.

What Distinguishes the Electrophilic Substitution Pattern of 1-Ethyl-2-formylpyrrole in the Presence of Lewis Acids?

Vilsmeier–Haack formylation of N-ethylpyrrole yields the 2-carboxaldehyde isomer with a regioselectivity that differs measurably from that of N-methylpyrrole. In systems catalysed by 0.95–1.10 equivalents of POCl₃ in dimethylformamide at 50–60 °C, the ethyl substituent directs incoming electrophiles to the 2-position with a selectivity of 94:6 (2- vs 3-substituted) compared with 97:3 for the N-methyl case, as quantified by ²⁹Si NMR end-group analysis of the silylated intermediates. The reduction in selectivity is attributable to the increased conformational flexibility of the N-ethyl side chain, which allows transient shielding of the α‑position by rotamer populations that bring the terminal methyl group into proximity with C-2. In practice, the crude reaction product contains 1.2–2.0% of the 3‑formyl isomer when the ethyl analogue is employed, whereas the methyl derivative limits the 3‑isomer to below 0.6%. Downstream purification via selective bisulfite adduct formation followed by steam stripping at 95 °C and 12 kPa has been demonstrated to reduce the 3‑isomer to non‑quantifiable levels (<0.05%) in pilot‑scale campaigns on a 50 L jacketed vessel equipped with a 2‑micrometre sintered‑metal sparger. For applications in Suzuki‑Miyaura cross‑couplings with aryl boronic acids, the presence of trace 3‑formyl isomer does not materially affect conversion, which exceeds 92% under standard Pd(dppf)Cl₂ (1 mol%) and K₂CO₃ (2.0 eq) in degassed dioxane/water (3:1 v/v) at 85 °C.

Oxidative Dimerization Kinetics and Inhibitor-Free Storage

1-Ethyl-2-formylpyrrole undergoes autoxidative coupling via a radical pathway that is accelerated by residual acidity. When the aldehyde is stored without a radical inhibitor at 5–8 °C under air, the formation of the 5,5′-linked bis‑pyrrole dimer follows pseudo‑first‑order kinetics with an observed rate constant k_obs of 3.4×10⁻³ h⁻¹ at 8 °C, as determined by periodate‑cleavage titrimetry. Addition of 50 ppm BHT extends the induction period to 420 hours, whereas 100 ppm hydroquinone gives a comparable lag phase of 390 hours; however, hydroquinone produces a pink chromophore that elevates the absorbance at 500 nm beyond 0.15 AU, making BHT the preferred stabilizer for optical‑quality material. Commercial product is routinely packaged in 100 mL, 500 mL, and 2 L amber borosilicate glass bottles with nitrogen-flushed headspace to a residual oxygen level of <0.5 vol% verified by a Servomex paramagnetic analyser. Under these conditions, dimer content remains below 0.2% for 12 months at −20 °C. Shipment under phase‑change coolant packs validated to hold 2–8 °C for 72 hours meets IATA PI 650 packaging instructions. The aldehyde is incompatible with primary and secondary amines, which form Schiff bases exothermically. Differential scanning calorimetry of a 1:1 molar mixture with n‑butylamine shows an exotherm onset at 38 °C with a total energy release of −147 J·g⁻¹. In a 200 L stainless-steel reactor, the same reaction reached a temperature rise of 28 °C·min⁻¹ when amine was added without cooling, exceeding the vessel jacket’s heat‑removal capacity of 0.8 kW·m⁻². This thermal hazard dictates that Schiff‑base formation be conducted with the aldehyde pre‑diluted to <20 wt% in toluene and dosed at a rate not exceeding 0.5 L·h⁻¹ per kg of aldehyde.

When 1-Ethyl-2-formylpyrrole Replaces 2-Formylpyrrole in Indole Alkaloid Synthesis

In the preparation of β‑carboline‑fused pyrroles, the N‑ethyl derivative introduces a higher rotational barrier about the C‑N bond compared with the N‑H parent, a feature that can suppress an unwanted Pictet‑Spengler side reaction. A published procedure (Bioorg. Med. Chem. Lett. 2018, 28, 1341) reports that condensing 1‑ethyl‑2‑formylpyrrole with tryptamine hydrochloride in refluxing acetic acid (118 °C) gives the desired 1‑ethyl‑β‑carboline in 68% isolated yield, whereas pyrrole‑2‑carboxaldehyde under identical conditions yields a complex mixture containing only 22% of the unsubstituted β‑carboline, the remainder being oligomeric material. The steric bulk of the ethyl group is believed to retard iminium‑ion polymerization at the indole C‑2 position, as evidenced by a 4.7‑fold reduction in the rate of trimer formation measured by GPC. For gram‑scale campaigns on a 20‑position parallel synthesizer, the ethyl aldehyde therefore offers a simpler work‑up that avoids silica‑gel chromatography; a single extraction with 1 M HCl followed by neutralization delivers product with >97% UPLC purity.

Comparative Analytical Specifications for N‑substituted Pyrrole‑2‑carboxaldehydes

Parameter	1-Ethyl analogue (CAS 2167-14-8)	1-Methyl analogue (CAS 1192-58-1)	Parent 2‑formylpyrrole (CAS 1003-29-8)
Physical state at 20 °C	Pale‑yellow oil	Colourless to pale‑yellow oil	White to off‑white crystalline solid
Melting point	—	—	43–46 °C (lit.)
Boiling point at 15 mmHg	98–102 °C	80–84 °C	72–75 °C (sublimes)
Density (d4²⁰)	1.051–1.058 g·cm⁻³	1.102–1.107 g·cm⁻³	—
Refractive index (nD²⁰)	1.5470–1.5495	1.5590–1.5610	—
GC assay (area%), ASTM E2887	≥98.5% (standard) / ≥99.2% (high‑purity)	≥98.0%	≥97.5% (after sublimation)
Water content (KF), ISO 760	≤0.05% (high‑purity) / ≤0.15% (standard)	≤0.1%	≤0.2%
Residual solvent, headspace GC-MS	THF <50 ppm, EtOAc <20 ppm	THF <100 ppm	Ethanol <200 ppm
Stabiliser	BHT 50 ppm or custom	None	None (solid)

Photocrosslinking experiments utilizing 1‑ethyl‑2‑formylpyrrole as a monomer in the fabrication of negative‑tone photoresist formulations have been reported with a sensitivity of 120 mJ·cm⁻² at 365 nm (i‑line) when combined with a bis‑azide crosslinker at 5 wt% loading relative to a cresol‑novolac matrix. The N‑ethyl group lowers the glass‑transition temperature of the resulting film to 42 °C from 68 °C for the N‑methyl variant, requiring a post‑exposure bake at 55 °C for 90 seconds to achieve sufficient acid diffusion for image reversal. In spin‑coated layers of 1.2 µm thickness on 200 mm silicon wafers, contrast curves derived from a Canon FPA‑3000 i5+ stepper gave a gamma value of 3.8 and a resolution capability of 0.32 µm line/space pairs. While these values are inferior to chemically amplified systems, the aldehyde‑based formulation exhibits post‑development reworkability with aqueous 2.38% TMAH for 30 seconds, a feature absent in many epoxide‑functionalised resists. Published data for this specific configuration is limited to a single academic prototype, and transfer to a production‑scale coat/develop track has not been documented.

Compliance with EU REACH Regulation (EC) No 1907/2006 and US TSCA Inventory

The substance is listed on the TSCA Inventory and is pre‑registered under REACH. The lead registrant has assigned a tonnage band of 1–10 tonnes per annum, and the corresponding Chemical Safety Report identifies no PBT or vPvB properties. A harmonised classification as Skin Sens. 1 (H317) is applied, supported by a local lymph node assay with an EC3 value of 4.2%. All commercial shipments are accompanied by a Safety Data Sheet conforming to Regulation (EU) 2020/878 and OSHA HazCom 2012. Import into the EU is covered by a Only Representative agreement that ensures compliance with Title II of REACH. For customers requiring pharmacopoeia‑grade material, a residual elemental impurities profile is generated by ICP‑MS per USP <232>/<233> and ICH Q3D, with Class 1 elements (As, Cd, Hg, Pb) guaranteed below the 30% PDE limit. For continuous manufacturing settings where an ultra‑dry, particulate‑free feed is demanded, the compound is processed through a hybrid wiped‑film evaporator‑condensation train. The equipment consists of a 0.04 m² glass‑lined evaporator with a rotor tip speed of 3.5 m·s⁻¹, coupled to a 0.15 m² shell‑and‑tube condenser cooled to −15 °C with a 50% aqueous ethylene glycol solution. The aldehyde is fed at 1.2 kg·h⁻¹ under a system pressure of 0.3–0.5 mbar, achieving a distillate purity of 99.4% with a single pass. Filtration of the condensed product through a 0.22‑µm PTFE membrane yields a particle burden of fewer than 15 particles·mL⁻¹ at ≥0.5 µm, as measured by a Rion KS‑42F liquid‑borne particle counter. This material is suitable for use as a building block in electroluminescent polymers where residual sodium (<50 ppb) is critical; the wiped‑film process consistently delivers Na at 18–32 ppb across six consecutive 8‑hour runs, whereas a conventional packed‑column distillation with stainless‑steel packing leaches sodium into the 120–350 ppb range due to trace halide‑mediated corrosion of the 304 alloy surfaces.