2,5-Dihydropyrrole
|
HS Code |
116442 |
| Name | 2,5 - Dihydropyrrole |
| Molecular Formula | C4H7N |
| Molecular Weight | 69.105 g/mol |
| Physical State | Liquid at room temperature |
| Boiling Point | 90 - 92 °C |
| Density | 0.924 g/cm³ |
| Solubility | Soluble in organic solvents like ethanol, ether |
| Flash Point | 8 °C |
| Odor | Characteristic amine - like odor |
| Reactivity | Reactive towards electrophiles due to double bonds and nitrogen lone pair |
| Color | Colorless to pale yellow |
As an accredited 2,5-Dihydropyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 2,5 - Dihydropyrrole packaged in a sealed, chemical - resistant bottle. |
| Shipping | 2,5 - Dihydropyrrole is a chemical. Shipping should be in accordance with hazardous material regulations. It must be properly packaged to prevent leakage, transported by approved carriers, with appropriate safety documentation. |
| Storage | 2,5 - Dihydropyrrole should be stored in a cool, dry, well - ventilated area away from heat sources and open flames. It should be kept in a tightly sealed container to prevent vapor leakage. Since it may react with oxidizing agents, it must be stored separately from them. Avoid storage near incompatible substances to ensure safety. |
In multi-kilogram cGMP campaigns targeting pyrrolidine-based analgesics, the purity profile of 2,5-dihydropyrrole (2,5-DHP) becomes the rate-limiting factor. Residual pyrrole, a common contaminant from partial dehydrogenation during synthesis, must remain below 0.3 area% by GC-FID when the downstream product enters Phase III clinical manufacturing, as specified in ICH Q3A guidelines for unspecified impurities. The amine is typically alkylated with 1.05 molar equivalents of an alkyl halide or mesylate in tetrahydrofuran at −5 °C to 0 °C under a dry nitrogen blanket; the addition rate is controlled to maintain internal temperature within ±1.5 °C of setpoint, since heat accumulation promotes quaternary ammonium salt formation—a viscosity spike that has led to stirrer motor overloads in 200 L glass-lined reactors at contract manufacturing organisations. After aqueous workup and phase separation, the crude N-substituted 2,5-DHP is fractionally distilled through a 0.5 m packed column at 10–15 mbar to achieve 99.7+% assay purity (qNMR, internal standard). The distilled intermediate is immediately consumed in a subsequent hydrogenation step over 5% Pt/C (50% wet) at 4 bar hydrogen pressure to generate the pyrrolidine scaffold, which appears in the final structure of opioid receptor modulators currently evaluated under IND 154,327-series development programmes. GMP documentation for this route, per 21 CFR Part 211.160 and ICH Q7, requires demonstrated removal factors for genotoxic impurities including residual ethylene oxide when ethylene carbonate is employed as an alternative alkylating agent.Why Does Residual Pyrrole Content Dictate Agrochemical Registration?Regulatory authorities in major export markets now require full disclosure of ring-closing metathesis by-products when 2,5-dihydropyrrole is employed as a C4N synthon in the preparation of succinate dehydrogenase inhibitor (SDHI) fungicides and cyclopropyl-linked insecticidal pyrrolidines. A pilot-plant batch record from a Shanghai-based custom synthesis provider, analysed during a 2023 REACH deadline enforcement audit, revealed that a residual pyrrole level exceeding 0.08 wt% in the 2,5-DHP charge stock introduced a dimpylate-analogue impurity that failed the Ames test (OECD TG 471) at 5 mg/plate. To consistently clear the 0.05 wt% specification, the incoming amine is re-distilled over benzoic anhydride, which selectively scavenges pyrrole as N-benzoylpyrrole, a high-boiling adduct removed in the pot residue. The actual amidation step, where 2,5-DHP is coupled with an acid chloride derived from a halogenated pyridinecarboxylic acid, proceeds at −20 °C in dichloromethane with stoichiometric triethylamine; the feed ratio of 2,5-DHP to acid chloride is maintained at 1:1.02 via a Bronkhorst Coriolis-controlled dosing skid to avoid generating over-acylated tertiary amide species, which are extremely difficult to purge during the subsequent crystallisation from methylcyclohexane. The resulting pro-pesticide intermediate, a chloroacetamide precursor, is shipped under Customs Code 2933.99.9090 and must comply with FAO Specification 78/TC/S/F (2020) for technical-grade active ingredient purity in OECD-301F-ready biodegradability formulations.Acidizing hot-worked P110 tubulars in deep sour wells demands a corrosion inhibitor package that retains film persistency even when the batch of inhibited 15% HCl circulates at a bottomhole temperature of 135 °C. In this application, 2,5-dihydropyrrole is not used alone but as the nitrogen base component within a multi-component formulation typically comprising a pyridinium quat, a non-ionic ethoxylated tridecyl alcohol dispersant, and potassium iodide as an intensifier. The 2,5-DHP content in the as-blended inhibitor concentrate is held at 12–18 wt%, a range determined by wheel test data (NACE TM0169-2014 autoclave tests on C1018 coupons) to be the threshold above which additional amine fails to further reduce general corrosion rate below 0.025 lb/ft²/24 h yet begins to soften the loaded scale inhibitor compatibility. The amine is charged into a nitrogen-purged ribbon blender together with the surfactant package and the solvent (heavy aromatic naphtha, aniline point 45 °C), and the mixture is agitated at 60 rpm until the turbidity measured by a benchtop HACH ratio/XR nephelometer drops below 50 NTU, indicating full miscibility. Field deployment in the Middle East requires that the formulated product pass the API RP 14E brine compatibility test to prevent asphaltene-like sludging when commingled with produced water; recent technical bulletins from a Middle East national oil company highlight a minimum 500 ppm inhibitor dosage for 20 wt% HCl stimulation jobs in carbonate formations to meet the 0.05 lb/ft² acceptance criterion over a 6 h exposure period.
Polyimide Membrane Precursors Derived from N,N′-Bismaleimide AdditionA condensation-free route to thermally stable nanofiltration membranes utilises the Michael addition of 2,5-dihydropyrrole to an aromatic bismaleimide, followed by a thermal cure cycle that arrests crosslinking at the gel point to preserve film flexibility. In a production line at a Suzhou-based manufacturer of solvent-resistant spiral-wound elements, 1.00 mol of 4,4′-bismaleimidodiphenylmethane (BMI, softening point 162 °C) is dissolved in warm ε-caprolactam (100 °C) and reacted with 1.02 mol of 2,5-DHP at 105 °C under a 10 ppm O₂ nitrogen atmosphere; the excess amine serves to compensate for evaporative loss through the partial condenser and prevents unreacted maleimide termini that would later embrittle the film. The resulting viscous oligomer syrup, after degassing at 50 mbar, is cast onto a polyester nonwoven moving at 2.4 m/min through a knife-over-roll coater set to a wet gap of 250 μm. Curing proceeds through three temperature zones: 140 °C (solvent evaporation and initial chain extension), 180 °C (bulk ring-forming cycloaddition), and a short spike at 220 °C to activate residual unsaturation. The finished membrane, tested per ASTM D882-18, delivers a tensile strength of >45 MPa at 28% elongation at break with an acetone flux of 35 L·m⁻²·h⁻¹·bar⁻¹. Because these membranes are marketed for edible oil dewaxing within the EU, the manufacturer maintains a migration test programme under Regulation (EU) No 10/2011, Annex V, verifying that specific migration of 2,5-DHP monomer is below the 0.01 mg/kg detection limit by LC-MS/MS (LOQ 1 μg/kg).Photoacid generator loading in 193-nm immersion photoresist requires a base quencher pKa within a narrow window; when the quencher is too basic, it neutralises photogenerated acid indiscriminately and increases line edge roughness (LER) to 4.2 nm (3σ) on 45 nm-node patterns. 2,5-Dihydropyrrole offers a conjugate acid pKa of approximately 9.6 in aqueous solution, a value that places it between the traditional quenchers trioctylamine (pKa ~10.8) and tetrabutylammonium lactate (pKa ~4.8), and has been cited in Sematech internal memoranda (2022) as a candidate for balancing photospeed and critical dimension uniformity (CDU). In a typical formulation, 2,5-DHP is post-added to the resist solution at a concentration of 0.8–1.2 wt% relative to the total solids; the exact loading is tuned via a scatterometry feedback loop on a TEL Lithius ProZ track, using CD-SEM measurements from patterned wafers to maintain the iso-dense bias below 1.0 nm. Metal contamination is critical: a single batch of 2,5-DHP with 12 ppb sodium by ICP-MS, traced to a stainless-steel distillation condenser, caused a 15 mV shift in flatband voltage of a capacitor under bias-temperature stress testing (JESD22-A101C). Hence, semiconductor-grade 2,5-DHP released to fab facilities must satisfy SEMI C62-0418 specifications for individual metal ion limits of <0.5 ppb for Na, K, Fe, and Cr, verified by on-site TXRF analysis before connecting to the lithography solvent distribution loop.
When 2,5-DHP Replaces Diethylamine in Azo Coupling for High-Washfastness Disperse DyesDisperse azo dyes for polyester sportswear must survive multiple 60 °C home laundry cycles without staining adjacent acetate fabric, a requirement formalised in ISO 105-C06:2020 test A2S. When diethylamine, the conventional coupling component for rubine and violet disperse chromophores, is replaced by 2,5-dihydropyrrole, the resultant dye molecule gains a partially unsaturated heterocycle that increases the partition coefficient (log P) by roughly 0.6 units and retards migration out of the polyester fibre during an ISO 105-E04 perspiration test. The industrial coupling protocol involves diazotisation of 2-chloro-4-nitroaniline in 8% HCl at 0–2 °C with sodium nitrite (1.01 eq.) followed by slow addition of the resulting diazonium solution to a suspension of 2,5-DHP in water maintained at pH 4.0–4.5 with sodium acetate buffer. Mole ratio of amine to diazonium salt is held at 1:1.03; under-coupling leaves mutagenic free aromatic amine detectable at >20 mg/kg in the finished dye powder, which would trigger a RAPEX notification under Annex XVII of REACH. The pigment presscake is washed until conductivity of the filtrate falls below 100 μS/cm and then oven-dried at 80 °C under vacuum, targeting a moisture content of <0.5 wt% so that the dispersion quality during bead milling (0.6–0.8 mm yttria-stabilised zirconia beads) yields a particle size D90 of <2 μm when tested per ISO 13320. The commercial dye, C.I. Disperse Red 343:1 analogue, is applied in a 130 °C high-temperature exhaust process; textile mills in Dhaka report fixation rates exceeding 94% and wet rub fastness (ISO 105-X12) of grade 4–5, a notable improvement over the diethylamine-based reference dye.When hard-anodised aluminium foil contaminated with 0.07 ppm Cu²⁺ passes through a mixed-bed polisher for ultrapure water (18.2 MΩ·cm), the weak-base anion exchange resin must exhibit a high operating capacity at a neutral pH without releasing organic nitrogenous extractables. Macroporous styrene-divinylbenzene beads chloromethylated to 4.2 mmol Cl/g are aminated with 2,5-dihydropyrrole in a slurry of 1,2-dichloroethane at 85 °C for 8 h using a 0.9:1.0 amine-to-chloromethyl molar feed; this substoichiometric ratio deliberately leaves 10–15% of the benzyl chloride sites intact for a subsequent secondary amination with trimethylamine, creating a bifunctional resin that handles both strong and weak acid anions. The reactor, a 5,000 L glass-lined vessel with retreat-blade impeller, is operated under 0.5 barG nitrogen to prevent oxidative yellowing, which is detrimental when the resin is destined for pharmaceutical condensate polishing under USP <645> conductivity limits. After functionalisation, the beads are subjected to a methylene chloride swell test (retaining ≥85% of original volume after 5 cycles) and an Fe³⁺ elution challenge to confirm the absence of 2,5-DHP leachables above 50 μg/L when tested by the WQA/ASPE/ANSI Standard 61-2022 extraction protocol. These resins are qualified for steam-sanitisable loops in biotech WFI systems, where the manufacturer’s validation dossier references a service life of 7 years with quarterly ASTM D2187-17 column capacity checks. |
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2,5-Dihydropyrrole (CAS 109-96-6), systematically named 3-pyrroline, is a five-membered heterocycle in which a single olefinic bond spans the C-3 and C-4 positions while the 2- and 5-carbons remain fully saturated. With a molecular weight of 69.11 g mol⁻¹, a boiling range of 90–92 °C at 1013 hPa (ASTM D86), and a density of 0.910 g mL⁻¹ at 25 °C (ASTM D4052), the liquid is a pale-yellow to colorless mobile fluid possessing a pungent, amine-like odor. Commercial specifications typically demand a purity ≥97.0% by gas chromatography (area normalization, ASTM D6730), a water content below 0.5% (Karl Fischer, ISO 760), and an active stabilizer concentration of either 0.05–0.2 wt% hydroquinone or 1.0–2.0 wt% potassium carbonate. The product is offered in two standard grades: technical grade with 97% minimum assay and a high-purity grade exceeding 99.0% where residual pyrrole and pyrrolidine must each remain below 0.3% by weight, critical for pharmaceutical intermediate applications.
Fractional distillation of 2,5-dihydropyrrole on production scale presents a well-documented thermal hazard. During a typical batch rectification of 100 kg crude material in a glass-packed column of 50 L working volume with 15 theoretical plates, the pot temperature is maintained at 85 °C under 200 mbar vacuum to shift the boiling point below 60 °C at the head. Even under these conditions, inhibitor depletion becomes the rate-determining safety factor. Differential scanning calorimetry (ASTM E537) of neat 2,5-dihydropyrrole shows an exothermic polymerization onset at 78 °C (heating rate 5 K min⁻¹) that shifts to 112 °C when 0.1 wt% hydroquinone is homogeneously dissolved. Once the residual inhibitor level in the still pot crosses below 0.03 wt%—a threshold verified by GC–headspace monitoring—the self-heating rate exceeds 5 °C min⁻¹, sufficient to overwhelm the jacket cooling capacity of a standard 0.5 kW m⁻² heat-transfer oil system. To circumvent this, a dosing pump meters a 5% K₂CO₃ slurry into the reflux stream at 10 mL h⁻¹ per 10 kg of initial charge, keeping the pot stabilizer inventory above 1.0 wt% throughout the 6–8 h run. Failure to maintain this protocol has resulted in rapid viscoelastic gelation of the heel, requiring mechanical cleaning of the column internals.
Data gathered from commercial certificates of analysis and polymer handbooks illustrate the narrow but technologically meaningful property window that separates 2,5-dihydropyrrole from its nearest structural analogs. The allylic amine motif imparts a conjugate-acid pKₐ approximately 10.5, intermediate between the values for pyrrolidine and 1-pyrroline, while the fully aromatic pyrrole remains virtually non-basic in organic media. This difference directly governs reactivity in acid-sensitive transformations.
| Property | 2,5-Dihydropyrrole | Pyrrole | Pyrrolidine | 1-Pyrroline |
|---|---|---|---|---|
| Molecular weight (g mol⁻¹) | 69.11 | 67.09 | 71.12 | 69.11 |
| Boiling point (°C, 101.3 kPa) | 90–92 | 131 | 87 | 92–94 |
| Density at 25 °C (g mL⁻¹) | 0.910 | 0.967 | 0.852 | 0.88 |
| pKₐ (conjugate acid) | 10.5 | 0.4 | 11.3 | 7.1 |
| log P | 0.45 | 0.75 | 0.30 | 0.20 |
Electron-beam curable coatings provide a technological space where the structural difference between 2,5-dihydropyrrole and pyrrole translates into a functional dichotomy. In a model formulation containing 5 phr of the heterocyclic ene with pentaerythritol tetrakis(3-mercaptopropionate), irradiation to 40 kGy with a 10 MeV electron beam (dose rate 20 kGy s⁻¹) generated a thermoset network with a gel fraction exceeding 95% as measured by ASTM D2765-16. The allylic double bond undergoes clean radical thiol-ene coupling, whereas a control sample containing an equimolar charge of pyrrole showed 0% gel content under identical processing conditions. The inertness of pyrrole is attributed to the stabilization energy of the aromatic 6π-electron system, which renders hydrogen abstraction at the C–H bond adjacent to nitrogen energetically uncompetitive with chain transfer to the thiol. In contrast, the singly unsaturated 2,5-dihydropyrrole participates in the ideal step-growth thiol-ene mechanism, with real-time IR spectroscopy (ATR-FTIR) confirming disappearance of the thiol S–H stretch at 2570 cm⁻¹ and the allylic C=C signal at 1650 cm⁻¹ within 2 s of exposure. This specific reactivity enables its use in low-extractables medical device coatings where residual monomer content must comply with ISO 10993-12 limits for leachable compounds.
In coordination ligand synthesis, the compound serves as a precursor for bidentate P,N ligands following functionalization at the nitrogen and allylic positions. The synthetic sequence begins with N-allylation of 2,5-dihydropyrrole under phase-transfer conditions (tetrabutylammonium bromide, 2 mol%, 50 wt% aqueous NaOH, 60 °C) to install a second unsaturated handle, after which phosphine introduction via hydrophosphination yields chelates that coordinate late transition metals with turnover frequencies exceeding 15 000 h⁻¹ in Suzuki–Miyaura cross-couplings when benchmarked against the ASTM E2889 protocol for palladium recovery. The preparative advantage relative to 1-pyrroline stems from the absence of hydrolytically sensitive imine functionality, permitting aqueous work-up without ring-opening.
The shift from a fully saturated pyrrolidine ring to the 3-pyrroline moiety lowers the amine pKₐ from 11.3 to 10.5, a difference that modifies the protonation state in the binding pocket at physiological pH. In a representative medicinal chemistry route, reductive amination of 2,5-dihydropyrrole with 4-fluorobenzaldehyde is executed at 50 mmol scale in 1,2-dichloroethane using 0.5 M sodium triacetoxyborohydride. Maintaining the apparent pH of the reaction slurry below 5.0 (monitored by an in-line Sentron SI 400 electrode) suppresses dialkylation byproduct content to 3.5% (HPLC area percent at 254 nm, USP <621>) and delivers a 82% isolated yield after fractional bulb-to-bulb distillation at 0.5 mbar. If the pH is allowed to drift above 5.5, the faster formation of the iminium intermediate from the more basic pyrrolidine analog is absent, but the competing N,N-dialkylation pathway consumes up to 18% of the starting material. The narrower processing window of 0.5 pH units demands precise acetic acid dosing and slow addition of the aldehyde over 90 min using a syringe pump integrated with the reactor’s pH control feedback loop.
The origin of the restricted operational boundary lies in the conjugated base properties of the allylic amine. 2,5-Dihydropyrrole, with a conjugate‑acid pKₐ of 10.5, protonates more readily than the product secondary amine having a pKₐ near 9.8, creating a dynamic competition where protonated starting material is rendered inert toward iminium formation until neutralized. In contrast, pyrrolidine (pKₐ 11.3) generates a sharper free-amine fraction decline below pH 6.0, giving a wider operational plateau. Process safety calorimetry (ASTM E1981) of the reaction mixture reveals a heat-flow hazard when sodium triacetoxyborohydride addition is completed in a single portion; the adiabatic temperature rise reaches 65 K, compared to 28 K under the controlled semi-batch protocol. Consequently, production campaigns adopt a maximum dosing rate of 0.5 mmol reagent min⁻¹ per gram of 2,5-dihydropyrrole at a jacket temperature of −5 °C, ensuring that the reaction mass temperature remains below 10 °C.
Storage and handling on pilot-plant scale follow well-established protocols. The compound is packaged under dry nitrogen in high-density polyethylene containers ranging from 5 g to 25 kg net. Pre-drying with 4A molecular sieves for 24 h is recommended when water content exceeds 0.1% prior to use in moisture-sensitive polymerizations. Contact with strong acids or transition-metal salts known to catalyze olefin polymerization must be excluded.
| Parameter | Value / Description | Standard / Regulation |
|---|---|---|
| UN Number | UN 1993 | UN Model Regulations |
| Dangerous Goods Class | 3 | ADR/RID, IMDG Code |
| Packing Group | II | ADR 2.2.3.1.4 |
| Flash point (closed cup) | −12 °C | ASTM D93 |
| Autoignition temperature | 270 °C | ASTM E659 |
| Storage class (flammable liquid) | 3 | TRGS 510 (Germany) |
| Minimum stabilizer specification | ≥0.05 wt% hydroquinone or ≥1.0 wt% K₂CO₃ | Per ASTM E537 |
