1-Pyrrolepropionitrile

Chlorfenapyr Synthesis Route via 1-Pyrrolepropionitrile: Stoichiometric Control and Hazardous Reagent Handling

The commercial manufacture of the miticide/insecticide chlorfenapyr (CAS 122453-73-0) depends on a convergent sequence in which 1-pyrrolepropionitrile functions as the pyrrole-carbonitrile scaffold for subsequent N-ethoxymethylation and polyhalogenation. In a typical batch protocol conducted in a 2000 L glass-lined reactor equipped with a retreat-curve impeller and a double mechanical seal, 1.00 molar equivalent of 1-pyrrolepropionitrile is dissolved in anhydrous N,N-dimethylformamide (DMF, water content <100 ppm by Karl Fischer) at 25 °C. Potassium carbonate (1.25 eq, milled to D50 <50 µm) is suspended, and chloromethyl ethyl ether (1.15 eq) is metered over 90 min while maintaining the jacket temperature at 20–28 °C; the dosing rate is calibrated to keep the exotherm below 0.5 °C/min. After GC confirmation of >99% conversion (HP-5 column, 30 m × 0.32 mm × 0.25 µm), the N-alkylated intermediate is extracted into dichloromethane and crystallized from n-heptane/toluene (4:1 v/v) to afford the ethoxymethyl derivative in 88% isolated yield with a purity of 98.7%. The critical bromination step proceeds in a hastelloy C-22 reactor at 40–45 °C using 1.95 eq of bromine delivered via a corrosion-resistant mass flow meter; the effluent Br₂/HBr off-gas is scrubbed in a 20 wt% NaOH packed column. Subsequent trifluoromethylthioether formation employs trifluoromethanesulfenyl chloride (1.05 eq) under 1.5 bar gauge nitrogen, with the intermediate held at −5 to 0 °C in a brine-cooled loop reactor to suppress disulfide dimerization. The final oxidation to the sulfoxide is carried out with 30% hydrogen peroxide (1.1 eq) in acetic acid at 55 °C, with in-situ FTIR monitoring (C–S–O absorption at 1050 cm⁻¹) determining the endpoint to prevent over-oxidation to the sulfone. The technical-grade chlorfenapyr product is dried under 10 mbar at 60 °C and must conform to FAO specification 570/TC (purity ≥ 940 g/kg, maximum water 5 g/kg, acetone insolubles <5 g/kg). Regulatory compliance anchors on EPA 40 CFR §180.618 (tolerances for chlorfenapyr residues on leafy vegetables, tuberous crops, and tree nuts) and the EU PPP Regulation 1107/2009; the active substance inclusion under Directive 2011/39/EU mandates a CIPAC MT 179 assay and a dioxin-like impurity threshold below 0.1 µg/kg TEQ. The terminal formulated product is a 240 g/L suspension concentrate (SC) or a 36% wettable granule (WG) for foliar application in cotton, citrus, and vegetable brassica crops.

The N-alkylation of pyrrole with acrylonitrile yields 1-pyrrolepropionitrile, which serves as the core scaffold for a class of potent histamine H3 receptor inverse agonists designed for narcolepsy and cognitive disorders. Subsequent catalytic hydrogenation of the nitrile to primary amine, followed by sulfonylation with 4-chlorobenzenesulfonyl chloride, forms the final pharmacophore. In a typical Kilolab batch recorded at scale, 1-pyrrolepropionitrile is dissolved in tetrahydrofuran (THF) and charged to a 100 L Hastelloy C-276 hydrogenation vessel containing 5% Pd/C (50% wet) at a catalyst loading of 2.5 wt% relative to the nitrile. The hydrogen pressure is maintained at 4 bar and the temperature at 35–40 °C; exotherm is controlled by jacket cooling. Complete conversion is confirmed by GC (HP-5 column, 30 m × 0.32 mm) when the nitrile peak area drops to <0.5%. After filtration through a 0.5 µm sintered-metal candle filter and atmospheric distillation, the resulting 1-(3-aminopropyl)pyrrole is isolated in 92% yield with gas chromatographic purity of 99.1%. The molar ratio of 1-pyrrolepropionitrile to sulfonyl chloride is controlled at 1.0:1.05 to minimize bis-sulfonamide formation, and the reaction is run in dichloromethane/water biphasic medium with sodium bicarbonate as acid scavenger. Compliance with ICH Q7 GMP for API starting materials requires residual palladium below 10 ppm (determined by ICP-OES per USP <233>) and genotoxic impurity monitoring for acrylonitrile (<1 ppm by GC-MS headspace). The terminal drug product, a Schedule V controlled substance in certain jurisdictions, falls under 21 CFR 314.50 for NDA submissions and must meet EP monograph purity criteria. This intermediate route is also used for the synthesis of dual orexin receptor antagonists, where the pyrrolepropionitrile manifold introduces key H-bond acceptor topology, and for selective serotonin 5-HT₂C agonists requiring a 5.0–7.5 mol% charge of the nitrile in a convergent fragment coupling under Pd-XPhos catalysis.

What impact does 1-Pyrrolepropionitrile exert on the solid electrolyte interphase in Ni-rich cathode systems?

In high-voltage NMC811/graphite pouch cells, 1-pyrrolepropionitrile functions as a nitrile-functionalized film-forming additive that preferentially oxidizes at the cathode surface during the first charge, forming a thin CEI layer that mitigates transition-metal dissolution and electrolyte solvent oxidation. Comprehensive cycling data collected in 1 Ah three-electrode pouch cells (N/P ratio 1.15, laminated aluminum pouch) demonstrate that addition levels between 0.8 and 1.5 wt% in a baseline electrolyte of 1 M LiPF₆ in EC/EMC (3:7 vol:vol) with 2 wt% FEC shift the capacity retention after 500 cycles at 4.4 V and 45 °C from approximately 78% to 91%, while the average Coulombic efficiency improves from 99.3% to 99.85%. Electrochemical impedance spectroscopy (EIS) at 10 kHz to 10 mHz reveals that the post-formation R_SEI increases only by 8% with the additive, versus a 35% increase in the additive-free control, indicating a thin and ionically conductive interphase. The additive also suppresses the decomposition of LiPF₆ by complexing with PF₅ Lewis acid, thereby reducing HF generation; post-cycling HF titrations in the electrolyte yield a value of <120 ppm compared to 380 ppm in the baseline.

Electrolyte preparation is carried out in a dry room with a dew point −40 °C inside an argon-filled glovebox (O₂ <0.1 ppm, H₂O <0.1 ppm). 1-Pyrrolepropionitrile, pre-dried over 4 Å molecular sieves for 72 h, is accurately weighed using a microbalance with 0.1 mg resolution and dissolved in the EC/EMC cosolvent before adding LiPF₆ salt. Final moisture content, measured by coulometric Karl Fischer titration (Metrohm 831 KF), must not exceed 10 ppm. Pouch cells are vacuum-filled with the prepared electrolyte and rested for 12 h at 25 °C before formation cycling: one cycle at C/20 CC charge to 4.4 V and CC discharge to 3.0 V, followed by two C/10 cycles for SEI stabilization. The formed cells are degassed under vacuum (−0.9 bar gauge) and heat-sealed. Regulatory testing must comply with IEC 62660-3 clause 7.3 (overcharge at 2C to 100% SOC) showing no thermal runaway, and UN 38.3.5 altitude simulation (≤11.6 kPa for 6 h) without leakage or venting. Registration under EU REACH requires documentation of the additive in the safety data sheet of the final electrolyte formulation, and the lithium cell must meet the EU Battery Directive 2006/66/EC and RoHS 2011/65/EU for lead and cadmium thresholds.

Electropolymerizable monomers containing a flexible nitrile-functionalized side chain enable fabrication of freestanding conductive films with enhanced adhesion to ITO-glass substrates. 1-Pyrrolepropionitrile is copolymerized with pyrrole at a feed molar ratio of 5–15 mol% via chemical oxidative polymerization in a 0.5 M FeCl₃ aqueous solution at 0–5 °C under nitrogen purge. The copolymer powder is filtered, washed with deionized water until the filtrate is colorless (conductivity <10 µS/cm), and dried under vacuum at 60 °C for 24 h. The intrinsic viscosity in N-methylpyrrolidone at 25 °C falls within 0.3–0.8 dL/g, and gel permeation chromatography against polystyrene standards indicates a weight-average molecular weight of 18,000–35,000 Da. Spin-coated films on ITO/glass are electrochemically cycled in a three-electrode cell with Ag/AgCl reference and Pt counter electrode; the cyclic voltammogram recorded at 50 mV/s between −0.5 and +1.2 V shows two distinct redox peaks corresponding to the polaron and bipolaron states, and the optical contrast at 550 nm reaches 42% after 200 cycles with 5.2 s response time. Electrochemical impedance at 0.01 Hz yields an ionic diffusivity of 2.8×10⁻¹⁰ cm²/s. The addition of a 5 mol% 1-pyrrolepropionitrile comonomer shifts the film’s tensile elongation at break from 1.2% (pure polypyrrole) to 3.8% (ASTM D882, 25 mm gauge length, 50 mm/min). Finished goods encompass electrochromic smart windows that modulate near-infrared transmission for building energy management, antistatic packaging trays thermoformed from 0.3 mm thick PS/PP laminate coated with the conductive copolymer, and corrosion-inhibiting primer coats for mild steel blasted to Sa 2½ (ISO 8501-1) where the polymer is deposited from a 3 wt% formic acid solution by dip-coating, delivering a corrosion potential shift of +180 mV in 3.5% NaCl per ASTM G59. Regulatory acceptance for these non-food industrial uses relies on REACH Annex XVII restrictions and RoHS 2011/65/EU compliance; no specific FDA clearance is required for building or packaging components that do not contact ingestible substances.

When 1-Pyrrolepropionitrile undergoes Grignard addition with alkylmagnesium halides, the resulting pyrolidine ketones serve as controlled-release precursors for muguet and almond odorants.

Reductive hydrolysis of the nitrile functionality—or, more commonly, direct nucleophilic attack of ethylmagnesium bromide on the electrophilic nitrile carbon in anhydrous tetrahydrofuran at 60–65 °C under nitrogen—produces a 1-pyrrolylpropyl ketone. After quenching with 20 wt% NH₄Cl solution and phase separation, the ketone is reduced with sodium borohydride (0.55 eq) in methanol at 10 °C to afford 1-(3-pyrrol-1-ylpropyl)-1-ethanol, which is subsequently esterified with acetic anhydride in the presence of 0.5 mol% DMAP catalyst (100 °C, 3 h) to yield 1-pyrrolylpropyl acetate. The crude ester is purified by fractional distillation (120 °C at 3 mmHg) to obtain a product with an olfactory detection threshold of 0.8 ng/L in air and a tenacity on blotter exceeding 72 h. The finished fragrance ingredient imparts a soft lily-of-the-valley character with a nutty heliotrope undertone and is commercialized as a proprietary captif to extend the hedonic profile in alkaline household cleaners. In a typical fine fragrance formulation, the compound is dosed at 0.05–0.5% w/w of the perfume concentrate, which corresponds to a final concentration in the consumer product (e.g., an ethanol-based Eau de Toilette, IFRA Category 4) of 0.008–0.08%. The addition ratio in the synthesis is set by the Grignard stoichiometry: 1.0 molar equivalent of 1-pyrrolepropionitrile to 1.25 eq of ethylmagnesium bromide to compensate for moisture and radical coupling by-products. The IFRA Standard for this ester does not impose a quantitative use restriction for category 4 products, but the manufacturer must issue a certificate of analysis demonstrating compliance with the EU Cosmetics Regulation 1223/2009 Annex III reference for leave-on skin products, as well as the IFRA 51st Amendment’s analytical methodology for peroxide values (<10 meq/kg). The fragrance intermediate is also extended to the 2-phenylethyl homologue, which has a broader floral tonality and finds application in fabric softener encapsulates where the surfactant-resistant pyrrole ring enhances deposition efficiency onto cotton substrates during the rinse cycle.

Reductive amination of 1-pyrrolepropionitrile over Raney nickel catalyst in the presence of ammonia and hydrogen at 80 °C and 50 bar pressure yields 1-(3-aminopropyl)pyrrole, a liquid latent accelerator for dicyandiamide-cured epoxy systems. The amine value of the isolated product, determined by perchloric acid titration in glacial acetic acid per ASTM D2074, is 430–450 mg KOH/g, and the Gardner color must remain <4 after 2 h at 180 °C to guarantee thermal latency during storage of a pre-mixed one-component adhesive. The accelerator is compounded into a DGEBA epoxy resin (epoxide equivalent weight 185–192 g/eq) at a level of 2–5 phr together with 8–10 phr micronized dicyandiamide (D90 <10 µm) and 1 phr fumed silica thixotrope. The resulting paste is dispensed through a 30 cc static mixer nozzle; gel time measured on a hot plate at 150 °C is controlled to 180 ± 20 s, a window that permits robotic bead application for automotive body-in-white hem flange bonding while avoiding premature vitrification in the oven. Lap shear strength on 1.6 mm electrogalvanized steel (CRS EG, wiped with methyl ethyl ketone) cures to 22 MPa after 30 min at 175 °C, tested according to ASTM D1002-10 with a crosshead speed of 13 mm/min. The fully cured network displays a glass transition temperature of 135 °C by DSC (second heat, 10 K/min) and a water absorption of 1.1 wt% after 24 h immersion in boiling water. Final products incorporating this accelerator include single-component structural adhesives meeting FMVSS 208 crashworthiness bond requirements, low-outgassing satellite solar panel inserts following ECSS-Q-ST-70-02C (TML <1.0%, RML <0.1%), and powder coatings for rebar intended for concrete embedment in seismic zones, where the amine moiety provides built-in corrosion inhibition. Contact with food is permissible under FDA 21 CFR 175.300 for repeat-use coatings provided the cured film is washed with 5% acetic acid at 66 °C for 2 h and passed through a total non-volatile extractives limit of 0.5 mg/in². The starting 1-pyrrolepropionitrile must be stored away from strong bases and at relative humidity <50% to prevent ring-opening hydrolysis, and batch-to-batch amination efficiency is monitored by tracking the residual nitrile content by FTIR (nitrile stretch at 2249 cm⁻¹) to a threshold of <0.2%.