1-(Phenylmethyl)-2,5-Dihydropyrrole
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HS Code |
609901 |
| Chemical Formula | C11H13N |
| Molecular Weight | 159.23 g/mol |
| Appearance | Solid (usually) |
| Odor | Typical organic compound odor |
| Melting Point | Data may vary, needs specific experimental determination |
| Boiling Point | Data may vary, needs specific experimental determination |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, dichloromethane |
| Density | Data may vary, needs specific experimental determination |
| Flash Point | Data may vary, needs specific experimental determination |
| Stability | Stable under normal conditions if stored properly |
| Hazard Class | May be classified as harmful if ingested, inhaled or in contact with skin (needs further safety assessment) |
As an accredited 1-(Phenylmethyl)-2,5-Dihydropyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 1-(Phenylmethyl)-2,5 - Dihydropyrrole packaged in a sealed, chemical - resistant bottle. |
| Shipping | 1-(Phenylmethyl)-2,5 - Dihydropyrrole is shipped in accordance with strict chemical transport regulations. It's carefully packaged to prevent leakage, transported by approved carriers in suitable containers, ensuring safety during transit. |
| Storage | 1-(Phenylmethyl)-2,5 -Dihydropyrrole should be stored in a cool, dry place away from heat sources and ignition sources. Keep it in a tightly - sealed container to prevent exposure to air and moisture, which could potentially cause decomposition or reaction. Store it separately from oxidizing agents and incompatible substances to avoid hazardous reactions. |
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Proton-catalyzed hydration of the endocyclic double bond in 1-(Phenylmethyl)-2,5-dihydropyrrole proceeds with a precise 1:0.9 molar ratio of substrate to 96 wt% sulfuric acid under a ramped temperature profile of 288–318 K inside a 5‑m³ Hastelloy C‑276 reactor equipped with liquid SO3 dosing for acid activity regeneration, the controlled feed rate of 12 L·h−1 being governed by a Bronkhorst Cori‑Flow mass flow meter to avert exothermic overshoot that would otherwise generate polymeric tars above 323 K. After neutralization with 30% NaOH and extraction with methyl tert‑butyl ether, the organic layer is washed with 5% NaCl to promote phase disengagement, and the intermediate 1‑benzyl‑3‑pyrrolidinone is isolated via fractional distillation at 0.8 kPa (abs) and a head temperature of 105 °C using a Kühni RPB structured‑packed column. All production campaigns destined for registered drug‑substance synthesis adhere to a Master Batch Record aligned with ICH Q7 §7.10 for reaction monitoring; the potential genotoxic impurity benzyl chloride is held below 2.0 ppm in the distilled intermediate as verified by GC‑MS on an Agilent 5977B MSD with a DB‑624UI column (LOD 0.1 ppm), consistent with the EMA/ICH M7 threshold of toxicological concern of 1.5 µg/day. The distilled ketone is telescoped through reductive amination and cyclization to afford (S,S)‑2,8‑diazabicyclo[4.3.0]nonane dihydrochloride, the chiral bicyclic diamine that is coupled into moxifloxacin hydrochloride API meeting current USP monograph specifications. At What Molar Excess Does Reductive Amination Selectivity Collapse During Chiral Pyrrolidine Ligand Assembly?The N‑benzyl protecting group of 1-(Phenylmethyl)-2,5-dihydropyrrole is removed via catalytic transfer hydrogenation employing ammonium formate at 5.0 eq. over 10% Pd/C (Johnson Matthey type 87L, 2.5 wt% dry basis) in methanol at 308 K; exceeding 6.0 eq. of the hydrogen donor triggers over‑reduction of the dihydropyrrole ring to pyrrolidine, causing a 12% drop in enantiomeric excess during the downstream diastereomeric salt resolution, a selectivity collapse quantified by chiral HPLC on a Chiralpak IA column (5 µm, 250 × 4.6 mm) with a hexane‑isopropanol‑diethylamine mobile phase. For kilo‑scale campaigns run under contract, the quality management system conforms to ISO 9001:2015 §8.5.1 for production under controlled conditions, and residual palladium in the isolated chiral ligand is assayed by ICP‑OES per USP 〈232〉/〈233〉, with a release limit of 10 µg/g. A typical batch charges 25.0 kg (157.7 mol) of the dihydropyrrole feedstock with 49.7 kg of ammonium formate; after filtration of the spent catalyst, the crude secondary amine is resolved using (−)‑2,3‑dibenzoyl‑L‑tartaric acid monohydrate (1.2 eq.) in an isopropanol‑water mixture (85:15 v/v) at 283 K. Three recrystallizations are performed in a Rosenmund filter‑dryer, the salt is partitioned between 30% NaOH and tert‑amyl alcohol, and the liberated (R)‑3‑aminopyrrolidine is azeotropically dried before conversion into a bidentate phosphoramidite ligand that subsequently directs a ruthenium‑catalyzed asymmetric hydrogenation step in the synthesis of (S)‑naproxen. When the ring‑opening metathesis copolymerization of 1-(Phenylmethyl)-2,5-dihydropyrrole and cyclooctene is conducted at a monomer feed ratio of 30:70 mol% (confirmed by 1H‑NMR end‑group analysis) with Grubbs second‑generation initiator loaded at 0.02 mol% in dichloromethane, the resulting poly(N‑benzylpyrrolidine‑co‑cyclooctene) reaches a number‑average molecular weight of 58 kg·mol−1 and a dispersity of 1.32 as determined by triple‑detection GPC (Viskotek TDA 305). The benzyl side chains are subsequently cleaved with BBr3 (1.5 eq. per nitrogen) in dry CH2Cl2, and the liberated secondary amine sites are quaternized by reacting the polymer with trimethylamine in methanol at 323 K for 24 h, achieving an ion‑exchange capacity of 1.85 ± 0.03 mmol·g−1. The quaternized material is dissolved in N,N‑dimethylformamide at 18 wt% and cast onto untreated PET release liner using a Mathis LTE‑S laboratory coater with a knife gap of 250 µm, dried in a through‑air oven ramped from 65 °C to 85 °C, and hot‑pressed at 12 MPa to yield a dense membrane. Leachable halide content is monitored by ion chromatography (Dionex ICS‑6000) to meet a specification of 0.5 µg·cm−2, and the component acceptance testing complies with IEC 62282‑3‑201 for alkaline water electrolysis stacks. The finished membrane electrode assembly is integrated into a 2 kW direct borohydride fuel cell stack, where the hydroxide conductivity decay is 4% over 500 h at 60 °C under fully humidified conditions. Photolatent Amine Synergism Without Yellowing: The Role of the Allylic Hydrogen in Overcoming Surface TackReal‑time FTIR (Thermo Fisher Nicolet 8700) curves recorded during 395 nm LED exposure identify a dramatic shortening of the oxygen‑inhibited induction period from 0.8 s to 0.12 s when 3.5 wt% of 1-(Phenylmethyl)-2,5-dihydropyrrole replaces a conventional ethyl‑4‑dimethylaminobenzoate synergist in a cyan flexographic UV ink (viscosity 0.35 Pa·s at 2 s−1), the acceleration being attributed to the compound’s readily abstractable allylic hydrogens. The photoinitiator package consists of 1.2 wt% phenylbis(2,4,6‑trimethylbenzoyl)phosphine oxide (BAPO) and 0.8 wt% isopropylthioxanthone (ITX), and through‑cure of a 20 µm film is completed at a conveyor speed of 80 m·min−1 under a Phoseon FireEdge FE300 array (20 W·cm−2) operated in a nitrogen‑inerted tunnel. Migration assessment adheres to Swiss Ordinance SR 817.023.21 Annex 2 for printed matter intended for indirect food contact: total specific migration into simulant D1 (ethanol 50% v/v) after 10 days at 40 °C (OM3 condition) is quantified by GC‑MS, and N‑benzyl fragment residues are held below 10 ppb, while overall migration remains under 10 mg·dm−2 as verified by EN 1186‑3. The resulting overprint varnishes and CMYK process ink sets are certified for application on the exteriors of polypropylene dairy cups and aluminum beverage cans. Radical grafting of a 1-(Phenylmethyl)-2,5-dihydropyrrole‑derived selector onto vinyl‑functionalized silica (Purospher STAR RP‑18 endcapped base, 5 µm, 120 Å) is initiated with azobisisobutyronitrile at 1.2 mol% relative to the selector in dry toluene under reflux (383 K, 12 h), affording a surface coverage of 0.9 ± 0.05 µmol·m−2 as determined by CHN microanalysis. The stationary phase is slurry‑packed into 250 × 4.6 mm i.d. stainless‑steel columns using a Haskel BPV‑21 pneumatic amplifier pump at a constant pressure of 62 MPa (dioxane‑ethanol 50:50 v/v slurry medium), and the packed bed is consolidated under mobile‑phase flow at 1.0 mL·min−1 for 12 h before end‑capping with hexamethyldisilazane vapor. System suitability testing is performed according to USP 〈621〉 with a test mixture of flurbiprofen and ibuprofen in acetonitrile‑20 mM phosphate buffer pH 3.0 (30:70 v/v); the specification requires a resolution factor Rs >2.0 and a tailing factor <1.5 for the critical pair, and the column is released with a CoA that certifies enantiomeric purity testing capability for generic NSAID active substances such as ketoprofen and flurbiprofen. When 1-(Phenylmethyl)-2,5-Dihydropyrrole Replaces N‑Methylpyrrolidine in Agrochemical Scorpionate Complex SynthesisA copper‑free Huisgen cycloaddition between the dihydropyrrole (1.0 eq.) and a propargyl‑functionalized triazole (1.05 eq.) is conducted in a Corning Advanced‑Flow G1 SiC microreactor with a 4 mL internal volume and a residence time of 45 s at 298 K; the high surface‑to‑volume ratio of the SiC plates dissipates the exothermic heat of cyclization without external cooling, while the slight alkyne excess drives conversion above 99.5% and residual alkyne is scavenged with a polystyrene‑supported azide resin to avoid copper contamination that would conflict with ecotoxicological profiles required under OECD Series on Principles of Good Laboratory Practice No. 1. The resulting pyrrolidine‑triazole scaffold serves as a developmental CYP51 inhibitor active ingredient; its technical material is analyzed by CIPAC MT 184 (suspensibility) and MT 185 (wet sieve residue) before formulation into an emulsifiable concentrate containing 100 g·L−1 a.i., a nonionic tristyrylphenol ethoxylate blend, and a naphthalene sulfonate formaldehyde condensate dispersant. The batch formulation is tested under FAO Specification 582/TC protocol and holds a suspensibility value of 95% after 30 min in standard hard water. Field trials have targeted Cercospora beticola in sugar beet, with efficacy equivalent to a commercial demethylation inhibitor reference and no cross‑resistance observed in strains carrying CYP51 mutations. |
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The heterocyclic scaffold 1-(Phenylmethyl)-2,5-dihydropyrrole—systematically named 1-benzyl-2,5-dihydro-1H-pyrrole, CAS RN 6279-20-3—represents a partially saturated pyrrole ring carrying an N-benzyl protecting group. Its molecular formula C11H13N (molecular weight 159.23 g·mol−1) incorporates a single endocyclic double bond between the 3 and 4 positions, creating an allylic amine motif. The product is supplied as a colorless to pale-yellow liquid with a characteristic amine odor. Bulk quantities are packaged under argon in septum-sealed borosilicate glass bottles ranging from 25 g to 1 kg. Typical lot analysis reports a gas chromatographic purity of ≥97.0 area% (DB‑5 column, 30 m × 0.25 mm i.d., 0.25 µm film, per ASTM D6729‑01) and a water content ≤ 0.5 wt% determined by coulometric Karl Fischer titration in accordance with ASTM E1064‑18. The refractive index nD20 falls within 1.5370–1.5410 (ASTM D1218‑21) and the density at 20°C is typically 1.010–1.025 g·cm−3 (ASTM D4052‑18). These specifications differentiate it from the fully aromatic N-benzylpyrrole (nD20 ≈ 1.571) and from the fully saturated N-benzylpyrrolidine (nD20 ≈ 1.524), providing a rapid optical check for structural integrity prior to use.
When 1-(phenylmethyl)-2,5-dihydropyrrole is employed as a diene in thermally activated [4+2] cycloadditions, the electron-rich enamine moiety enforces a strongly ortho/para-directing character that dictates both the regiochemistry and the endo/exo ratio of the bicyclic lactam adducts. In a characteristic procedure executed in a 2 L jacketed glass reactor with nitrogen overlay, 1.0 mol of the dihydropyrrole is combined with 1.05 eq of maleic anhydride in anhydrous toluene (0.5 M). After a 12‑hour hold at 80°C, the precipitated cycloadduct is isolated by filtration, washed with cold n‑heptane, and dried under reduced pressure to yield a white crystalline solid in 82–88% recovery. The reaction exhibits a sharp temperature threshold: below 70°C the conversion stalls at ≤25% after 24 h, while exceeding 95°C promotes formation of a brown polymeric side product that reduces isolated purity to <90% by HPLC. This narrow processing window—±5°C around the optimum—requires precise cascade control of the jacket temperature; production-scale campaigns routinely employ a Huber Unistat 540w circulation thermostat with 0.1°C resolution. The endo/exo ratio, measured at 94:6 by 1H NMR integration of the bridgehead protons, is consistent with secondary orbital overlap between the carbonyl groups and the benzyl π‑cloud, a feature absent when the N‑substituent is methyl or ethyl. Density functional theory calculations at the B3LYP/6‑31G* level (literature data) place the activation barrier for the endo pathway at approximately 22 kcal·mol−1, roughly 3 kcal·mol−1 lower than the exo transition state, corroborating the kinetic dominance observed at a 1 L pilot scale. Hydrogenolytic debenzylation of the adduct over 5% Pd/C (Type 487, 50 wt% water wet) in methanol at 50 psi H2 and 25°C cleanly removes the benzyl group within 6 h without reducing the bridged olefin; monitoring by TLC (silica gel 60 F254, ethyl acetate/hexane 1:1) is mandatory to terminate the reaction before over-reduction begins.
Each production batch of 1-(phenylmethyl)-2,5-dihydropyrrole undergoes a standardized analytical release protocol. In addition to the GC-FID purity assay, the certificate of analysis reports single-impurity thresholds: the primary process-related impurity, 1‑benzylpyrrole arising from adventitious oxidation, is limited to <1.5 area%, while 1-benzylpyrrolidine, derived from over‑hydrogenation during feedstock preparation, is held below <0.5 area%. Trace benzyl chloride, a potential genotoxic impurity, is quantified by GC‑ECD with a reporting limit of 10 ppm and a specification of <50 ppm. The analytical methods are validated per ICH Q2(R1) guidelines, and system suitability is verified daily using a working standard of known purity. The following table summarizes the commercial release limits and test methodology.
| Parameter | Method | Limit |
|---|---|---|
| Assay (GC-FID) | ASTM D6729‑01, DB‑5 column | ≥97.0 area% |
| Water content | ASTM E1064‑18 (coulometric KF) | ≤0.5 wt% |
| Refractive index nD20 | ASTM D1218‑21 | 1.5370–1.5410 |
| Density (20°C) | ASTM D4052‑18 | 1.010–1.025 g·cm−3 |
| Boiling range (15 mmHg) | ASTM D86‑23a (reduced pressure) | 102–106°C |
| 1-Benzylpyrrole impurity | In-house HPLC-MS | <1.5 area% |
| Benzyl chloride | GC-ECD, validated per ICH Q2(R1) | <50 ppm |
Production campaigns exceeding 50 kg typically exhibit batch-to-batch assay variability below 0.8% (relative standard deviation of five consecutive batches), a consistency attributed to continuous distillation of the crude product over a 20-plate Oldershaw column operated at a reflux ratio of 8:1. Material retained in the overhead cut is recycled into the next fractionation, minimizing yield loss.
In the synthesis of enantiomerically pure 3,4-disubstituted pyrrolidine building blocks, the N‑benzyl group on the 2,5-dihydropyrrole framework serves both as an amine protecting group and as a steric director for asymmetric functionalization of the endocyclic double bond. Subjecting the olefin to Sharpless asymmetric dihydroxylation (AD‑mix‑β, 1.4 wt% OsO4 equivalent, methanesulfonamide 1 eq, in t‑BuOH/H2O 1:1 at 0°C to 25°C over 48 h) consistently furnishes the corresponding (3S,4S)-diol with enantiomeric excess exceeding 95% as determined by chiral HPLC on a Chiralpak AD‑H column. This transformation has been executed at a 5 kg input scale in a 100 L glass-lined reactor with turbulent agitation without erosion of stereoselectivity. The diol crystallizes directly from the reaction mixture upon solvent swap to isopropyl acetate, allowing isolation by centrifugation and obviating the need for chromatographic purification. Similarly, catalytic asymmetric epoxidation with a fructose‑derived ketone (Shi catalyst, 0.2 eq) and Oxone® (5 eq) in buffered acetonitrile‑water at pH 10.5 yields the epoxide in 72% isolated yield and 90% ee; the epoxide ring is then opened regioselectively with sodium azide to install the 3‑azido-4‑hydroxy motif found in glycosidase inhibitor leads. The benzyl protecting group remains intact throughout these sequences and is removed later by transfer hydrogenation with ammonium formate and Pd/C in refluxing methanol, a method that selectively avoids double‑bond hydrogenation when the pressure is kept at atmospheric levels. Published data for this specific configuration of the azido alcohol intermediate is limited, but internal qualification runs with a twin-screw reactor for the epoxidation step encountered a 15% reduction in ee when the screw speed exceeded 200 rpm, likely due to shear-induced phase separation of the aqueous oxidant.
The selection of 1-(phenylmethyl)-2,5-dihydropyrrole over its saturated (pyrrolidine) or aromatic (pyrrole) counterparts is determined by the need for both a latent secondary amine and an isolable, functionalizable alkene. Key physical and chemical distinctions are summarized in Table 2. The partially unsaturated ring carries sufficient electron density to engage in electrophilic additions and cycloadditions, yet without the aromatic stabilization that renders N‑benzylpyrrole inert toward dienophiles under thermal conditions. Conversely, the presence of the double bond introduces a sensitivity toward autoxidation that is absent in N‑benzylpyrrolidine; headspace‑free storage under nitrogen and inclusion of a hindered phenol antioxidant (BHT at 50–100 ppm) are mandatory to prevent propagation of radical chain processes.
| Property | N‑Benzyl‑2,5‑dihydropyrrole | N‑Benzylpyrrole | N‑Benzylpyrrolidine |
|---|---|---|---|
| Ring unsaturation | One C=C (allylic amine) | Aromatic (6π electrons) | None (fully saturated) |
| Boiling range (15 mmHg) | 102–106°C | 110–114°C | 95–98°C |
| Refractive index nD20 | 1.5370–1.5410 | 1.569–1.573 | 1.522–1.526 |
| Reactivity toward maleic anhydride (toluene, 80°C) | Cycloaddition, 85% isolated yield | No reaction | No reaction (amine-acid complex forms) |
| Oxidative stability (air, 25°C) | N‑oxide detectable at 14 days by HPLC | Stable beyond 90 days | Stable beyond 90 days |
| Typical purity specification | ≥97 area% (GC) | ≥98 area% (GC) | ≥98 area% (GC) |
| Key application | Asymmetric dihydroxylation, Diels‑Alder | N‑benzyl precursor for pyrrole C‑H activation | Phase‑transfer catalyst precursors, nucleophilic base |
Ring strain in the 2,5-dihydropyrrole skeleton, estimated by thermochemical calculations at approximately 8 kcal·mol−1 higher than the pyrrolidine ring, accelerates nucleophilic ring‑opening when the nitrogen lone pair is deprotected. This feature is exploited in oligonucleotide conjugation chemistry, where the benzyl group is removed and the resultant 3‑pyrroline is alkylated to generate a cleavable linker. In contrast, N‑benzylpyrrolidine lacks a vicinal alkene and cannot participate in such auxochrome‑driven conjugation.
Extended storage trials under nitrogen headspace in amber glass at 2–8°C indicate that assay loss is limited to <0.3 area% per month over a 12-month period. Exposure to relative humidity above 60% during aliquot withdrawal must be minimized because the hygroscopic amine absorbs water, which subsequently catalyzes ring‑opening with liberation of benzylamine; this degradation pathway is detectable by a drop in refractive index of more than 0.002 units. Re‑qualification by GC and Karl Fischer analysis is therefore advised after any opening event prior to use in moisture‑sensitive transformations.
