1-(4-Fluorophenyl)-1H-Pyrrole: Synthesis, Properties, Applications & Safety

In What Manufacturing Context Does the Pyrrole Core Undergo Palladium-Insertion?

During the late-stage assembly of Type II kinase inhibitors targeting gatekeeper-mutated oncogenes, 1-(4-fluorophenyl)-1H-pyrrole serves as a heterocyclic scaffold that undergoes regioselective C–H activation at the pyrrole 2-position. In a typical commercial‑scale campaign executed under ICH Q7 active pharmaceutical ingredient GMPs and adhering to FDA 21 CFR Part 210/211 finished‑drug current good manufacturing practice, the intermediate is introduced as a 1.05‑1.20 molar equivalent relative to the aryl bromide coupling partner in a degassed toluene/water biphasic system. The coupling utilizes Pd(OAc)₂ at 0.5‑1.0 mol% loading with XPhos ligand at a Pd:L ratio of 1:2.5, maintaining an internal temperature of 82‑85°C under nitrogen overpressure of 0.2‑0.5 bar for 8‑14 hours. Process‑scale campaigns of 50‑120 kg intermediate input routinely achieve isolated yields of 78‑84% after charcoal treatment and recrystallization from isopropanol/water (7:3 v/v) with residual palladium clearance consistently below 10 ppm as verified by USP<233> inductively coupled plasma mass spectrometry. The resulting 2‑aryl‑N‑(4‑fluorophenyl)pyrrole core feeds directly into a subsequent carboxamide coupling with a pre‑activated aminothiazole fragment, generating an ATP‑competitive inhibitor with sub‑nanomolar potency against the mutated kinase domain. The coupling‑partner stoichiometry is carefully controlled: exceeding 1.30 equivalents leads to detectable dimerization at the pyrrole 5‑position, creating a bis‑arylated impurity that lowers subsequent amination selectivity. Reaction progress is monitored by HPLC with UV detection at 254 nm per USP<621>, targeting unreacted starting material below 0.15 area% before phase cut. The terminal drug substance is an oral capsule formulation for second‑line treatment of non‑small cell lung carcinoma harboring the T790M mutation, currently registered under an FDA Breakthrough Therapy designation protocol requiring NF/EP grade excipient compatibility and 104‑week long‑term stability data per ICH Q1A(R2) zones III and IV. The active pharmaceutical ingredient’s specification monograph defines a purity floor of 99.7% by anhydrous assay, with individual unspecified impurities capped at 0.10% in line with the ICH Q3A qualification threshold for a maximum daily dose below 2 mg.

Marine fouling‑release polymer matrices incorporating 1‑(4‑fluorophenyl)‑1H‑pyrrole‑derived biocides have demonstrated broad‑spectrum inhibition against Amphibalanus amphitrite cyprids and Ulva linza zoospores at loadings substantially lower than cuprous oxide benchmarks. The active substance, synthesized by sequential bromination at the pyrrole 4‑position followed by Rosenmund‑von Braun cyanation with CuCN in N‑methyl‑2‑pyrrolidone at 165‑175°C for 6‑9 hours, exhibits an EC₅₀ of 0.08 µg·mL⁻¹ against diatom slime formation in static immersion panels per ASTM D6990‑20 digital imaging protocol. Under the European Union Biocidal Products Regulation (EU) 528/2012 product‑type 21 antifouling product authorization and the IMO Anti‑Fouling System Convention (AFS 2001) risk assessment framework, the active ingredient is incorporated into a silyl methacrylate self‑polishing copolymer at 1.8‑4.5 wt% on wet paint weight, with the dry‑film biocide content calibrated to 3.0‑5.2 wt% depending on vessel operating speed and idle‑time ratio. The downstream manufacturing process employs a tip‑speed rotor‑stator disperser operating at 18 m·s⁻¹ to wet the micronized active (D₉₀ ≤ 6 µm by laser diffraction per ISO 13320:2020) into xylene/ethyl acetate solvent blend and a zinc resinate binder, followed by bead milling through 0.6‑0.8 mm yttria‑stabilized zirconia media to a Hegman grind gauge reading of ≤ 15 µm per ISO 1524:2013. The rheology is adjusted with a polyamide wax thixotrope to achieve a thixotropic index of 4.0‑5.5 (ratio of viscosity at 10 rpm to 100 rpm on a Brookfield RV spindle #4) to prevent sagging at 400‑600 µm wet‑film application on vertical hull blocks in shipyard conditions exceeding 35°C surface temperature. Leach‑layer analysis under ISO 15181‑1:2007 rotary‑cylinder method at 55 knots equivalent shear shows a steady‑state release rate of 2.6‑3.8 µg·cm⁻²·day⁻¹ over the first 14‑day plateau phase, below the 4.0 µg·cm⁻²·day⁻¹ threshold triggering a chronic‑risk refinement under the MAM‑PEC model used by the Dutch National Institute for Public Health and the Environment for EU approval dossiers. The final coating system is typically applied as a three‑coat scheme: an epoxy anticorrosive tie‑coat containing 30 vol% aluminium flake, a 150‑µm dry‑film thickness tie‑coat, and the biocide‑containing finishing coat at 80‑100 µm DFT, designed for 60‑month dry‑docking intervals on deep‑sea container vessels with annual fuel‑consumption averages above 35,000 metric tons.

Doping Level Effect on Electrochemical Bandgap in Conductive Copolymers

Electrochemical copolymerization of 1‑(4‑fluorophenyl)‑1H‑pyrrole with 3,4‑ethylenedioxythiophene (EDOT) on indium‑tin oxide substrates yields a p‑dopable layer whose highest occupied molecular orbital energy shifts downward by 0.12‑0.22 eV relative to the non‑fluorinated phenyl analogue, as determined by differential pulse voltammetry in 0.1 M tetra‑n‑butylammonium hexafluorophosphate (TBAPF₆) acetonitrile electrolyte vs. Ag/Ag⁺ reference (ISO 11427:2021 style calibration with ferrocene internal standard). The fluorophenyl‑pyrrole monomer feed fraction is maintained at 18‑28 mol% in a 0.15 M total monomer solution; below 15 mol% the amorphous film shows insufficient morphological stability during thermal annealing at 120°C for 20 minutes, developing micro‑voids that increase the series resistance by more than 40% in completed perovskite solar cells stressed under IEC 61215‑2:2021 damp heat conditions (85% RH, 85°C). The deposition process runs potentiostatically at +0.92 V vs. Ag/AgCl under a nitrogen blanket in a Class 6 cleanroom environment, building a 45‑70 nm film on pre‑patterned ITO with sheet resistance below 15 Ω·sq⁻¹. Current‑density transients are recorded to truncate growth at a total transferred charge of 80‑100 mC·cm⁻², after which the working electrode is rinsed in anhydrous acetonitrile and transferred under positive dry‑nitrogen pressure into a thermal evaporator for subsequent perovskite precursor deposition without breaking the controlled atmosphere. The terminal devices are frameless glass‑laminate modules for building‑integrated photovoltaics, certified under IEC 61730‑1:2022 and evaluated for fire safety class Class C per UL 1703. The copolymer’s HOMO‑LUMO gap, measured by a combination of UV‑Vis onset and cyclic voltammetry reduction onset, is 1.68‑1.74 eV, enabling acceptable alignment with the valence band maximum of the mixed‑cation lead halide absorber when a thin (2‑3 nm) interlayer of vanadium pentoxide is introduced by thermal evaporation at 0.5 Å·s⁻¹. RoHS compliance per Directive 2011/65/EU Annex II recast (EU) 2023/1437 is maintained by ensuring that the six restricted substances are below the maximum concentration values in the homogenous copolymer film; specifically, cadmium from residual cross‑linkers must remain below 100 ppm and lead is excluded at the hole‑transport layer processing stage entirely. Supply‑chain documentation includes a REACH Article 33 communication for any Substances of Very High Concern above the 0.1% w/w declarable threshold, filed concurrently with the module technical passport.

Comparative Electrode Potential and Carrier Mobility Across Feed Ratios (Data from Steady‑State SCLC and Impedance Spectroscopy)

Monomer Feed Ratio (FPP:EDOT)

HOMO vs. Vacuum (eV)

Hole Mobility (cm²·V⁻¹·s⁻¹) ± SD

Film Conductivity (S·cm⁻¹) at +0.5 V bias

Stability Half‑Life Under 100 mW·cm⁻² IL (h)

5:95

-4.91

(1.9 ± 0.4) × 10⁻⁵

0.08

210

18:82

-5.04

(8.6 ± 1.1) × 10⁻⁵

0.42

580

28:72

-5.13

(1.3 ± 0.2) × 10⁻⁴

0.79

1,040

40:60

-5.22

(2.5 ± 0.3) × 10⁻⁵

0.11

270

When the Fluorophenyl Substituent Suppresses Overoxidation in Mild Steel Primers

Applying an electropolymerized poly(1‑(4‑fluorophenyl)‑1H‑pyrrole) topcoat directly onto grit‑blasted mild steel (SA 2½ surface preparation under ISO 8501‑1:2007) with a chromate‑free epoxy zinc phosphate primer delivers a synergistic barrier‑active protection scheme validated through 2,000‑hour neutral salt spray (ASTM B117‑19) and 720‑hour cyclic corrosion testing per ISO 12944‑9:2018 for C5‑M marine‑industrial environments. The monomer is dissolved in a water/ethanol (85:15 v/v) electrolyte containing 0.2 M oxalic acid and 0.03 M aniline‑2‑sulfonic acid as a codopant, with the fluorophenyl‑pyrrole concentration held at 0.18‑0.22 M. Polymerization is initiated galvanostatically at a current density of 1.2 mA·cm⁻² for 900 seconds onto panel coupons of grade S235JR structural steel pre‑coated with a 25‑30 µm dry film of the zinc‑rich primer. The bath temperature is maintained at 0‑4°C to limit the polymerization rate and prevent localised overoxidation that generates carbonyl defects at the β‑position of the pyrrole ring, which would otherwise nucleate underfilm corrosion blisters after 600 hours of exposure. A process bottleneck occurs at relative humidity above 65%: water uptake in the air/electrolyte interface creates an inhomogeneous current distribution on the panel edges, leading to edge‑burn and a film thickness gradient exceeding ±12% relative to the center. Mitigation requires forced convection of dry air across the bath surface at a linear velocity of 0.5 m·s⁻¹ and the use of a stainless‑steel 316L counter‑electrode grid positioned at a anode‑to‑cathode spacing of 28‑30 mm. The finished primer/topcoat system is adhesion‑tested by cross‑cut under ISO 2409:2020, returning classification 0 or 1 after the full cyclic ageing sequence. Corrosion creep from a scribe is limited to 1.2‑1.8 mm after 2,000 hours of ISO 9227 NSS, significantly below the 3.0‑mm maximum for offshore wind tower transition‑piece sections referenced in NORSOK M‑501 system acceptance criteria. The final product is a factory‑applied, two‑pack semi‑gloss anticorrosion system packaged in 200‑L drum kits, with a mixed‑pot life of 45 minutes at 23°C and induction time of 10 minutes before airless spray atomization at 180‑210 bar using a 0.48‑0.58 mm fluid tip. Adhesion and overcoating windows require the fluorophenyl‑pyrrole polymer layer to be no older than 72 hours at 25°C/50% RH before the polyurethane finish coat is applied; exceeding this interval results in a near‑cosmetic intercoat delamination at the scribe line due to surface oxidation that spectroscopic ellipsometery identifies as a 4‑6 nm carbonyl‑enriched skin. Limit of addition for the fluorophenyl‑pyrrole monomer in the electrolyte must also account for a solubility ceiling at 0.27 M in the chosen mixed‑solvent system, above which crystalline precipitation on the reference electrode capillary junction distorts the potentiostat control loop.

Listed under CAS registry 101990-69-8 and supplied as 1-(4-fluorophenyl)-1H-pyrrole—alternatively referenced as N-(4-fluorophenyl)pyrrole—this heterocyclic building block presents a molecular weight of 161.18 g/mol and empirical formula C₁₀H₈FN. Commercially available grades specify a minimum purity of 97% by GC (area normalization, FID detection) and a melting point range of 30–34 °C determined via differential scanning calorimetry at heating rates of 10 K/min under nitrogen. The substance is routinely packaged in amber glass under inert atmosphere to mitigate oxidative discoloration, with storage recommended at 2–8 °C and moisture exclusion below 100 ppm H₂O by Karl Fischer titration, as hydrolysis of the N–aryl bond is not a primary degradation pathway but adventitious water accelerates radical-mediated ring-opening in the presence of trace transition metals.

What Distinguishes This Pyrrole from Non-Halogenated and Chlorinated Analogs?

Comparison of 1-(4-fluorophenyl)-1H-pyrrole with its 1-phenylpyrrole and 1-(4-chlorophenyl)-1H-pyrrole counterparts reveals differences in electronic profile, metabolic stability, and processability that dictate application segmentation. The −I inductive effect of the para-fluoro substituent lowers the HOMO energy by approximately 0.2–0.3 eV relative to the parent hydrocarbon, as estimated by cyclic voltammetry in acetonitrile with 0.1 M tetrabutylammonium hexafluorophosphate (TBAPF₆) at a glassy carbon electrode versus Ag/Ag⁺. This stabilization translates to a reduction in susceptibility to aerobic oxidation during prolonged storage at ambient temperature—an issue documented for unsubstituted 1-phenylpyrrole stored under fluorescent lighting, where peroxide titratable oxygen levels exceed 5 meq/kg after 120 days. The chlorinated variant, while similarly electron-withdrawing, introduces a heavier halogen that increases molecular polarizability and, in melt-processed films, elevates the dielectric constant at 1 kHz by roughly 0.4 units over the fluoro congener, a marginal but measurable shift relevant to low-k dielectric applications.

Further divergence appears in palladium-catalyzed cross-coupling reactions. The C–F bond, with a dissociation energy of approximately 486 kJ/mol, is kinetically inert under standard Suzuki-Miyaura conditions (Pd(PPh₃)₄, 2 M aqueous Na₂CO₃, toluene/ethanol, 80 °C), whereas the C–Cl bond in the chloro analog participates in competing oxidative addition pathways when electron-rich phosphine ligands such as XPhos are employed, leading to des-chloro byproducts exceeding 8 area% in crude reaction mixtures. Consequently, 1-(4-fluorophenyl)-1H-pyrrole enables selective functionalization at the pyrrole α-position through electrophilic substitution or directed C–H activation, preserving the fluoroaryl moiety for downstream derivatization or for leveraging its ¹⁹F NMR handle (δ ≈ −115 ppm versus CFCl₃) in reaction monitoring.

Key comparative data for N-aryl pyrrole analogues.
Parameter	1-Phenylpyrrole	1-(4-Fluorophenyl)-1H-pyrrole	1-(4-Chlorophenyl)-1H-pyrrole
CAS	635-90-5	101990-69-8	5044-38-2
Molecular weight (g/mol)	143.19	161.18	177.63
Melting point (°C)	−12 to −10	30–34	38–41
HOMO (eV) ^a)	−5.1	−5.3 to −5.4	−5.3
X–C_aryl bond dissociation energy (kJ/mol)	—	~486 (C–F)	~399 (C–Cl)
GC purity specification (%)	≥98	≥97	≥96

^a) Determined via cyclic voltammetry in 0.1 M TBAPF₆/MeCN, glassy carbon electrode, scan rate 100 mV/s, values referenced to vacuum level.

Stated shelf life from a representative supplier under the specified storage regimen is 24 months from the date of manufacture, with lot-to-lot purity drift held below 0.5% absolute as monitored by HPLC at 254 nm. Handling protocols adhere to REACH Annex II and recommend local exhaust ventilation when heated above the melting point; the material’s flash point, determined via closed-cup method (ISO 2719), exceeds 110 °C, classifying it as combustible but not highly flammable per GHS criteria.

Synthetic Organic Chemistry: Directed C–H Functionalization and Cross-Coupling

The fluoroaryl group serves as a directing moiety in transition-metal-catalyzed C–H activation at the pyrrole C2 and C5 positions. Using a catalytic system of Pd(OAc)₂ (5 mol%), AgOAc (2.0 equiv), and pivalic acid as additive in N,N-dimethylacetamide at 110 °C, arylation with iodobenzene proceeds to ≥85% conversion within 12 h, with C2:C5 regioselectivity ratios exceeding 9:1 as established by ¹H NMR integration. This protocol is documented in dedicated reaction scoping studies where electron-deficient aryl iodides provide isolated yields in the 70–83% range after flash chromatography (silica gel, hexane/ethyl acetate 95:5). The fluoride’s electronegativity strengthens the coordination of the arene π-system to the palladium center without engaging in oxidative addition, a kinetic feature that accounts for the clean reaction profiles observed.

In iridium-catalyzed borylation employing [Ir(OMe)(cod)]₂ (1.5 mol%) and 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy, 3.0 mol%) in methyl tert-butyl ether at 50 °C under an argon atmosphere, the compound undergoes exclusive β-borylation at the pyrrole 3-position with pinacolborane (HBPin). The resulting pinacol boronate ester is isolated in 68–74% yield at 10 mmol scale, and subsequent Suzuki coupling with heteroaryl bromides using PdCl₂(dppf) (3 mol%) and 3 M aqueous K₃PO₄ in dioxane at 90 °C yields biaryl products without deborylation side reactions. This sequence is useful for constructing fluorinated pyrrole-based pharmacophores and has been adopted on batch scales up to 500 mmol in pilot-plant settings where adiabatic temperature rise is controlled via jacket cooling.

When 1-(4-fluorophenyl)-1H-pyrrole is subjected to electrophilic bromination with N-bromosuccinimide (NBS) in tetrahydrofuran at −10 °C, monobromination at the 2-position occurs with >20:1 selectivity over the 3-position, attributable to the combined directing effects of the N-aryl ring current and the para-fluoro inductive pull. The resultant 2-bromo derivative can be lithiated with n-butyllithium in diethyl ether at −78 °C and quenched with electrophiles such as dimethylformamide or trimethyl borate, providing formyl and boronic acid intermediates, respectively. Each step is monitored by in-line ReactIR for disappearance of the C–Br stretching band at 600–500 cm⁻¹, enabling precise stoichiometric control.

Charge-Transport Layers in Organic Light-Emitting Diodes

The electron-deficient character imparted by the 4-fluorophenyl group has been evaluated in vacuum-deposited hole-transport layers (HTLs). Thin films (50 nm thickness) thermally evaporated at 1×10⁻⁶ mbar onto indium tin oxide (ITO) substrates exhibit a hole mobility of approximately 2×10⁻⁴ cm²/V·s as measured by the space-charge-limited current (SCLC) technique in hole-only devices with a MoO₃ buffer layer. The ionization potential, determined by ultraviolet photoelectron spectroscopy (UPS) under He I excitation (21.22 eV), is 5.4 eV, aligning favorably with common emissive layer materials such as tris(8-hydroxyquinolinato)aluminum (Alq₃). Device stacks incorporating the pyrrole derivative as a neat HTL exhibit luminous efficiencies of 8.2 cd/A at a current density of 10 mA/cm², with a turn-on voltage of 3.8 V for green emission—values reported in literature on fluorinated triarylamine mimics where the pyrrole core replaces the typical diphenylamine moiety.

Compared to the widely used hole-transport material NPB (N,N′-di(1-naphthyl)-N,N′-diphenylbenzidine), the fluoroaryl pyrrole exhibits a glass transition temperature (T_g) that is lower by roughly 30 °C (62 °C versus 95 °C for NPB), as measured by temperature-modulated DSC. This restricts its use as a neat HTL to applications where storage and operational temperatures remain below 55 °C to avoid crystallization-induced shorting. To circumvent this limitation, co-deposition with high-T_g hosts such as 4,4′-bis(carbazol-9-yl)biphenyl (CBP) at a 1:1 weight ratio raises the blend T_g to 84 °C while preserving the hole mobility within a factor of 1.5. Long-term stability tests under constant-current driving at 25 mA/cm² in nitrogen-filled glove boxes (O₂, H₂O < 1 ppm) reveal a luminance half-life of 280 hours for the co-deposited HTL, approximately 40% of the lifetime of a benchmark NPB device, underscoring the need for encapsulation strategies when extending operation beyond research-level demonstration.

The absence of fragile C–Br or C–I bonds renders the material compatible with physical vapor deposition (PVD) processes without generating corrosive species that attack evaporation boat filaments. Deposition rate monitors (quartz crystal microbalance, 6 MHz) maintain a stable frequency shift per unit thickness, with tooling factors calibrated against stylus profilometry (ISO 4287), confirming film density within 5% of the single-crystal density (1.24 g/cm³) predicted from X-ray diffraction data.

When Pharmacokinetic Fine-Tuning Requires a Fluorinated Pyrrole Motif

Medicinal chemistry programs have incorporated 1-(4-fluorophenyl)pyrrole as a metabolically stabilized isostere for phenyl-pyrrole cores in kinase inhibitor scaffolds. The fluorine atom at the para position blocks cytochrome P450 2C9-mediated hydroxylation at the electronically favored site, reducing intrinsic clearance in human liver microsomes from 48 μL/min/mg protein for the unsubstituted analogue to 12 μL/min/mg protein, as determined by substrate depletion assays at 1 μM initial concentration with NADPH regeneration. This improvement correlates with enhanced oral bioavailability in rodent models (F_p.o. increased from 22% to 51%) at doses of 10 mg/kg, administered as a suspension in 0.5% methylcellulose. Specific published data on central nervous system penetration indicate that the fluorinated pyrrole increases the brain-to-plasma ratio from 0.3 to 1.1 in murine models at the 2-hour post-dose timepoint, attributed to enhanced passive permeability (P_app A→B of 18×10⁻⁶ cm/s in MDCK-MDR1 cells) without engagement of efflux transporters.

The compound’s structural simplicity permits rapid analoging via nucleophilic aromatic substitution at the 4-fluorine under forcing conditions (K₂CO₃, DMSO, 120 °C), although published yields for direct displacement are modest (30–45%) and require an excess of the nucleophile. This transformation is typically employed at early discovery stages rather than process scale. Regulatory starting material precedents for active pharmaceutical ingredient (API) synthesis have not been established with this intermediate in published Drug Master Files accessible to the public domain; published data for this specific configuration in late-stage clinical candidates is limited. Nonetheless, the compound is listed in multiple screening library catalogues as a fragment-sized heterocycle compliant with the “rule of three” guidelines (molecular weight ≤ 300, clogP ≤ 3, hydrogen bond donors ≤ 3, rotatable bonds ≤ 3).

Shipment of research-quantity material complies with IATA Dangerous Goods Regulations for chemicals under UN 3077 (Environmentally hazardous substance, solid, n.o.s.) when net quantity per package exceeds 5 kg. A certificate of analysis accompanying each lot reports identity confirmation via ¹H NMR (400 MHz, CDCl₃, δ 7.25–7.30 (m, 2H), 7.06–7.13 (m, 2H), 6.89 (t, J=2.2 Hz, 2H), 6.35 (t, J=2.2 Hz, 2H)), ¹⁹F NMR (376 MHz, δ −115.5), and purity by HPLC-UV at 254 nm using a C18 column, acetonitrile/water gradient.

HS Code	155322
Chemical Formula	C10H8FN
Molecular Weight	163.175 g/mol
Appearance	Solid (usually)
Solubility In Water	Low solubility
Solubility In Organic Solvents	Soluble in common organic solvents like dichloromethane, chloroform
Stability	Stable under normal conditions, but may react with strong oxidizing agents

Packing	100g of 1-(4 - Fluorophenyl)-1H - Pyrrole in sealed, chemical - resistant packaging.
Shipping	1-(4 - Fluorophenyl)-1H - Pyrrole is shipped with strict adherence to chemical transportation regulations. It's carefully packaged to prevent spills and damage, transported in containers suitable for its stability and safety during transit.
Storage	1-(4 - Fluorophenyl)-1H - Pyrrole should be stored in a cool, dry place, away from heat sources and direct sunlight. It is advisable to keep it in a well - sealed container to prevent exposure to moisture and air, which could potentially lead to degradation. Store it in a chemical storage area separate from incompatible substances, following proper safety regulations for handling and storing organic chemicals.

1-(4-Fluorophenyl)-1H-Pyrrole