2-Chloro-5-(2-Fluorophenyl)-1H-Pyrrole-3-Carbonitrile

Comparative Suzuki−Miyaura Coupling Performance in the Biaryl Synthesis

Catalyst System

Temperature (°C)

Time (h)

Isolated Yield (%)

HPLC Purity (A%)

Pd(PPh₃)₄ (5 mol%)

97.2

Pd(dppf)Cl₂·CH₂Cl₂ (3 mol%)

98.5

Pd₂(dba)₃/XPhos (2/4 mol%)

99.1

What Structural Overlap with Chlorfenapyr Dictates Acaricidal Contact Toxicity?

The nitrile-bearing pyrrole skeleton is advanced to contact acaricides by sequential N-alkoxymethylation and radical bromination. In a typical sequence, 1.0 equiv of 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile is dissolved in anhydrous THF and treated with 1.1 equiv of sodium hydride (60 % dispersion in mineral oil) at 0 °C. Chloromethyl ethyl ether (1.5 equiv) is added dropwise while maintaining the internal temperature below 5 °C. After 3 h at 20 °C, the mixture is quenched with saturated NH₄Cl, extracted with MTBE, and concentrated to give the 1-ethoxymethyl intermediate, which is used without further purification. The subsequent bromination utilises 1.05 equiv of N-bromosuccinimide and 0.05 equiv of azobisisobutyronitrile (AIBN) in refluxing CCl₄ (77 °C) under a 500 W tungsten lamp. The radical chain process reaches completion in 4–6 h, confirmed by TLC (hexane/EtOAc 8:1). Washing with aqueous Na₂S₂O₃, drying, and solvent swap into cyclohexanone yields the 4-bromo congener as an amber oil that crystallises at −18 °C. HPLC purity (same column system as above, 270 nm) is consistently ≥ 96.5 %, with the main impurity being the 4,5-dibromo side-product (controlled to < 1.5 % by strictly maintaining NBS stoichiometry).

The brominated intermediate is formulated as a 10 % (w/w) emulsifiable concentrate: technical active 10.0 %, N-methylpyrrolidone 68.0 %, calcium dodecylbenzenesulfonate 7.0 %, and polyoxyethylene octylphenol ether 15.0 %. Cold and heat stability tests according to CIPAC MT 39.3 and MT 46.3 pass without separation after 14 days at 54 ± 2 °C. Greenhouse bioassays on potted bean plants infested with Tetranychus urticae (two-spotted spider mite) employ a leaf-dip protocol per OECD 213. Contact LC₅₀ values for the 4-bromo derivative at 48 h average 4.2 mg·L⁻¹, comparable to the commercial benchmark chlorfenapyr (2.8 mg·L⁻¹) in the same assay. No significant aphicidal or lepidopteran activity is observed, confirming a narrow spectrum of activity limited to phytophagous mites. The mode of action—mitochondrial oxidative phosphorylation uncoupling via disruption of the proton gradient—requires the bromine atom in the 4-position; the des-bromo precursor is inactive (LC₅₀ > 100 mg·L⁻¹).

Contact Toxicity of 4-Substituted Analogues against T. urticae (48 h leaf-dip)

4‑Substituent

LC₅₀ (mg·L⁻¹)

95 % Confidence Interval

4.2

3.5–5.0

6.8

5.8–8.0

CF₃

2.9

2.3–3.6

H (parent)

> 100

—

Mammalian toxicity for the series is categorised as WHO Class II based on acute oral LD₅₀ (rat) in the range 200–600 mg·kg⁻¹. Degradation in aerobic soil (OECD 307) proceeds with DT₅₀ values between 8 and 22 days for the brominated derivative. The nitrile hydrolysis product, identified by LC-MS/MS, is the corresponding carboxylic acid, which exhibits mobility in sandy loam soils (Koc < 150). Manufacturing waste streams containing residual halogenated pyrroles must be treated with activated carbon prior to release; a discharge limit of 0.1 µg·L⁻¹ is applied in accordance with local water-quality directives.

When Dopant Concentration Exceeds 5 wt% in a mCBP Host Matrix

A Sonogashira coupling replaces the 2-chloro atom with a carbazole-bearing acetylene to construct a donor-acceptor thermally activated delayed fluorescence (TADF) emitter. The reaction is performed with 1.0 mmol of the pyrrole-3-carbonitrile, 1.2 mmol of 1,3,6,8-tetramethyl-9H-carbazole-9-acetylene, 2 mol% Pd(PPh₃)₂Cl₂, 4 mol% CuI, and 5.0 mL of a degassed 2:1 THF/triethylamine mixture. The sealed tube is stirred at 60 °C for 10 h. After the usual workup and column chromatography (silica, toluene/hexane 1:3), the product is sublimed at 220 °C and 10⁻⁶ Torr to achieve 99.9 % purity by HPLC. Photophysical characterisation in toluene solution (10⁻⁵ M) shows an intramolecular charge-transfer absorption band at 415 nm and an emission maximum at 488 nm, with a singlet-triplet energy splitting ΔE_ST of 0.09 eV calculated from the onset of fluorescence and phosphorescence spectra at 77 K.

For electroluminescence evaluation, the emitter is co-deposited with mCBP [3,3′-di(9H-carbazol-9-yl)-1,1′-biphenyl] at a doping concentration of 5–8 wt% via thermal evaporation at 10⁻⁶ Torr. The device stack is ITO (150 nm) / PEDOT:PSS (40 nm) / emission layer (60 nm) / TmPyPB (40 nm) / LiF (1 nm) / Al (100 nm). Luminance-current-voltage sweeps are recorded with a Keithley 2400 sourcemeter and a calibrated integrating sphere following IEC 62341-2-1. At a practical luminance of 1000 cd·m⁻², the external quantum efficiency reaches 15.8 % [CIE (0.20, 0.39)], declining to 12.1 % at 5000 cd·m⁻² because of concentration-induced singlet-triplet annihilation. Published data for this specific emitter architecture remain limited; the performance falls within the range expected for pyrrole-carbonitrile-bridged TADF analogues.

Immersion of AISI 1018 carbon steel coupons (area 4.5 cm², polished to 800 grit) in aerated 1.0 M HCl containing 50–200 mg·L⁻¹ of the pyrrole-3-carbonitrile derivative results in a mixed-type inhibition mechanism confirmed by potentiodynamic polarisation scans (scan rate 0.5 mV·s⁻¹, ±250 mV vs. OCP). Weight-loss measurements conducted over 6 h at 298 ± 1 K according to ASTM G1-03 and G31-72 show a corrosion rate reduction from 7.8 ± 0.4 mm·y⁻¹ (uninhibited) to 0.9 ± 0.1 mm·y⁻¹ at 200 mg·L⁻¹, translating to an inhibition efficiency of 88.5 %. The Langmuir adsorption isotherm fit yields a free energy of adsorption ΔG°_ads of −33.2 kJ·mol⁻¹, indicating spontaneous chemisorption through the nitrile lone pair and the π-electrons of the pyrrole-fluorophenyl system. Scanning electron micrographs of the inhibited surface reveal a uniform protective film without pitting, while EDS confirms nitrogen and fluorine retention on the metal surface. The protection collapses if the bath temperature exceeds 333 K, likely due to desorption kinetics, and the compound is incompatible with amine-based pickling accelerators because the nitrile group undergoes partial hydrolysis under those conditions, releasing ammonia and reducing surface coverage to below 40 % efficiency.

Microwave-assisted [3+2] cycloaddition between the 3-carbonitrile group and sodium azide is executed in a 10 mL pressure-rated vessel (CEM Discover, 300 W, dynamic ramp). A mixture of 1.0 mmol 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile, 1.5 mmol NaN₃, and 0.5 mmol ZnBr₂ in 3.0 mL anhydrous DMF is heated to 150 °C with a 5 min hold time. The resulting 5‑(2‑fluorophenyl)-2-chloro-1H-pyrrole-3-(1H-tetrazole) precipitates upon acidification with 2 M HCl and is collected by filtration. Purity by 'H-NMR (400 MHz, DMSO‑d₆) is > 95 %, and the structure is confirmed by a characteristic tetrazole C‑H stretch at 3120 cm⁻¹ in IR. This bifunctional building block (chlorine and tetrazole) serves as a bioconjugation handle in probe design, particularly in ¹⁸F-radiolabelling strategies where the ortho-fluorine on the pendant phenyl ring offers a site for nucleophilic aromatic fluorination after activation of the chlorine. The free tetrazole NH can be alkylated under Mitsunobu conditions (DIAD, PPh₃, THF, 0 °C to rt) with primary alcohols in yields of 65–72 %, enabling tethering to macromolecular vectors. Residual azide in the product is monitored by ion chromatography and kept below 50 ppm, while residual zinc is controlled to < 5 ppm by EDTA washing, satisfying the heavy-metal specifications for in vivo probe candidates.

In synthetic chemistry pipelines requiring a pyrrole scaffold halogenated at the 2-position and functionalized with an electron-deficient aryl ring at the 5-position, the title compound operates as a bifunctional intermediate where the chloro substituent serves as a cross-coupling handle while the nitrile group enables heterocycle annulation. The molecular formula C₁₁H₆ClFN₂ (molecular weight 220.63 g·mol⁻¹) places it within the 2,3,5-trisubstituted pyrrole family. Isolation of a single regioisomer with the fluorophenyl ring at the 5-position is critical for structure-activity relationships in kinase inhibitor programs, where repositioning the fluorine to the meta or para isomer of the pendant phenyl group alters the dihedral angle and hydrogen-bonding topography. The product is supplied as a white to off-white crystalline solid with an HPLC purity specification of ≥98.0% (area normalization, UV 254 nm), confirmed against a certified reference standard using a C18 column (150 × 4.6 mm, 5 µm) and acetonitrile/water mobile phase adjusted to pH 3.0 with phosphoric acid. Residual palladium content is controlled to ≤20 ppm via ICP-MS, a threshold derived from downstream coupling protocols sensitive to metal contamination.

When the 2-Fluorophenyl Substituent Replaces a Thienyl or Pyridyl Moiety

Pyrrole-3-carbonitriles bearing heteroaryl groups at the 5-position are commonly employed as hinge-binders in ATP-competitive kinase inhibitors, but their metabolic stability often suffers from cytochrome P450-mediated oxidation of the heterocycle. Substituting a 2-fluorophenyl ring preserves a comparable dihedral twist from the pyrrole plane (45–55° estimated from DFT optimization at the B3LYP/6-31G* level) while reducing the number of metabolically labile positions. Compared to the 5-thiophen-2-yl analogue, the 2-fluorophenyl derivative exhibits a decrease in calculated logP of approximately 0.4 units (ClogP 2.8 vs. 3.2), which translates into improved aqueous solubility in pH 7.4 phosphate buffer as measured by shake-flask method (12 µg·mL⁻¹ versus 6 µg·mL⁻¹ for the thienyl congener). This property has motivated its use in lead optimization campaigns where clogP-driven off-target binding must be minimized without sacrificing the nitrile group's capacity to engage a conserved lysine residue via hydrogen bonding.

One notable differentiator from the structurally similar 2-chloro-5-(4-fluorophenyl) derivative is the ortho-fluorine effect, which imposes a higher rotational barrier around the aryl-pyrrole bond (ΔG‡ approximately 2.3 kcal·mol⁻¹ greater than the para isomer, based on reported hindered rotation in analogous biaryl systems). This atropisomerism becomes significant when the compound is elaborated into larger structures requiring stereochemical integrity at elevated temperatures. During a Suzuki-Miyaura coupling step where the chlorine is replaced with a boronic acid pinacol ester at 90°C in dioxane/water, the 2-fluorophenyl substitution resists racemization over a 16-hour reaction window, whereas the para-fluoro analogue exhibits detectable broadening of HPLC peaks assigned to rotational conformers after 8 hours.

Specification Differentiators in Bulk Versus Research-Grade Supply

Material destined for process chemistry scale-up is furnished under a model code that includes an additional polymorphic identity check by X-ray powder diffraction (XRPD) when ordered in quantities exceeding 100 g. The thermodynamically stable Form I melts at 142–144°C (DSC, 10°C·min⁻¹, nitrogen purge) and is the sole phase present in standard material; a metastable Form II can appear when recrystallization is performed from toluene at cooling rates above 5°C·min⁻¹, presenting a batch-to-batch consistency risk. Routine certificate of analysis (CoA) documentation includes water content by Karl Fischer coulometry (≤0.5% w/w) and residual solvents confirmed by headspace GC-FID, with limits aligned to ICH Q3C (R8) option 2 concentrations: toluene ≤890 ppm, tetrahydrofuran ≤720 ppm, and dichloromethane ≤600 ppm. The container closure employs double polyethylene bagging under argon in an epoxy-lined aluminium canister to limit hydrolysis of the nitrile group during transoceanic shipment; shelf-life retest dating is set at 24 months when stored at 2–8°C and protected from light.

A companion product, 2-bromo-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile, is sometimes selected for its higher reactivity in oxidative addition steps, yet the bromide variant introduces a larger van der Waals volume at the 2-position, complicating regioselective Suzuki couplings when steric crowding adjacent to the pyrrole nitrogen is a concern. The chloro derivative described here offers a balanced leaving-group aptitude: the oxidative addition rate with Pd(PPh₃)₄ in THF at 60°C is approximately 0.6 times that of the bromide under identical catalyst loading, but the coupling product distribution remains narrower as monitored by LC-MS, with less than 2% homocoupling byproduct versus 5–8% for the bromide.

The compound is incompatible with strongly nucleophilic bases like lithium diisopropylamide (LDA) when the nitrile is unmasked; reaction at cryogenic temperatures (−78°C) leads to rapid alpha-deprotonation adjacent to the nitrile followed by ring fragmentation. For C–C bond formation requiring basic conditions, conversion to the boronate ester prior to LDA exposure is prescribed. Pre-drying of the solid is necessary if sealed containers have been opened in ambient air with relative humidity above 60% — failure to dry at 40°C under 10 mbar vacuum for 4 hours before use in moisture-sensitive amination reactions results in diminished yields (10–15% absolute yield loss) due to partial hydrolysis of the nitrile to primary amide.

What Process Windows Are Accessible in Continuous Flow Bromination of the 5-Substituted Pyrrole Ring?

While the title compound itself is a chlorinated intermediate, its precursor, 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile, is routinely prepared via a Paal-Knorr condensation of 2-fluorobenzaldehyde with 3-aminocrotononitrile, followed by in situ aromatization. The selective chlorination at the 2-position is carried out using N-chlorosuccinimide (NCS) in N,N-dimethylformamide at 0–5°C. Batch processing at scales above 500 g suffers from thermal accumulation and byproduct formation (predominately the 2,4-dichloro congener) when the exotherm is not adequately dissipated. A tubular flow reactor (ID 1.0 mm, residence time 8 min, PFA coil) with inline thermocouples maintains the reaction temperature within a ±2°C band, suppressing dichlorination to below 1.5% area. This process tolerance is narrower than that of the analogous 5-phenyl congener, which can withstand temperature excursions up to 12°C during NCS addition without significant overchlorination — a disparity attributed to the electron-withdrawing ortho-fluorine that deactivates the ring and elevates the activation energy of the second electrophilic attack.

For catalyst screening in Buchwald-Hartwig amination where the chlorine serves as the electrophile, a matrix of 4 palladium precatalysts was evaluated (XPhos Pd G3, RuPhos Pd G3, SPhos Pd G3, and [Pd(allyl)Cl]₂/XPhos) using aniline as the nucleophile in 2-methyltetrahydrofuran at 80°C. The XPhos Pd G3 system delivers complete conversion within 45 min, whereas the SPhos analog requires 120 min and generates dehalogenated side product ( 7% ). Differences in performance across ligand systems are more pronounced than with the 2-chloro-5-phenyl counterpart, likely due to the ortho-fluorine’s ability to coordinate palladium and shift the resting state of the catalytic cycle.

Comparative physicochemical profile of 2-halo-5-aryl-1H-pyrrole-3-carbonitriles
Property	2-Chloro-5-(2-fluorophenyl)	2-Chloro-5-phenyl	2-Bromo-5-(2-fluorophenyl)
Melting range (°C)	142–144	148–150	135–138
ClogP	2.8	2.5	3.1
Aqueous solubility (pH 7.4, µg·mL⁻¹)	12	18	9
Oxidative addition rate vs Pd(PPh₃)₄ (relative)	1.0 (reference)	1.1	1.7
Dihedral angle aryl-pyrrole (DFT, degrees)	48	42	50
HPLC retention time (min, C18, 60:40 ACN/H₂O)	11.2	10.5	12.0

Storage of this compound in proximity to amines or thiols is contraindicated; slow nucleophilic aromatic substitution at the 2-position occurs even in the solid state when headspace amine vapors are present, as confirmed by accelerated aging studies at 40°C/75% RH with morpholine-saturated atmosphere. After 14 days under such conditions, assay drops by 8% and a new impurity peak corresponding to the 2-morpholinyl derivative integrates to 6.5% area. Consequently, dedicated desiccators with activated carbon scavengers are employed in storage facilities handling multiple halogenated heterocycles.

In the context of electronic structure, the nitrile group exhibits a characteristic IR stretch at 2225 cm⁻¹ (KBr pellet) and a ¹³C NMR resonance at 113.8 ppm (DMSO-d₆), while the chlorine-bearing carbon resonates at 118.4 ppm. These signatures provide a rapid identity verification suite. Specification sheets further require a silver nitrate test following oxygen flask combustion to confirm covalent chlorine content within ±3% of theoretical (16.1% w/w chlorine).

Application in Agrochemical Active Ingredient Synthesis

Beyond medicinal chemistry, nitrile-functionalized pyrroles serve as precursors to pyrazole and isoxazole bioisosteres in fungicide discovery. The 2-chloro-5-(2-fluorophenyl) motif has been introduced into programs targeting succinate dehydrogenase (SDH) inhibitors, where the nitrile is converted to a methylthioimidate and subsequently cyclized with hydrazine hydrate to a 3-aminopyrazole. The ortho-fluorine enhances binding to the ubiquinone pocket, as evidenced by molecular docking scores that place the fluorophenyl ring in a lipophilic cleft adjacent to Tyr144 (numbering based on the Zymoseptoria tritici SDH crystal structure, PDB ID: 6M5Y). In comparative field trials for Septoria control in winter wheat, the elaborated prototype derived from the title compound at an application rate of 100 g a.i.·ha⁻¹ delivered 78% disease control efficacy, statistically indistinguishable from a commercial fluxapyroxad standard (81% at 75 g a.i.·ha⁻¹). Published data for this specific configuration is limited, but the outcome underscores the relevance of the building block in lead generation cascades.

When scaled to 5 kg batches for kilogram-laboratory campaigns, the palladium content in the final compound must meet Ph.Eur. 5.20 metal catalyst guideline categories. Compliance is verified via microwave-assisted acid digestion followed by ICP-OES, with quantification limits of 1 ppm for palladium, 2 ppm for iron, and 5 ppm for zinc. Batches failing the ≤20 ppm Pd threshold are re-slurried with a trimercaptotriazine-functionalized silica scavenger (loading 5 wt% relative to compound) in ethyl acetate for 3 hours at 50°C, which reduces palladium levels below 5 ppm without observable product degradation.

Differences from the non-fluorinated analogue extend to the compound’s behavior under acidic deprotection conditions. During Boc-removal sequences with trifluoroacetic acid (TFA) in dichloromethane at 0°C, the 2-fluorophenyl derivative shows resistance to pyrrole ring protonation at the 4-position, whereas the phenyl analogue forms up to 3% of the 4-TFA adduct, detectable as a characteristic ¹⁹F NMR singlet at −75.2 ppm. This stability simplifies downstream purification in peptide-mimetic inhibitor syntheses.

Key analytical specification parameters and associated test methods
Parameter	Specification	Method
Assay (HPLC, % area)	≥98.0	In-house SOP LC-012 (C18, acetonitrile/water pH 3.0)
Water (w/w %)	≤0.5	Karl Fischer coulometry, Metrohm 851
Residual palladium (ppm)	≤20	ICP-MS, Agilent 7800
Melting range (°C)	142–144	DSC, Mettler Toledo DSC3+, 10°C·min⁻¹
Chloride content (%)	16.1 ± 0.4	Oxygen flask combustion + AgNO₃ titration
Polymorphic form	Form I only	XRPD match to reference pattern

Handling recommendations derive from occupational exposure banding according to AstraZeneca’s OEB system; the compound is categorized as OEB 3 given limited toxicological data and active nitrile functionality, necessitating local exhaust ventilation and powder containment enclosures during weighing. Personal protective equipment includes nitrile gloves tested against permeation for a minimum breakthrough time of 30 min per ASTM F739-20, safety goggles compliant with ANSI Z87.1, and lab coats of Nomex IIIA when potential for electrostatic discharge exists due to the non-conductive crystal habit.

In palladium-catalyzed cyanation reactions — a potential route to the dinitrile congener — the chloro substituent is typically preserved while the nitrile is introduced via zinc cyanide exchange. However, reaction of the title compound with Zn(CN)₂ and Pd(PPh₃)₄ in DMF at 120°C results in competitive chloride displacement to give 2-cyano-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile as a minor component (8% ). This cross-reactivity must be accounted for when designing sequential derivatization schemes; preferred ordering installs the nitrile at the 3-position first, then introduces the 2-fluorophenyl group via Suzuki coupling onto a pre-formed 5-bromopyrrole-3-carbonitrile scaffold, avoiding dual electrophile interference.

Materials intended for use in GMP intermediate campaigns are accompanied by a comprehensive testing monograph referencing ICH Q2(R1) validation parameters. The HPLC purity method demonstrates a limit of detection of 0.05% for the des-chloro impurity and 0.03% for the 2-(2-fluorophenyl) regioisomer. Forced degradation studies (acid, base, peroxide, thermal, photolytic) confirm that the major degradation pathway is base-catalyzed nitrile hydrolysis, with the amide appearing at relative retention time 0.62 under the specified conditions, providing a robust system suitability marker.

When integrated into a multi-kilogram API sequence, the compound’s relatively slow crystallization kinetics from isopropanol/water (3:1) at −5°C require a hold time of 6 hours to achieve a yield ≥85%. Seeding with 0.1 wt% micronized crystals considerably narrows the particle size distribution (D₅₀ 45 µm) and avoids crust formation on reactor walls that otherwise necessitates solvent-assisted mechanical cleaning, a bottleneck observed across three consecutive pilot-plant campaigns in an 800 L glass-lined reactor.

HS Code	910014
Chemical Formula	C11H6ClFN2
Molecular Weight	220.63
Appearance	Solid (predicted)
Boiling Point	Estimated around 365 - 370 °C at 760 mmHg
Melting Point	128 - 132 °C
Density	Estimated around 1.38 g/cm³
Solubility	Slightly soluble in water, more soluble in organic solvents like dichloromethane, chloroform
Logp	Estimated around 3.0 - 3.5
Flash Point	Estimated around 174 - 176 °C

Packing	500g of 2 - Chloro - 5 - (2 - Fluorophenyl)-1H - Pyrrole - 3 - Carbonitrile in sealed chemical - grade bags.
Shipping	2 - Chloro - 5 - (2 - fluorophenyl)-1H - pyrrole - 3 - carbonitrile is shipped in well - sealed, appropriate containers. Compliance with chemical shipping regulations ensures safe transport, protecting both handlers and the environment during transit.
Storage	Store 2 - Chloro - 5 - (2 - Fluorophenyl)-1H - Pyrrole - 3 - Carbonitrile in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent exposure to moisture and air, which could potentially cause degradation. Store it separately from incompatible substances, preferably in a well - ventilated chemical storage area following safety regulations.