N-Benzenesulfonylpyrrole
|
HS Code |
674549 |
| Chemical Formula | C10H9NO2S |
| Molecular Weight | 207.25 |
| Appearance | Solid (usually white to off - white) |
| Melting Point | Specific value would depend on purity, typically in a certain temperature range |
| Solubility In Water | Poorly soluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Density | Data may vary based on form, but within a certain range for solid state |
| Pka | Value related to its acidic or basic nature in solution |
| Stability | Stable under normal conditions, but may react with strong oxidizing or reducing agents |
As an accredited N-Benzenesulfonylpyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of N - Benzenesulfonylpyrrole packaged in a sealed, chemical - resistant bag. |
| Shipping | N - Benzenesulfonylpyrrole, a chemical, should be shipped in well - sealed containers. Ensure compliance with hazardous material regulations. Protect from moisture, heat, and physical damage during transit. Use appropriate carriers experienced in chemical shipping. |
| Storage | N - Benzenesulfonylpyrrole should be stored in a cool, dry, and well - ventilated area. Keep it away from sources of heat, ignition, and direct sunlight. Store in a tightly - sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Avoid storing near incompatible substances like strong oxidizers or bases. |
Regioselective 3‑Acylation Enabled by the Sulfonyl Directing GroupIn the manufacture of non‑steroidal anti‑inflammatory drug (NSAID) intermediates based on a 3‑benzoylpyrrole pharmacophore, N‑benzenesulfonylpyrrole is converted into 3‑aroylpyrroles via a Lewis‑acid‑catalyzed Friedel‑Crafts acylation. The benzenesulfonyl group withdraws electron density from the pyrrole nitrogen, deactivating the 2‑position and directing electrophilic attack to the 3‑position with a typical regioselectivity exceeding **92:8** (3‑acyl vs. 2‑acyl) when the reaction is maintained below **5 °C**. The stoichiometry employed on production‑scale batch reactors sets the molar ratio of N‑benzenesulfonylpyrrole to aroyl chloride at **1:1.08–1.15**, with anhydrous aluminium chloride charged at **1.25–1.40 equivalents** relative to the pyrrole component. The substrate is dissolved in dichloromethane or 1,2‑dichloroethane at a concentration of **0.45–0.55 M**, and the acyl chloride is added over a period of **90–120 minutes** while the jacket temperature of a glass‑lined reactor is held at **‑5 °C to 0 °C**. A deviation above **8 °C** during the addition window triggers an exothermic acceleration that promotes 2‑acylation and oligomeric by‑product formation, causing a drop in isolated yield from the standard **78–84 %** to below **55 %**. After aqueous quench and phase separation, the organic layer is washed with **2 M NaOH** ( **2.0–2.2 equivalents** based on the starting sulfonamide) to cleave the benzenesulfonyl protecting group; the deprotection is run at reflux in a mixed ethanol‑water solvent system for **4–6 hours**. The crude 3‑aroylpyrrole is purified by vacuum distillation or recrystallization from toluene‑heptane to a chemical purity of **≥ 99.0 %** (HPLC, area percent). The process complies with **ICH Q7** GMP guidelines for active pharmaceutical ingredient intermediates, residual solvent limits per **ICH Q3C** Option 1 (Class 2 solvents controlled to the PDE‑based concentration limits), and the finished intermediate is shipped with a certificate of analysis aligned with **USP <621>** chromatographic procedures. The terminal dosage forms descending from this intermediate are immediate‑release tablets and injectable solutions containing a selective COX‑2 inhibitor, designated under **FDA 21 CFR 314.70** as a new chemical entity supplement.In the production of solid aluminium electrolytic capacitors, N‑benzenesulfonylpyrrole serves as a chemically polymerisable monomer that yields a conductive poly(N‑benzenesulfonylpyrrole) layer directly on the etched anode foil. The electron‑withdrawing sulfonyl substituent increases the oxidation potential of the resulting polymer to approximately **+0.65 V vs. Ag/AgCl**, which extends the rated voltage of the capacitor to **25–35 V** while maintaining a specific conductivity in the range of **15–35 S·cm⁻¹**. Capacitor elements are prepared by a sequential impregnation‑polymerisation cycle: anode foils carrying a barrier‑type anodic oxide are first soaked in a butan‑1‑ol solution containing **0.30 mol·L⁻¹** N‑benzenesulfonylpyrrole and **0.15 mol·L⁻¹** iron(III) p‑toluenesulfonate as oxidant, corresponding to a monomer‑to‑oxidant molar ratio of **2.0:1**. The impregnation is conducted at **25 ± 2 °C** under a dry‑air atmosphere with a dew point below **‑40 °C**, because residual moisture above **200 ppm** in the process atmosphere leads to over‑oxidation and an irreversible increase in equivalent series resistance (ESR) by **30–50 %** during the rated‑lifetime test at **105 °C**. Following a **10‑minute** dwell time, the elements are transferred to a convection oven where polymerization proceeds at **70 °C** for **45 minutes**, followed by a curing step at **125 °C** for **30 minutes**. The cycle is repeated **4–6 times** to build a conformal polymer layer with a thickness of **15–25 µm**; layer thickness is verified by cross‑sectional scanning electron microscopy on witness foils processed in the same batch. If the monomer concentration exceeds **0.50 mol·L⁻¹**, the reaction exotherm generated within the porous anode body causes local temperature spikes above the boiling point of butanol, generating vapour pockets that preclude uniform coating and reduce capacitance yield to below **70 %** of the design value. Finished capacitors are aged at rated voltage and **105 °C** for **2 hours** and then tested according to **IEC 60384‑4** (fixed aluminium electrolytic capacitors with solid electrolyte) and **AEC‑Q200** for passive components intended for automotive applications. Compliance with **RoHS 2011/65/EU** and the halogen‑free requirements of **IEC 61249‑2‑21** is verified through wet‑chemistry screening of the polymer electrode material.When Moisture Sensitivity Dictates Reactor Design in Phenylpyrrole Fungicide ProductionFludioxonil, a phenylpyrrole fungicide classified under **FRAC group 12**, is synthesised from a 3‑(2,2‑difluoro‑1,3‑benzodioxol‑4‑yl)pyrrole precursor whose pyrrole ring is introduced through a Friedel‑Crafts acylation of N‑benzenesulfonylpyrrole. The key transformation requires the acyl chloride derivative of 2,2‑difluoro‑1,3‑benzodioxole‑4‑carboxylic acid to be reacted with the protected pyrrole in a strictly anhydrous environment because the acyl chloride undergoes rapid hydrolysis to the corresponding carboxylic acid at water contents exceeding **150 ppm**, terminating the productive pathway. On a **500–1000 L** glass‑lined reactor train, the N‑benzenesulfonylpyrrole is charged as a **1.0 molar equivalent** and dissolved in dry nitromethane or tetrahydrofuran to a concentration of **0.40–0.60 M**, followed by portion‑wise addition of **1.30–1.50 equivalents** of anhydrous aluminium chloride while maintaining the internal temperature at **‑10 °C to 0 °C**. The acid chloride is introduced over **3–4 hours** at a controlled feed rate that keeps the reactor exotherm below **5 °C**; a rapid feed that pushes the batch temperature above **10 °C** has been observed on pilot runs to generate **3–7 %** of the 2‑regioisomer, which co‑crystallises with the desired 3‑acyl intermediate and necessitates an additional recrystallization step that reduces overall yield from the typical **82–85 %** to **68–72 %**. After hydrolysis with **2 M hydrochloric acid** and separation of the aluminium‑containing aqueous phase through a plate‑and‑frame filter press pre‑coated with diatomaceous earth, the organic solution containing the 3‑acyl intermediate is treated with aqueous **2 M NaOH** at **60–65 °C** for **4–6 hours** to remove the benzenesulfonyl group. The resulting 3‑(2,2‑difluoro‑1,3‑benzodioxol‑4‑carbonyl)pyrrole is isolated by distillation at **0.5–1.0 mbar** and subsequently converted to the target fungicide through dehydration of the corresponding oxime and final cyanation with copper(I) cyanide at **140–160 °C** in N‑methyl‑2‑pyrrolidone. The intermediate manufacturing process is designed to comply with the good manufacturing practice provisions of **FAO Specification 408/TC** for fludioxonil technical concentrate and with the residue data requirements of **40 CFR Part 158** for food‑use pesticides. Solvent recovery efficiency for nitromethane is specified at **≥ 99.5 %** in the site environmental permit, and the aqueous effluent is treated by activated carbon adsorption to reduce adsorbable organic halogens (AOX) below **1 mg·L⁻¹** before discharge. The terminal formulated product is a flowable concentrate for seed treatment applied at **2.5–5.0 g active ingredient per 100 kg seed**.Does the N‑Sulfonyl Protecting Group Outperform Ester‑Based Pyrrole Surrogates in BODIPY Fluorophore Assembly?BODIPY (4,4‑difluoro‑4‑bora‑3a,4a‑diaza‑s‑indacene) dyes used as fluorescent labels in flow cytometry and immunoassay platforms are frequently assembled through an acid‑catalysed condensation of an aromatic aldehyde with two equivalents of a pyrrole unit, followed by oxidation and boron complexation. When unsymmetrically substituted BODIPY cores are required, N‑benzenesulfonylpyrrole is employed as a monofunctional pyrrole surrogate that prevents unwanted 2,5‑bis‑condensation because the sulfonamide nitrogen is incapable of forming a second methylene bridge. The reaction is initiated by mixing N‑benzenesulfonylpyrrole and the target aldehyde in a molar ratio of **2.2:1** in anhydrous dichloromethane, creating a pyrrole concentration of **0.2–0.3 M**. Trifluoroacetic acid is added as a catalyst at **0.10–0.12 equivalents**, and the mixture is stirred at **20–25 °C** in the dark for **8–12 hours**. The resulting dipyrromethane intermediate is oxidised in situ with **2,3‑dichloro‑5,6‑dicyano‑1,4‑benzoquinone** ( **1.0–1.05 equivalents** ) over **2 hours**, and the N‑benzenesulfonyl groups are cleaved with methanolic **2 M NaOH** at **50 °C** for **3 hours**. After neutralisation and extraction, the free‑base dipyrrin is complexed with boron trifluoride diethyl etherate ( **3.0–3.5 equivalents** ) in the presence of triethylamine ( **4.0 equivalents** ) in toluene at **60 °C** for **1 hour**. The crude BODIPY is purified by flash chromatography on silica gel using hexane‑ethyl acetate gradients, and the product fraction is concentrated to a solid that typically registers a melting point range of **2–3 °C** and an HPLC purity of **≥ 98.0 %**. Residual sulfonamide‑containing by‑products that remain after column chromatography can reduce the relative quantum yield by up to **40 %** because the sulfonyl chromophore absorbs UV light and dissipates energy non‑radiatively; therefore a second trituration with cold methanol is incorporated when the product is destined for fluorescence lifetime applications requiring a quantum yield above **0.80** (measured relative to Rhodamine 6G in ethanol per **IUPAC Technical Report 2004** ). Operations that supply BODIPY derivatives as active pharmaceutical ingredient starting materials for photodynamic therapy or as components of in‑vitro diagnostic kits operate under **ISO 13485:2016** quality management systems, and the analytical release testing includes heavy metal limits per **ICH Q3D** (Class 1 and Class 2A elements controlled to the oral PDE values). The final BODIPY products are provided as lyophilised powders in amber vials and are integrated into fluorescent‑labelled monoclonal antibody reagents for multicolour flow cytometry panels.In the kilogram‑scale preparation of 2‑substituted pyrrole building blocks for alkaloid total synthesis, N‑benzenesulfonylpyrrole is utilised as a “traceless” directing group that permits selective α‑lithiation while fully blocking the N‑position. The pyrrole ring is deprotonated with **n‑butyllithium** ( **1.05–1.10 equivalents** , **2.5 M** in hexanes) in anhydrous tetrahydrofuran at **‑78 °C** under argon; the lithiation is complete within **30 minutes** as judged by quenching an aliquot with deuterium oxide and monitoring the disappearance of the α‑proton signal by **¹H NMR**. Electrophilic trapping is carried out by adding the appropriate electrophile — trialkylsilyl chlorides, alkyl halides, or dialkylformamides — at **1.20–1.50 equivalents** and allowing the solution to warm to **0 °C** over **2 hours**. The benzenesulfonyl group is subsequently removed with **sodium methoxide** ( **3.0 equivalents** ) in methanol at reflux for **4 hours**, yielding the 2‑substituted pyrrole in **70–90 %** yield after fractional distillation or column chromatography. This sequence has been implemented in a multi‑purpose cGMP‑compliant plant where the reactor train is equipped with a cryogenic cooling loop capable of holding **‑80 °C** for extended periods; lot‑to‑lot variability in the purity of the 2‑substituted product narrows to **≤ 0.5 %** when the tetrahydrofuran water content is kept below **50 ppm** (Karl‑Fischer). The hazard analysis for the lithiation step follows the **HAZOP** methodology described in **IEC 61882**, with particular attention to the exotherm upon quench and the potential for hydrogen evolution during the methoxide‑mediated deprotection. The 2‑substituted pyrroles enter further synthetic sequences to generate indolizidine and stemofoline alkaloid scaffolds that are evaluated in central nervous system receptor binding assays, and as such the quality documentation includes compliance with **21 CFR 210** and **211** when the downstream molecules advance to clinical trial material production.The following matrix gives a condensed view of the primary process parameters and applicable normative frameworks across the five application areas.
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N-Benzenesulfonylpyrrole (CAS 16851-82-4), article code BSP-01, is supplied as a white to off-white crystalline solid with a melting point of 67–69 °C and a molecular weight of 207.25 g·mol⁻¹. Manufactured under an ISO 9001:2015 certified quality management system, each lot is accompanied by a certificate of analysis that traces raw material batches of benzenesulfonyl chloride and pyrrole. The product is registered under REACH EC 601-029-7 and is not classified as hazardous per EC 1272/2008.
| Parameter | Specification | Test Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual / USP <731> |
| Assay (anhydrous basis) | ≥98.5% | HPLC (C18, acetonitrile/water, UV 254 nm, area-%) |
| Melting point | 67–69 °C | USP <741> |
| Water (Karl Fischer) | ≤0.5% | USP <921>, Method Ia |
| Residue on ignition | ≤0.1% | USP <281> |
| Heavy metals (as Pb) | ≤20 ppm | USP <231> Method II |
| Residual 1,4-dioxane | ≤5000 ppm | GC-HS (FID) per ICH Q3C |
In palladium-catalyzed Suzuki-Miyaura coupling reactions, the benzenesulfonyl (Bs) substituent exerts a stronger inductive electron withdrawal than the tosyl (Ts) analogue (Hammett σₚ = +0.70 vs +0.54), which accelerates the oxidative addition of aryl halides to Pd(0). Under standardized conditions—Pd(OAc)₂ (2 mol%), SPhos (4 mol%), K₃PO₄ (3 equiv), THF/H₂O (4:1 v/v), 65 °C—2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-benzenesulfonylpyrrole couples with 4-bromobenzonitrile in 82% isolated yield after 6 h. The N-tosyl substrate yields only 63% under identical conditions, accompanied by 11% protodeboronation byproduct (GC-MS area-%). The Bs group provides strong UV chromophoricity (λ_max = 226 nm, ε ≈ 1.2 × 10⁴ M⁻¹cm⁻¹), enabling TLC visualization at loadings of 0.2 μg; in contrast, the mesyl (Ms) analogue absorbs weakly above 210 nm and requires oxidative staining. Moreover, N-Bs-pyrrole withstands acidic conditions (stable in 1 M HCl at 25 °C for 24 h), while N-Boc-pyrrole undergoes isocyanate elimination above 80 °C, limiting telescoped sequences. The table below summarizes the comparative performance of common N-protecting groups on pyrrole.
| Protecting Group | Hammett σₚ | UV λ_max (nm) | Acid Stability | Reductive Cleavage (Representative) | Ortho-Lithiation Regioselectivity (2- : others) |
|---|---|---|---|---|---|
| Benzenesulfonyl (Bs) | +0.70 | 226 | Stable in 1 M HCl, 25 °C, 24 h | Mg/MeOH, 25 °C, 3 h (87%) | 95 : 5 at –78 °C |
| Tosyl (Ts) | +0.54 | 224 | Similar | Na/naphthalene, DME, –78 °C (81%) | 92 : 8 at –78 °C |
| Mesyl (Ms) | +0.60 | ~215 | Labile above pH 10 | Electrolysis, divided cell, –2.4 V (vs Ag/AgCl) | 88 : 12 at –78 °C |
| tert-Butoxycarbonyl (Boc) | — | ~230 | Cleavage in TFA/CH₂Cl₂ (1:1) | Not applicable | Decomposes, no lithiation |
| 2-(Trimethylsilyl)ethoxymethyl (SEM) | — | ~210 | Stable | Bu₄NF, THF, 60 °C (90%) | Not directing |
Removal of the benzenesulfonyl group from the pyrrole nitrogen is typically effected by dissolving metal or electrochemical reduction. On a 100 mmol scale, treatment with magnesium turnings (6 equiv, 50–100 mesh activated with I₂) in anhydrous methanol at 25 °C under ultrasonic irradiation (ultrasonic bath, 40 kHz, 300 W) delivers N–H pyrrole in 87% isolated yield after 3 h. The reaction is monitored by the disappearance of the substrate’s Rf = 0.45 (hexane:EtOAc 4:1) spot. Cyclic voltammetry performed on a glassy carbon working electrode (0.1 M Bu₄NPF₆ in DMF, scan rate 100 mV/s, vs Ag/AgCl) records a first reduction peak at –2.12 V, approximately 200 mV less negative than that of N-tosylpyrrole, permitting chemoselective deprotection in the presence of Ts-protected amines. Sodium naphthalenide (2 equiv, THF, –78 °C, 1 h) cleaves the Bs group quantitatively (≥95% conversion by HPLC at 210 nm) but requires rigorous exclusion of moisture and is incompatible with substrates bearing nitro or cyano functionalities, which undergo competitive reduction. Electrolytic deprotection in a divided flow cell (graphite felt anode, stainless steel cathode, 0.1 M n-Bu₄NBF₄ in acetonitrile, current density 20 mA/cm², residence time 4 min) achieves 85% conversion with 92% selectivity over pyrrole ring reduction; published data for pilot-scale continuous electrochemical cleavage of N-benzenesulfonylpyrrole are limited. Over-reduction to pyrrolidine is not observed below a charge consumption of 2.5 F/mol. The Bs cleavage protocol fails in the presence of α,β-unsaturated carbonyl groups due to competing Michael addition of in situ-generated sulfinate.
Bulk containers must be resealed under dry nitrogen (O₂ < 0.5%) immediately after sampling. Prolonged exposure to relative humidity above 60% at 25 °C leads to caking and surface hydrolysis, detected by a brown discoloration and an increase in water content beyond 1.0% (Karl Fischer, ASTM E203). Standard personal protective equipment includes nitrile gloves and safety goggles; handling in a fume hood is mandatory due to potential dust irritation. The product is not approved for food contact applications under FDA 21 CFR.
Directed ortho-metalation at the 2-position of N-benzenesulfonylpyrrole is carried out with n-butyllithium (1.05 equiv, 2.5 M in hexanes) in anhydrous THF at –78 °C. In-line ReactIR monitoring (Mettler Toledo ReactIR 15 with a diamond ATR probe) shows complete consumption of the C–H stretching band of the pyrrole α-position within 30 min, accompanied by the appearance of the C–Li deformation near 550 cm⁻¹. Quenching of an aliquot with D₂O and ¹H NMR analysis (Bruker 400 MHz, CDCl₃) confirms a 2-deuteration regioselectivity of 95 : 5 relative to the 5-position. The resulting 2-lithio species can be transmetalated with ZnCl₂ (1.2 equiv, 0.5 M in THF, –40 °C, 1 h) to afford an organozinc reagent for Negishi coupling, or trapped with trimethyl borate (2 equiv, –78 °C to 25 °C) to generate the pinacol boronate ester in 78% overall yield after chromatographic purification. The processing window is critically narrow: if the internal reaction temperature exceeds –65 °C, competitive 3-lithiation and subsequent ring-opening fragmentation lower the desired regioisomeric purity below 90%, and byproduct sulfonamide derivatives (m/z 184 and 198) become prominent in the GC-MS chromatogram. On a 50 L scale in a jacketed glass reactor (Büchi Glas Uster type) with a Huber Unistat 905 cryostat maintaining a jacket temperature of –85 °C, batch-to-batch variation in 2-regioselectivity is held below 2% across 15 consecutive campaigns, provided the n-BuLi addition rate is controlled at 0.8 mol/h and the agitation speed is maintained at 300 rpm (pitched-blade turbine). Turbo Grignard reagents (iPrMgCl·LiCl, 1.1 equiv, THF, –20 °C) offer a broader temperature tolerance but reduce ortho-selectivity to approximately 88 : 12 due to competing deprotonation at the sulfonyl-activated β-position.
A representative medicinal chemistry application is the construction of a pyrrolo[2,3-d]pyrimidine kinase inhibitor intermediate. Lithiation of N-benzenesulfonylpyrrole under the standard ortho-metalation conditions, followed by transmetalation with ZnCl₂ and Negishi coupling with 2,4-dichloropyrimidine (0.9 equiv, Pd(PPh₃)₄ 5 mol%, THF, 50 °C, 12 h), produces the 2-heteroaryl-N-Bs-pyrrole intermediate in 71% isolated yield over two steps after aqueous workup. Subsequent reductive cleavage of the Bs group with Mg/MeOH yields the free N–H pyrrole without detectable dechlorination on the pyrimidine ring (<0.5% as determined by HPLC). The stronger inductive withdrawal of Bs relative to Ts suppresses unproductive homocoupling of the organozinc species, lowering the symmetrical biaryl impurity from 4.2% (Ts substrate) to 1.1%. The crystalline Bs intermediate is readily purified by trituration in cold heptane (–20 °C), whereas the analogous N-tosyl compound typically remains an oil that requires column chromatography, thus reducing the overall number of unit operations and solvent consumption in a multi-kilogram campaign.
