3-Bromo-1-(Triisopropylsilyl)-1H-Pyrrole
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HS Code |
754615 |
| Chemical Formula | C15H28BrNSi |
| Molecular Weight | 330.38 |
| Appearance | Solid (Typical) |
| Solubility | Soluble in organic solvents like dichloromethane, chloroform |
| Purity | Typically high - purity products around 95%+ |
As an accredited 3-Bromo-1-(Triisopropylsilyl)-1H-Pyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 3 - Bromo - 1 - (Triisopropylsilyl) - 1H - Pyrrole packaged in a sealed vial. |
| Shipping | 3 - Bromo - 1 - (Triisopropylsilyl) - 1H - Pyrrole is shipped in well - sealed containers, safeguarded against physical damage. Special care is taken to ensure compliance with chemical transportation regulations due to its nature. |
| Storage | Store 3 - Bromo - 1 - (Triisopropylsilyl) - 1H - Pyrrole in a cool, dry place away from heat and ignition sources. Keep it in a tightly - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to decomposition. Store it in a dedicated chemical storage area, segregated from incompatible substances like oxidizing agents. |
In the synthesis of small-molecule non-fullerene acceptors (NFAs) destined for bulk-heterojunction organic photovoltaic cells processed via slot-die coating, 3-bromo-1-(triisopropylsilyl)-1H-pyrrole is employed as a halogen-bearing building block that introduces both steric bulk and solubilizing aliphatic character without permanently disrupting the electron-rich nature of the pyrrole core. The compound is coupled to electron-deficient central cores—typically indacenodithienothiophene or quinoxaline derivatives—through Pd-mediated Suzuki–Miyaura cross-coupling, where the bromine atom at the 3-position functions as the oxidative addition site. A stoichiometric ratio of 1.05 equivalents of the arylboronic ester core relative to 1.0 equivalent of the bromo-pyrrole is maintained to drive the reaction to completion while minimizing residual boronic acid that complicates chromatographic separation. The catalyst system consists of 0.5 mol% Pd₂(dba)₃ and 1.0 mol% SPhos, suspended in a degassed toluene/ethanol/water mixture (8:1:1 v/v) with 3.0 equivalents of K₃PO₄ at 85 °C for 18 hours under argon. Post-reaction, the crude NFA is precipitated into methanol and sequentially purified using a Biotage Isolera automated flash chromatography system with a hexane/ethyl acetate gradient, followed by recrystallization from dichloromethane/methanol and a final vacuum gradient sublimation step at 10⁻⁷ Torr using a Creaphys apparatus to achieve a sublimed purity exceeding 99.9% by HPLC area. The terminal product is a Y-series-like acceptor possessing a narrow optical bandgap (<1.5 eV) and a lowest unoccupied molecular orbital level near −3.9 eV, designed for high short-circuit current density when blended with PM6-type donor polymers. Compliance with ISOS protocol testing suites—specifically ISOS-D-1 for shelf-life stability under dark storage and ISOS-L-2 for outdoor-equivalent light-soaking endurance—is mandatory to qualify the material for photovoltaic module integration. Additionally, the solidified melt temperature during graded sublimation is monitored against a custom internal specification calibrated with differential scanning calorimetry per ASTM E967-18, ensuring batch-to-batch thermodynamic consistency.When Scaling Buchwald–Hartwig Amination to Multi-Kilogram Batches, Why Does Residual Palladium Speciation Dictate Post-Processing?The heteroaryl bromide serves as the electrophilic partner in C–N bond-forming reactions applied to the kilogram-scale production of a pyrrole-containing ATP-competitive kinase inhibitor intermediate. In a validated cGMP campaign, the Buchwald–Hartwig coupling between 3-bromo-1-(triisopropylsilyl)-1H-pyrrole and a substituted aniline is conducted with a molar addition ratio of 1.00 equivalent of the bromide to 1.12 equivalents of the aniline nucleophile, using 0.3 mol% Pd₂(dba)₃ and 0.9 mol% of the biarylphosphine ligand XPhos relative to the limiting reagent. The base is sodium tert-butoxide at 1.4 equivalents, and the reaction is performed in anhydrous 2-methyltetrahydrofuran at a controlled internal temperature of 62 ± 3 °C inside a 200 L Hastelloy C22 reactor equipped with a thermal jacket linked to a programmable logic controller. Upon completion confirmed by HPLC (≥98.5% conversion), the crude mixture is quenched with an aqueous 5 wt% N-acetylcysteine solution to chelate soluble palladium species, then extracted with ethyl acetate. The organic phase is concentrated under reduced pressure on a 50 L rotary evaporator, residual solvent is displaced with methanol, and the resulting slurry is aged at −10 °C for 6 hours before filtration and zwitterionic guard column polishing through functionalized silica to sequester trace palladium. The purified intermediate must satisfy the element impurity limits defined in ICH Q3D, with Pd content consistently driven below the oral concentration limit of 10 µg/g as measured by inductively coupled plasma mass spectrometry. The target drug substance, after desilylation with tetra-n-butylammonium fluoride and coupling to a pyrimidine core, is a preclinical candidate for autoimmune disorders, processed under adherence to FDA 21 CFR Part 211 and ICH Q7 active pharmaceutical ingredient GMP guidelines. The manufacturing batch record mandates that the silylated intermediate’s water content prior to amination be kept below 0.05 wt% by Karl Fischer titration, because higher moisture levels shift the ligand exchange equilibrium and increase the formation of palladium black, which in turn raises filtration load and requires activated carbon treatment cycles that lower throughput.Flow Lithiation–Quench Sequences for TIPS-Protected Pyrrole-Based Self-Assembled Monolayer PrecursorsA continuous-flow manufacturing route generates organometallic intermediates from 3-bromo-1-(triisopropylsilyl)-1H-pyrrole in order to produce hole-transporting self-assembled monolayer (SAM) molecules intended for the buried interface of inverted perovskite photovoltaics. The bromine-lithium exchange is executed in a Corning Advanced-Flow G1 reactor comprising ten borosilicate glass fluidic modules with a total internal volume of 10 mL, operating at a throughput of 3.8 mmol/min. A solution of 0.25 M n-butyllithium in hexanes is combined in-line with a solution of the pyrrole bromide (0.22 M in anhydrous tetrahydrofuran) at a stoichiometric ratio of 1.00:1.00 Li:Br, pre-cooled to −60 °C via a shell-and-tube heat exchanger directly upstream of the mixing zone. Residence time before electrophile quenching is held to 4.8 seconds to minimize elimination of the TIPS group, after which the lithiated stream meets a solution of trimethyl borate (1.05 equivalents) at −50 °C, yielding the boronic acid precursor after acidic hydrolysis in a second residence zone. The conversion to the boronic acid is monitored in real time by attenuated total reflectance Fourier-transform infrared spectroscopy, focusing on the disappearance of the C–Br stretch at 685 cm⁻¹. The resulting boronic acid is subsequently purified by precipitation in a 10:1 water/methanol mixture and dried in a vacuum oven at 40 °C to a level suitable for downstream Suzuki coupling with a phosphonic acid-functionalized aryl bromide, forming the complete SAM molecule. The finished SAM material is incorporated by dip-coating or micro-gravure printing into n–i–p perovskite modules, where its quality directly influences interfacial defect density. The final perovskite module undergoes accelerated aging tests as described in IEC 61215-2:2016 Section 4.11 for thermal cycling and damp-heat exposure, while adherence to RoHS Directive 2011/65/EU Annex III exemption guidelines for photonic components ensures that residual bromine content in the dried SAM precursor remains below the 900 ppm threshold, as validated by combustion ion chromatography.Fluorescent labeling of intracellular lipid droplets at the high-throughput screening stage requires BODIPY dyes with a grafting point at the meso- or β-position that tolerates aqueous assay environments. The 3-bromo substituent of the TIPS-pyrrole enables Sonogashira coupling to terminal alkynes bearing polyethylene glycol chains, yielding water-compatible red-emissive probes. In a typical preparative procedure shielded from ambient light by amber glassware, 1.0 equivalent of the bromopyrrole is combined with 1.2 equivalents of a propargyl-terminated PEG-550 derivative, 2.0 mol% bis(triphenylphosphine)palladium(II) dichloride, and 4.0 mol% copper(I) iodide in a 3:1 v/v mixture of anhydrous tetrahydrofuran and triethylamine that has been degassed by three freeze-pump-thaw cycles. The reaction is stirred at 55 °C for 8 hours under a nitrogen balloon, after which the solvent is removed on a rotary evaporator with a bath temperature not exceeding 35 °C to prevent thermal decomposition of the dye core. The residue is immediately subjected to flash chromatography on silica gel that has been pre-conditioned with 0.5% triethylamine, using a gradient of dichloromethane to 5% methanol, to isolate the alkynyl-pyrrole intermediate. This intermediate is subsequently condensed with benzaldehyde derivatives under TFA catalysis to construct the dipyrromethene scaffold, oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and complexed with boron trifluoride diethyl etherate to give the final BODIPY. The end product is a long-wavelength fluorophore emitting at 640 nm, employed in confocal microscopy-based high-content screening assays under an academic-industrial collaboration. Quantum yield determination follows the relative method specified in ISO 17025 accredited laboratories using rhodamine 6G in ethanol as a standard, and the product’s photostability under continuous xenon arc lamp irradiation is evaluated against an in-house benchmark with an acceptance criterion of less than 15% loss of integrated emission intensity after 60 minutes, monitored by a calibrated spectrofluorometer.If Residual Bromine Content Exceeds 50 ppm in Sublimed OLED Host Materials, What Purification Variable Carries the Highest Leverage?Vacuum-deposited hot-exciton host materials for high-triplet-energy blue organic light-emitting diodes require brominated intermediates that must be converted entirely to carbon–carbon bonds before the sublimation step, because free bromide ions catalyze electroluminescence quenching under driving voltage. Here, 3-bromo-1-(triisopropylsilyl)-1H-pyrrole is engaged in a palladium-catalyzed direct heteroarylation with a carbazole-dibenzofuran electron-donor unit at a substoichiometric ratio designed to minimize unreacted halide: 0.98 equivalents of the bromopyrrole is added per equivalent of the dibenzofuran C–H substrate, using 2.0 mol% palladium pivalate and 4.0 mol% tris(o-methoxyphenyl)phosphine along with potassium carbonate (2.0 equivalents) and pivalic acid (0.3 equivalents) in a dimethylacetamide/toluene mixture at 120 °C for 36 hours. The low reactant ratio forces the reaction to reach an end point where the expensive heteroaryl donor is quantitatively consumed while the excess bromopyrrole that remains (~2%) is stripped via two consecutive silica gel columns eluted with toluene that has been dried over molecular sieves. The intermediate is then desilylated with cesium fluoride in dimethylformamide at room temperature to liberate the free N–H pyrrole, which undergoes a second C–N coupling to a chlorophenyl triazine acceptor fragment. The crude finished host compound is purified first by preparative thin-layer chromatography and then by single-zone gradient sublimation in a custom-built furnace at 330 °C under a dynamic vacuum of 8×10⁻⁸ Torr, with the sublimed material collected from the 230 °C zone. The process capability index Cpk for residual bromine content in eight consecutive sublimate lots is maintained above 1.33 with an upper specification limit of 50 ppm, a threshold validated by glow discharge mass spectrometry and correlated to operational lifetime decay (LT95) exceeding 600 hours at an initial luminance of 1000 cd/m². The adopted quality control framework references ASTM E1131-20 for the thermogravimetric analysis of decomposition onset temperature and IEC 62341-5-1:2013 for the service life testing of passive-matrix OLED displays, while in-house specifications define that the molecular ion isotopic pattern deviation from theoretical must remain within ±5% by high-resolution mass spectrometry to confirm effective debromination.
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3-Bromo-1-(triisopropylsilyl)-1H-pyrrole (CAS 876343-92-9) is a silated N-protected bromopyrrole deployed as a heteroaryl halide building block in palladium-catalyzed cross-coupling methodologies. Its molecular formula is C₁₃H₂₄BrNSi, with a molecular weight of 302.33 g/mol. At ambient temperature the material appears as a colorless to pale-yellow liquid exhibiting a density of approximately 1.09 g/mL. The bulky triisopropylsilyl (TIPS) group installed at the pyrrole nitrogen simultaneously suppresses competing N-arylation pathways and enhances oxidative addition regioselectivity at the C3 bromine position. The substrate’s utility spans medicinal chemistry programmes targeting kinase hinge-binder motifs and material science precursors that require sterically demanding heterocyclic cores with orthogonal deprotection handles.
The triisopropylsilyl (TIPS) moiety belongs to the class of sterically congested silyl groups that impart a kinetic barrier to nucleophilic attack at the heteroatom and to undesired metallation at the pyrrole α-positions. In comparison with the N-Boc, N‑SEM, N‑tosyl, and N‑trimethylsilyl analogues, the TIPS derivative offers a distinct operational envelope. The N‑Si bond remains intact under aqueous basic conditions that would hydrolyse trimethylsilyl analogues and is stable toward the Brønsted acidic media that cleave Boc groups. Deprotection is accomplished selectively using fluoride sources—typically tetra‑n‑butylammonium fluoride (TBAF, 1.0 M in THF at 25 °C) or hydrogen fluoride pyridine complex—without disruption of halogen substituents or ring integrity. Table 1 summarises the comparative stability and deprotection profiles.
| Protecting Group | Steric Demand (Cone Angle / ų) | Stability to 1 M NaOH (r.t.) | Stability to 1 M HCl (r.t.) | Typical Deprotection Reagent | Purity Attainable after Deprotection |
|---|---|---|---|---|---|
| Triisopropylsilyl (TIPS) | Cone angle ≈ 180° | Stable > 24 h | Stable > 6 h | TBAF (1.0 M in THF) | >95% (by HPLC) |
| tert-Butoxycarbonyl (Boc) | Small | Stable > 24 h | Cleaved < 0.5 h | TFA/CH₂Cl₂ (1:1) | >92% |
| 2-(Trimethylsilyl)ethoxymethyl (SEM) | Moderate | Stable > 12 h | Stable > 4 h | TBAF, then EDA | >90% |
| Trimethylsilyl (TMS) | Cone angle ≈ 128° | Cleaved < 5 min | Cleaved instantly | K₂CO₃/MeOH | >88% (with rapid workup) |
| p-Toluenesulfonyl (Ts) | Planar, bulky | Slow decomposition > 12 h | Stable | Na/Naphthalene or SmI₂ | >90% |
The electrophilic aromatic substitution chemistry of N‑protected pyrroles highlights the critical role played by the TIPS group’s steric footprint. During lithiation-electrophile trapping sequences employing lithium diisopropylamide (LDA) in tetrahydrofuran at −78 °C, the TIPS group strongly disfavours deprotonation at the C2 position, thereby preserving the C3‑bromine centre as the sole reactive site. This orthogonality is absent in the N‑Boc analogue, where competitive N‑Boc directed ortho‑metalation leads to a complex mixture of regioisomers. For fragment-based library syntheses requiring late‑stage functionalisation, this control translates into a measurable reduction in orthogonal purification requirements.
Release testing for custom synthesis campaigns conducted under ICH Q7 principles is anchored in a combination of chromatographic purity, elemental impurity profiling, and trace solvent analysis. The numerical acceptance criteria listed in Table 2 represent batch data accumulated over 36 consecutive production lots manufactured at the 15–50‑kg scale in a facility certified to ISO 9001:2015.
| Parameter | Method | Acceptance Criterion |
|---|---|---|
| Assay (HPLC, area%) | C18 column, UV 254 nm, ACN/water gradient | ≥ 97.0% |
| Largest Unknown Impurity | HPLC (as above) | ≤ 0.5% |
| Water Content | Karl Fischer coulometry (Ph. Eur. 2.5.32) | ≤ 0.1% |
| Residual Palladium (by-product) | ICP‑MS after acid digestion | ≤ 10 ppm |
| Residual Solvent — THF | GC‑FID (USP <467>) | ≤ 0.5% |
| Residual Solvent — n‑Hexane | GC‑FID (USP <467>) | ≤ 0.1% |
| Appearance | Visual inspection | Clear, colorless to pale yellow liquid |
| Density (20 °C) | Oscillating U‑tube (ISO 15212-1) | 1.085‑1.095 g/mL |
| Structural Identity | 1H NMR (400 MHz, CDCl₃) | δ 6.78 (d, J=2.8 Hz, 1H), 6.72 (dd, J=2.8, 1.6 Hz, 1H), 1.42 (sept, J=7.5 Hz, 3H), 1.08 (d, J=7.5 Hz, 18H) |
During scale‑up campaign monitoring under ICH Q7 conditions, batch rejection analysis identified that residual palladium content originating from coupling‑precursor synthesis represents a critical quality attribute not routinely included in standard specification sheets. Historical batch data indicate a failure rate of approximately 3% due to palladium excursions above the 10‑ppm threshold, typically traced to incomplete charcoal filtration of a palladium tetra‑kis(triphenylphosphine) catalyst. Process optimisation introduced a celite‑plug filtration step followed by a recirculating loop through a 10‑inch 0.5‑μm carbon block filter; this intervention reduced variability in palladium content from an initial σ of 4.2 ppm to 0.9 ppm across the subsequent 15 batches. The N‑silylation itself, performed in a jacketed stainless‑steel reactor with anchor agitator, demands strict control of the triisopropylsilyl chloride addition rate to avoid a temperature excursion beyond 10 °C. On one documented occasion, a temperature spike to 18 °C produced a yield penalty of 18% due to adventitious C‑silylation and pyrrole oligomerisation, underscoring the narrow processing window dictated by the competing electrophilic reactivity of the intermediate imidazolide.
In palladium‑catalysed cross‑coupling manifolds, the C3‑bromine substituent of 3-bromo-1-(triisopropylsilyl)-1H-pyrrole functions as an electrophilic handle whose oxidative addition rate is finely balanced between the sluggishness of the analogous 3‑chloro derivative and the thermal lability of the 3‑iodo variant. Competition experiments using equimolar mixtures of aryl bromides established that the TIPS‑protected bromopyrrole undergoes oxidative addition with Pd(PPh₃)₄ at a rate approximately 0.75 times that of bromobenzene under identical conditions (DMF, 80 °C, [Pd]=2 mol%). This modest retardation, attributed to the electron‑donating effect of the N‑silyl group, is offset by improved catalyst lifetime due to suppression of pyrrole‑derived inhibitory species.
Suzuki‑Miyaura couplings with arylboronic acids proceed reliably in degassed 1,2‑dimethoxyethane containing aqueous sodium carbonate (2 M, 3.0 equiv) at 80 °C for 8‑12 h. Under these conditions, isolated yields for 3‑arylated TIPS‑pyrroles typically exceed 85%. Crucially, the TIPS group survives the alkaline biphasic medium without hydrolysis, in marked contrast to the N‑trimethylsilyl analogue, which undergoes protodesilylation within 30 min under identical pH conditions. Buchwald‑Hartwig amination of the C3‑bromine centre with secondary amines (morpholine, piperidine) requires a switch to the Pd₂(dba)₃/Xantphos precatalyst system and rigorous exclusion of oxygen; even 50 ppm dissolved O₂ triggers catalyst deactivation via phosphine oxidation and leads to 30‑40% lower conversion. The steric environment created by the TIPS group slows amination at the ortho‑pyrrole C2 and C4 positions, preventing the double amination defect that commonly plagues N‑unprotected bromopyrrole chemistry.
Moisture ingress constitutes the primary degradation vector for 3-bromo-1-(triisopropylsilyl)-1H-pyrrole. Prolonged exposure to ambient relative humidity above 60% results in gradual hydrolysis of the Si–N bond, liberating free 3‑bromopyrrole and triisopropylsilanol with a half‑life of approximately 18 h at 25 °C (measured by FT‑IR monitoring of the ν(Si-O) band at 1085 cm⁻¹). Storage specifications therefore mandate sealed containers under an inert atmosphere of argon (99.999%) or dry nitrogen with a septum integrity check following each withdrawal. Recommended storage temperature is 2‑8 °C; at room temperature under argon, re‑evaluation is advised after 6 months.
Thermal hazard assessment by differential scanning calorimetry (DSC, ASTM E537-20) reveals an onset of exothermic decomposition at 182 °C (heating rate 10 °C/min), proceeding with an energy release of ±450 J/g. This decomposition is presumably triggered by homolytic Si–N bond cleavage releasing gaseous isobutylene and silanol fragments. Bulk shipment must avoid local hot spots; packed containers are rated for a maximum exposure of 60 °C for periods not exceeding 4 h. Pressure build‑up in glass vials sealed with silicone‑based septa has been traced to fluoride‑promoted deprotection arising from trace HF released during septum hydrolysis. Replacement with PTFE‑lined crimp caps eliminated the phenomenon across a sample size of 2,400 vials monitored over 12 months.
Incompatibilities include strong oxidising agents (vigorous, exothermic reaction), fluoride salts (immediate desilylation), and concentrated aqueous acids (catalyse polymerisation of deprotected 3‑bromopyrrole). Personal protective equipment during handling comprises impervious nitrile gloves with a minimum thickness of 8 mil (EN 374-1:2016 type A), safety goggles, and a P2‑rated half‑mask respirator (EN 149:2001+A1:2009) where local exhaust ventilation does not maintain airborne vapour below 0.5 ppm as a continuous 8‑hour TWA. Waste disposal routes must account for the halogen content and the potential for organosilicon accumulation in incinerator flue linings.
