Thiazole, 2-Bromo-5-Nitro-
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HS Code |
629313 |
| Chemical Formula | C3HBrN2O2S |
| Molecular Weight | 225.02 g/mol |
| Appearance | Solid (likely yellow - colored, typical for nitro - containing compounds) |
| Melting Point | Data needed |
| Boiling Point | Data needed |
| Solubility In Water | Low solubility, due to non - polar thiazole ring and hydrophobic groups |
| Solubility In Organic Solvents | Soluble in polar organic solvents like DMSO, DMF |
| Density | Data needed |
| Flash Point | Data needed |
| Vapor Pressure | Very low at room temperature |
As an accredited Thiazole, 2-Bromo-5-Nitro- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 2 - Bromo - 5 - nitro - thiazole in 100g sealed bottles for chemical packaging. |
| Shipping | 2 - Bromo - 5 - nitro - thiazole is shipped in well - sealed, corrosion - resistant containers. They are carefully packaged to prevent breakage and leakage. Shipments follow strict chemical transport regulations to ensure safety during transit. |
| Storage | Thiazole, 2 - Bromo - 5 - Nitro - should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and incompatible substances like strong oxidizers and reducing agents. Store it in a tightly sealed container, preferably made of corrosion - resistant materials, to prevent leakage and exposure to air or moisture. |
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Installations handling bulk 2-Bromo-5-Nitrothiazole must account for its dual reactivity profile: the C2 bromine serves as a leaving group in nucleophilic aromatic substitution and transition-metal-catalyzed cross-couplings, while the C5 nitro group withdraws electron density, activating the C2 position and simultaneously providing a site for reduction. The solid exhibits moderate lability under ambient moisture, necessitating storage at ≤ 60% RH. Incompatibility with strong aqueous bases is documented due to ring-opening hydrolysis at elevated temperatures exceeding 80°C. Palladium-Catalyzed C2 Arylation in Nitazoxanide Intermediate AssemblySynthesis of the 2-acetamido-5-nitrothiazole pharmacophore via the bromide precursor avoids the low-yielding nitration of 2-aminothiazole. In a standard Suzuki-Miyaura protocol, 2-Bromo-5-Nitrothiazole couples with 4-acetamidobenzeneboronic acid pinacol ester under an inert argon blanket. A catalyst system of Pd(PPh₃)₄ at 2.0 mol% loading in a 3:1 DME/2.0 M Na₂CO₃ (aq) mixture is maintained at 82°C for 16 hours. HPLC monitoring (C18 column, 254 nm) confirms consumption of the bromide. Post-reaction, the organic layer is washed with brine, dried over anhydrous MgSO₄, and concentrated. The crude residue is recrystallized from ethanol to afford 2-(4-acetamidophenyl)-5-nitrothiazole in yields typically ranging between 78-85% at 0.5 mol scale. Process failure modes include protodebromination under wet conditions or catalyst poisoning by sulfide impurities, which are mitigated by pre-treating the bromide with activated carbon prior to reaction. Production-scale batch reactors require hastelloy C-22 wetted surfaces due to trace HBr liberation at prolonged reaction times. Exotherm onset during catalyst activation is critical; a 5°C deviation above the setpoint accelerates homocoupling of the boronic acid, reducing yield by 10-15% and generating difficult-to-remove biphenyl impurities that persist in the final API unless preparative HPLC is deployed. The 5-nitro group remains intact throughout; nitazoxanide’s final acetylation step is subsequently performed on the heterocyclic core under neat acetic anhydride at 45°C. What Limits Selective C5 Nitro Reduction in the Presence of the C2 Bromine Leaving Group?Preserving the C2 bromine while reducing the C5 nitro to the 5-amino derivative is a synthetic challenge due to the pronounced lability of the heterocyclic bromide under hydrogenolytic conditions. Standard catalytic hydrogenation (Pd/C, 10 wt%, 1 atm H₂, ethanol) results in extensive hydrodebromination within 30 minutes, contaminating the product with 2-amino-5-aminothiazole. Selective reduction is achieved using non-hydrogen-transfer methods. Iron powder in aqueous ammonium chloride at 65°C provides the 2-bromo-5-aminothiazole intermediate without debromination. The heterogeneous reaction is exothermic; controlled addition of HCl to maintain pH 4.5-5.0 is necessary to keep iron species in solution and prevent passivation. Work-up involves basification with NH₄OH to pH 9, extraction with ethyl acetate, and vacuum distillation. Batch yield of the free base is 82%. The amine must be stored under nitrogen at -20°C as it discolours rapidly via aerobic oxidative coupling at ambient temperature. This intermediate is then employed in diazotization and Sandmeyer-type sequences to install alternative C5-functionality without eliminating the bromine handle.
In electrophilic bromination sequences where the nitro group has been reduced, the 2-bromo-5-aminothiazole serves as a versatile scaffold. Direct iodination or chlorination at the 4-position is achievable, though published data for this specific ring configuration indicates substantial reliance on experimental screening rather than predictive methods. The amine group must be protected as the tert-butyl carbamate (Boc) before further C-functionalization to avoid competing N-arylation. Deprotection is carried out with 4N HCl in dioxane at 0°C to suppress thiazole ring cleavage. Construction of the 5-Nitrothiazole Moiety in Pesticide Lead Optimization2-Bromo-5-Nitrothiazole undergoes copper-mediated Ullmann coupling with substituted phenols to generate diaryl ethers screened as protoporphyrinogen oxidase (PPO) inhibitors. Reaction conditions require anhydrous DMF, K₂CO₃ as base, and CuI at 10 mol%. The mixture is heated at 110°C under nitrogen for 24 hours. In glass-lined reactors, critical process parameters include strict moisture exclusion; water content > 0.05% in the solvent stream leads to hydrolysis of the C2-bromine to the hydroxy analogue, which subsequently forms dimeric ethers. Following cooling to ambient temperature, the reaction is quenched with 5% aqueous ammonia and extracted into MTBE. The 2-((4-chlorophenoxy)-5-nitrothiazole product crystallizes from hexane/ethyl acetate (9:1) as pale yellow needles. Herbicidal activity against Amaranthus retroflexus in greenhouse trials has been correlated with the presence of the intact nitro group; replacement with cyano or trifluoromethyl diminishes contact activity by an order of magnitude. Physical blending of the active ingredient into suspension concentrate (SC) formulations reveals a cold storage instability specific to this heterocyclic bromide. Formulations stored at 0°C for 14 days show Ostwald ripening with crystal growth exceeding 50 microns. This is rectified by wet-milling the technical material with an anionic polymeric dispersant and incorporating 5% glycerol as an antifreeze agent, maintaining particle size distribution (D90) at ≤ 3.0 µm per ASTM E2490-08 (2020) assessments. Crop safety profiling dictates a differentiated application rate for post-emergence turf uses, defined by ISO 14419:2010 liquid retention testing. Runoff concentrations exceeding 200 ppb in artificial rain tests correlate with phytotoxicity to St. Augustinegrass, establishing a strict upper window for foliar residue limits at 0.05 kg a.i./ha per application. Where Does the Nitro-Activated Halogen Outperform Standard 2-Bromothiazole in Materials Synthesis?The enhanced electron deficiency conferred by the 5-nitro group accelerates aromatic nucleophilic substitution (SNAr) at the C2 position by a factor of approximately 10³ compared to unsubstituted 2-bromothiazole. This rate acceleration is exploited in the preparation of thiazole-based nonlinear optical (NLO) chromophores. In a donor-π-acceptor architecture, the thiazole ring serves as the auxiliary acceptor. Reaction with 4-(dimethylamino)thiophenol in DMSO at 25°C proceeds quantitatively within 2 hours using 1.1 eq of cesium carbonate as base, whereas the non-nitrated analogue requires heating to 80°C and 24 hours. The resulting 2-((4-(dimethylamino)phenyl)thio)-5-nitrothiazole is purified by silica gel chromatography (hexane/chloroform, 3:2). Thermal stability under nitrogen, as assessed by TGA (ASTM E1131-20), reveals a decomposition onset at 265°C, with a 5% weight loss at 285°C. Hyperpolarizability (β) measurements via hyper-Rayleigh scattering at 1064 nm indicate a static value of 45 × 10⁻³⁰ esu, suitable for electro-optic polymer guest-host systems. Poling of the chromophore in a polycarbonate host matrix at 165°C with an applied field of 80 V/µm yields an electro-optic coefficient (r33) of 12 pm/V at 1310 nm. Temporal stability is limited by the chromophore’s moderate thermal mobility; relaxation to 80% of the initial r33 value occurs within 300 hours at 85°C. This restricts device operating conditions to ≤ 70°C.
A distinct utility emerges in photoacid generator (PAG) studies for photolithography. Irradiation of 2-Bromo-5-Nitrothiazole at 365 nm in acetonitrile yields a C2 cation equivalent, releasing HBr with a quantum yield of 0.12 at this wavelength. This property is utilized in two-component epoxy photoresist systems where the liberated acid initiates cationic ring-opening polymerization of bis(cycloaliphatic) epoxide resins. Imaging tests on a Karl Suss MA6 aligner with a post-exposure bake of 95°C for 3 minutes resolve features of 5 µm line/space. Maintaining shelf stability in formulated material prior to exposure requires incorporation of a base quencher, typically 0.5 wt% trioctylamine, to prevent dark polymerization. Pot life extends from 8 hours to over 96 hours at 25°C with this additive. However, at loadings above 2.0 wt%, the amine quencher reacts directly with the thiazole bromide via SNAr, consuming the PAG and rendering the resist photospeed impractically slow. Structural Modifications Avoiding Amine Adducts in Oilfield Corrosion Inhibitor FormulationsAttempts to utilize the bromide in formulating quaternary ammonium corrosion inhibitors for HCl-stimulated carbonate reservoirs demonstrate a rapid failure pathway absent in standard benzyl chloride intermediates. Direct nucleophilic attack by fatty tertiary amines (e.g., C12-C14 dimethylamines) on the C2-Br center occurs smoothly in isopropanol at 60°C, yielding the quaternary thiazolium salt. However, coupon testing under NACE TM0193-2019 conditions (15% HCl, carbon steel C1018, 93°C) reveals that the 5-nitro substituent is readily reduced to an unstable amino species by the metallic surface, triggering polymerization and formation of a non-protective film that increases localized pitting. Inhibitor loading of 2000 ppm results in a corrosion rate of 450 mpy, compared to 25 mpy for a standard quinoline-based control. The 5-nitro group is conclusively identified as incompatible with downhole conditions exceeding 80°C in acidic reducing environments, limiting the bromide’s scope to surface facility injection where redox potentials remain above that required for nitro group transformation. |
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A heterocyclic scaffold designated systematically as 2-bromo-5-nitro-1,3-thiazole, assigned CAS 3034-48-8 and commonly catalogued under the synonym 2-bromo-5-nitrothiazole, constitutes a pale yellow crystalline solid that has gained strategic importance as a difunctional synthon in medicinal chemistry and agrochemical discovery. Its substitution pattern—a bromine atom at the C2 position and a strongly electron-withdrawing nitro group at C5—activates the ring for selective cross-coupling while simultaneously anchoring a versatile handle for downstream reduction, nucleophilic aromatic substitution, or cyclocondensation. Production-scale demand for this intermediate has been driven by its role in the synthesis of kinase-targeted oncology candidates, next-generation neonicotinoid analogues, and thiazole-containing conjugated materials for organic electronics. Typical shipments are packaged under argon in amber glass bottles of 25 g, 100 g, or 500 g, with custom lots available in fiber drums lined with antistatic polyethylene for quantities up to 25 kg.
The oxidative addition step of Pd(0) into the C–X bond governs catalyst turnover frequency in Suzuki-Miyaura, Buchwald-Hartwig, and Sonogashira couplings. The C–Br bond dissociation energy in 2-bromo-5-nitrothiazole is estimated at approximately 285 kJ mol⁻¹, placing it between the substantially more inert C–Cl analogue (approx. 327 kJ mol⁻¹) and the labile but light-sensitive C–I derivative (approx. 213 kJ mol⁻¹). In practical terms, 0.5–1.0 mol% Pd(PPh₃)₄ in anhydrous DME with 2.0 eq. aqueous K₂CO₃ achieves full conversion with phenylboronic acid within 4 h at 65 °C for the bromo compound; the corresponding 2-chloro-5-nitrothiazole requires 2.0 mol% catalyst, a biarylphosphine ligand such as SPhos, and temperatures of 85–100 °C to reach comparable rates. Conversely, the iodo derivative suffers from rapid homocoupling and protodehalogenation under basic conditions, generating up to 12–18% des-halo impurity that co-elutes with the product during flash chromatography. These differences, verified across multiple pilot campaigns in 500 L glass-lined reactors, position the brominated thiazole as the optimum balance of reactivity, stability, and impurity control for a broad portfolio of palladium-mediated arylations.
Operation in a manufacturing environment imposes constraints beyond synthetic chemistry. When aliquots of 2-bromo-5-nitrothiazole were stored in clear borosilicate glass under ambient fluorescent lighting (400–700 nm, 500 lux) over a 10-day period, HPLC area-percent purity dropped from 98.9% to 93.4%, with a corresponding deepening of color from pale yellow to orange-brown. LC-MS analysis identified the primary degradation pathway as photo-promoted debromination yielding 5-nitrothiazole and trace oligomeric species. Consequently, all bulk packaging must employ amber glass or opaque HDPE containers, and charging into reactors is conducted under subdued red light when feasible. The solid is hygroscopic; exposure to relative humidity above 60% at 25 °C increases moisture content by 0.8% w/w within 24 h, measured by Karl Fischer coulometric titration per ASTM E203. Process chemists routinely pre-dry incoming lots in a vacuum tray oven at 35 °C and ≤10 mbar for at least 12 h before any palladium-catalyzed step, because residual water quenches boronic acids and retards transmetalation. Differential scanning calorimetry at 10 °C min⁻¹ under nitrogen reveals an endothermic melt with a sharp onset at 48.5–51.2 °C followed by an exothermic decomposition event initiating at 234 °C (peak at 267 °C, energy release 1.12 kJ g⁻¹). This exotherm is more energetic than that of 2-chloro-5-nitrothiazole (decomposition onset 252 °C, 0.67 kJ g⁻¹) and necessitates careful temperature control during solvent removal in batch distillations; engineering controls specify jacket temperatures no higher than 70 °C on rotary evaporators processing more than 200 g of residue. Incompatibility with strong nucleophiles manifests rapidly: addition of sodium methoxide to a 0.1 M solution in THF at 20 °C triggers an immediate color change and exothermic discharge, with the corresponding C2 methoxide derivative precipitating alongside intractable tar if the addition rate exceeds 0.5 mL min⁻¹. No such violent response is noted with secondary amines below 40 °C; acylation of piperazine proceeds smoothly and is frequently employed for library synthesis in early-phase drug discovery.
Commercial access is structured around three distinct grades, each governed by a specific set of analytical release criteria. The table below collates the parameters applied at an ISO 9001:2015 production site operating under ICH Q7 GMP guidance for pharmaceutical intermediates.
| Parameter | Research Grade Limit | High-Purity Grade Limit | Test Method |
|---|---|---|---|
| Assay (HPLC, area%) | ≥ 98.0% | ≥ 99.0% | In-house method; C18, 254 nm, MeCN/water + 0.1% TFA |
| Water content | ≤ 0.5% | ≤ 0.2% | Karl Fischer, ASTM E203 |
| Residual solvents | ≤ 0.5% total | ≤ 0.2% total; no single Class II solvent above ICH Q3C option 2 limits | GC-HS, USP <467> Procedure A |
| Melting range (capillary) | 48–52 °C | 49–51 °C | Ph.Eur. 2.2.14 |
| Appearance | Pale yellow crystalline powder | Pale yellow crystalline powder, free of dark particles | Visual inspection under 1000 lux against white tile |
| Heavy metals (as Pb) | ≤ 20 ppm | ≤ 10 ppm | Ph.Eur. 2.4.8 Method C |
| Sulfated ash | ≤ 0.5% | ≤ 0.1% | ASTM D874 |
The principal impurity in sub-optimal lots is the debromination product 5-nitrothiazole, which is suppressed through storage procedures already described. Regioisomeric contamination with 2-bromo-4-nitrothiazole has been detected by ¹H NMR (diagnostic singlet at δ 8.05 vs. δ 8.32 for the desired isomer) and can originate from nitration of 2-bromothiazole when mixed-acid conditions are not stringently regulated below −5 °C. A robust synthetic process employing acetyl nitrate in acetic anhydride at −10 to −5 °C generates the 5-nitro isomer with regio-isomeric purity exceeding 97:3.
The electron-deficient nature of the thiazole ring permits selective reduction of the nitro group without concomitant displacement of the bromine, provided hydrogen pressure and catalyst activity are carefully controlled. A representative procedure adopted on 100 L scale uses 5% palladium-on-carbon (water-wet, 50% loaded, 0.2 mol% Pd relative to substrate) in ethanol at 1.2 bar hydrogen and 25 °C. After 6 h of vigorous agitation with a gas dispersion impeller, conversion exceeds 99%, affording 2-bromo-5-aminothiazole as an off-white solid after filtration through a celite pad. In contrast, the 4-nitro isomer requires 3.0 bar hydrogen and exhibits 8–15% over-reduction to 2-bromo-4-aminothiazoline, a ring-saturated impurity that demands orthogonal purification. The aminothiazole derived from the 5-nitro compound serves as a strategic pivot for diazotization: treatment with 1.1 eq. NaNO₂ in 48% HBr at 0 °C followed by CuBr‑promoted Sandmeyer reaction yields 2,5-dibromothiazole in 82% isolated yield, a critical monomer for organic semiconducting polymers. This sequence illustrates a key differentiator from the regioisomeric series; starting from 2-bromo-4-nitrothiazole, the analogous Sandmeyer route generates 2,4-dibromothiazole, which has historically been less utilized in polymer electronics due to steric hindrance from the adjacent bromine atoms during Stille polycondensation.
Variability in commercial sourcing has become a decisive factor in selecting a halogenated thiazole for kilogram-scale process development. Lead times for 2-bromo-5-nitrothiazole from qualified producers in China and India average 4 to 6 weeks for a 50 kg batch with full certificates of analysis. By contrast, 2-iodo-5-nitrothiazole often carries 12 to 16-week lead times and a cost multiplier of 2.7× to 4.3× per mole, largely attributed to the higher precious-metal catalyst loadings and cryogenic conditions required for its synthesis. Users transitioning from the chloro derivative to the bromo derivative in established manufacturing chains report a net reduction in cycle time of 18–25% for Suzuki coupling stages, validated by parallel runs in 2000 L reactors using Inconel heating coils. Nevertheless, the chloride remains economically preferred for simple SNAr telescoped sequences where the reaction is conducted in refluxing DMF (153 °C) with K₂CO₃; under these forcing conditions, the bromide generates 9–14% more impurity related to nucleophilic displacement at the bromine position by adventitious water, as tracked by in-process HPLC samples drawn every 30 min.
Regioisomeric shifting of the nitro group from C5 to C4 fundamentally redistributes the π-electron density of the thiazole nucleus, impacting both electrophilic aromatic substitution and charge-transfer behavior. In 2-bromo-5-nitrothiazole, the computed (DFT, B3LYP/6-311+G**) atomic charges place the highest positive potential at C4, rendering it the primary site for nucleophilic attack; this regiochemistry has been exploited to install alkylamino substituents at C4 while preserving the nitro and bromine functionalities, a motif recurrent in ROCK kinase inhibitor scaffolds. Flipping the nitro to C4 diverts electrophilic reactivity to C5, opening pathways to 2-bromo-4-nitro-5-arylthiazoles through direct C–H functionalization. Additionally, the 5-nitro isomer has found application as a dipolarophile in [3+2] cycloadditions with azomethine ylides; the LUMO energy is lowered sufficiently (−2.89 eV calculated) to engage without Lewis acid catalysis, while the 4-nitro analogue (LUMO −2.61 eV) demands microwave irradiation. These electronic differences translate into tangible material parameters: thin films of donor–acceptor polymers containing 2,5-thiazole connectivity exhibit bathochromic shifts of 45–70 nm in UV-vis absorption relative to their 2,4-linked counterparts, a result confirmed via spin-coated films on ITO/glass substrates measured under an inert atmosphere with an integrating sphere spectrophotometer.
Characterization of the bulk substance by the routine analytical suite confirms structural identity with high fidelity. Proton NMR in CDCl₃ (400 MHz) records a single aromatic resonance at δ 8.32 (s, 1H), strongly deshielded by the geminal nitro group; the absence of additional signals in the aromatic window is diagnostic for the absence of regioisomeric contamination. ¹³C{¹H} NMR (100 MHz) displays signals at δ 148.5 (C5), 142.7 (C2), and 131.4 (C4). Electron impact GC-MS (column: 30 m × 0.25 mm DB-5 MS, 1.0 µm film) yields a retention index of approximately 1180 and a molecular ion at m/z 208/210 ([M]⁺, characteristic 1:1 bromine isotope cluster), with major fragmentation ions at m/z 162 (loss of NO₂) and m/z 129 (loss of Br). Long-term stability testing under ICH climatic zone II conditions (25 °C / 60% RH, 36 months) in double polyethylene bags inside fiber drums shows 0.15% assay loss per annum when sealed under nitrogen with 2 g of molecular sieve desiccant.
