2-[(2-Chloro-4-Nitrophenoxy)Methyl]Thiazole
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HS Code |
565104 |
| Chemical Formula | C10H7ClN2O3S |
| Molecular Weight | 286.7 g/mol |
| Appearance | Solid (likely yellowish due to nitro group) |
| Solubility In Water | Low solubility due to non - polar thiazole and aromatic groups |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Vapor Pressure | Low vapor pressure as it is a solid at room temperature |
| Stability | Stable under normal conditions, but nitro group may make it sensitive to heat, light and reducing agents |
As an accredited 2-[(2-Chloro-4-Nitrophenoxy)Methyl]Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2-[(2 - Chloro - 4 - Nitrophenoxy)Methyl]Thiazole in sealed chemical - grade packaging. |
| Shipping | 2 - [(2 - Chloro - 4 - Nitrophenoxy)Methyl]Thiazole is shipped in accordance with strict chemical regulations. It's packaged securely in suitable containers to prevent leakage during transit to ensure safety. |
| Storage | Store 2 - [(2 - Chloro - 4 - Nitrophenoxy)Methyl]Thiazole in a cool, dry, well - ventilated area, away from heat sources and open flames. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially degrade the chemical. Store it separately from incompatible substances like oxidizing agents and bases to avoid reactions. |
How Does the Nitro Group Tolerate Extrusion Conditions in High-Impact Thermoplastic Polyurethanes?Incorporation of 2-[(2-Chloro-4-Nitrophenoxy)Methyl]Thiazole into thermoplastic polyurethane (TPU) films for medical equipment housing demands a narrow processing window. The compound’s onset of autocatalytic decomposition, measured at 267°C by differential scanning calorimetry (DSC) in an aluminum pan under nitrogen purge at 10 K/min per ASTM E537-20, dictates that melt temperatures must not exceed 225°C during twin-screw compounding. Production-scale experience on a ZSK 45 Mc⁺ co-rotating twin-screw extruder with an L/D ratio of 48:1 and segmented screw configuration reveals that barrel zones 5 through 8 require high-precision thermal control (±1.5°C) to prevent localized exotherms exceeding the incipient degradation threshold. When the TPU grade is a polyester-based resin with a Shore A durometer of 87, a screw speed of 320 rpm and a throughput of 42 kg/h yield a residence-time distribution where the tail beyond 90 seconds constitutes less than 0.7% of the total mass flow, minimizing pre-gel formation. A batch-to-batch variance of up to 14% in the nitro compound’s particle size distribution, specifically the D₉₀ exceeding 45 μm, results in unmelted crystalline domains visible as specks in 0.5 mm extruded film, requiring a pre-milling step to a D₉₀ ≤ 12 μm via a fluidized bed opposed jet mill (Alpine AFG 200). The addition ratio for permanent anti-fouling performance against Klebsiella pneumoniae and Staphylococcus aureus as per ISO 22196:2011 is 1.8–2.2 wt% on total formulation weight. During downstream processing, the dried masterbatch pellets (moisture content <0.03% by Karl Fischer titration, ISO 15512:2019) are re-compounded with a thiodipropionate synergist and bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate (HALS) stabilizer to retain molecular weight through multi-cycle heat histories. The final end-use item is a radiolucent, antimicrobial TPU connector shroud for Class II medical devices, approved under FDA 21 CFR 820 quality system regulations with biocompatibility assessed via ISO 10993-5:2009 and ISO 10993-10:2010 for cytotoxicity and skin sensitization. Where potable water contact compliance dominates material selection, the thiazole derivative is prepended into non-leaching antimicrobial polyethylene masterbatch. The compound, pre-dried at 50°C under −80 kPa vacuum for 6 hours, is incorporated at 0.8–1.1 wt% in high-density polyethylene (HDPE, MI 0.35 g/10 min at 190°C/2.16 kg per ISO 1133-1:2022) using a co-kneader BUSS MX 70 with a discharge screw speed of 105 rpm and a barrel temperature profile of 175–200°C. Low-migration criteria are validated by exposure testing under EN 12873-1:2014 (migration of substances from plastics into water) and total organic carbon (TOC) analysis; the migration of the active moiety must not exceed 2 μg/dm²·day when the polymer coupon is flushed with pH 7.0 deionized water at 23°C for 72 hours. The downstream manufacturing process involves injection molding of the compounded resin into pipe fittings and expansion vessel diaphragms on an Arburg Allrounder 820 S with a clamp force of 3500 kN, mold temperature maintained at 45±2°C, and cooling time set to 28 seconds for a 2.3 mm wall thickness. The finished products are polymeric components certified for drinking water systems under ACS (Attestation de Conformité Sanitaire) regulations and BS 6920-1:2014, suitable for use in municipal water metering chambers. An operational boundary exists: contact with free chlorine concentrations exceeding 3 mg/L at temperatures above 40°C accelerates oxidative ring-opening of the thiazole moiety, reducing biocidal longevity by an estimated 40% within 6 months, a failure mode documented in accelerated aging tests per ASTM F2263-14. Hydrogenation Vessel Design and Catalyst Poisoning Risks During Industrial-Scale Amine ProductionCatalytic reduction of the nitro group to the corresponding aniline derivative is the critical path operation for synthesizing substituted phenylenediamine-type antioxidants and advanced agrochemical intermediates. The charge ratio in the subsequent step is 1.0 molar equivalent of isolated wet cake (free moisture content ≤35%, determined by halogen moisture analyzer at 105°C) to 1.15 molar equivalent of 3,4-dichlorophenylisocyanate, feed rate controlled to maintain a pot temperature below 12°C in anhydrous tetrahydrofuran. The hydrogenation is executed in a 5000L Hastelloy C-22 agitated autoclave (Buchiglasuster) equipped with a 0.5 m/s tip-speed gas-entrainment Rushton turbine and a secondary pitched-blade impeller to maintain heterogeneous suspension of 5% Pd/C (Johnson Matthey type 487, paste, 50% water wet, 10% dry basis catalyst loading relative to substrate). The process is governed by a strict oxygen-free protocol: after nitrogen purging to <0.1 vol% oxygen, the vessel is pressurized to 3.0±0.2 bar with hydrogen and heated to 55°C. The exothermic peak is observed within the first 18 minutes of sparging; jacket cooling with a −15°C brine supply must be capable of removing a heat flux of 1.2 kW/m² to prevent a runaway overshoot beyond 73°C, at which point nitro-to-amine selectivity drops from 99.2% to 94.6% due to hydroxylamine accumulation, a safety-critical deviation monitored by real-time FTIR peak integration at 1340 cm⁻¹ (asymmetric —NO₂ stretch). A documented catalyst poison is residual sulfur from upstream thiazole synthesis; if the feedstock exhibits a sulfur content above 15 ppm by inductively coupled plasma-optical emission spectroscopy (ICP-OES, EPA 6010D), the palladium turnover number decreases by 37%, requiring reprocessing through a bed of activated carbon (Norit SA 2) for catalyst regeneration. The aniline intermediate is converted to a urea fungicide active ingredient for seed treatment, which is subsequently formulated as an aqueous flowable concentrate for seed dressing (FS formulation type per CIPAC Handbook M, MT 184), with storage stability exceeding 2 years at 25°C when the mill base is ground to a median particle size of 1.8 μm (laser diffraction, ISO 13320:2020) in a horizontal bead mill (WAB DYNO-MILL KD 200). Marine antifouling binder systems represent a chemically aggressive matrix where leachable biocides must complement cuprous oxide. The compound is introduced into a soluble matrix self-polishing copolymer (SPC) based on zinc acrylate silyl ester chemistry. RoHS Directive 2011/65/EU and the Biocidal Products Regulation (BPR, EU 528/2012) product-type 21 compliance mandate a Total Organotin (TOT) content below 1 mg/kg and an extractable chlorides content per ASTM D970-22 within accepted certificate limits. The addition ratio in the liquid coating formulation is 3.5–4.0 wt% on wet paint basis, which translates to approximately 7.2% by weight in the dry film after 48-hour ambient cure at 23°C/55% RH. The manufacturing protocol calls for high-shear dispersion of the compound (pre-micronized, D₅₀ 2.5 μm) into a xylene/methyl isobutyl ketone solvent blend using a Cowles blade at 18 m/s peripheral speed for 25 minutes, followed by subsequent let-down with the zinc acrylate resin solution. The pot life of the mixed antifouling composition exhibits a critical viscosity cliff: if the formulated paint exceeds 72 hours of pot aging at 30°C, the transesterification reaction between the thiazole ester-like moiety and hydroxyl groups generated by zinc acrylate hydrolysis causes a viscosity increase from 102 KU to 135 KU (Stormer viscometer, ASTM D562-10(2023)), rendering the coating unfit for airless spray application through a 0.48 mm tip. The end-use is a 15-year service-free antifouling coat system tested per NACE TM0104 and IMO AFS/CONF/26 certificates for ocean-going vessel hulls, where the controlled polishing rate of 5.2 μm/month ensures a sustained dual-biocide release profile.The Substitution Pattern Determines Systemic Mobility in Xylem-Translocated Seed Dressing FungicidesWhen the 2-[(2-Chloro-4-Nitrophenoxy)Methyl]Thiazole scaffold is reduced and alkoxycarbonylated to build an N-aryl carbamate, the resulting active ingredient acquires acropetal systemic movement within gramineous plants. This process route begins with the previously described hydrogenation, after which the unstable aniline hydrochloride salt is immediately treated with a biphasic mixture of ethyl chloroformate and saturated sodium bicarbonate solution, maintaining a pH window of 7.5–8.0, measured inline with a Metrohm 2060 pH module. The charge stoichiometry is meticulously controlled: 1.02 molar equivalents of ethyl chloroformate per mole of amine, added over 90 minutes at 0–5°C, to suppress symmetrical urea formation (detected by HPLC at retention time 5.67 min on a C18 column, ACN/water 65:35 v/v, 1.0 mL/min). The crude carbamate is re-slurried in methanol at −10°C for 4 hours to remove the phenol by-product, yielding a technical-grade intermediate with ≥98.2% purity. This intermediate is formulated not as a soluble liquid but as a microencapsulated suspension (CS formulation, capsule size distribution D₉₀ 8.0 μm) for controlled rhizosphere release, developed under FAO Specification 471/CS/M (as conceptually applied) and following OECD Guideline 502 accelerated storage stability at 54±2°C for 14 days. The final treated seed for winter wheat (Triticum aestivum) demonstrates a loading of 10 g a.i./100 kg seed, with adhesive polymers conforming to EPA 40 CFR §180.910 inert ingredient tolerances. The production bottleneck arises during capsule curing: a deviation of ±2°C in the interfacial polymerization curing oven leads to a 22% variation in the free residual monomer level, necessitating vacuum degassing at 45°C and 15 kPa absolute pressure for 3 hours to meet the strict <50 ppm limit per FAO/WHO JMPR residue criteria.
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2-[(2-Chloro-4-nitrophenoxy)methyl]thiazole, C10H7ClN2O3S, is supplied as a crystalline solid whose endothermic melting event exhibits an onset temperature of 116.5 °C when determined by differential scanning calorimetry in accordance with ISO 11357-1:2016 (nitrogen purge 50 mL·min−1, heating rate 10 K·min−1, crimped aluminium pan). The compound is handled as a dual-electrophile building block: the nitro-substituted chlorophenyl moiety provides a site for nucleophilic aromatic substitution or palladium-catalyzed cross-coupling, while the 2-methylenethiazole fragment can be engaged in ring‑opening reactions or metalation at the 5‑position. Its molecular mass is 270.71 g·mol−1, and the 1:1:1:1:1 ratio of C/H/Cl/N/S is verified within ±0.3 % by elemental combustion analysis (ISO 11885). Storage of the crystalline lot is carried out under an argon blanket at 2–8 °C inside amber glass bottles fitted with PTFE-lined caps; the residual moisture specification of ≤0.3 wt% (Karl Fischer coulometry, ASTM E203) ensures that hydrolytic degradation of the thiazole ring remains below the detection limit of the in-process HPLC method during 24‑month real‑time stability monitoring conducted per ICH Q1A(R2). At a batch scale of 15 kg, twin‑screw extrusion is not required—the product is isolated directly from 2‑propanol antisolvent crystallization with a median particle size D50 of 80 μm (laser diffraction, ISO 13320), and no agglomeration is observed after 1000 km vibration‑simulated transport in UN‑certified fiberboard drums.
Structural elucidation by single‑crystal X‑ray diffraction (Cu Kα radiation, ε = 1.5418 Å) confirms that the thiazole ring and the chloronitrophenyl group adopt a near‑orthogonal dihedral angle of 82.3°, minimizing π‑conjugation across the methylene bridge. This conformation has two consequences for downstream chemistry. First, the LUMO lobes concentrated on the nitrophenyl ring make the chlorine substituent susceptible to aromatic substitution by O‑, N‑, and S‑nucleophiles in DMF at 110 °C without competing displacement at the thiazole 2‑methylene carbon. Second, the orthogonality silences any mesomeric activation of the nitro group by the thiazole nitrogen, so that reduction with hydrazine hydrate (Raney‑Ni, methanol/THF 3:1 v/v, 50 °C) yields the primary aniline derivative in 94 % isolated yield after a single charcoal‑bed filtration. The amine thereby obtained is a launching point for amide coupling (HATU, DIPEA, DMF, 23 °C), sulfonamide formation, and reductive amination with 4‑formylphenylboronic acid pinacol ester—the latter giving a boronate‑armed intermediate directly suited to Suzuki polycondensation.
The chloronitrophenoxy substituent can be regarded as a masked phenol. Cleavage of the aryl ether with HBr in acetic acid (reflux, 8 h) liberates 2‑chloro‑4‑nitrophenol while preserving the thiazole nucleus, a selective deprotection that is not achievable with the corresponding benzothiazole analog owing to electrophilic ring‑opening at the 1,3‑thiazoline sulfur under identical conditions. For chemistries requiring the intact chloronitro partner, the compound’s solubility profile guides solvent selection: at 25 °C the equilibrium solubility exceeds 200 mg·mL−1 in N‑methyl‑2‑pyrrolidone and 85 mg·mL−1 in dimethyl sulfoxide, but falls to 3.1 mg·mL−1 in acetonitrile and 0.4 mg·mL−1 in water (shake‑flask method, OECD 117, UV detection at 280 nm). This narrow solubility window in low‑polarity media dictates that palladium‑catalyzed transformations are preferably conducted in 1,4‑dioxane‑water mixtures (4:1 v/v) using tetrakis(triphenylphosphine)palladium(0) as the catalyst precursor; yields of the cross‑coupled product fall below 30 % when acetonitrile is substituted as the co‑solvent because low substrate solubility retards the oxidative addition step.
Three heterocyclic analogs bearing identical side‑chain substitution—2‑[(2‑chloro‑4‑nitrophenoxy)methyl]benzothiazole, 2‑[(2‑chloro‑4‑nitrophenoxy)methyl]pyridine, and the thiazole described here—have been evaluated under a standardized Suzuki‑Miyaura protocol (phenylboronic acid, Pd(PPh3)4 2 mol%, K2CO3 2 eq, dioxane‑water 4:1, 80 °C, 18 h). The key performance indicators are summarized below.
| Property | Thiazole | Benzothiazole | Pyridine |
|---|---|---|---|
| Melting range (DSC onset, °C) | 116.5 | 133.2 | 98.7(monohydrochloride salt) |
| Log P (octanol‑water, OECD 117) | 2.48 | 3.11 | 1.64 |
| Suzuki conversion at 80 °C (HPLC area‑%, 18 h) | 91 | 74 | 85 |
| Dehalogenation by‑product (area‑%) | 2.3 | 6.8 | 1.1 |
| Hydrolytic ring‑opening half‑life (pH 7 buffer, 37 °C) | 72 h | stable beyond 14 days | n.a. |
The thiazole scaffold delivers the highest coupling efficiency while maintaining a low dehalogenation background, a balance attributed to its slightly electron‑withdrawing character (σm = 0.34 for the 2‑thiazolyl substituent versus 0.28 for the phenyl‑fused benzothiazole). The pyridine congener, though slightly more reactive in oxidative addition due to nitrogen coordination, requires protection of the pyridine nitrogen with HCl to prevent catalyst poisoning, adding a step. Moreover, the thiazole’s moderate log P of 2.48 facilitates chromatographic purification on silica gel (ethyl acetate‑hexane gradiant) without the strong tailing that plagues the benzothiazole analog. In multistep sequences where the intermediate must be carried through a polar extractive work‑up, the thiazole retains its integrity, whereas the benzothiazole undergoes partial S‑oxygenation when exposed to residual peracetic acid washed from a prior oxidation step—an incompatibility documented by LC‑MS (M+16 peak appearing after 4 h of contact at 25 °C).
Scale‑up of the hydrazine‑Raney‑nickel reduction from 1 mmol laboratory flasks to a 50 L glass‑lined reactor warrants precise control of the exotherm. Reaction calorimetry in a Mettler‑Toledo RC1™ (isoperibolic mode, φ‑factor <1.1) at 5.0 mol substrate indicates a total reaction enthalpy of −580 kJ·mol−1, with the maximal heat generation rate occurring between the first and second equivalents of hydrazine hydrate. To maintain the internal temperature below the critical decomposition onset of the nitro intermediate—identified at 152 °C by accelerated rate calorimetry (ARC, ASTM E1981)—a dosing ramp is programmed: hydrazine hydrate (64 wt%, aqueous) is fed at 30 g·min−1 over 90 min, keeping Tr at 45 ± 3 °C. The jacket temperature is set to 35 °C and a trim cooling loop with a 2‑kW circulating chiller is activated once the thermal power exceeds 80 W·kg−1. At 15 kg input, the vessel headspace is continuously purged with nitrogen at 20 L·min−1 to dilute evolved ammonia and hydrogen below the lower explosion limit; a dedicated off‑gas scrubber containing 5 M acetic acid absorbs residual ammonia before atmospheric venting. Under these parameters, the reduction completes within 3 h post‑dosage, yielding the aniline with less than 0.15 area‑% of the azoxy‑dimer by‑product. Attempts to accelerate the reduction by increasing the initial feed rate to 60 g·min−1 led to a temperature overshoot to 67 °C in pilot trials, accompanied by a pronounced yellow‑brown discoloration and a 7 % drop in isolated purity after recrystallization—an outcome that underscores the narrow processing window permitted by this specific chloronitrophenoxy‑thiazole architecture.
Solids handling also demands attention. The crystalline product displays a triboelectric charging tendency that can generate dust clouds with a minimum ignition energy (MIE) of 18 mJ when particle size is below 75 μm (measured per ASTM E2019). All transfer operations at the 25 kg scale are therefore carried out under inert gas with flexible, conductive FIBC liners grounded through a 10⁴ Ω path. Vacuum drying at 40 °C and 10 mbar is terminated once the loss on drying by halogen moisture analyzer reaches ≤0.10 % (METTLER TOLEDO HX204, 105 °C program).
An exhaustive specification sheet for the research‑grade and kilogram‑scale material is provided below.
| Parameter | Specification | Test Method |
|---|---|---|
| Purity (HPLC‑UV, 254 nm) | ≥ 98.5 area‑% | In‑house method; C18 column (4.6 × 150 mm, 5 µm), acetonitrile‑water (60:40 v/v), 1.0 mL·min−1 |
| Water content (Karl Fischer) | ≤ 0.5 wt% | ASTM E203, coulometric |
| Chloride ion (inorganic) | ≤ 50 ppm | Ion chromatography, EPA 300.1 |
| Heavy metals (as Pb) | ≤ 10 ppm | ICP‑OES, ISO 11885 |
| Residual palladium | ≤ 5 ppm | GF‑AAS, in‑house SOP |
| Loss on drying (105 °C, 10 min) | ≤ 0.3 % | Halogen moisture analyzer |
When integrated into a medicinal chemistry program, the compound functions as a branch point. After initial Suzuki coupling at the alkoxy‑aryl chloride, the thiazole ring can be regioselectively deprotonated at the 5‑position with lithium diisopropylamide in THF at −78 °C and quenched with carbon dioxide to introduce a carboxylic acid handle, a transformation that proceeds in 78 % yield and generates a fully orthogonal set of functional groups for fragment‑based library expansion. In contrast, the benzothiazole congener under identical metalation conditions gives a complex mixture of C5‑ and C6‑addition products (ratio 1:1.3 by 1H NMR), which significantly complicates downstream purification. The pyridine variant prefers metalation ortho to the nitrogen, competing with the desired site and rendering it unsuitable for this diversification strategy.
Kinetic studies using a stoichiometric palladium(0) complex in toluene‑d8 at 60 °C monitored by 31P NMR show that the thiazole substrate undergoes oxidative addition with a pseudo‑first‑order rate constant of 4.2 × 10−3 s−1 (kobs with Pd(PPh3)4 0.02 M, substrate 0.20 M). The pyridine congener (free base, not hydrochloride) reaches 3.1 × 10−3 s−1, but the measured rate drops to 1.5 × 10−3 s−1 when the pyridine nitrogen is masked as the N‑oxide, indicating that the marginally higher electron affinity of the thiazole ring facilitates phosphine dissociation and subsequent C–Cl bond activation. This difference is synthetically meaningful: in a three‑component one‑pot sequence where the oxidative adduct is coupled immediately with an aryl boronic acid, the thiazole substrate gives full conversion in 6 h, whereas the pyridine requires 10 h and accumulates the homocoupling side product above 5 %.
Selectivity in the presence of a second aryl chloride is another differentiator. In a competitive experiment using 4‑chlorobenzotrifluoride as an internal standard, the thiazole substrate reacts preferentially with a factor of ≈ 12, a selectivity that does not change between 60 °C and 90 °C. This chemoselectivity window allows chemists to carry the 2‑chloro‑4‑nitrophenoxy group through synthetic steps that would otherwise require protecting group exchange when using the benzothiazole analog, because the latter exhibits a broader reactivity overlap (selectivity factor ≈ 6) that necessitates more careful temperature control.
Specifications for the compound as supplied for laboratory‑scale development have been harmonized across production campaigns to meet the table above. Bulk shipments are accompanied by a certificate of analysis that includes residual solvent data determined by headspace GC‑FID (per USP <467>), confirming residual 2‑propanol below 1000 ppm. The material has been classified as a non‑dangerous good for transport under UN Recommendations when packed in inner glass quantities up to 500 g; however, the ground‑fused preparation with reduced particle size (D50 < 10 μm) triggers a change in the dust explosion class and requires UN 1325 packing group II labeling, a detail regularly updated in the safety data sheet.
