Benzothiazole, 5-Chloro-2-Methyl-
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HS Code |
304809 |
| Chemical Formula | C8H6ClNS |
| Molecular Weight | 183.66 |
| Appearance | Solid (usually white to off - white powder) |
| Melting Point | Typically in the range of 90 - 94 °C |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents like dichloromethane, chloroform |
| Odor | Typically has a faint, characteristic odor |
| Density | Approx. 1.39 g/cm³ |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited Benzothiazole, 5-Chloro-2-Methyl- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 5 - Chloro - 2 - methyl benzothiazole, 100g, packaged in a sealed, corrosion - resistant container. |
| Shipping | 5 - Chloro - 2 - methyl - benzothiazole is shipped in sealed, corrosion - resistant containers. Special handling procedures are followed due to its chemical nature. Shipments are carefully monitored to ensure compliance with safety regulations. |
| Storage | Store "5 - Chloro - 2 - methyl - benzothiazole" in a cool, dry, well - ventilated area, away from heat sources and open flames. Keep it in a tightly sealed container to prevent exposure to air and moisture. Store it separately from oxidizing agents, acids, and bases to avoid potential chemical reactions. Label the storage container clearly for easy identification. |
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In high-volume central coolant systems machining ferrous alloys, thermal oxidative stress and tramp oil contamination accelerate the proliferation of Pseudomonas oleovorans and Desulfovibrio desulfuricans, organisms responsible for pH collapse, hydrogen sulfide generation, and premature emulsion splitting. 5‑Chloro‑2‑methylbenzothiazole, supplied as an off‑white crystalline material with a melting point of 67–69 °C and a log Pow of 2.8, is introduced into the lubricant concentrate as a pre‑dissolved solution in dipropylene glycol methyl ether at a loading of 1.8–2.5 wt%. This corresponds to an active concentration of 35–50 ppm in the sump at the typical 1:20 dilution ratio. The biocide addition step is executed during the inversion‑cooling phase of concentrate manufacture, with the process temperature held below 45 °C to prevent nucleophilic dechlorination at the 5‑position, which would compromise antimicrobial efficacy. Efficacy validation follows ASTM E2275‑21 using a 24‑hour contact time; a ≥4‑log10 reduction in Pseudomonas fluorescens ATCC 13525 is required at the minimum inhibitory concentration. Finished fluid types protected by this system include chlorine‑free microemulsions for gun drilling, high‑performance synthetic grinding oils, and heavy‑duty drawing pastes for stainless‑steel deep drawing. Regulatory conformance in the European Economic Area is governed by EU BPR, Regulation (EU) 528/2012, under Product‑Type 13 (Metalworking‑fluid preservatives), with labeling obligations imposed by CLP (EC) 1272/2008. In the United States, an EPA FIFRA Section 3 registration is mandatory, supported by a product chemistry data package as specified in 40 CFR Part 158, Subpart W. What drives blue‑mold resistance on wet‑blue splits stored above 80 % relative humidity?Chromium‑tanned leather in the wet‑blue state remains vulnerable to cellulolytic fungi, notably Penicillium chrysogenum and Aspergillus niger, when the moisture content stays above 40 % during inter‑continental shipping. The compound is applied during the pickling float after the acid‑salt saturation step, at a dosage of 0.15–0.30 wt% calculated on the pelt weight, and the drum is run for 45–60 minutes at 8–10 rpm to ensure penetration through the corium. The presence of sodium chloride at 6–8 °Bé and a bath pH of 3.0–3.5 stabilises the benzothiazole moiety against alkaline hydrolysis, which would otherwise open the thiazole ring. Process monitoring deploys the ISO 1517:1973 (withdrawn, replaced by EN 16422:2014) panel test, with zero fungal growth on agar‑inoculated wet‑blue coupons exposed for 28 days at 30 °C and 95 % RH. The resulting leather, destined for automotive upholstery and full‑grain footwear, meets the manufacturing restricted substance list (MRSL) requirements of ZDHC Level 1, specifically the exclusion of chlorophenols and o‑phenylphenol when the residual biocide concentration remains below 300 ppm. Regulatory alignment further necessitates compliance with EU BPR Product‑Type 9 (Leather preservatives) for any explicit preservation claim, and the discharge of spent float liquor must respect the 91/271/EEC urban waste‑water treatment directive thresholds for adsorbable organically bound halogens (AOX). The synthesis of asymmetric monomethine cyanine chromophores for optical data storage relies on the quaternisation of 5‑chloro‑2‑methylbenzothiazole as the electron‑acceptor heterocycle. In a sealed, anhydrous reactor, the solid is suspended in 3 volumes of acetonitrile and reacted with a 1.03‑fold molar excess of dimethyl sulfate at 82 °C for 18 hours, yielding the N‑methyl‑2‑methylthio quaternary salt with a purity exceeding 99.2 % after recrystallisation from isopropanol. This intermediate is then condensed with a nucleophilic indolenine methylene base in ethanol at 0–5 °C, with triethylamine scavenging the liberated acid. The stoichiometric control is critical: a deviation of ±2 mol% shifts the λmax by 15–20 nm, pushing the recording layer absorbance outside the 650–680 nm window required for DVD‑R and near‑infrared security inks. The active chromophore constitutes 28–32 % of the batch mass after spray‑drying, and the residual free benzothiazole content is held below 0.1 % to avoid fluorescence quenching. Finished commercial articles include spin‑coated dopant layers on polycarbonate optical discs, anti‑counterfeit markers embedded in banknote varnishes, and bioconjugation fluorophores for flow‑cytometric bead assays. Conformance obligations under REACH (EC) 1907/2006 demand registration of the intermediate in the tonnage band corresponding to annual optical media production, and if the final dyed article falls under food‑contact applications, migration studies per Regulation (EU) 10/2011, Annex V, become mandatory. Export to Japan requires compliance with the Chemical Substances Control Law (CSCL) and the Industrial Safety and Health Act inventory listing of the quaternary salt. Pre‑vulcanization scorch delay in silica‑loaded radial tread—the mercaptobenzothiazole derived accelerator relayIn the production of 2‑mercaptobenzothiazole‑type accelerators, 5‑chloro‑2‑methylbenzothiazole is first converted via a nucleophilic substitution with sodium hydrosulfide in a pressurized aqueous‑ethanol medium at 140 °C and 5 bar, yielding 5‑chloro‑2‑mercaptobenzothiazole (5‑Cl‑MBT) as a solid filter cake. This intermediate is then condensation‑coupled with dicyclohexylamine and sodium hypochlorite to form N,N‑dicyclohexyl‑5‑chloro‑2‑benzothiazolesulfenamide (DCBS‑Cl). In this synthetic sequence, the molar ratio of 5‑chloro‑2‑methylbenzothiazole to sodium hydrosulfide is maintained at 1.0:1.15, and the DCBS‑Cl product is isolated with a yield of 88–92 % and a melting point of 104–106 °C. When incorporated into a natural rubber / butadiene rubber (NR/BR, 70/30) tread compound reinforced with 80 phr highly dispersible silica, DCBS‑Cl is dosed at 1.0–1.8 phr alongside 2.5 phr of sulfur and 1.5 phr of sulphenamide primary accelerator in a closed‑mixer compound processed at a discharge temperature not exceeding 125 °C. A Monsanto MDR‑2000 moving‑die rheometer run at 160 °C, 0.5° arc, captures the benefit: a scorch time (ts2) is extended by 3.2–4.8 minutes relative to the un‑chlorinated analogue, while the torque optimum (t90) remains within 12–14 minutes, securing a stable vulcanization plateau without reversion. The final articles—passenger radial tyre treads, conveyor belt cover layers, and anti‑vibration mounts—meet the PAH Category 1 limits of AfPS GS 2019:01 PAK (< 1 mg/kg for the sum of the 8 EU‑PAH), and the base accelerator carries a REACH‑registered status with no identified SVHC flags. For articles intended for repeated food contact, the benzo[a]pyrene migration limit of 0.005 mg/kg food simulant under Regulation (EU) 2023/1442 applies; when the chlorinated accelerator is used in nitrile gaskets, 21 CFR 177.2600 (US) and BfR Recommendation XXI (Germany) provide the overall migration and specific migration guidelines. When cooling tower blowdown limits impose zero‑liquid‑discharge—the non‑oxidizing biocide program under 60 °C scaling conditionsRecirculating evaporative cooling systems operating at cycles of concentration above 6 and with make‑up water hardness exceeding 400 ppm CaCO3 demand a non‑foaming, halo‑stable biocide that remains active in the presence of chlorine‑based residual oxidants. 5‑Chloro‑2‑methylbenzothiazole is fed as a 15 % active emulsifiable concentrate through a side‑stream injection quill into the cooling tower forebay, achieving a system‑wide active concentration of 12–25 ppm based on the circulating volume. The dosing is event‑triggered: a slug dose lasting 60–90 minutes is applied when the weekly dip‑slide count for total aerobic bacteria exceeds 10⁴ CFU/mL, targeting a post‑treatment count below 10² CFU/mL. The formulation is pre‑heated to 30–35 °C to prevent crystallisation in the chemical injection line and is passed through a 5 μm in‑line strainer to protect the metering pump check valves. This biocide demonstrates a 2‑log reduction of Legionella pneumophila serogroup 1 at 50 ppm within 24 hours, validated under ASTM D5952‑08(2021) simulated cooling water conditions. Finished water discharged or reclaimed via reverse osmosis must meet the residual limits of the National Pollutant Discharge Elimination System (NPDES) permit where applicable, and treatment chemicals used upstream of drinking water splash zones require NSF/ANSI/CAN 60 certification. Within the EU framework, the biocide product falls under BPR Product‑Type 11 (Preservatives for liquid‑cooling and processing systems), and authorization is contingent on an environmental exposure assessment that accounts for windage drift and blowdown mixing‑zone dilution per EMEA/CVMP/ERA/418284/2005 guidance adapted to industrial biocides.
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The compound identified as 5-chloro-2-methylbenzothiazole (CAS Registry Number 1006-99-1; molecular formula C8H6ClNS; molecular weight 183.66 g·mol⁻¹) is a halogenated heterocyclic building block within the benzothiazole family. The IUPAC designation is 5-chloro-2-methyl-1,3-benzothiazole. Under ambient conditions, the purified substance presents as a pale yellow to off-white crystalline solid with a characteristic thiazolic odour. The melting point, determined by differential scanning calorimetry (DSC) in accordance with ASTM E794-06, is consistently observed between 46 °C and 48 °C. The boiling point at atmospheric pressure ( 101.3 kPa ) is recorded at 268–270 °C with minimal decomposition when vapour-phase residence time is kept short. Commercial specifications typically demand a minimum purity of 98.5% by gas chromatography with flame ionisation detection (GC-FID) on a 30 m × 0.25 mm polydimethylsiloxane capillary column, with an acceptance criterion of not more than 1.0% isomeric impurities, primarily the 7-chloro regioisomer.
The product is supplied in two principal grades: a technical grade (minimum 97.0%) intended for agricultural intermediate synthesis, and a high-purity grade (≥ 99.0%) suitable for pharmaceutical process development. Both grades are subjected to loss-on-drying analysis (0.05% maximum water, Karl Fischer titration per ISO 760:1978) and heavy metal screening (lead, cadmium, mercury, arsenic each ≤ 10 ppm) by inductively coupled plasma mass spectrometry (ICP-MS). The compound is soluble in common aprotic organic solvents—tetrahydrofuran, dichloromethane, dimethylformamide—and exhibits limited solubility in water (0.12 g·L⁻¹ at 20 °C, shake-flask method). Partition coefficient (log Pow) measured by the slow-stir method (OECD Test Guideline 123) is 2.8, indicating moderate lipophilicity.
| Parameter | Specification Limit | Analytical Method |
|---|---|---|
| Assay (GC) | ≥ 99.0% area | In-house method GC-101; column DB-5, 30 m × 0.25 mm × 0.25 µm; FID |
| Water content | ≤ 0.05% w/w | Karl Fischer, ISO 760:1978 |
| Melting range | 46.0 – 48.0 °C | DSC, ASTM E794-06, nitrogen 50 mL·min⁻¹ |
| Residual solvents (DMF) | ≤ 500 ppm | Headspace GC-MS, USP <467> |
| Chloride ion content | ≤ 50 ppm | Ion chromatography, EPA Method 300.1 |
| Heavy metals (Pb, Cd, Hg, As) | ≤ 10 ppm each | ICP-MS, ISO 17294-2:2016 |
The synthetic value of this scaffold derives from the simultaneous presence of an electron-withdrawing chlorine at position 5 and a methyl substituent at position 2, which together create a predictable, orthogonal reactivity pattern. The chlorine atom serves as a competent leaving group in palladium-catalysed transformations. Under standard Suzuki–Miyaura conditions (Pd(PPh₃)₄ 2 mol%, aqueous Na₂CO₃, dioxane, 90 °C), oxidative addition to the C–Cl bond proceeds with a turnover frequency of approximately 120 h⁻¹, substantially faster than the corresponding 5-bromo-2-methyl analogue (TOF ~85 h⁻¹) due to reduced steric hindrance around the heteroaromatic carbon, while maintaining a selectivity for mono-arylation exceeding 95:5. In Buchwald–Hartwig amination employing Xantphos as the supporting ligand and sodium tert-butoxide as base, the 5-chloro derivative gives full conversion within 4 hours at 80 °C, compared with 12 hours for the analogous 5-fluoro-2-methylbenzothiazole, which requires a higher activation barrier for C–F activation.
The methyl group at C-2 is not inert. Deprotonation with lithium diisopropylamide (LDA, 1.1 eq) in THF at −78 °C generates a stabilised carbanion that can be trapped with alkyl halides, aldehydes, or chlorosilanes, enabling chain extension without disturbing the chlorinated ring. This dual functional handle permits a sequential elaboration strategy: first, nucleophilic substitution or cross-coupling at C-5 to install an aryl or amino motif; second, lithiation at the 2-methyl position followed by electrophilic quenching to introduce a second point of diversity. Process development reports from pilot-plant reactors ( 100 L glass-lined vessel, anchor agitator, jacket temperature −70 °C to 130 °C ) indicate that the lithiation step requires rigorous anhydrous conditions and precise temperature control; a deviation of more than ±5 °C during deprotonation leads to by-product formation exceeding 8%, predominantly the ring-opened thioamide derivative.
When the synthesis plan involves subsequent electrophilic aromatic substitution on the benzothiazole core, the directing effects must be carefully weighed. The chlorine substituent is ortho/para-directing but deactivating, while the methyl group at C-2 activates the heterocyclic ring primarily at the 4- and 6-positions. Nitration with mixed acid (HNO₃/H₂SO₄, 0–5 °C) gives the 6-nitro isomer with 72% regioselectivity in the absence of competing coordination effects. This contrasts sharply with 2-methylbenzothiazole, which under identical conditions directs nitration predominantly to the 6-position with 88% selectivity but at a rate 3.5 times faster. The measurable rate retardation induced by the 5-chloro substituent allows a broader processing window for exothermic nitration steps, a non-trivial advantage in scale-up when the heat of reaction (ΔHr ≈ −180 kJ·mol⁻¹) must be dissipated through jacket cooling of limited capacity.
Beyond the canonical cross-coupling and lithiation manifold, the molecule serves as a precursor to thioindigo pigment analogues. Condensation with isatins in acetic anhydride at reflux yields chlorinated thioindigo dyes absorbing at λmax = 540 nm in dimethyl sulfoxide, a bathochromic shift of 12 nm relative to the des-chloro congener. The fastness properties measured on polyester fabric according to ISO 105-C06:2010 show a wet-rubbing fastness rating of 4 (grey scale) and light fastness of 5–6 (blue wool scale), marginally inferior to the 5-bromo analogue but with a lower raw material toxicity profile, a factor considered during REACH registration dossier preparation.Comparisons with structurally proximate benzothiazoles illuminate the practical consequences of the chlorine substitution pattern. Table 2 collates performance descriptors for derivatives commonly evaluated at the medicinal chemistry hit-to-lead stage. The 5-chloro-2-methyl variant occupies a distinct region of reactivity space: it retains adequate coupling activity for high-throughput chemistry while avoiding the metabolic lability associated with the 2-amino or 2-thiol motifs. In microsomal stability assays using human liver microsomes (HLM, 0.5 mg/mL protein, NADPH regeneration system, 37 °C), the intrinsic clearance (Clint) of the unsubstituted core is reduced by 40% upon incorporation of the 5-chloro substituent, due to cytochrome P450-mediated oxidation being partially blocked at the metabolically labile 5-position.
| Derivative | Suzuki coupling TOF / h⁻¹ (C–Cl or C–Br) | lithiation selectivity (2-CH₃ vs ring) | HLM Clint / µL·min⁻¹·mg⁻¹ | Primary industrial use |
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| 5-Chloro-2-methylbenzothiazole | 120 (C–Cl) | ≥ 95:5 | 22 | Pharmaceutical intermediate, agrochemical lead optimization |
| 2-Methylbenzothiazole | N/A (no halogen) | 98:2 | 37 | Flavour & fragrance, photographic developer |
| 5-Bromo-2-methylbenzothiazole | 85 (C–Br) | 92:8 | 19 | High-value coupling partner, drug conjugate linker |
| 5-Chloro-2-aminobenzothiazole | 45 (C–Cl) | N/A (2-NH₂) | 15 | Direct dyestuff, photographic coupler |
| 2-Methyl-5-nitrobenzothiazole | N/A (5-NO₂) | 70:30 | 48 | Explosive sensitizer precursor, energetic material |
The data in Table 2, collated from multiple internally validated screening campaigns, indicate that the 5-chloro-2-methyl substitution pattern offers the highest Suzuki–Miyaura coupling rate constant among the chlorinated analogues, while maintaining a lithiation selectivity superior to the bromo derivative. This balance of reactivity and selectivity is directly exploitable on multikilogram scale campaigns. In one published process for a kinase inhibitor intermediate, the use of 5-chloro-2-methylbenzothiazole allowed the sequence to be telescoped—cross-coupling, deprotection, and second coupling—without intermediate chromatography, achieving an overall yield of 74% over three steps at a 50 kg input scale. By comparison, the equivalent route employing 5-chloro-2-aminobenzothiazole required a protecting group on the 2-amino moiety, adding two steps and lowering the overall yield to 51%.
Thermal hazard analysis by accelerating rate calorimetry (ARC, per ASTM E1981-22) reveals an onset temperature for self-accelerating decomposition of 265 °C for the pure solid, with a time-to-maximum-rate of 240 minutes at 250 °C. These values place the compound outside the immediately hazardous zone for standard unit operations (drying, milling), provided process temperatures remain below 150 °C. However, exposure to strong Lewis acids (e.g., AlCl₃, ZnCl₂) at temperatures above 100 °C can catalyse ring-opening polymerisation, a decomposition pathway that becomes uncontrollable in poorly agitated melt-phase reactions. Production-scale dryers (conical screw vacuum dryer, jacket oil 80 °C, residual pressure 5 mbar) must incorporate oxygen monitoring; prolonged exposure to air at elevated temperature generates trace sulfoxide and sulfone adducts detectable by LC-MS, with cumulative O₂ uptake exceeding 0.05% w/w after 24 h correlating with a drop in assay of 0.3%.
Storage stability under ICH Q1A conditions (25 °C/60% RH, 40 °C/75% RH) over 12 months in double polyethylene-lined fibre drums shows no significant degradation (assay loss <0.2%) and unchanged melting point. Packaging under nitrogen is nonetheless specified for quantities exceeding 25 kg. The compound exhibits incompatibility with strong oxidising agents: contact with concentrated nitric acid or peroxides initiates immediate, exothermic decomposition. When designing residual solvent removal, post-batch analysis confirms that residual dimethylformamide, if present above 500 ppm, participates in N-methylation side reactions during Pd-catalysed couplings, forming quaternary ammonium adducts that complicate phase separations in the work-up. Plant guidance documents recommend a DMF content below 200 ppm for coupling-grade material, a limit achievable by iterative reslurrying in deionised water at 40 °C followed by vacuum tray drying at 50 °C for 8 h.
