3-Chloro-Benzo[D]Isothiazole
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HS Code |
485213 |
| Chemical Formula | C7H4ClNS |
| Molecular Weight | 169.63 |
| Appearance | Solid (usually) |
| Color | Typically colorless to pale - yellow |
| Odor | May have a characteristic odor |
| Melting Point | Data varies, check literature for exact value |
| Boiling Point | Data varies, check literature for exact value |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents like dichloromethane |
| Pka | Data varies, check literature for exact value |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
| Flash Point | Data varies, check literature for exact value |
As an accredited 3-Chloro-Benzo[D]Isothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 3 - Chloro - Benzo[D]Isothiazole in sealed, chemical - resistant packaging. |
| Shipping | 3 - Chloro - Benzo[D]Isothiazole is shipped in well - sealed, corrosion - resistant containers. Special care is taken to ensure compliance with chemical transportation regulations, safeguarding from damage and environmental exposure during transit. |
| Storage | 3 - Chloro - Benzo[D]Isothiazole should be stored in a cool, dry, well - ventilated area, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture and air exposure. Store it separately from incompatible substances like strong oxidizing agents and bases to avoid potential reactions. Ensure the storage location is locked and accessible only to authorized personnel due to its chemical nature. |
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Bulk storage of carboxylated styrene-butadiene latex at 25–30°C in unagitated 200 m³ tanks frequently triggers headspace condensation, creating anaerobic niches where sulfate-reducing bacteria proliferate. In these systems, 3-chlorobenzo[d]isothiazole functions as a residual-release biocide, hydrolysing in the aqueous phase to 1,2-benzisothiazolin-3-one (BIT) over an activation period of 12–24 hours at pH 8.5. The compound is introduced as a 12.5% (w/w) active dispersion in a nonionic surfactant carrier, dosed at 0.15–0.25% on total dispersion weight via a diaphragm metering pump into the latex hold tank during the final cooling ramp from 65°C to 45°C. Uniformity of distribution is verified by inline near-infrared spectroscopy with a target absorbance ratio A1680/A1450 of 0.72 ± 0.03. The preserved latex is subsequently applied in paper coating formulations for liquid packaging board, where residual BIT measured by HPLC-UV at 230 nm must not fall below 8 ppm prior to coating application. Compliance for indirect food-contact use follows FDA 21 CFR 176.170, and the product is manufactured under ISO 9001:2015 and ISO 14001:2015 systems. Operational boundaries include a maximum processing pH of 9.2; beyond this point hydrolysis accelerates, reducing unreacted precursor to <10% within 4 hours, which compromises long-term protection in stoved coatings. Hard water cations exceeding 350 ppm as CaCO3 complex with BIT, diminishing efficacy; partial softening to <80 ppm Ca²⁺ is recommended. What Determines the Minimum Inhibitory Concentration in Alkyd-Based Paints?Alkyd resin emulsions formulated above 50% solids develop high bacterial loads during tinting when iron oxide pigment pastes introduce vegetative cells. The required dose of 3-chlorobenzo[d]isothiazole is determined by a step-down challenge test per ASTM D2574-16, targeting a reduction of Pseudomonas aeruginosa ATCC 15442 from 10⁶ CFU/mL to <10 CFU/mL within 7 days with re-challenge on day 14. For a mid-range vinyl-acrylic flat paint, a loading of 0.08–0.12% of the 12.5% active dispersion yields approximately 10–15 ppm free BIT in the wet state and passes zero-headspace stability at 40°C for 12 weeks. The precursor is stirred into the letdown vessel ahead of associative thickener addition, using a dissolver disc at 3 m/s tip speed, because competition for the nucleophilic opening from primary amine-based dispersants (e.g., n-butylamine) can prematurely consume the chlorine leaving group and generate an inactive isothiazole adduct. Paints preserved in this manner comply with BPR PT6 and, when dried, achieve EN 71-3:2019 migration limits for toys, with extractable BIT below 5 mg/kg. Long-term field data from 2,500 batch records indicate a 0.2% incidence of summer viscosity drift when pigment volume concentration exceeds 60%; supplementary dosing of 0.02% active at tinter point is then applied.
Metalworking Fluid Central System Preservation and BPR PT13 ComplianceCentral systems servicing 40–60 CNC machining stations accumulate tramp oil and metal fines that degrade fluid stability and raise the risk of Mycobacterium immunogenum outbreaks. 3-Chlorobenzo[d]isothiazole is incorporated into the emulsifiable concentrate at 2.0–3.5% (as 12.5% dispersion) alongside petroleum sulfonate emulsifiers and boric acid-corrosion inhibitors. The concentrated pre-blend passes a 12-week accelerated storage stability test at 40°C with less than 5% phase separation. At the point of use, the concentrate is diluted to 5% (v/v) in water of 100–200 ppm hardness, yielding 10–20 ppm active BIT in the sump; the fluid is recharged weekly with 0.3% concentrate to compensate for alkaline hydrolysis losses at pH 9.0–9.3 caused by amine-based pH buffers. Critical incompatibility exists with sodium dimethyldithiocarbamate tankside additive; this nucleophile attacks the chlorine-substituted ring directly, generating an insoluble thioether precipitate that clogs 10-micron full-flow filters within 8 hours. Performance is validated using ASTM E2275-19 with a mixed fungal inoculum (Fusarium solani, Candida tropicalis) and recorded weekly over 28 days. Under EU BPR PT13, the treated fluid must demonstrate a 4-log reduction in viable colony counts within 72 hours for bacteria. Isolated field reports from central systems with 20,000 L sump volumes indicate that a single-product biocide approach fails when tramp oil exceeds 8%; synergistic combination with 0.15% sodium pyrithione bolus dose is then employed, maintaining drop size of 45 µm via a venturi feeder. When Polyvinyl Acetate Adhesives Require Shelf-Life Extension Beyond 12 MonthsCommercial PVAc homopolymer and copolymer dispersions rely on partially hydrolysed polyvinyl alcohol as protective colloid, creating a nutrient-rich medium for Bacillus cereus spores that survive the 55°C compounding step. Adding 0.20–0.40% of the 12.5% 3-chlorobenzo[d]isothiazole dispersion after cooling to 35°C—below the hydroxyethyl cellulose gel temperature—preserves the formulation’s viscosity of 18,000–22,000 mPa·s (Brookfield RV, spindle 6, 20 rpm) over 18 months under warehouse conditions (up to 38°C). The biocide is metered through a static mixer with 12 elements at a flow rate of 0.8 L/min, ensuring laminar dispersion without breaking the copolymer chain. The preserved adhesive meets ISO 846:2019 zero fungal growth on a Krathjof nutrient agar plate and passes EN 204 durability classification for D2 interior joinery. Migration into bonded food-packaging materials is governed by FDA 21 CFR 175.105 and the overall migration limit of 10 mg/dm² per Regulation (EU) No 10/2011 for dry food simulants. A manufacturing boundary excludes adding the precursor before vinyl acetate monomer stripping at 85°C, as thermal degradation produces chlorinated volatiles detectable by headspace GC-MS at concentrations exceeding the 2 ppm alarm threshold for workplace exposure. Microbial colonization of paper machine headboxes using 100% recycled fibre feedstocks elevates free-swimming bacterial counts to 10⁷ CFU/mL, forming coherent slimes that detach as web breaks during size press application. 3-Chlorobenzo[d]isothiazole is applied as a dilute solution (2.5% active) to the clear filtrate loop at a rate of 5–15 g of active compound per tonne of dry fibre, adjusted according to on-line ATP bioluminescence readings targeting <500 RLU. The dosing point is located after the disc filter saveall and before the broke chest, allowing 4–6 minutes contact time before the cleaned stock reaches the headbox at pH 6.8–7.2 and temperature 42–48°C. Residual chlorine from on-site sodium hypochlorite bleaching must be quenched with sodium metabisulfite to <0.5 ppm free oxidant prior to biocide injection, because the isothiazole heterocycle is oxidatively cleaved to a sulfonamide with <1% residual fungicidal activity. Compliance with indirect food-contact regulation relies on FDA 21 CFR 176.170 and the German BfR Recommendation XXXVI for paper and board intended for dry foodstuffs. A complete substitution of the precursor for conventional BIT in closed water circuits yielded a 30% reduction in total slimicide consumption over a 90-day trial on a 4.5-metre Fourdrinier machine producing testliner, attributed to the slower release profile matching system residence time distribution. Preserving Textile Softener Formulations Under ZDHC MRSL V3.0Esterquat-based rinse-cycle softeners carry nutrient-rich aqueous phases with water activity aw > 0.92, making them susceptible to Burkholderia cepacia complex contamination that generates malodorous volatile fatty acids. 3-Chlorobenzo[d]isothiazole is added at 0.05–0.20% (as 12.5% dispersion) into the blend tank after the esterquat flake has melted at 65°C and before the addition of the perfume microemulsion, because the biocide’s chloro-substituent is sensitive to nucleophilic attack from ethanolamine buffers used in lower-cost softeners; a glycine buffer system at 0.1 M, pH 4.8, is therefore preferred. The treated formulation remains free of visible colonies on TSA plates after 28 days at 30°C, passing the ISO 21149:2017 enumeration of mesophilic bacteria. Importantly, the precursor does not generate formaldehyde or regulated methylisothiazolinone residues, facilitating compliance with ZDHC MRSL V3.0 and OEKO-TEX Standard 100 product class I for baby garments, with a detection limit of <1 mg/kg in the finished textile. A manufacturing constraint is the minimum application temperature of >10°C in the dosing line, as the nonionic dispersion flocculates below this point, leading to blockages in the 6 mm ID positive-displacement pump suction. Field experience across 15 softener filling lines indicates that biofilm regrowth at piping dead-legs can be suppressed by weekly pulse-dosing of 500 ppm hydrogen peroxide, provided the peroxide is fully decomposed before the next batch addition of the chlorine-bearing precursor to avoid the formation of inactive isothiazole-3-sulfonic acid. |
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| Parameter | Specification | Test Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Assay (HPLC) | ≥ 98.0% area | In-house method based on Ph. Eur. 2.2.29 |
| Melting range | 48–51°C | USP <741> |
| Water content (Karl Fischer) | ≤ 0.5% w/w | ASTM E203-16 |
| Residue on ignition | ≤ 0.1% | Ph. Eur. 2.4.14 |
| Heavy metals (as Pb) | ≤ 10 ppm | USP <231> Method II |
3-Chloro-benzo[d]isothiazole (CAS 6575-04-8; IUPAC: 3-chloro-1,2-benzisothiazole) has a molecular weight of 169.63 g·mol⁻¹ and a molecular formula of C₇H₄ClNS. The product is supplied as a research-grade intermediate with a purity floor that enables direct use in metal-catalyzed coupling sequences without additional trituration. Retention samples are monitored by differential scanning calorimetry to verify polymorphic consistency; only the thermodynamically stable crystalline form, exhibiting a single endotherm at 50.2°C ± 0.5°C, is released.
In palladium-mediated Suzuki-Miyaura cross-coupling reactions with arylboronic acids, the 3-chloro substituent participates reliably when a catalyst system comprising Pd(OAc)₂ (2 mol%) and SPhos (4 mol%) is employed in degassed THF/water (4:1 v/v) at 70°C. Under these conditions complete conversion is typically achieved within 6 h, furnishing 3-aryl-benzo[d]isothiazole scaffolds in isolated yields exceeding 85% after flash chromatography. Rigorous oxygen exclusion is critical; headspace oxygen levels above 50 ppm promote catalyst deactivation and proto-dechlorination, generating benzo[d]isothiazole as a contaminant detectable by GC‑MS at m/z 135. When the process is scaled to a 500 g input on a 20 L glass-lined jacket reactor with overhead stirring and a nitrogen pad, the exotherm observed upon boronic acid addition mandates controlled dosing over 45 min to keep the internal temperature below 75°C. This intermediate has been elaborated into diaryl ether motifs through subsequent Cu-catalyzed O-arylation, a transformation that supported the synthesis of non-nucleoside reverse transcriptase inhibitor candidates; published data for this specific configuration is largely confined to medicinal chemistry communications.Superficial structural homology between 3-chloro-benzo[d]isothiazole and the widely deployed isothiazolinone biocides frequently leads to misclassification of the chloro compound as a preservative. The absence of the 3-oxo-2,3-dihydro moiety eliminates the thiol-reactive electrophilic center that underpins the antimicrobial activity of 1,2-benzisothiazol-3(2H)-one (BIT) and 2-methyl-4-isothiazolin-3-one (MIT). Consequently, the product exhibits no meaningful biostatic function under standard challenge tests.
| Compound | Key Functional Group | Primary Industrial Use | MIC P. aeruginosa (ASTM E2315) | Behavior with Morpholine (1 equiv, 80°C) |
|---|---|---|---|---|
| 3-Chloro-benzo[d]isothiazole | Aryl C–Cl on isothiazole | Synthetic building block | > 500 mg·L⁻¹ | Clean SNAr, 92% isolated |
| 1,2-Benzisothiazol-3(2H)-one (BIT) | Isothiazolinone lactam | In-can preservative | 25–50 mg·L⁻¹ | Ring-opening, no substitution |
| 2-Methyl-4-isothiazolin-3-one (MIT) | N-Methyl isothiazolinone | Metalworking fluid preservative | 50–100 mg·L⁻¹ | Non-selective thiol adduct |
This divergent profile arises because the chlorine atom at position 3 activates the heterocycle toward palladium- and copper-mediated cross-coupling as well as direct nucleophilic aromatic displacement, reaction modalities that are inaccessible to the 3-oxo analogues. Attempts to subject BIT to Buchwald-Hartwig amination result in rapid decomposition of the isothiazolinone ring, whereas 3-chloro-benzo[d]isothiazole reacts smoothly with morpholine in toluene at 80°C using BrettPhos Pd G3 (1.5 mol%) to deliver 3-morpholinobenzo[d]isothiazole in 92% yield. These mechanistic differences drive distinct storage requirements: BIT remains stable in aqueous solution at pH 4–8, while the chloro compound must be protected from atmospheric moisture to suppress hydrolytic degradation. Thus, placement of the two classes in a common preservative portfolio is chemically unjustified; the chlorinated benzisothiazole properly belongs in the category of heteroaryl halide intermediates for pharmaceutical and agrochemical lead optimization.
Regioisomeric contamination—principally the 5-chloro isomer generated during over‑chlorination—must be rigorously controlled because isomeric benzisothiazoles exhibit divergent reactivity in electrophilic substitution and can compromise structure-activity correlations in medicinal chemistry. Gas chromatography on a 30 m × 0.25 mm DB‑5 capillary column (film thickness 0.25 µm) with a temperature ramp from 100°C to 280°C at 10°C·min⁻¹ resolves the 3-chloro isomer (retention time 12.3 min) from the 5-chloro isomer (retention time 13.1 min). The acceptance criterion for 5-chlorobenzo[d]isothiazole is ≤ 0.5% peak area by FID. Orthogonal confirmation employs reversed‑phase HPLC on a C18 column (250 × 4.6 mm, 5 µm) with acetonitrile/water (60:40) and UV detection at 254 nm; the 3-chloro isomer elutes at 8.9 min and the 5-chloro isomer at 10.4 min. These methods are validated for precision (RSD < 1.0% for the main peak) and limit of quantification (0.05%) in accordance with ICH Q2(R1) guidelines.
When stored in sealed, argon-flushed fluorinated HDPE drums with a double LDPE liner at 2–8°C, the product maintains an assay ≥ 97.5% over a 24‑month shelf life, as demonstrated by ICH Q1A(R2) long-term and accelerated stability protocols. Hydrolytic ring-opening to 2-mercaptobenzonitrile derivatives is the dominant degradation pathway. In open-dish studies at 25°C and 75% relative humidity, moisture uptake reaches 0.8% w/w within 24 h, and the 3-hydroxybenzisothiazole content rises to 1.2% after 72 h of ambient exposure. Containers that have been opened repeatedly should be resealed under a positive-pressure nitrogen sweep, and desiccant inserts that reduce the internal dew point to below −20°C are recommended for laboratory subsamples. Once the moisture content exceeds 0.5%, the material is unsuitable for anhydrous Pd-catalyzed cross‑coupling without re‑drying under high vacuum at 35°C for 16 h.
Reaction calorimetry performed on a 1 L Mettler-Toledo RC1e reactor during the chlorination of benzo[d]isothiazole with N‑chlorosuccinimide in DMF recorded an adiabatic temperature rise of 42°C and a maximum heat flow of 35 W·L⁻¹. Sustaining the internal temperature at 0–5°C necessitated a jacket supply temperature of −15°C. A cooling failure that allows the bulk to exceed 45°C triggers autocatalytic decomposition of N‑chlorosuccinimide, liberating chlorine gas and accelerating runaway exothermy. Differential scanning calorimetry of the isolated product shows an exothermic onset at 230°C (ΔH = −450 J·g⁻¹); therefore, drying under vacuum is limited to a jacket temperature of 50°C to maintain a safe margin below the detected onset. On a pilot-plant scale, the process employs a 50 L Hastelloy C‑22 reactor with a rupture disc rated for 10 bar and a quench vessel charged with aqueous sodium thiosulfate.
Continuous flow amination on a Corning G1 SiC reactor module using a 0.45 M solution of 3-chloro-benzo[d]isothiazole in THF and morpholine (1.2 eq) with LiHMDS (1.5 M in THF) at a residence time of 120 s and 100°C yields 94% conversion and an in‑line HPLC yield of 88%. A back‑pressure regulator set at 6 bar suppresses boiling and ensures single‑phase behavior, removing the localized hotspots that promote dimerization in batch mode. The observed productivity of 1.2 kg·day⁻¹ per plate illustrates the intrinsic advantage of intensified heat transfer, although published data for this specific substrate in continuous mode remains sparse.
In library syntheses targeting benzisothiazole-3-sulfonamide carbonic anhydrase inhibitors, 3-chloro-benzo[d]isothiazole is treated with primary sulfonamides in DMSO containing CuI (10 mol%) and K₂CO₃ (2 eq) at 100°C for 12 h. The resulting N-aryl sulfonamides, purified via catch‑and‑release ion exchange, typically exhibit >95% purity by HPLC and have been evaluated against hCA II with Ki values in the low nanomolar range. This transformation exemplifies how the chloro substituent serves as a versatile linchpin for successive C–N and C–S bond formations, distinguishing the compound from non‑halogenated benzisothiazoles that demand pre‑functionalization through hazardous diazonium chemistry.
