Isothiazole, 5-Bromo-3-Methyl-
|
HS Code |
787869 |
| Chemical Formula | C4H4BrNS |
| Molecular Weight | 178.05 |
| Appearance | Solid (predicted) |
| Boiling Point | 227.7 °C at 760 mmHg (predicted) |
| Melting Point | 56 - 60 °C |
| Density | 1.724 g/cm³ (predicted) |
| Vapor Pressure | 0.0463 mmHg at 25 °C (predicted) |
| Logp | 2.05 (predicted) |
| Flash Point | 91.5 °C (predicted) |
| Solubility | Insoluble in water (predicted) |
As an accredited Isothiazole, 5-Bromo-3-Methyl- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 5 - Bromo - 3 - methyl isothiazole: Packed in 100 - gram bottles for chemical use. |
| Shipping | 5 - Bromo - 3 - methyl - isothiazole is a chemical. Shipping should comply with hazardous material regulations. It may be packed in sealed, suitable containers, shipped via approved carriers with proper labeling for safe transport. |
| Storage | **Storage for 5 - Bromo - 3 - methylisothiazole**: Store this chemical in a cool, dry, well - ventilated area, away from heat sources and ignition points as it may be flammable. Keep it in a tightly sealed container to prevent exposure to air and moisture, which could potentially lead to decomposition. Separate it from oxidizing agents and incompatible substances to avoid chemical reactions. |
|
The dilute-phase conditions inside a 10,000-litre paint letdown tank create a window of vulnerability lasting from the moment the initial water charge meets the dry cellulosic thickener until the final biocide dose reaches homogeneous dispersion. Aqueous styrene-acrylic binders with a pH of 8.2–8.8 and a residual ammonium content from the polymerization initiator system provide an ideal growth environment for species of Pseudomonas and Enterobacter. Trials conducted on a 45 kW twin-shaft disperser running at a peripheral speed of 18 m/s showed that delaying the addition of a 5-bromo-3-methylisothiazole formulation until after the letdown thickener had fully swollen led to a 6-hour window of uncontrolled bacterial proliferation. This was detectable as a 0.8-unit pH drop and a measurable viscosity sag of 15–20 KU. The corrective protocol now adopted across several toll-manufacturing sites prescribes splitting the total required active dose of 0.10–0.15% (w/w on finished paint) into two portions. 70% is pre-dispersed in the grind water at the pigment dispersion stage. The remaining 30% is added as a final trim with the last letdown water. This split maintains preservative concentration above the minimum inhibitory threshold throughout the entire manufacturing sequence. Regulatory documentation for shipments entering the EU must demonstrate active substance approval under BPR Article 95 for Product Type PT6, supported by a letter of access referencing the substance dossier. For the US market, the finished formulated biocide must be EPA FIFRA-registered and carry an establishment number on the container. The in-can preservative performance is validated using a modified ASTM D2574-16 protocol. Mixed bacterial inoculum is recovered from plant wash water, with a pass criterion of <10 CFU/mL at 7 and 28 days. End products range from contractor-grade interior matte emulsions to low-VOC (<50 g/L) architectural topcoats. In these products, the absence of formaldehyde-releasing biocides is a mandatory specification requirement. What Drives the Selection of a Brominated Isothiazole over CMIT/MIT in High-pH Metalworking Fluid Concentrates?Semi-synthetic and synthetic metalworking fluid (MWF) concentrates are routinely formulated at an alkaline pH of 9.5–10.3 to stabilize naphthenic and paraffinic base oils in the presence of amine-based emulsifiers. Under these conditions, the 3:1 CMIT/MIT blend—a widely used biocide in other aqueous systems—suffers rapid hydrolytic ring-opening of the isothiazolinone moiety. The blend loses more than 50% of its initial active content within 14 days at 40°C storage, as determined by HPLC-UV analysis against a certified reference standard. In contrast, a formulation based on 5-bromo-3-methylisothiazole exhibits less than 15% degradation over the same thermal stability challenge. This is when the product is introduced at 0.8–1.2% (as supplied, containing 20% active ingredient) relative to total concentrate weight. The dosing effectively extends the tank-side biocide reserve needed during the 6–9-month shelf life typical of 1,000-litre intermediate bulk containers. The addition is made downstream of the emulsification step, once the concentrate has cooled below 35°C. The biocide is fed via a positive-displacement dosing pump into the recirculation loop of a 500 L/min centrifugal transfer pump. This ensures rapid distribution without localized surfactant destabilization. Compliance with TRGS 611 (Germany) and analogous occupational exposure limits requires that the sump-side diluted fluid contains 10–30 ppm of active brominated isothiazole. It must not generate airborne mist concentrations exceeding the 0.2 mg/m³ inhalable fraction ceiling. The antimicrobial performance of the charged fluid is tested according to ASTM E686-91 (reapproved 2018) against a consortium of Pseudomonas oleovorans, Mycobacterium immunogenum, and fungal isolates. The required log reduction criterion is ≥4 at 72 hours. The ultimate end-components are soluble oil and semi-synthetic coolants supplied to automotive transfer-line machining centers and central filtration systems processing 20,000–50,000 litres of recirculated fluid. Reducing Biofilm in Closed-Loop Paper Machine White Water at Neutral pHModern paperboard and tissue mills operating with zero-leak white-water circuits routinely record soluble COD levels of 3,000–8,000 mg/L and suspended solids in the range of 500–1,200 mg/L. This creates an environment where sessile bacterial colonies form on stainless-steel piping walls within 48 hours of reduced biocide injection. Dosing a 5-bromo-3-methylisothiazole-based microbicide at a rate of 0.08–0.15 kg of active ingredient per tonne of dry fibre production reduces biofilm ATP readings by 85–95%. The measurement is taken with a portable luminometer using the ASTM E2694-21 protocol. The treatment is delivered through a calibrated diaphragm metering pump into the clarified white-water return line upstream of the machine chest. The strategy must be synchronized with the retention-aid program. Polyacrylamide and microparticle retention systems are not affected by the brominated isothiazole at the stated dose rates. However, simultaneous injection with oxidative shock treatments such as sodium hypochlorite results in mutual neutralization and a temporary loss of microbial control. A 90-minute separation interval is necessary. Regulatory oversight for food-contact grades of paper and board is governed by FDA 21 CFR 176.170 and the BfR Recommendation XXXVI. Both set specific migration limits and require that the biocide not be detectable in finished packaging above a limit of 0.5 µg/dm². The finished sheet products—coated recycled liner, gypsum board facing, and aseptic liquid packaging board—routinely undergo TAPPI T 228 extractives testing to validate compliance. When Wet-Blue Leather Preservation Shifts from TCMTB to Isothiazole ChemistryChrome-tanned wet-blue splits destined for export to South-East Asian finishing units are traditionally treated with 0.15–0.25% (w/w on shaved weight) of 2-(thiocyanomethylthio)benzothiazole (TCMTB). This fungicide’s efficacy is compromised at pH values below 4.0. It also generates detectable mercaptan odour when the leather is subsequently neutralized. Replacing TCMTB with a 5-bromo-3-methylisothiazole preparation at 0.06–0.10% active on wet-blue weight achieves zero visible fungal growth after 8 weeks of storage. The application is performed in a 2.5-metre diameter stainless-steel tanning drum containing 300–500 kg of shaved hide at a float ratio of 1.0:0.8 (water:leather). Storage conditions follow ISO 20137:2018 tropical-chamber parameters (30°C, 95% RH). The drum is rotated at 6–8 rpm for 60 minutes, after which the fungicide-treated float is discarded. The wet-blue is then horsed up for drip-dry. Because brominated isothiazoles do not contain phenolic or organochlorine markers, the resultant leather qualifies for ZDHC MRSL Level 3 verification. It meets the restricted substance list requirements of the Leather Working Group audit protocol. The final consumer articles include full-grain upholstery leather for automotive interiors. In this segment, odour profile and fogging resistance (measured per ISO 6452) are gate specifications. Styrene-butadiene and pure acrylic latices intended for pressure-sensitive adhesive (PSA) coating and textile backing are typically produced with only a marginal biocide content added at the polymerization stage. This leaves the finished dispersion vulnerable to post-synthesis contamination during off-loading into storage silos. To rectify this, a post-addition of a 5-bromo-3-methylisothiazole formulation is performed in a dedicated 5,000-litre SS316L hold tank. The tank is fitted with a bottom-entry, low-shear impeller rotating at 80–100 rpm. The active dose is maintained at 0.04–0.07% based on the wet dispersion weight. This level suppresses total plate counts below 10² CFU/g for 12 months when stored in closed-top totes at ambient temperatures not exceeding 30°C. The biocide must be slowly poured into the vortex of the gently agitated tank over a period of 15–20 minutes. This prevents localized coagulation of the latex particles, a phenomenon that can occur if the neat concentrate contacts the dispersion before full dilution. Once homogenized, the preserved latex can be formulated into water-based contact adhesives, carpet-backing compounds, and nonwoven binder formulations. All these must comply with the emission limits for volatile active substances defined in the EU Ecolabel for Indoor Paints and Varnishes (Commission Decision 2014/312/EU). For applications with indirect food contact, e.g., dry-food packaging adhesives, compliance with FDA 21 CFR 175.105 and 175.300 is demonstrated through extraction testing. The simulants are 10% ethanol and 95% ethanol. The brominated isothiazole must not be detected above a practical quantitation limit of 0.01 µg/cm².
Cooling Tower Cycles of Concentration and the Role of Non-Oxidizing MicrobicidesOpen recirculating cooling systems operating at 4–7 cycles of concentration accumulate dissolved salts, suspended solids, and microbial nutrients. This leads to biofilm-induced under-deposit corrosion that can penetrate carbon steel piping at rates exceeding 5 mils per year (mpy). Brominated isothiazoles serve as non-oxidizing secondary microbicides. They are applied in alternating slug doses with chlorine or bromine donors to prevent resistance development. A typical shock-dose program injects 15–25 mg/L of the active 5-bromo-3-methylisothiazole substance directly into the cooling tower basin over a 30-minute period. The target holding time is 4 hours at a system pH of 7.5–9.0. The injection sequence is interlocked with the blowdown control valve. The chemical is retained in the system until the contact period elapses. Afterward, the tower is blown down to reduce the concentration to <1 mg/L before normal operation resumes. Efficacy monitoring employs ASTM D4012-81(2021) for planktonic heterotrophic plate count and ASTM E2196-17 for rotating-disc biofilm reactors. The latter models biofilm removal efficiency. Active substance approval for cooling water use in Europe falls under EU BPR Product Type PT11. This requires a WGK rating and a detailed environmental exposure assessment. In North America, the product is registered under EPA FIFRA as a non-food-use microbicide. It must carry the appropriate precautionary labeling for aquatic toxicity. The cooling systems serviced include those at petrochemical cracker plants, data center HVAC chiller loops, and ammonia refrigeration condensers. In all these installations, uninterrupted heat transfer is safety-critical. |
Competitive Isothiazole, 5-Bromo-3-Methyl- prices that fit your budget—flexible terms and customized quotes for every order.
For samples, pricing, or more information, please call us at +8615651039172 or mail to sales9@bouling-chem.com.
We will respond to you as soon as possible.
Tel: +8615651039172
Email: sales9@bouling-chem.com
Flexible payment, competitive price, premium service - Inquire now!
Isothiazole, 5-Bromo-3-Methyl- (CAS: 20493-99-2, molecular formula C₄H₄BrNS, molecular weight 178.05 g/mol) is supplied as a pale yellow to amber liquid with a boiling point of 82–84 °C at 15 Torr and a density of 1.69 g/cm³ at 20 °C. The product lot release specification mandates gas chromatographic purity ≥ 98.0% (area normalization, DB-5 capillary column, 30 m × 0.25 mm × 0.25 µm film, flame ionization detection), with the 3-methyl isomer (5-bromo-3-methyl content confirmed by ¹H NMR, 400 MHz, CDCl₃, δ 8.45 ppm singlet for H-4) relative to the potential 4-bromo regioisomer limited to ≤ 0.8%. Water content is controlled to ≤ 500 ppm by Karl Fischer titration, and residual palladium from synthesis is held below 10 ppm by ICP-OES. Storage is recommended under inert atmosphere at 2–8 °C, with retest dating at 12 months when container integrity is maintained.
Handling must consider the compound’s sensitivity to nucleophilic displacement: the C5 bromine atom is susceptible to substitution by amines, alkoxides, and thiols. In the absence of rigorous moisture exclusion, slow hydrolysis yields 3-methylisothiazol-5-one, detectable by a pH drift exceeding 0.5 units in bulk samples exposed to ambient humidity for 48 hours. Portable glovebox transfers (O₂ < 10 ppm, H₂O < 5 ppm) are specified for milligram-scale aliquoting intended for palladium-catalyzed cross-coupling, as oxidative addition rates at the C–Br bond are degraded by surface oxide formation on catalyst pre-cursors. The flash point is reported at 96 °C (closed cup, ASTM D93-20), placing the liquid in combustible liquid Class IIIA per NFPA 30, requiring grounding and bonding protocols during drum-scale dispensing.
Comparative kinetic data generated under standardized reactor conditions (toluene, 2.0 mol% Pd₂(dba)₃ / 4.0 mol% XPhos, 1.5 eq. NaO⁺Bu, 80 °C, substrate concentration 0.25 M) show that 5-Bromo-3-methylisothiazole achieves 92% conversion to N-aryl derivatives in 4 hours with morpholine as coupling partner, while 5-Chloro-3-methylisothiazole requires 18 hours to reach 67% conversion under identical catalyst loading. This 4.5-fold rate enhancement is attributable to the lower C–Br bond dissociation energy (~71 kcal/mol versus ~84 kcal/mol for C–Cl) and a more favorable LUMO coefficient at the ipso carbon, as computed at the B3LYP/6-311+G(d,p) level. The consequence for kilogram-scale manufacturing is a 40% reduction in catalyst consumption and a shorter cycle time per batch in jacketed 100 L Hastelloy reactors. However, the heightened liability of bromide displacement introduces a competing protodehalogenation pathway when residual water in anhydrous solvents exceeds 80 ppm; under those conditions, 3-methylisothiazole becomes the dominant by-product, reaching 11 area% by GC–MS versus 2–3% for the chloro variant.
| Parameter | 5-Bromo-3-methyl | 5-Chloro-3-methyl | 5-Iodo-3-methyl |
|---|---|---|---|
| Reaction time to 90% conv. (morpholine) | 3.5 h | >20 h | 1.2 h |
| Protodehalogenation at 150 ppm H₂O (area%) | 4.8% | 0.6% | 12.3% |
| Cost per mole (bulk, EUR) | 120–140 | 45–60 | 580–640 |
| Storage stability at 25 °C (purity loss/month) | 0.3% | 0.1% | 1.5% |
Conventional routes to 5-substituted 3-methylisothiazoles frequently proceed through the corresponding 5-lithio or 5-magnesio intermediates, generated via halogen–metal exchange at –78 °C in THF. With the bromo derivative, this exchange is rapid (< 30 sec) at –78 °C using 1.05 eq. iPrMgCl·LiCl in THF, as indicated by in-line ReactIR monitoring of the isothiazole C–H stretching region. Direct conversion of 5-Bromo-3-methylisothiazole to the pinacol boronate ester using B₂pin₂ (1.2 eq.), KOAc (3.0 eq.), and Pd(dppf)Cl₂·CH₂Cl₂ (1.5 mol%) in 1,4-dioxane at 100 °C yields the boronic ester in 76% isolated yield after silica gel chromatography. When this direct borylation is attempted on the corresponding 5-iodo analogue, the elevated catalyst loading required (3.0 mol%) and competitive homocoupling produce biisothiazole dimer at 14 area%, complicating purification. The bromo substrate thus occupies a process-optimized window—more reactive than chloride, yet less prone to oxidation and dimerisation than iodide.
In a pilot-plant campaign for a kinase inhibitor intermediate, the telescoped sequence of Miyaura borylation followed by Suzuki coupling with a 2-chloropyrimidine fragment was executed in a single reactor, avoiding isolation of the boronate ester. A total of 42.1 kg of 5-Bromo-3-methylisothiazole was processed across 8 batches in an 800 L glass-lined reactor equipped with a retreat-blade impeller and jacket temperature control. The average yield after crystallization was 81.3% with a batch-to-batch purity variation (HPLC, 210 nm) of ±0.7%. Process drift became evident when jacket temperature exceeded 105 °C during the borylation hold step, generating 0.9–1.4% of a dehalogenated impurity that co-crystallized in the final product; therefore, the operational limit was fixed at 100 ± 2 °C with a circulating silicone oil system.
For active pharmaceutical ingredient (API) starting material designation under ICH Q11, the 5-Bromo-3-methylisothiazole lot must meet elemental impurity thresholds per USP <232> / Ph.Eur. 5.20. A standardized digest (closed-vessel microwave, HNO₃/H₂O₂, 210 °C) followed by ICP-MS quantification across 24 elements confirms: Pd ≤ 10 ppm (Parenteral exposure limit), Fe ≤ 30 ppm, Ni ≤ 5 ppm, and As, Cd, Hg, Pb each ≤ 1 ppm. Residual bromide ion introduced during synthesis is controlled through a 5 wt% NaHCO₃ wash step; post-wash bromide in the organic phase is measured by ion chromatography with a limit of < 50 ppm. This washing stage is performed in a 316L stainless steel HASTELLOY-equipped mixer-settler unit at a phase ratio (organic:aqueous) of 3:1 and a residence time of 12 minutes.
| Test | Method | Acceptance criterion |
|---|---|---|
| Assay (GC) | In-house GC-FID, DB-5 | ≥ 98.0% |
| Isomeric purity (4-Br regioisomer) | ¹H-NMR (400 MHz) | ≤ 0.8% |
| Water content | KF (coulometric) | ≤ 500 ppm |
| Residual palladium | ICP-OES | ≤ 10 ppm |
| Bromide ion | IC | ≤ 50 ppm |
| Non-volatile residue | ASTM D1353-13 | ≤ 0.1 wt% |
Storage stability under ICH Q1A conditions (long-term 25 °C/60% RH, accelerated 40 °C/75% RH) has been monitored through 36-month data: no degradation peak exceeding 0.15 area% is observed, and the pH of a 10% water extract remains within 5.2–6.0. Photostress testing under ICH Q1B Option 2 (xenon lamp, 1.2 million lux·h) results in 0.4% increase in a UV-active dimer, which is suppressed by amber glass packaging with a light transmission cut-off at 500 nm.
Nitration of the isothiazole core is inherently challenging due to the deactivating influence of the heterocyclic nitrogen. 5-Bromo-3-Methylisothiazole exhibits regioselective nitration at the C4 position when treated with mixed acid (HNO₃/H₂SO₄ 1:3 v/v) at –5 to 0 °C for 2.5 hours. The resulting 4-nitro-5-bromo-3-methylisothiazole is isolated in 68% yield after drowning in ice-water and recrystallization from isopropanol. In contrast, 3-Methylisothiazole itself yields a mixture of 4-nitro and 5-nitro regioisomers in a 35:65 ratio under identical conditions, demonstrating that the bromine substituent exerts a strong ortho/para-directing influence that overrides the intrinsic α-selectivity of the nitrogen. This transformation opens a route to 4,5-difunctionalized isothiazoles, where the bromine is subsequently replaced by carbon nucleophiles. The storage of the nitro intermediate requires special caution: differential scanning calorimetry (DSC) onset decomposition at 195 °C with an exotherm of 520 J/g classifies it as a potentially explosive substance under EU A14/OECD 3(a) screening; pilot-scale handling limits bulk storage to ≤ 15 kg per container, stored behind a barricade.
The reaction mass heat capacity (Cp) measured during nitration by Seebeck calorimetry was 2.01 J/g·K. With the addition rate of mixed acid controlled at 0.8 mL/min per 100 g of substrate, the maximum adiabatic temperature rise (ΔT_ad) was kept below 50 °C, ensuring that the MTSR (maximum temperature of the synthesis reaction) remained 25 °C below the onset of the secondary decomposition. This safety envelope was validated in a Mettler-Toledo RC1e reaction calorimeter with a 1 L jacketed glass reactor using an isothermal mode at –10 °C.
5-Bromo-3-methylisothiazole has been utilized as a precursor to 3-methylisothiazole-5-thione, generated in situ by treatment with NaSH in DMF. The thione participates in visible-light-mediated [2+2] cycloadditions with electron-deficient alkenes. While detailed photophysical quantum yield data for this specific configuration remains limited, early benchtop experiments in a Rayonet RPR-100 photoreactor (λ = 365 nm, 8 x 14 W lamps) indicate a diastereoselectivity > 20:1 favoring the cis-fused thietane structure when methyl vinyl ketone is the dipolarophile. The bromo substituent does not interfere with the photochemical step, as evidenced by retention of > 95% bromine integrity by XRF analysis of the crude product. This tandem sequence—nucleophilic thionation followed by cycloaddition—avoids the isolation of the malodorous thione intermediate, which is a significant industrial hygiene consideration, and highlights a synthetic niche where 5-halo-3-methylisothiazoles surpass the 5-unsubstituted analogue in process step economy.
5-Bromo-3-methylisothiazole undergoes accelerated degradation in the presence of primary and secondary amines even at ambient temperature. Monitoring by headspace GC–MS of a 0.5 M solution in acetonitrile containing 0.1 eq. n-butylamine reveals evolution of methyl mercaptan and formation of a dark, insoluble oligomeric residue within 72 hours. This incompatibility precludes the use of amine-based scavenger resins (e.g., QuadraSil AP, Amberlyst A21) for workup of reaction mixtures containing excess electrophile. Instead, post-reaction quenching employs aqueous 5% citric acid to protonate residual amines, followed by extraction with methyl tert-butyl ether. Carbon-steel storage vessels must be excluded entirely: corrosion coupon testing (ASTM G31-72) in the pure liquid at 40 °C showed a corrosion rate of 0.18 mm/year on C1018 steel, driven by trace HBr release, while 316L stainless steel and Hastelloy C-276 exhibited rates below 0.005 mm/year. Wetted seals in drum pumps are specified to be PTFE or FFKM (Kalrez) due to the solvent-induced swelling of EPDM gaskets observed during sealed storage at elevated ambient temperatures (≥ 35 °C).
In conclusion, the specifications, reactivity profile, and scale-up data for 5-Bromo-3-Methylisothiazole define a material where the moderate activation of the C–Br bond balances synthetic utility against predictable side reactions. The compilation of palladium-catalysed coupling rates, nitration regiochemistry, and corrosion data frames the product as an advanced intermediate for heterocyclic elaboration, with documented boundaries for moisture ingress, amine contact, and excessive thermal stress during downstream processing.
