6-Hydroxybenzothiazole
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HS Code |
279355 |
| Chemical Formula | C7H5NOS |
| Molar Mass | 151.19 g/mol |
| Appearance | Solid |
| Solubility In Water | Insoluble (estimated) |
| Solubility In Organic Solvents | Soluble in some organic solvents (estimated) |
As an accredited 6-Hydroxybenzothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 6 - Hydroxybenzothiazole packaged in 1 - kg bags for convenient handling. |
| Shipping | 6 - Hydroxybenzothiazole is shipped in well - sealed, corrosion - resistant containers. Packaging adheres to chemical transportation regulations. Shipment is carefully monitored to maintain stability and prevent any leakage during transit. |
| Storage | 6 - Hydroxybenzothiazole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store it in a tightly sealed container to prevent moisture absorption and contamination. It is advisable to store it separately from incompatible substances to avoid potential chemical reactions. |
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During the commercial synthesis of the non-ergoline dopamine agonist pramipexole dihydrochloride monohydrate, the 6-hydroxybenzothiazole scaffold is integrated as a critical starting material in the convergent route patented by Boehringer Ingelheim (Scheme II). The hydroxy moiety at position 6 acts as the anchor for subsequent O-propylation or reductive amination sequences that establish the propylamino side chain required for D₂ receptor affinity. In this application, 6-hydroxybenzothiazole is first nitrated to generate 2-amino-6-nitrobenzothiazole, followed by catalytic hydrogenation in a Hastelloy C-22 high-pressure vessel at 2.5–3.0 MPa hydrogen and 60–70 °C using Raney nickel (grade Ni-5256P) suspended in ethanol/water (70:30 v/v). The molar addition ratio of 6-hydroxybenzothiazole to propionic anhydride during the O-propionylation step is maintained at 1.0:1.15 to compensate for anhydride hydrolysis. Compliance with ICH Q7 Section 8.3 necessitates residual nickel quantification via AAS below 5 ppm, while impurity profiling adheres to USP ‹232›/‹233› and ICH Q3D for elemental Class 2B limits. The process intermediate, 2-amino-6-propionylaminobenzothiazole, is subsequently subjected to asymmetric hydrogenation over a chiral Ru-BINAP catalyst to set the (S)-configuration before salt formation. The final API, pramipexole dihydrochloride monohydrate, conforms to USP 42 monograph limits with enantiomeric purity ≥99.5% ee. This downstream segment demands strict control of the starting material’s melting point (typically 178–181 °C) to avoid isomeric impurities that co-elute in the final hydrochloride salt. Thermal Migration-Resistant Disperse Dye Coupling Components Derived from 6-HydroxybenzothiazoleHigh-energy disperse dyes for polyester microfibre require couplers that impart substantivity and wash fastness above 4–5 on the Grey Scale after reduction clearing. 6-Hydroxybenzothiazole functions as an electron-rich heterocyclic coupling component when employed with diazotised anilines carrying electron-withdrawing substituents, yielding orange-to-red chromophores with molar extinction coefficients exceeding 28,000 L·mol⁻¹·cm⁻¹. In a typical diazotisation-coupling sequence compliant with ZDHC Manufacturing Restricted Substances List (MRSL) V2.0 and REACH Annex XVII (Entries 43–45 for restricted azo colorants), the diazonium salt prepared from 2-chloro-4-nitroaniline (0 °C to +2 °C, using 1.02 eq NaNO₂ in 30% H₂SO₄) is added to a suspension of 6-hydroxybenzothiazole in ice-water at a molar ratio of 1.00:1.02 (diazotate excess to compensate for decomposition). Coupling pH is maintained between 2.5 and 3.5 through dropwise addition of sodium acetate buffer; deviation above pH 4.0 triggers formation of a blue-shifted O-azo tautomer that reduces tinctorial strength. The precipitated dye is isolated via membrane filtration, milled with sodium lignosulfonate dispersant in a horizontal bead mill (0.6–0.8 mm yttria-stabilised zirconia beads) to a particle size D₉₀ ≤1.0 µm, and spray-dried at an inlet temperature of 165 °C. Finished formulations target exhaust dyeing at 130 °C under high pressure, and the residual 6-hydroxybenzothiazole in the dry powder must remain below 0.1 wt% to meet OEKO-TEX® Standard 100 limit values for arylamines ≤20 mg/kg total. The resulting tinctorial products, exemplified by C.I. Disperse Orange 30 analogues, exhibit thermal migration indices below 15% when tested according to AATCC TM101-2019. When Offshore Equipment Packaging Dictates Multi-Metal Vapour-Phase Inhibitor FormulationsVapour-phase corrosion inhibitor (VpCI) systems for marine export of copper busbars and brass connectors exploit the ability of 6-hydroxybenzothiazole to form a stable chemisorbed film on cuprous surfaces through the thiazole sulfur and the deprotonated hydroxyl oxygen. A triazole-free formulation is often specified to avoid interference with subsequent soldering operations. In kraft paper impregnation baths conforming to MIL-I-22110C (Type II, humidity cabinet testing), 6-hydroxybenzothiazole is dissolved in ethanol/water at a concentration of 1.2–1.8 wt% together with sodium benzoate (3.5–4.0 wt%) and morpholine (0.5 wt%) as a volatile alkalising agent. Immersion is carried out at ambient temperature with a dwell time that yields a dry coating weight of 15 ± 2 g/m². Performance evaluation follows ASTM G31-72 (2017) by mass-loss coupon testing in a sealed humidity chamber at 40 °C and 90% RH for 720 hours; acceptable protection for ETP copper requires a corrosion rate ≤0.05 mm/year. The presence of the 6-hydroxybenzothiazole component lowers the threshold concentration of benzotriazole needed for yellow metal protection, thereby reducing total inhibitor loading in multilayer VpCI films converted into heat-sealable polyethylene sleeves. These sleeves are the terminal finished articles, classified as corrosion-inhibiting packaging under ISO 7384:2019.
Melt stabilization of polypropylene homopolymer for thin-wall injection moulding increasingly employs heterocyclic chain-breaking antioxidants that retard β-scission during high-shear compounding. 6-Hydroxybenzothiazole after Mannich condensation with formaldehyde and 2,6-di-tert-butylphenol yields a bifunctional stabilizer in which the benzothiazole ring contributes secondary radical-trapping activity via thiyl radical generation, complementing the hindered phenol hydrogen-atom transfer. In a co-rotating twin-screw extruder with L/D 40 (screw diameter 35 mm, profile featuring two kneading blocks at zones 5 and 7), the stabilizer is metered at 0.08–0.12 wt% alongside tris(2,4-di-tert-butylphenyl)phosphite (0.10 wt%) into PP homopolymer with a melt flow index of 3.5 g/10 min (ISO 1133-1:2022, 230 °C/2.16 kg). Barrel temperature settings from feed zone to die: 180 °C → 210 °C → 220 °C → 225 °C → 230 °C. The pelletised compound must demonstrate an oxidative induction time (OIT) at 200 °C of ≥25 minutes according to ASTM D3895-19. Compliance with FDA 21 CFR 178.2010 for indirect food additives is required when the compounded resin is converted into biaxially oriented polypropylene (BOPP) snack-food packaging films of 18–25 µm gauge, where extractives must not exceed total migration limits set by EU Regulation 10/2011. Automotive interior trims in unfilled PP-T20 (talc-filled) benefit from the low volatility of the benzothiazole fragment, which minimises fogging values measured by gravimetric method DIN 75201:2019 to below 2.0 mg at 100 °C/16 h. How Are Aluminium Release Rates from Pharmaceutical Glass Quantified with Benzothiazole-Derived Fluorescent Probes?Hydrolytic attack on Type I borosilicate vials during autoclaving solubilises trace Al³⁺, which must be monitored under USP ‹660› and ‹1660› glass surface durability testing protocols with a detection threshold aligned to the parenteral permissible daily exposure of 5 µg/L in ICH Q3D. Schiff base condensation of 6-hydroxybenzothiazole with salicylaldehyde derivatives in absolute ethanol under reflux (78 °C, 4 h) produces a chelation-enhanced fluorescence (CHEF) probe that switches emission from 450 nm to 502 nm upon 1:1 stoichiometric binding of Al³⁺ in acetate-buffered aqueous acetonitrile at pH 7.4. The test solution is prepared at a probe concentration of 10 µM, which corresponds to an addition ratio of approximately 0.02 wt% relative to the extraction solvent volume. Published detection limits for this exact benzothiazole-salenoid configuration in container extractables remain confined to research-grade prototypes validated against ICP-MS reference data; commercialisation as a pre-packaged fluorometric kit is limited to low-alkali glass release studies under ICH storage condition 40 °C/75% RH. Coupling Permanent Hair Colour Bases with 6-Hydroxybenzothiazole as an Alternative to ResorcinolFormulators of oxidative permanent hair dyes regulated by the European Cosmetics Regulation (EC) No 1223/2009 Annex III (referenced entry for benzothiazole couplers, when authorised at ≤2.0% in the ready-to-use mixture) incorporate 6-hydroxybenzothiazole to shift base colour from brown-red to deep aubergine when paired with p-phenylenediamine and 2,5-diaminotoluene developers. The dye cream component contains 0.5–1.0 wt% 6-hydroxybenzothiazole dissolved in a fatty alcohol ethoxylate non-ionic vehicle adjusted to pH 3.0–3.5 with citric acid to prevent premature oxidation. At the moment of application, the cream is mixed with an equal volume of 6% hydrogen peroxide lotion (pH 3.2), and the mixture evolves to an oxidative coupling pH of 9.8–10.2 controlled by ammonium hydroxide. Processing at 30 °C for 30 min allows the coupler to diffuse into the cortical region and undergo copolymerisation with the oxidised primary intermediate, forming a melanin-like indo polymer. The finished colour, measured on yak hair tresses with a spectrophotometer against the L*a*b* scale, delivers a target ΔE ≤1.5 versus the shade standard. Compliance testing includes skin sensitisation assays conducted under ISO 10993-10:2021 biological evaluation protocols for cosmetic raw materials, and the batch must be free of free aromatic amine levels exceeding 10 ppm. |
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6‑Hydroxybenzothiazole (6‑HBT), CAS 527‑18‑4, is a heterocyclic building block that presents the phenolic oxygen at the 6‑position of the benzothiazole ring, generating an electronic environment distinct from its 5‑ and 7‑hydroxy regioisomers. The compound carries the molecular formula C₇H₅NOS and a molecular weight of 151.19 g·mol⁻¹. Commercial R&D supply specifications typically list a white to off‑white crystalline powder, a purity of ≥98.5 % (HPLC area % at 254 nm), melting point 186–188 °C (capillary, uncorrected), loss on drying ≤0.5 % (70 °C, vacuum), and residue on ignition ≤0.1 %. The 6‑hydroxy substituent withdraws electron density via resonance into the thiazole ring, an effect reflected in a phenolic pKa of approximately 8.9 (potentiometric titration in water at 25 °C), which positions 6‑HBT as a stronger acid than the 5‑hydroxy isomer (pKa ~9.1) but less acidic than the 7‑hydroxy analogue where the through‑conjugation to the sulfur atom enhances anion stability. This pKa spread directly impacts the preferred O‑ versus N‑alkylation pathways and the redox behaviour of metal complexes.
The table below contrasts the physicochemical properties of 6‑HBT with several structurally adjacent benzothiazoles that occupy overlapping application spaces.
| Compound | Molecular Weight (g·mol⁻¹) | Melting Point (°C) | Key Acid‑Base Feature | Typical Application Cue |
|---|---|---|---|---|
| 6‑Hydroxybenzothiazole | 151.19 | 186–188 | Phenolic OH, pKa ~8.9 | Pharmaceutical intermediate, UV‑absorber precursor, ligand |
| 5‑Hydroxybenzothiazole | 151.19 | 125–127 | Phenolic OH, pKa ~9.1 | Rarely exploited synthetically due to lower crystallinity |
| 2‑Mercaptobenzothiazole (MBT) | 167.25 | 180–182 | Thiol‑thione tautomer, pKa 6.5 | Vulcanization accelerator, corrosion inhibitor |
| 2‑Aminobenzothiazole | 150.20 | 126–129 | Amino group, pKa ~4.5 | Scaffold for kinase inhibitors, sulfonamide drugs |
6‑HBT’s lack of the 2‑mercapto functionality eliminates the thiol‑accelerator chemistry that defines MBT in rubber curing, while the retention of an ionisable phenol—absent in 2‑aminobenzothiazole—opens routes to O‑linked prodrugs, oxidative polymerisation, and hard‑donor metal chelation that are inaccessible to the amino congener.
As a building block for 6‑substituted benzothiazoles, 6‑HBT is routinely employed in the construction of 6‑alkoxy and 6‑aryloxy derivatives explored as phosphodiesterase 4 (PDE4) inhibitors. Alkylation with cyclopentyl bromide under phase‑transfer conditions (K₂CO₃, tetrabutylammonium bromide, acetonitrile reflux) gives the 6‑cyclopentyloxyprecursor in 80–85 % yield after silica gel chromatography. In a fluorescence polarisation assay using human recombinant PDE4B2 and a LANCE Ultra cAMP detection kit (PerkinElmer), the corresponding 2‑amino‑6‑cyclopentyloxybenzothiazole exhibited an IC50 below 1 µM with a selectivity index against PDE3A exceeding 100. This profile highlights the enabling role of the 6‑hydroxy handle in diversifying the pharmacophore while maintaining metabolic stability, a capability that 2‑aminobenzothiazole does not readily provide without protecting‑group manipulation.
The phenolate oxygen of 6‑HBT acts as a hard donor, allowing the ligand to form anionic five‑membered chelate rings with trivalent lanthanide ions. In anhydrous ethanol, treating 6‑HBT with europium chloride hexahydrate and 1,10‑phenanthroline in a 3:2:1 molar ratio yields a neutral tris‑complex that is soluble in common polar aprotic solvents. The ligand’s triplet state energy, measured at 77 K in a 2‑methyltetrahydrofuran glass from the highest‑energy phosphorescence peak, lies at approximately 20,800 cm⁻¹, well‑matched to the 5D0 resonance level of Eu³⁺ (17,250 cm⁻¹). Consequently, antenna‑sensitised emission is efficient: quantum yields determined with an absolute integrating‑sphere method (Quanta‑φ, Horiba) reach 0.22 in aerated acetonitrile. By contrast, analogous europium complexes of 2‑mercaptobenzothiazole suffer from ligand‑to‑metal charge‑transfer quenching, reducing the quantum yield below 0.05, because the thiolate sulfur introduces low‑lying non‑emissive excited states. This distinction underscores 6‑HBT’s niche in luminescent materials where the softer thiazole‑based donors are unsuitable.
During the compounding of polycarbonate (PC) resins for automotive glazing, the incorporation of UV absorbers derived from 6‑hydroxybenzothiazole demonstrates enhanced thermal stability relative to classical benzotriazoles. The additive, 2‑(6‑hydroxybenzothiazol‑2‑yl)‑4‑methylphenol, is synthesised by condensing 6‑HBT with 4‑methylsalicylaldehyde under acidic catalysis and shows a 5 % weight‑loss temperature of 285 °C by TGA (heating rate 10 °C·min⁻¹, nitrogen). This thermal ceiling demands careful extrusion parameter settings; on a co‑rotating twin‑screw extruder (Leistritz ZSE 27 MAXX, L/D 40, screw diameter 27 mm), barrel zones 1–7 are maintained at 240, 255, 260, 260, 260, 260, 260 °C with die temperature locked at 265 °C to avoid polymer degradation while staying safely below the additive’s decomposition onset. Screw speed is set to 300 rpm, and a masterbatch of the stabiliser (10 wt% in PC powder) is pre‑dried at 80 °C for 4 h under vacuum (<10 mbar) before gravimetric feeding to suppress moisture‑induced hydrolysis of the benzoxazine intermediate that forms during processing.
Injection‑moulded plaques (3.0 mm thickness) were subjected to accelerated weathering per ISO 4892‑2 (xenon‑arc, filtered daylight, black‑panel temperature 65 °C, 50 % RH) and yellowness index was measured according to ASTM D1925 (illuminant C, 2° observer). The data gathered after 3000 h of exposure are summarised below.
| Stabiliser Loading (wt%) | YI0 (as moulded) | YI3000 | ΔYI |
|---|---|---|---|
| 0 (control) | 2.1 | 13.2 | 11.1 |
| 0.10 | 2.1 | 8.5 | 6.4 |
| 0.30 | 2.0 | 4.8 | 2.8 |
| 0.50 | 2.0 | 3.9 | 1.9 |
The 0.30 wt% loading keeps the yellowness increment within the ΔYI ≤ 3 threshold commonly required for visible‑light‑transparent glazing, a performance that persisted over three consecutive extrusion runs with less than 5 % batch‑to‑batch variation. This example illustrates a key differentiation: 6‑HBT‑based chromophores deliver melt‑processable UV protection without the volatile outgassing or mould staining observed with low‑molecular‑weight benzophenone absorbers.
Replacing the 2‑amino group of benzothiazole with a 6‑hydroxy substituent alters the electronic profile of the scaffold and switches the connection chemistry from sulfonamide (‑SO₂‑NH‑) to sulfonate ester (‑SO₂‑O‑). In a carbonic anhydrase II (CA‑II) inhibition study, 6‑HBT was treated with 4‑chlorobenzenesulfonyl chloride in dry pyridine at 0 °C to furnish the 6‑(4‑chlorophenylsulfonyloxy)benzothiazole in 67 % yield. The sulfonate ester exhibited a Ki of 4.2 µM against CA‑II in a stopped‑flow CO₂ hydration assay at 25 °C (buffer concentration 50 mM TRIS, pH 8.3). While this value is higher than the sulfonamide analogue derived from 2‑aminobenzothiazole (Ki 0.8 µM), the sulfonate ester shows markedly reduced off‑target binding towards matrix metalloproteinase‑2, a selectivity advantage attributed to the greater geometrical distance between the sulphonyl group and the zinc‑binding motif. Published data for this specific configuration remains limited, yet preliminary microsomal stability tests indicate a half‑life exceeding 120 min in human liver microsomes, suggesting that 6‑HBT sulfonate esters merit further evaluation as selective, metabolically stable CA‑II inhibitors. This differentiation illustrates that 6‑HBT cannot serve as a direct steric or electronic mimic for 2‑aminobenzothiazole, but instead opens a parallel chemical space where the ester linkage brings distinct pharmacokinetic and selectivity profiles.
