5-Thiazolecarbonyl Chloride, 4-Methyl-2-Phenyl-
|
HS Code |
484899 |
| Chemical Formula | C11H8ClNO2S |
| Molecular Weight | 253.706 |
| Appearance | Solid (usually a powder or crystalline solid) |
| Physical State At Room Temperature | Solid |
| Melting Point | Data may vary, check specific sources |
| Boiling Point | Data may vary, check specific sources |
| Solubility In Organic Solvents | Soluble in some common organic solvents like dichloromethane, chloroform |
| Solubility In Water | Insoluble in water |
| Odor | May have a pungent or characteristic odor |
| Stability | Stable under normal conditions, but reactive with water and nucleophiles |
| Reactivity | Reactive towards nucleophiles due to the presence of the carbonyl chloride group |
| Flash Point | Data may vary, check specific sources |
As an accredited 5-Thiazolecarbonyl Chloride, 4-Methyl-2-Phenyl- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 4 - Methyl - 2 - phenyl - 5 - thiazolecarbonyl chloride in sealed chemical - grade bottle. |
| Shipping | 5 - Thiazolecarbonyl Chloride, 4 - Methyl - 2 - Phenyl - is shipped in well - sealed, corrosion - resistant containers. It's transported under controlled conditions to prevent contact with moisture and incompatible substances, ensuring safe transit. |
| Storage | Store “5 - Thiazolecarbonyl Chloride, 4 - Methyl - 2 - Phenyl -” in a cool, dry, well - ventilated area, away from heat sources and open flames. Keep it in a tightly sealed container to prevent contact with moisture, which could initiate hydrolysis. Store it separately from incompatible substances like bases and reactive metals to avoid chemical reactions. |
Production-scale rubber compounding lines operating a 1.5-metre two-roll mill with a friction ratio of 1:1.15 and a nip gap maintained at 2.5 mm incorporate the accelerator intermediate manufactured from 5-thiazolecarbonyl chloride, 4-methyl-2-phenyl- at addition levels of 0.9–1.4 phr relative to the elastomer matrix—typically a blend of natural rubber (Standard Malaysian Rubber CV60) and butadiene rubber (BR9000) at a 70/30 weight ratio—alongside 2.5 phr of rhombic sulphur, 5.0 phr of indirect-process zinc oxide, and 2.0 phr of stearic acid. The synthesis of the accelerator itself proceeds via a thiolation step wherein the acid chloride is first converted to the corresponding thioester with ethanethiol in anhydrous tetrahydrofuran under nitrogen, then cleaved with sodium hydrosulphide to yield 2-phenyl-4-methyl-5-thiazolethiol; this thiol intermediate is subsequently oxidised to the symmetric disulphide using hydrogen peroxide in isopropyl alcohol at 35–40 °C, achieving a melting point of 123–126 °C and typical purity of ≥98.5 % by HPLC. On the compounding floor, the pre-weighed accelerator is added in the second masterbatch stage after carbon black (N330, 50 phr) has been fully incorporated, and the batch is sheeted off at a dump temperature not exceeding 110 °C to avoid premature scorch. Cure behaviour is analysed on a moving-die rheometer in accordance with ASTM D5289-19a; the formulation exhibits a minimum torque (ML) typically 12–18 % higher than that of a conventional N-cyclohexyl-2-benzothiazolesulphenamide (CBS) control at equal loading, while the scorch time (ts2) is reduced by approximately 20–30 %, narrowing the processing window and necessitating precise temperature control during calendering. Vulcanisation is conducted in a multi-platen hydraulic press at 160 °C for a duration equivalent to t90 + 2 minutes per 2 mm of plaque thickness. Finished rubber goods—automotive engine mounts and anti-vibration bushings—must comply with REACH (EC) No 1907/2006 for SVHC-free declarations, and where the components are intended for repeated food-contact use, the formulation requires migration testing under FDA 21 CFR 177.2600 Type II conditions with a total extractives limit of ≤ 50 mg/dm². A key processing constraint arises when ambient relative humidity exceeds 65 %: the acid chloride-derived intermediate shows hygroscopicity at the thiol stage, and adsorbed moisture leads to disulphide reversion during compounding, evidenced by erratic MH values and surface bloom on cured test sheets; therefore, pre-drying of the accelerator in a vacuum oven at 40 °C for 4 hours is mandatory whenever RH surpasses the 60 % threshold.What specific stoichiometric deviations affect coupling yield with substituted anilines during synthesis of an SDHI-type fungicide intermediate?In the manufacture of a broad-spectrum carboxamide fungicide intermediate intended for formulation as a 280 g/L suspension concentrate active against Mycosphaerella fijiensis in banana plantations, the Schotten-Baumann condensation of 5-thiazolecarbonyl chloride, 4-methyl-2-phenyl- with 3-(trifluoromethyl)aniline is carried out in a 1,000 L glass-lined reactor equipped with a jacket capable of holding −10 °C brine, an overhead condenser, and a pH-controlled dosing station. The molar ratio of acid chloride to amine is maintained at 1:1.03 — a 3 mol% excess of amine — to fully consume the acyl chloride and avoid corrosive hydrolysis by-products; the amine is pre-dissolved in dichloromethane (6 volumes relative to chloride weight) containing 1.05 equivalents of triethylamine as an HCl scavenger, and the acid chloride is metered in over 120 minutes while the internal temperature is strictly kept between −5 °C and 0 °C. Any excursion above +3 °C accelerates amide hydrolysis and leads to a drop in isolated yield from the typical 92–94 % to below 80 %. After aqueous work-up and vacuum distillation of the solvent, the technical-grade intermediate is crystallised from ethanol to achieve a purity of ≥97.0 % by GC-FID. The downstream formulation process converts the dry technical active into a 280 g/L SC via wet bead milling in a horizontal agitated media mill (Netzsch LME series) with 0.6–0.8 mm yttria-stabilised zirconia beads; a lignosulphonate-based dispersant at 4.5 wt% on formulation weight and a silicone defoamer at 0.15 wt% are employed, and the suspension is milled to a particle-size distribution D50 < 1.8 μm and D90 < 5.0 μm measured by laser diffraction per CIPAC MT 187. The finished product falls under EPA 40 CFR Part 180 tolerance assessment for residues on banana, and must additionally meet the FAO/WHO Joint Meeting on Pesticide Specifications requirements for suspendibility (>90 % after 30 min per CIPAC MT 184) and persistent foam (< 25 mL). A notable processing constraint emerges when the plant water hardness exceeds 350 ppm CaCO₃: calcium-salt precipitation destabilises the SC, resulting in Ostwald ripening and a viscosity surge beyond 800 mPa·s at 20 s⁻¹; water softening to ≤ 150 ppm prior to milling is therefore standard protocol.
Optical brightener synthesis for cellulosic laundry powders via DSD acid couplingIn an aqueous acetone medium at pH 8.5–9.0, the acid chloride is reacted with 4,4′-diaminostilbene-2,2′-disulfonic acid at a molar ratio of 2.2:1, and the resulting thiazole-capped bis-amide is acidified, filtered, and spray-dried to a free-flowing granular brightener that satisfies EU Detergent Regulation (EC) No 648/2004 Annex VII for heavy-duty laundry powders and the fluorescence intensity requirement of GB/T 13171.1-2009. Interfacial polycondensation between 5-thiazolecarbonyl chloride, 4-methyl-2-phenyl- and 1,6-hexanediamine carried out in a water/dichloromethane biphasic system alkalinised to pH 10.5–11.0 with sodium carbonate generates a high-molecular-weight poly(thiazole-amide) possessing an inherent viscosity of 0.82–0.95 dL/g (m-cresol, 30.0 °C, 0.5 g/dL) measured in accordance with ISO 307:2019. The molar stoichiometry of diamine to diacid chloride is deliberately offset to 1:0.98 to cap the chains with amino end-groups, thereby facilitating subsequent reactive extrusion with maleic anhydride-grafted polypropylene (PP-g-MAH) as a compatibiliser. On a pilot-scale continuous polycondensation unit comprising a static mixer for initial emulsification and a 25 mm co-rotating twin-screw extruder (L/D 48) with a split-feed configuration, the organic phase containing the diacyl chloride at 12.5 wt% in dichloromethane and the aqueous diamine solution containing 0.5 w/v% sodium lauryl sulphate as a phase-transfer promoter are pumped at ratios that yield a residence time of 3.2 min in the mixing zone; the extruder zones are profiled from 5 °C at the feed throat to 180 °C at the vent port, where the solvent is stripped under vacuum. Downstream, the dried granulate is injection-moulded on a 150-tonne clamping press into ASTM D638-14 Type I tensile bars and ISO 294-1 plaques. The semi-crystalline polymer exhibits a glass transition temperature of 147 °C (midpoint, DSC ISO 11357-2) and a melting endotherm at 267 °C, enabling short-term heat resistance up to 240 °C for connector housings in underhood automotive electrical systems. Compliance testing encompasses UL 94 V-0 at thickness 0.8 mm and RoHS Directive 2011/65/EU Annex II restrictions on phthalates and lead. Semi-finished components — particularly wire harness clips and ignition coil bobbins — must not exhibit relative permittivity above 3.5 at 1 MHz (IEC 60250) and should retain >85 % of their initial tensile strength after 1,000 hours of thermal ageing at 200 °C. Processing notes indicate that exposure of the acid chloride to ambient air with a dew point above −5 °C causes partial hydrolysis to the corresponding carboxylic acid, which acts as a monofunctional chain stopper and depresses molecular weight; consequently, the monomer is stored under dry nitrogen and transferred via a closed-loop system to the pre-mix vessel. This polyamide application yields functional parts that replace metal inserts in lightweight vehicle architectures.When a novolac-based i-line photoresist formulation incorporates a dissolution inhibitor bearing the 2-phenyl-4-methylthiazole carbonyl moietyAddition of the dissolution inhibitor (DI) synthesised by esterification of the acid chloride with a selected bisphenolic ballast — typically 2,2-bis(4-hydroxyphenyl)propane — at loadings of 8.0–12.0 wt% of total solids in a resist mixture comprising cresol-formaldehyde novolac resin (Mw 4,500–6,000 g/mol, dissolution rate 35–45 nm/s in 0.26 N TMAH) and a 5.0 wt% photoactive diazonaphthoquinone (DNQ) sensitiser, results in a suppression of the dark-film dissolution rate by a factor of 12–15× and a photobleachable contrast (γ) exceeding 4.2 under 365 nm exposure at 65 mJ/cm². The resist is spun coated onto 200 mm silicon wafers primed with hexamethyldisilazane, yielding a film thickness of 1.05 μm after a soft-bake at 90 °C for 60 s on a proximity hotplate; post-exposure bake is performed at 110 °C for 60 s, and development is carried out in 0.26 N tetramethylammonium hydroxide (TMAH) puddle for 45 s. The patterned wafers pass through a 300 mm cluster tool for reactive-ion etching, where the thiazole-containing DI provides sufficient etch resistance to achieve a selectivity of 4.8:1 over polysilicon in a Cl₂/HBr plasma. In semiconductor fabs operating under SEMI S2-1216 safety guidelines for chemical distribution and SEMI C28-0718 specifications for trace metal contamination (each metal cation ≤ 5 ppb), the dissolution inhibitor must be prepared in ultrapure methyl amyl ketone and filtered through a 0.02 μm PTFE capsule to eliminate particle shedding. A documented process window constraint exists for relative humidity during spin coating: at RH above 45 %, moisture absorption by the novolac matrix alters the dissolution kinetics of the DI, widening the critical dimension (CD) distribution across the wafer by ±8 nm at the 0.35 μm node; therefore, coating tracks are maintained at 22.5 ± 0.5 °C and 40 ± 2 % RH. The finished device layer — a gate-level pattern in a mixed-signal application-specific integrated circuit (ASIC) — relies on this formulation to achieve 0.35 μm lines and spaces with a 3σ linewidth roughness below 5.8 nm by top-down CD-SEM. |
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Introduced into the fine-chemical catalog as 5-thiazolecarbonyl chloride, 4-methyl-2-phenyl- (CAS 54001-63-3), this heterocyclic acyl halide is supplied as a pale-yellow to off-white crystalline solid with a molecular formula of C11H8ClNOS and a molecular weight of 237.71 g mol⁻¹. The single lot released under ISO 9001:2015-certified quality management typically exhibits a melt onset at 94.2 °C by differential scanning calorimetry (DSC) at 10 K min⁻¹, with the melting range spanning 92–96 °C when determined in a Büchi M-565 capillary apparatus according to Ph. Eur. 2.2.14. The carbonyl chloride functionality, located at the 5-position of the thiazole ring and ortho to a ring sulfur, imposes an electrophilicity sufficient to acylate weakly nucleophilic anilines in dichloromethane at 0–5 °C without added tertiary base, a kinetic feature that distinguishes it from the corresponding benzoic acid chlorides where 4-dimethylaminopyridine catalysis is standard.
Certificate-of-analysis data from 12 consecutive production campaigns, executed in 500 L glass-lined reactors at a contract manufacturing organization operating under ICH Q7, show a median HPLC purity (area-%, 254 nm) of 99.3 % with an interquartile range of 0.4 %. The HPLC method employs an Agilent ZORBAX Eclipse Plus C18 column (4.6 × 150 mm, 3.5 µm), mobile phase 0.1 % trifluoroacetic acid in water/acetonitrile (gradient 30 % to 90 % MeCN over 20 min), and the retention time of the main peak is verified against a reference standard stored at −20 °C under argon. Single impurity limits are set at ≤0.15 % for the hydrolyzed carboxylic acid (4-methyl-2-phenylthiazole-5-carboxylic acid) and ≤0.10 % for the des-chloro symmetrical anhydride. Water content by Karl Fischer coulometry (ISO 760, oven method at 120 °C) is controlled to ≤500 ppm; moisture ingress during sampling in environments exceeding 40 % RH can elevate this value within minutes, mandating an in-process blanket of dry nitrogen (dew point ≤ −70 °C).
Hydrolysis of the acid chloride moiety follows pseudo-first-order kinetics in wet solvents with an observed half-life of approximately 18 min in tetrahydrofuran containing 0.5 % v/v water at 25 °C, as monitored by ReactIR 15 with a diamond ATR probe. Storage stability under the manufacturer’s recommended conditions (2–8 °C, amber glass under argon) has been demonstrated over 36 months; the open-vessel exposure trial at 25 °C/60 % RH showed 2.8 % degradation to the free acid within 4 h. For kilogram-scale operations, the compound is charged from a glovebox purged with <0.1 ppm O₂ directly into the reaction solvent pre-dried over activated 3 Å molecular sieves. The strong exotherm associated with addition to primary amines (ΔTad estimated at −120 kJ mol⁻¹ by RC1 reaction calorimetry) requires dosing at a controlled rate to keep the internal temperature below 10 °C in 2 M THF solutions; release of HCl necessitates an acid scavenger, with stoichiometric triethylamine causing a color shift to deep orange when local pH drops below 3 due to transient thiazole ring protonation.
In contrast to the analogous benzoyl chlorides, the C5-carbonyl chloride of this thiazole displays a markedly reduced sensitivity to nucleophilic solvent residues because the thiazole sulfur atom exerts a –I effect that moderates the carbonyl carbon’s δ+ character. Hammett substituent constants (σm for the thiazol-5-yl fragment estimated at +0.35) place its electron-withdrawing capacity between that of a 3-chlorophenyl and a 4-nitrophenyl group, a property exploited in the synthesis of slow-release amide prodrugs where the acylation rate must be matched to the deprotonation rate of the amine hydrochloride salt. This property is reflected in the specification for residual ethanol (≤200 ppm by headspace GC–FID, Agilent DB-624 column, 30 m × 0.32 mm, 1.8 µm), as ethanol is a particularly persistent process solvent from the final recrystallization step in ethyl acetate/hexane mixtures.
Pharmaceutical process chemists employ this acid chloride as a key synthon for protease-activated antibody-drug conjugate (ADC) linkers. The thiazole nucleus, when coupled to a peptide N-terminus through an amide bond at the 5-carbonyl position, exhibits a dihedral angle of 15–25° between the thiazole plane and the amide group (B3LYP/6-31G(d) gas-phase optimization), which restricts rotational freedom and influences the conjugate’s plasma stability. In a published kilogram-scale campaign for an antimitotic payload, the coupling of 5-thiazolecarbonyl chloride, 4-methyl-2-phenyl- with an N-methyl-valine-citrulline dipeptide in dimethylacetamide at −5 °C furnished the desired intermediate in 82 % isolated yield after plug filtration through silica gel 60 (35–70 µm). The major byproduct, arising from bis-acylation at the citrulline ureido nitrogen, is suppressed by maintaining the free amine concentration below 0.05 M during the semi-batch addition. This side reaction is practically absent when the 4-methyl substituent is replaced by a bulkier cyclopropyl group, indicating a steric shielding effect of the 4-position on the acid chloride’s approach trajectory.
Direct comparative batch data between 5-thiazolecarbonyl chloride, 4-methyl-2-phenyl- and its des-methyl congener, 2-phenylthiazole-5-carbonyl chloride (CAS 16132-98-6), illustrate the electronic and steric consequences of the 4-methyl group. Under identical amidation conditions (1.0 eq pyridine, dichloromethane, 0.5 M, 0 °C, 1.05 eq aniline), the 4-methyl compound reached 95 % conversion within 45 min, while the des-methyl analogue required 105 min for equivalent conversion (HPLC, 254 nm). The rate acceleration is attributed to a +I effect of the methyl group raising the electron density in the thiazole ring and consequently increasing the nucleofugality of the chloride leaving group through enhanced thiazolium character in the transition state. Conversely, the des-methyl compound demonstrates a 7 °C higher melting point (101–103 °C vs. 92–96 °C) and exhibits greater crystal packing stability in ambient shipments to tropical zones (ICH Q1E stability zone IVb, 30 °C/75 % RH), where the 4-methyl variant showed 0.8 % agglomeration after 6 months in a HDPE drum compared to 0.2 % for the des-methyl solid.
| Parameter | Method | Acceptance Criterion | Typical Result |
|---|---|---|---|
| Assay (HPLC, 254 nm) | In-house SOP 7.3.2, ISO 17025 validated | ≥ 98.5 % | 99.2 % |
| Melting range | Ph. Eur. 2.2.14, capillary | 92–96 °C | 93.5–94.8 °C |
| Water content | ISO 760, oven KF | ≤ 500 ppm | 210 ppm |
| Residual solvents | USP <467>, HS-GC-FID | Ethyl acetate ≤ 5000 ppm Hexane ≤ 290 ppm | 1200 ppm / 80 ppm |
| Chloride (ionic) | Ion chromatography (DIN EN ISO 10304-1) | ≤ 0.5 % w/w | 0.12 % w/w |
| Sulfated ash | Ph. Eur. 2.4.14 | ≤ 0.1 % | 0.03 % |
The presence of ionic chloride above 0.5 % w/w is a proven indicator of bulk hydrolytic degradation during storage and has been correlated with elevated dimeric anhydride formation when the material is used in the next synthetic step without recrystallization. A root-cause analysis performed on a rejected 25 kg lot traced the chloride excursion to a damaged drum gasket that allowed humidity ingress during ocean freight; this lot required re-slurrying in dry hexane to restore anhydride levels to ≤0.2 %. The process engineering change that followed specified a PTFE-lined, nitrogen-pressurized drum closure and inclusion of a humidity indicator card in each shipment container.
| Property | 5-Thiazolecarbonyl chloride, 4-methyl-2-phenyl- | 2-Phenylthiazole-5-carbonyl chloride | 4-Methylthiazole-5-carbonyl chloride |
|---|---|---|---|
| CAS | 54001-63-3 | 16132-98-6 | 57305-09-2 |
| Molecular weight | 237.71 g mol⁻¹ | 223.68 g mol⁻¹ | 161.61 g mol⁻¹ |
| Melt onset (DSC, 10 K min⁻¹) | 94.2 °C | 101.5 °C | 48–52 °C (cap.) |
| Acylation rate (kobs, 0 °C, 0.5 M DCM with aniline) | 0.042 min⁻¹ | 0.018 min⁻¹ | 0.11 min⁻¹ |
| Hydrolytic half-life (THF/0.5 % H₂O, 25 °C) | 18 min | 27 min | 9 min |
| Typical application | ADC linkers, kinase hinges | PET tracer precursors | Fungicide intermediates |
The 4-methyl-2-phenyl pattern delivers a unique balance of steric protection at the electrophilic carbon and the electronic activation needed for room-temperature coupling while retaining sufficient chlorine lability to avoid the aggressive activation required by 2,4-disubstituted oxazole-5-carbonyl chlorides, where pKa differences of the conjugate acids necessitate HATU/DIPEA activation for amide formation. In kilogram-scale batches, the product’s flowability, measured as Carr’s compressibility index (18 %), places it in the “fair” flow category, and the use of a mechanical agitator in the feed hopper of a continuous oscillatory baffle reactor (COBR) has eliminated the bridging that previously caused 3 % dosing variability when a simple loss-in-weight feeder was operated at 5–10 kg h⁻¹.
Thermal safety data from adiabatic calorimetry (Phi-Tec II) indicate the onset of self-sustaining decomposition at 180 °C, with a maximum self-heat rate of 2.4 K min⁻¹ at 220 °C. The material is therefore classed as non-shock-sensitive under UN Test Series 3(a) but must be stored away from localized heat sources exceeding 120 °C. For synthesis in aprotic dipolar solvents above 80 °C, process safety assessments mandate that the reactor’s jacket temperature be interlocked with a reaction mass thermocouple and the controller tuned for a maximum rate of heat input not exceeding 8 W kg⁻¹ to prevent a runaway scenario initiated by salt-catalyzed polymerization of the thiazole ring. Published data for this specific configuration is limited above 150 °C, and scale-up campaigns are typically limited to 100 kg reactor charges pending further calorimetric study.
