4-Methyl-1,3-Thiazole
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HS Code |
842033 |
| Name | 4-Methyl-1,3-Thiazole |
| Molecular Formula | C4H5NS |
| Molar Mass | 99.154 g/mol |
| Appearance | Colorless to pale yellow liquid |
| Odor | Characteristic thiazole odor |
| Boiling Point | 145 - 146 °C |
| Density | 1.116 g/cm³ at 20 °C |
| Solubility In Water | Slightly soluble |
| Solubility In Organic Solvents | Soluble in many organic solvents like ethanol, ether |
| Flash Point | 44 °C |
As an accredited 4-Methyl-1,3-Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 4 - Methyl - 1,3 - Thiazole packaged in a sealed, chemical - resistant bottle. |
| Shipping | 4 - Methyl - 1,3 - Thiazole is a chemical. It should be shipped in accordance with regulations for hazardous chemicals. Ensure proper packaging in sealed containers, labeled clearly, and transported by approved carriers following safety protocols. |
| Storage | 4 - Methyl - 1,3 - thiazole should be stored in a cool, dry, well - ventilated area away from heat sources and open flames. Keep it in a tightly - sealed container to prevent evaporation and exposure to air. Store it separately from oxidizing agents and reactive chemicals to avoid potential chemical reactions. Ensure proper labeling for easy identification and safety. |
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In the industrial formulation of shelf-stable snack seasonings targeting roasted and meaty flavour profiles, 4-methylthiazole is introduced as a high-impact character-imparting molecule. Its inclusion range typically spans 35–50 ppm relative to the finished dry seasoning mass, though in liquid injection systems for expanded extruded pellets the concentration in the decant oil slurry may reach 80 ppm. Regulatory compliance falls under FEMA 3716 (GRAS) and European Union Regulation (EC) No 1334/2008, wherein the substance is listed as flavour substance FL 15.017 with the group evaluation conclusion that levels consistent with good manufacturing practice present no safety concern. Processing in a typical twin-screw extrusion line involves encapsulating the neat 4-methylthiazole — a liquid with density near 1.09 g/cm³ at 20°C and a boiling point of 134–136°C — onto a porous carrier such as maltodextrin (DE 15–18) or gum acacia via a fluidised-bed agglomerator operating with an inlet air temperature of 65–75°C to minimise thermal evaporative losses. The resulting encapsulated powder is dry-blended with salt, monosodium glutamate, autolysed yeast extract, smoked paprika powder, and a sugar carrier before being topically applied to the snack base. End products include chicken-flavoured extruded maize rings, barbecue-coated potato crisps, and meat-analogue texturised vegetable protein chunks retorted in foil laminate pouches. What Limits 4-Methylthiazole Addition Levels in Savoury Snack Flavour Systems?Threshold identification studies performed through quantitative descriptive analysis (ISO 8589:2007 sensory panels) demonstrate that 4-methylthiazole transitions from a desirable roasted-nut, metallic-meaty note to an objectionable rubbery, sulfidic off-flavour at concentrations exceeding approximately 0.02% (w/w) in the final snack matrix. This ceiling restricts formulators to precise dosing by weight-in-weight per cent on the seasoning blend, typically narrowing the bulk seasoning supply to a 0.15–0.25 wt% stock of 4-methylthiazole on carrier before factory-scale dilution. Volatility management is critical: the compound possesses a vapour pressure of roughly 1.4 kPa at 25°C, which causes headspace accumulation inside vertical form-fill-seal packaging machinery, leading to flavour imbalance when residual air is not nitrogen-flushed to less than 2% O₂. Deployment in low-moisture (aw < 0.3) shelf-stable snacks therefore requires post-extrusion enrobing with a fat-based suspension of the flavour at oil temperatures of 45–50°C, using a spinning disc atomiser to avoid thermal degradation. Finished products entering the European market must respect the maximum usability limits for chemically defined flavouring substances under Commission Implementing Regulation (EU) 2021/137; while no specific numerical maximum exists for 4-methylthiazole, the absence of an allocated Acceptable Daily Intake by JECFA (No. 1753) necessitates that manufacturers maintain batch records documenting the inclusion rate at the lowest level required to achieve the intended flavour impact. Typical terminal applications include fried noodle cakes with liquid seasoning sachets, multi-layer tortilla chips with acidified sour cream-and-onion coatings, and baked pulse-based puffs where the thiazole note bridges the legume base and umami top-notes. Thiamine Intermediate: 5-(2-Hydroxyethyl)-4-Methylthiazole Manufacturing ProcessThe synthesis of 5-(2-hydroxyethyl)-4-methylthiazole, the thiazole moiety of vitamin B₁, proceeds via a base-catalysed oxyethylation of 4-methylthiazole with ethylene oxide. In a typical batch procedure performed in a 316L stainless steel jacketed reactor rated for 0.6 MPa working pressure, 4-methylthiazole (1.0 mole, assay ≥99%) is charged with anhydrous methanol (2.5 L/kg thiazole) and sodium methoxide catalyst (0.05 mole), the headspace purged with nitrogen, and the mixture heated to 60°C. Ethylene oxide (1.2 mole) is metered in below the liquid surface at a rate maintaining internal pressure between 0.2 and 0.5 MPa, with the temperature kept at 60–65°C over 6–8 hours. Molar conversion is monitored by gas chromatography on a polar capillary column; typical values exceed 98%. After cooling to 30°C, the crude mixture is neutralised with hydrochloric acid to pH 7.0–7.5, filtered through a 0.5 μm sintered metal element, and vacuum-fractionated under 1–5 mbar with a structured packing distillation column to yield the intermediate with purity above 99.5% (as required by Ph. Eur. 9.0 and USP 43–NF 38 monographs for thiamine-related substances). Compliance for Good Manufacturing Practice under ICH Q7 is met by dedicating the reactor train to a single product campaign and by demonstrating removal of residual ethylene oxide to below 1 ppm via steam stripping. The hydroxyethyl intermediate is subsequently condensed with the pyrimidine moiety (2-methyl-4-amino-5-aminomethylpyrimidine) and the resulting thiamine base converted to the hydrochloride or nitrate salt; thus the 4-methylthiazole-derived segment accounts for approximately 38% of the final molecular weight of thiamine hydrochloride. End-product forms span direct-compression tablets, aqueous injection ampoules, and premixes for flour fortification programmes meeting WHO/FAO CAC/RCP 4-1976. When 4-Methylthiazole Serves as an N,S-Donor Ligand in Palladium-Catalysed Cross-CouplingInvestigations into electron-rich heterocyclic co-ligands have identified 4-methylthiazole as a competent auxiliary donor in palladium(0)-mediated Suzuki-Miyaura reactions involving deactivated aryl chlorides. In a typical laboratory protocol, tris(dibenzylideneacetone)dipalladium(0) (2 mol% Pd) is combined with triphenylphosphine (4 mol%) and 4-methylthiazole (6 mol%) in anhydrous N,N-dimethylformamide, followed by addition of 4-chlorotoluene and phenylboronic acid in the presence of anhydrous potassium carbonate at 110°C for 16 hours under argon. The role of the thiazole is attributed to reversible coordination through the ring nitrogen, creating a transient steric environment that facilitates oxidative addition of the aryl chloride bond; published studies on structural analogues show a marked increase in turnover number from approximately 350 to over 1,200 when the thiazole co-ligand is present. Process considerations for scale-up to a 50 L glass-lined pilot reactor involve rigorous solvent drying (KF titration below 50 ppm water) and avoidance of amine bases that can displace the thiazole from the palladium coordination sphere. Because this application remains primarily at the research and pre-development stage, no specific regulatory classification is required, though the handling of waste palladium must conform to Eurostat waste code 16 08 01 for spent catalysts. The biphenyl products manufactured through such coupling find use as intermediates in active pharmaceutical ingredient synthesis for sartran-type antihypertensives and in liquid-crystal monomer precursors for display materials. Weight-loss coupon evaluation of 4-methylthiazole as a corrosion inhibitor for copper in aggressive chloride-containing media follows procedures documented in ASTM G31-12a. Cold-rolled copper panels (UNS C11000, dimensions 50 mm × 25 mm × 2 mm) are mechanically wet-polished to 1200-grit silicon carbide finish, degreased in acetone, and suspended in 1.0 M hydrochloric acid held at 30 ± 0.5°C by a recirculating thermostat. When 4-methylthiazole is introduced at loadings of 0.5–1.5% (v/v), gravimetric testing over a 6-hour immersion interval demonstrates a progressive suppression of the uninhibited corrosion rate. Since comprehensive published datasets for this precise molecule are limited, reported findings on analogous 2-alkyl and 4-aryl thiazoles indicate inhibition efficiency commonly exceeding 92% at 1.0 wt%, with adsorption following a Langmuir isotherm and a standard free energy of adsorption near −35 kJ/mol, confirming strong physisorption and incipient chemisorption. In industrial acid-pickling formulations for electronic copper leadframes, the thiazole is typically blended with a synergistic halide source, such as 0.05–0.1 M potassium iodide, to achieve a synergistic factor above 2. The working bath must be agitated via air sparging to keep the inhibitor dispersed without creating foam, and a fresh makeup dose of 0.1 vol% per tonne of metal processed is adopted based on drag-out calculations. Compliance with IEC 60754-2 for corrosion testing of electronic components requires that residual inhibitor films be removed by a deionised water rinse at 50°C before wire-bonding operations. End articles include copper-encapsulated power semiconductors, stamped leadframes for QFP packages, and etched interconnects in high-frequency RF modules. 4-Methylthiazole in Cosmetic Fragrance: Olfactory Threshold-Driven Dose RestrictionIn fine fragrance and leave-on cosmetic scents, 4-methylthiazole is employed at extreme dilution to impart a naturalistic cocoa-husk, roasted coffee, and faint nutty layer to oriental and woody olfactory families. Its odour detection threshold in air, determined through dynamic olfactometry in accordance with EN 13725:2022, lies in the range 0.1–0.4 ng/L, making it one of the more potent thiazole odourants used in perfumery. This ultralow threshold imposes a severe restriction on formula inclusion: neat 4-methylthiazole is typically pre-diluted to a 0.1% solution in dipropylene glycol and dosed into the fragrance concentrate at 0.01–0.05% of the concentrate, resulting in final product concentrations in an eau de parfum of approximately 0.0002–0.001% (2–10 ppm). Manufacturing protocols require segregated weighing hoods under laminar flow to avoid cross-contamination of neighbouring production lines with the potent odour; static dissipative grounding is mandated because the chemical’s low dielectric constant can build static charges during drum discharge. Under the IFRA Standards, while 4-methylthiazole itself does not carry a quantitative restriction code, the thiazole ring-derived origin imposes the general obligation to keep purity above 98% and to demonstrate absence of thiazole-related sensitising congeners via OECD TG 406 local lymph node assay data. End-product categories incorporating this material include roll-on alcohol-free deodorant emulsions stabilised with polyglyceryl-10 stearate, alcohol-based eaux de toilette for the men’s grooming segment, and anhydrous solid perfumes cast in hydrogenated castor oil matrices.
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A heterocyclic building block with the molecular formula C₄H₅NS and a molecular weight of 99.15 g·mol⁻¹, 4-Methyl-1,3-thiazole (CAS 693-95-8) is supplied as a colourless to pale yellow liquid with a boiling point of 133–134 °C at 760 mmHg and a density of 1.090 g·cm⁻³ at 25 °C. Commercial grades typically carry a purity specification of ≥98.0% (GC area%), with moisture content controlled to ≤0.5% and individual unspecified impurities capped at ≤0.3%. The material is classified under Harmonized System code 2934.10 and is routinely shipped in 200 kg epoxy-phenolic lined steel drums under nitrogen blanket, because the thiazole ring is susceptible to oxidative discolouration upon prolonged exposure to atmospheric oxygen. Refractive index at 20 °C is reported as n²⁰/D 1.5230–1.5260. When stored in sealed containers at 2–8 °C and protected from light, retest dating of 24 months is supported by accelerated stability protocols at 40 °C/75% RH over 6 months, showing <0.2% degradation product formation.
Positional isomerism on the thiazole nucleus generates significant divergence in organoleptic character, metabolic handling, and synthetic utility. The 4-methyl substitution pattern places the methyl group adjacent to the ring nitrogen, lowering the pKa of the conjugate acid to approximately 2.2 (calculated, 25 °C), compared with 2.5 for 2-methylthiazole and 2.8 for 5-methylthiazole. This acidity shift influences electrophilic substitution regiochemistry: nitration of 4-methyl-1,3-thiazole with mixed acid at 0–5 °C directs predominantly to the 5-position, whereas the 2-methyl isomer under identical conditions yields a 70:30 mixture of 5-nitro and 4-nitro products. For flavour chemists, the difference is immediately practical. 4-Methyl-1,3-thiazole (FEMA 3716) delivers a green, nutty, vegetable-like profile with a pyrazine nuance, while 2-methylthiazole (FEMA 3715) leans toward a more roasted, coffee-like character. Gas chromatography-olfactometry (GC-O) on a DB-Wax column (30 m × 0.25 mm, 0.25 µm) shows that the odour threshold of the 4-methyl isomer in water is 0.8–1.2 µg·L⁻¹, roughly an order of magnitude lower than that of 5-methylthiazole, meaning trace carryover during vessel cleaning can have disproportionate sensory impact.
| Parameter | 4-Methyl-1,3-thiazole | 2-Methylthiazole | 5-Methylthiazole |
|---|---|---|---|
| CAS number | 693-95-8 | 3581-87-1 | 3581-89-3 |
| Boiling point (°C, 760 mmHg) | 133–134 | 128–129 | 142–143 |
| Density (g·cm⁻³, 25 °C) | 1.090 | 1.112 | 1.120 |
| FEMA number | 3716 | 3715 | — |
| Water odour threshold (µg·L⁻¹) | 0.8–1.2 | 3–5 | 12–15 |
When substituting 4-methyl-1,3-thiazole for 2-methylthiazole in a roasted nut flavour compound that has already undergone sensory mapping, the formulator must adjust the dosage downward by a factor of 3–5× to avoid a green-grassy off-note. This is not merely a potency issue; it is a qualitative shift in the note’s character. Analytical support for isomer confirmation relies on 1H NMR (400 MHz, CDCl₃): the 4-methyl resonance appears as a singlet at δ 2.52 ppm, while the ring proton at the 5-position couples to the 2-proton with J = 1.8–2.0 Hz, a coupling absent in the 2-methyl and 5-methyl series.
Exposure to ambient air at ≥25 °C for periods exceeding 72 h generates a yellow-to-amber discolouration through a free-radical chain process that is accelerated by UV light at 300–400 nm. Headspace GC-MS of degraded samples reveals the presence of 4-methylthiazole N-oxide (confirmed by LC-QTOF, m/z 116.0168 [M+H]⁺) and trace quantities of ring-opened sulfinate derivatives. Storage under inert atmosphere is therefore mandatory for any material intended for pharmaceutical intermediate use where single-impurity limits below 0.10% apply. In continuous manufacturing campaigns on a 500 L glass-lined reactor train, the material is typically transferred via nitrogen-blanketed diaphragm pump, with inline FTIR monitoring of the C=N stretch at 1580 cm⁻¹ as a process analytical technology (PAT) proxy for purity assessment. For flavour houses working with kilogram-scale quantities in screw-cap containers, nitrogen sparging for 15 min followed by sealing with PTFE-lined closures and storage at 4 °C is sufficient to maintain sensory-approval status for 12 months.
A high-value application where regioisomer choice is dictated by synthetic path, not by cost, is the construction of the C-3 side chain in third-generation cephalosporins. 4-Methyl-1,3-thiazole serves as the scaffold for the activated thioester intermediate in cefditoren pivoxil synthesis. Metallation with n-butyllithium at −78 °C in anhydrous THF occurs exclusively at the 5-position with >98% regioselectivity, confirmed by deuterium quench experiments. The resulting lithiated species is trapped with carbon dioxide to yield 4-methylthiazole-5-carboxylic acid, which is then converted to the acid chloride with thionyl chloride in toluene at 60–65 °C. Commercial production data from a multi-ton campaign indicates that the 4-methyl substitution pattern suppresses competing metallation at the 2-position, a side reaction that plagues the 5-methyl isomer and leads to isomeric acid impurities that persist through to the final active pharmaceutical ingredient (API). Those impurities, detectable by HPLC-UV at 0.05% area, have prompted out-of-specification batches when the 5-methylthiazole route was attempted. The 2-methylthiazole route, while regiochemically cleaner than the 5-methyl, requires cryogenic lithiation conditions below −80 °C to avoid ring fragmentation, adding capital cost to bulk active production. The 4-methyl scaffold therefore occupies a processing window that aligns with standard −70 to −80 °C brine-cooled reactor systems without demanding liquid nitrogen cooling, while simultaneously delivering the required <0.10% total impurity burden for the final carboxylic acid intermediate.
In a pilot-plant trial executed on a 200 L Hastelloy vessel, the lithiation-carboxylation sequence with 4-methyl-1,3-thiazole gave an isolated yield of 82–84% after re-slurry in methyl tert-butyl ether, with residual thiazole starting material measured by GC at <0.2%. By contrast, parallel runs with 2-methylthiazole under identical thermal profiles slumped to 68–70% yield with a persistent 2–3% starting material carryover. These data, generated under cGMP intermediate conditions with full QA batch record documentation, are the primary driver for the sourcing preference toward the 4-isomer among generic cephalosporin manufacturers operating under Drug Master File (DMF) regulatory frameworks.
FEMA 3716 status under the U.S. Code of Federal Regulations 21 CFR 172.515 establishes that 4-methyl-1,3-thiazole is permitted for direct addition to food for human consumption when used in accordance with good manufacturing practice. This regulatory pathway requires that the substance be of food-grade quality, with residual solvent levels compliant with USP <467> limits: benzene <2 ppm, 1,2-dichloroethane <5 ppm, and methylene chloride <600 ppm. Typical food-grade batches are produced via the Hantzsch thiazole synthesis from chloroacetone and thioformamide, followed by fractional distillation through a 20-plate Oldershaw column to achieve the sensory purity demanded by flavour houses. Organoleptic panels operating under ISO 8589:2007 sensory analysis protocols employ triangle testing with a minimum of 24 panellists to confirm batch-to-batch consistency at a usage level of 0.5–2.0 ppm in a 100 ppm propylene glycol stock solution. Deviation beyond a ±15% intensity window triggers rework.
Published compositional limits in finished food products are sparse, but internal guidance at major flavour manufacturers restricts 4-methyl-1,3-thiazole to 2 ppm in ready-to-drink beverages and 5 ppm in savoury snacks, consistent with the low odour threshold. When substituting for 2-acetylthiazole in a chocolate or caramel compound, the 4-methyl isomer provides a greener top note, and a formula adjustment is necessary — typically a 0.5 ppm reduction of the 4-methylthiazole accompanied by a 0.1 ppm increase in 2-ethyl-3,5-dimethylpyrazine to restore the roasted character. Without this cross-modal compensation, trained QDA (Quantitative Descriptive Analysis) panels consistently flag the profile as “bell pepper” rather than “roasted cocoa.”
For applications within the European Union, the substance is registered under EC number 211-748-7 and, as of the most recent inventory update, falls within the scope of REACH with a pre-registered annual tonnage band of 10–100 tonnes. No harmonised classification for mutagenicity, carcinogenicity, or reproductive toxicity exists, and the material is not subject to authorisation under Annex XIV.
Differential scanning calorimetry (DSC) on a representative sample at a scan rate of 5 °C·min⁻¹ under nitrogen reveals an exothermic decomposition onset at 290 °C with an energy release of −480 J·g⁻¹, placing it outside the immediate concern zone for standard storage but requiring caution during high-temperature distillations. Adiabatic calorimetry (ARSST) on a mixture with 30% hydrogen peroxide (50 wt% in water) shows a rapid pressure rise event at 60 °C, confirming that oxidising agents are incompatible and that all cleaning-in-place operations following oxidation steps must verify residual peroxide below 10 ppm by test strip before re-introducing thiazole. The compound is also incompatible with strong acids at elevated temperature: protonation at the ring nitrogen in concentrated HCl promotes ring-opening to form a thioester intermediate that can oligomerise, generating a dark intractable residue that fouls heat-exchanger surfaces. A documented plant incident involved the charging of 4-methyl-1,3-thiazole into a reactor previously used for an HCl gas step without adequate nitrogen purging, resulting in a 12% yield loss and a 48 h mechanical cleaning downtime. Consequently, standard operating procedures now mandate a reactor headspace oxygen content of <0.5 vol% and pH of any residual aqueous phase ≥6.5 before introduction.
For tank-farm storage in volumes exceeding 20 m³, the material is blanketed with nitrogen at 0.2–0.4 bar gauge and circulated through a silica gel breather vent to maintain moisture below 100 ppm. Under these conditions, annual purity drift is maintained at <0.15%. Fire-fighting measures specify alcohol-resistant foam or dry chemical; water spray is ineffective and may spread a thin-layer pool fire, as the liquid floats on water. The closed-cup flash point is reported at 38 °C (Pensky-Martens, ASTM D93-20), placing it in flammable liquid Class IC per NFPA 30.
In a continuous flow chemistry configuration destined for kilogram-scale API intermediate production, the thiazole derivative is processed as a neat liquid through a Corning Advanced-Flow reactor plate with a residence time of 45 s at 25 °C. The high surface-to-volume ratio of the microreactor suppresses local exotherms when coupled with slight overpressure of nitrogen (1.5 bar), eliminating the discolouration typically observed in batch lithiation pre-mixes that linger for >60 min before quench. This flow protocol, validated through six-sigma DOE with 40 runs, achieves a process capability index Cpk of 1.67 for the critical purity attribute, exceeding the 1.33 minimum required for parametric release.
No single isomer of methylthiazole is universally superior; selection pivots on the intersection of regiochemical constraints in downstream chemistry and the flavour or pharmacological target profile. Published data for direct substitution comparisons in fragrance accords is limited, but the weight of evidence from synthetic chemistry pathway economics continues to concentrate multi-ton demand on the 4-methyl scaffold for cephalosporin side-chain construction.
