5-Iodothiazole
|
HS Code |
735211 |
| Chemical Formula | C3H2IN3S |
| Molar Mass | 255.03 g/mol |
| Appearance | Solid (usually a powder) |
| Solubility In Water | Low solubility |
| Solubility In Organic Solvents | Moderate solubility in some organic solvents |
| Odor | Odorless (usually) |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 5-Iodothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 5 - Iodothiazole packaged in 100 - gram vials for secure storage and handling. |
| Shipping | 5 - Iodothiazole is shipped in well - sealed, corrosion - resistant containers. It's handled with care to prevent spills. Shipment is compliant with chemical transportation regulations, ensuring safe delivery. |
| Storage | 5 - Iodothiazole should be stored in a cool, dry place, away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store it separately from incompatible substances, like strong oxidizers or reducing agents, in a designated chemical storage area to ensure safety. |
The reactivity of the C–I bond in 5-iodothiazole toward palladium-catalyzed cross-coupling underpins its role in the synthesis of 5-arylthiazole-containing pharmacophores. In a standard Suzuki–Miyaura protocol for kinase inhibitor fragment libraries, the heteroaryl iodide is combined with a substituted phenylboronic acid (1.05–1.2 eq.) in a degassed mixture of 1,2-dimethoxyethane and 2M aqueous Na₂CO₃ (3:1 v/v). Tetrakis(triphenylphosphine)palladium(0) is charged at 1.5–2.5 mol% relative to the iodide, and the biphasic system is heated to 80–85°C under nitrogen for 8–14 hours. Process-scale adaptations replace Pd(PPh₃)₄ with PdCl₂(dppf)·CH₂Cl₂ (0.8 mol%) and use toluene/ethanol/water mixtures to simplify phase separation. Residual palladium must be reduced below 10 ppm to meet ICH Q3D limits; a common sequence post-reaction involves treatment with 5 wt% activated carbon functionalized with trimercaptotriazine at 60°C, followed by filtration through a 0.5 µm polytetrafluoroethylene cartridge and recrystallization from n-heptane/ethyl acetate (4:1). HPLC monitoring with UV detection at 254 nm ensures the 5-arylthiazole target peak exceeds 98.5 area%. The resulting intermediates feed into multi-step sequences to prepare ATP-competitive tyrosine kinase inhibitors; for example, further functionalization of the 5-(4-hydroxyphenyl)thiazole adduct with a chloro-substituted pyrimidine carbamate yields analogues of the BCR-ABL inhibitor dasatinib, where the arylthiazole motif replaces the native 2-amino-5-thiazolecarboxamide unit for structure – activity relationship exploration. Compliance for pharmaceutical intermediates demands full traceability under EU GMP Part II (ICH Q7) for starting materials, with impurity profiling per EMA/CHMP/ICH guideline Q3A(R2), residual solvent levels validated against Ph. Eur. 5.4, and elemental impurities confirmed by USP <232>/ <233>. Shipment classification typically falls under UN 2811 (toxic organic solid, n.o.s.) and requires Safety Data Sheets reflecting GHS categories Skin Irrit. 2 and Eye Irrit. 2A assigned via Regulation (EC) No 1272/2008.
Can the heavy-atom effect of iodine be exploited in thiazole-based triplet photosensitizers?The intrinsic heavy-atom effect of the iodine substituent on 5-iodothiazole can be utilized before the C–I bond is ever broken. Direct Knoevenagel condensation between 5-iodothiazole-4-carbaldehyde — obtained in >85% yield via Vilsmeier – Haack formylation of the parent iodide — and 1,2,3,3-tetramethyl-3H-indolium iodide in acetonitrile with piperidine (5 mol%) at 70°C for 1 h generates an unsymmetrical monomethine cyanine. The presence of the iodine atom at position 5 enhances spin-orbit coupling, raising the intersystem crossing rate constant (kISC) and delivering a triplet quantum yield measured in deaerated ethanol at 0.62 ± 0.04 using nanosecond laser flash photolysis. This enables the dye to photosensitise ground-state molecular oxygen to singlet oxygen (1O₂) with a quantum yield ΦΔ of 0.48 (determined by 1,3-diphenylisobenzofuran bleaching at 414 nm). For preclinical photodynamic therapy formulations, the photosensitizer is encapsulated in 10–20 nm micelles of poly(ethylene glycol)-block-poly(lactic acid) via thin-film hydration and extruded through a polycarbonate membrane under 3 bar nitrogen pressure. The aqueous dispersion is irradiated at 532 nm (Nd:YAG laser, 100 mW cm⁻²) in cellular assays using HeLa cells, where IC50 values in the low micromolar range are achievable after 30 min exposure. Manufacturing controls for such a dye must exclude transition-metal residues that could quench the triplet state; a metal-free route using organocatalytic condensation is therefore preferred. Analytical release includes HRMS (ESI-TOF, mass error < 3 ppm), ¹H and ¹³C NMR purity > 97%, and heavy-metal screening by ICP-OES with limits conforming to ICH Q3D Option 1 for parenteral excipients. The photoactive classified product is shipped under amber glass packaging with desiccant and labelled “Keep away from light” per EU GHS P 235. Donor – Acceptor copolymers incorporating thiazole as a π‑deficient unit5-Iodothiazole serves as the electron-deficient monomer in Stille polycondensation for all-conjugated donor–acceptor (D–A) copolymers targeted at organic photovoltaics. In a representative synthesis of poly[(5,6-difluoro-2,1,3-benzothiadiazole-4,7-diyl)-alt-(thiazole-2,5-diyl-5-aryl)], the diiodo monomer 2,5-diiodo-4-(4-(2-ethylhexyloxy)phenyl)thiazole — prepared from 5-iodothiazole via lithiation and functionalization — is co-polymerized with 2,2′-(perfluorobenzothiadiazole-4,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) under Suzuki conditions, or alternatively with a bis-trimethylstannyl donor monomer under Stille coupling. The Stille route charges the diiodothiazole monomer (1.00 eq.), 2,5-bis(trimethylstannyl)thieno[3,2-b]thiophene (1.00 eq.), Pd₂(dba)₃ (2 mol%), and tri(o-tolyl)phosphine (8 mol%) into anhydrous chlorobenzene (0.1 M with respect to monomer), and the system is subjected to microwave heating at 150°C for 45 min in a sealed PTFE vessel. Work-up involves precipitation into methanol (10 volumes), sequential Soxhlet extraction with methanol, acetone, hexane, and finally chlorobenzene. The chlorobenzene fraction yields the target polymer with number-average molecular weight (Mn) ranging from 18 000 to 34 000 g mol⁻¹ and dispersity Đ 1.8–2.4 as determined by high-temperature GPC in 1,2,4-trichlorobenzene at 150°C against polystyrene standards. Thin-film fabrication for device testing uses a blend of the polymer (10 mg mL⁻¹) with PC71BM (1:1.5 w/w) spin-coated from o-dichlorobenzene at 800 rpm onto PEDOT:PSS-coated ITO substrates, followed by thermal annealing at 110°C for 10 min under nitrogen. Power conversion efficiencies of optimized devices typically fall in the 6.5 – 8.2 % range under AM 1.5 G illumination ( 100 mW cm⁻²) with external quantum efficiency maxima at 580 nm exceeding 65%. Compliance with the EU RoHS Directive 2011/65/EU for electronic components requires tin content below 0.1 wt% from the Stille monomer residue, necessitating an additional aqueous ammonium sulfide wash step that decreased residual tin to < 50 ppm. The polymer storage must be under dry, dark conditions at −20°C to suppress aggregation-induced broadening of the absorption onset.
When late‑stage functionalization demands orthogonal reactivity in bioconjugation probesThe iodine atom of 5-iodothiazole enables a sequential chemoselective strategy: Sonogashira alkynylation followed by copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) installs a thiazole-tethered fluorophore onto a biomolecular scaffold. First, 5-iodothiazole is reacted with 4-ethynyl-N,N-dimethylaniline (1.3 eq.) in the presence of PdCl₂(PPh₃)₂ (3 mol%), CuI (6 mol%), and triethylamine (2 eq.) in anhydrous DMF at 50°C for 4 h under argon. The resulting 5-((4-(dimethylamino)phenyl)ethynyl)thiazole is isolated by silica plug filtration and loaded at 1.2 eq. into a CuAAC reaction with an azide-functionalized BODIPY dye (1.0 eq.), using CuSO₄·5H₂O (10 mol%) and sodium ascorbate (20 mol%) in t-BuOH/H₂O (1:1) at 23°C for 12 h. The dual-labelled conjugate is purified via semipreparative reversed-phase HPLC (C18, MeCN/H₂O + 0.1‰ TFA gradient) to furnish the probe in 62–78% overall yield. Live-cell imaging on HeLa cells at 2 µM probe concentration reveals conspicuous mitochondrial localization, confirmed by MitoTracker Red CMXRos co-localization coefficients (Pearson’s >0.92). Such reagents are supplied as lyophilized powder (1 mg vials) under argon, certified for research-use-only (RUO). The documentation package includes a certificate of conformity with specifications built on USP <795> compounding principles and a statement that the material has not been sterilized or sterilized by gamma irradiation. Transport classification as UN 3077 (environmentally hazardous substance, solid, n.o.s.) applies due to the intrinsic aquatic toxicity of the unreacted alkyne intermediate, requiring triple packaging per IATA packing instruction 956 for air freight. |
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5‑Iodothiazole is routinely manufactured under cGMP for supply as an advanced intermediate; critical quality attributes are listed below, with analytical methods aligned to pharmacopoeial general chapters and ASTM protocols.
| Parameter | Test Method | Research Grade Specification | Bulk Intermediate Specification |
|---|---|---|---|
| Assay (anhydrous basis) | HPLC‑UV, 254 nm, C18, MeCN/0.1 % H₃PO₄ | ≥97.0 % | ≥99.0 % |
| Melting range | DSC, 10 K/min, nitrogen purge | 42–46 °C | 43–45 °C |
| Water (KF) | ASTM E203 | ≤0.5 % | ≤0.1 % |
| Residual palladium | ICP‑MS, USP ⟨233⟩ | Report value | ≤10 ppm |
| Heavy metals (as Pb) | USP ⟨231⟩ Method II | ≤20 ppm | ≤10 ppm |
| Appearance | Visual inspection | Off‑white to pale yellow solid | White to off‑white solid |
The elevated bulk specification reflects purification by recrystallisation from heptane/ethyl acetate (3:1 v/v) and subsequent vacuum drying (50 °C, 10 mbar, 24 h). This protocol reduces regioisomeric 4‑iodothiazole to below 0.15 % and eliminates the faint yellow tint that indicates trace free iodine.
The halogenated heterocycle 5‑iodothiazole (C₃H₂INS, CAS 105600‑25‑7, molecular weight 211.02 g·mol⁻¹) serves as a versatile electrophilic building block in medicinal and agrochemical synthesis. As a crystalline solid with a melting range of 42–46 °C, it offers distinct handling advantages over the liquid 2‑ and 4‑iodothiazole isomers. Commercial availability at research‑grade (≥97 %, HPLC at 254 nm) and bulk quantities (custom kilogram‑scale batches) enables use from early‑stage discovery through process development. The compound’s regiochemistry places the iodine substituent in a para‑like position relative to the endocyclic nitrogen, imparting unique electronic properties that influence oxidative addition rates in cross‑coupling reactions. Typical applications include Suzuki–Miyaura, Sonogashira, and Buchwald–Hartwig couplings to construct biaryl, alkyne, and amino‑thiazole scaffolds found in kinase inhibitors, GPCR modulators, and antifungal agents. Residual iodine content and regioisomeric purity are assayed by quantitative 1H NMR (CDCl₃, 400 MHz) and HPLC‑UV against a certified reference standard.
Under standard Suzuki–Miyaura conditions (Pd(PPh₃)₄, K₂CO₃, DMF/H₂O 4:1, 80 °C), 5‑iodothiazole consistently exhibits a lower activation barrier for oxidative addition relative to the 2‑iodo isomer, a trend attributed to the reduced electron density at the C–I bond in the 5‑position. Density functional theory calculations place the LUMO energy of 5‑iodothiazole approximately 0.3 eV below that of 2‑iodothiazole, facilitating polarised transition states. In practice, this translates to faster reaction times and higher conversion at lower catalyst loadings, though the difference narrows when employing electron‑rich phosphine ligands such as XPhos or SPhos. Conversely, 4‑iodothiazole, which is often generated via selective lithiation‑iodination of thiazole, presents an intermediate electronic profile but suffers from a propensity for protodeiodination under basic aqueous conditions, reducing isolated yields by 5–15 % compared to the 5‑iodo analogue. The following table summarises representative performance data compiled from multiple Pd‑catalysed couplings with phenylboronic acid.
| Halothiazole Isomer | Catalyst System | Temperature (°C) | Typical Isolated Yield Range (%) | Dominant Side Reaction |
|---|---|---|---|---|
| 5‑Iodothiazole | Pd(PPh₃)₄ (0.5 mol %) | 80 | 85–93 | Homocoupling (<3 %) |
| 2‑Iodothiazole | Pd(PPh₃)₄ (1.0 mol %) | 90 | 70–82 | Dehalogenation |
| 4‑Iodothiazole | Pd(PPh₃)₄ (1.0 mol %) | 80 | 65–78 | Protodeiodination |
| 5‑Iodothiazole | Pd₂(dba)₃ / XPhos | 60 | 90–97 | None significant |
Because 5‑iodothiazole maintains a higher oxidative addition propensity without an unacceptable increase in homocoupling, it has become the preferred coupling partner for fragments functionalised at the thiazole C‑5 position. Residual catalyst removal, however, requires rigorous aqueous work‑up and treatment with metal‑scavenging agents (e.g., trimercaptotriazine on silica) to meet ICH Q3D elemental impurity thresholds.
Photolytic cleavage of the C–I bond in crystalline 5‑iodothiazole proceeds detectably under ambient fluorescent lighting, a degradation pathway largely absent in the bromo analogue. In a controlled stability study, samples stored in clear borosilicate vials under 1000‑lux cool‑white fluorescent light at 25 °C and 60 % RH exhibited an assay decrease of 2.8 % after 48 h, as measured by HPLC area % (UV detection at 254 nm, C18 column, acetonitrile/0.1 % phosphoric acid gradient). Iodine liberation was confirmed by a starch‑iodide test, and dimeric by‑products with masses corresponding to 5,5′‑bithiazole were identified via LC‑MS. To suppress this light‑induced decomposition, the compound is packaged in amber glass under an argon blanket with a desiccant pouch. Long‑term storage at −20 °C is recommended; under these conditions, the assay remains above 96.5 % over 24 months. Process development groups handling multi‑kilogram quantities in a production environment often implement a “lights‑off” protocol during charging and sampling, using red‑LED headlamps and amber‑coated reactor sight glasses. Failure to control light exposure has been observed to cause colour shifts from off‑white to tan within 8 h, and accelerated stability testing at ICH Q1A conditions (40 °C/75 % RH) shows a degradation rate that approximately doubles for every 10 °C increment above −10 °C. The photodegradation quantum yield was determined to be 0.12 at 313 nm, implicating the thiazole π→π* transition as the primary initiator; therefore, UV‑blocking packaging is mandatory for ambient shipment.
In a 100‑L glass‑lined reactor equipped with a retreat‑curve impeller, the charging of molten 5‑iodothiazole (maintained at 50 °C) introduces a critical exotherm risk if the material contacts strong bases such as potassium tert‑butoxide above 80 °C. Differential scanning calorimetry (DSC) at a ramp rate of 4 K/min records an onset of thermal decomposition at 185 °C with an energy release of 650 J/g, necessitating careful temperature control and inert atmosphere. Iron and copper contaminants, which can leach from stainless‑steel ancillary equipment, catalyse the decomposition pathway, lowering the onset temperature by 15–20 °C. For this reason, all process‑contact surfaces are passivated or made of Hastelloy C‑276, and iron content is monitored by ICP‑OES with a control limit of <5 ppm. Reaction calorimetry (Mettler‑Toledo RC1) during a representative borylation with bis(pinacolato)diboron and Pd(dppf)Cl₂ revealed that a semi‑batch feed of pre‑dissolved potassium acetate limits the instantaneous heat flow to 35 W/L, whereas direct solid addition caused a spike to 110 W/L and a 12 °C temperature overshoot, reducing yield by 3.5 %. The addition sequence in coupling reactions is deliberately arranged to avoid pre‑mixing the iodide with Pd(0) sources before the base is present, minimising the formation of inactive palladium aggregates. Gas‑evolution from dehalogenation side reactions is managed by a 0.2‑bar(g) nitrogen sweep through the condenser, and the oxygen content in the headspace is maintained below 0.5 % to avoid catalyst oxidation.
Substituting 5‑iodothiazole for 5‑bromothiazole in a palladium‑catalysed C–N coupling with a primary amide (Buchwald–Hartwig) reduced the optimum catalyst loading from 1.0 mol % Pd₂(dba)₃ / 2.2 mol % Xantphos to 0.15 mol % Pd and 0.33 mol % ligand, while maintaining a reaction temperature of 80 °C. The iodide’s superior leaving‑group ability shortened the reaction time from 18 h to 6 h, translating to a 30 % increase in throughput in the same vessel. However, the higher cost of the iodide starting material (typically a factor 2.5–3.5× compared to the bromide on a molar basis) must be offset against the savings in catalyst, solvent, and waste treatment. Lifecycle inventory assessments from a CMO indicated that the reduction in palladium usage alone reduced the heavy‑metal load in the aqueous waste by 85 %, simplifying wastewater treatment below the local consent limit of 0.5 mg/L Pd. The process team also noted that the absence of bromine avoided the formation of corrosive HBr gas during work‑up, reducing the need for scrubber capacity. Nevertheless, the iodide variant introduces a new challenge: iodide ions generated post‑coupling can poison palladium catalysts in downstream hydrogenation steps if not thoroughly removed via aqueous washes with sodium thiosulfate (5 % w/w) or ion‑exchange resins. Iodide carryover above 50 ppm has been shown to fully inhibit a subsequent nitro‑group reduction at 3 bar H₂ and 25 °C, a problem not observed when using the bromide. Process mass intensity (PMI) for the iodide‑based route was calculated at 18 kg/kg API, versus 24 kg/kg for the bromide, driven largely by reduced solvent volumes in the coupling and work‑up stages.
Trace metal specifications for GMP intermediates derived from 5‑iodothiazole are typically governed by ICH Q3D. Residual palladium is controlled to <10 ppm via treatment with a silica‑bound scavenger (e.g., SiliaMetS DMT) followed by a hot filtration through a 0.45 µm PTFE membrane. The elemental impurity profile is verified by ICP‑MS according to USP ⟨233⟩; in routine batch release, a three‑batch moving average of 6.2 ppm Pd, 3.8 ppm Cu, and <2.5 ppm Fe was maintained over 12 consecutive batches. Water content is determined by Karl Fischer titration (ASTM E203) with an acceptance criterion of <0.2 % w/w for anhydrous applications, as moisture >0.5 % promotes hydrolysis of the thiazole ring under acidic conditions. 5‑Iodothiazole itself is classified as a skin irritant (GHS Category 2) and should be handled in a fume hood with nitrile gloves; no specific OEL has been published, but internal occupational hygiene monitoring maintains airborne concentration below 0.01 mg/m³ as an 8‑hour TWA. The compound is incompatible with strong oxidising agents; contact with concentrated nitric acid leads to vigorous decomposition with iodine vapour release above 40 °C. Shipping of bulk quantities is conducted in UN‑rated fiber drums with polyethylene liners under a nitrogen pad, and the material is classified as a class‑9 environmentally hazardous substance for maritime transport (UN 3077) when the iodine content exceeds reporting thresholds.
