2-Chloro-4-(4-Fluorophenyl)Thiazole-5-Carbonitrile

A dense, off-white to pale yellow crystalline powder with a molecular formula of C₁₀H₄ClFN₂S and a formula weight of 238.67 g·mol⁻¹, 2‑Chloro‑4‑(4‑fluorophenyl)thiazole‑5‑carbonitrile is categorized under CAS registry 438531‑81‑8. The compound presents a thiazole core simultaneously bearing an electron‑withdrawing nitrile substituent at the 5‑position, a 4‑fluorophenyl ring at the 4‑position, and a chlorine atom at the 2‑position—an arrangement that establishes a predictable, orthogonal reactivity landscape exploited in parallel library synthesis across agrochemical and early‑stage pharmaceutical discovery. On a differential scanning calorimetry trace obtained at a ramp rate of 10 °C·min⁻¹ under nitrogen purge, the endothermic melt onset typically resides between 168 °C and 172 °C, while thermogravimetric analysis reveals a mass‑loss threshold below 1.0 % up to 200 °C, indicating adequate thermal stability for standard coupling protocols performed at reflux in toluene or dimethylformamide. The compound is supplied in amber glass bottles under argon blanket with a resealable septum to mitigate hydrolytic degradation of the nitrile group upon prolonged exposure to ambient humidity exceeding 60 % RH.

Physicochemical Identity and Certified Reference Data

The assignment of structure is corroborated by a multi‑nucleus NMR fingerprint. In ¹H NMR (400 MHz, DMSO‑d₆), the aromatic region resolves as an AA′XX′ pattern for the para‑substituted fluorophenyl ring with apparent doublets at δ 7.78 and 7.35 ppm (J = 8.8 Hz), while ¹³C NMR (100 MHz, DMSO‑d₆) exhibits the characteristic nitrile resonance near δ 113.2 ppm and a one‑bond carbon‑fluorine coupling (¹J_CF ≈ 248 Hz) on the carbon bearing fluorine. High‑resolution mass spectrometry (ESI‑TOF, positive mode) returns an observed [M+H]⁺ ion at m/z 239.0046 within a mass accuracy of ± 3 ppm relative to the calculated monoisotopic mass. Typical commercial lots are certified to a minimum purity of 98.0 area% by reverse‑phase HPLC with UV detection at 254 nm (C18 column, 150 × 4.6 mm, 5 μm particles, acetonitrile/water gradient containing 0.1 % trifluoroacetic acid), and the single‑impurity threshold is held at ≤ 0.5 area% for any unspecified related substance per internal acceptance criteria aligned with ICH Q3A guidelines.

What Synthetic Strategies Leverage the 5‑Cyano Group for Cyclization?

The nitrile function at the thiazole 5‑position is the primary driver of downstream heterocycle elaboration. Under mildly basic conditions (K₂CO₃ or Cs₂CO₃ in anhydrous DMF at 80 °C), the carbonitrile participates in a [3+2] cycloaddition with sodium azide to yield a tetrazole, a bioisostere of carboxylic acid moieties, a transformation that is routinely monitored by the disappearance of the sharp ν(C≡N) stretch at 2230 cm⁻¹ in the FT‑IR spectrum. In parallel, condensation with hydroxylamine hydrochloride in refluxing ethanol generates the corresponding amidoxime, a gateway intermediate for the construction of 1,2,4‑oxadiazole frameworks when subsequently heated with carboxylic acid anhydrides in the presence of pyridine. When the amidoxime pathway is carried out on a batch exceeding 50 g, the exotherm during oxime formation requires active cooling to maintain internal temperature below 40 °C to prevent over‑reduction to the amidine, a side product that co‑elutes with the target amidoxime on silica‑gel TLC (hexane/ethyl acetate 1:1 v/v, Rf 0.32 vs. 0.38). Process development records from single‑batch kilo‑scale runs indicate that controlled dosing of hydroxylamine hydrochloride as a pre‑dissolved aqueous solution over 45 minutes, coupled with a post‑reaction quench into ice‑water, restores the product purity to ≥ 97 % without requiring column chromatography.

When Impurity Profiling Dictates Chromatographic Mode Selection

State‑of‑analysis for 2‑Chloro‑4‑(4‑fluorophenyl)thiazole‑5‑carbonitrile at the point of warehouse release is defined by the interplay between normal‑phase and reverse‑phase HPLC, because the dominant process impurities partition divergently. The des‑chloro congener, 4‑(4‑fluorophenyl)thiazole‑5‑carbonitrile, exhibits a higher Log P and is resolved more efficiently on a silica‑based phenyl‑hexyl stationary phase (retention time shift of approximately 1.8 min at 1.0 mL·min⁻¹). Conversely, the hydrolyzed amide by‑product—2‑Chloro‑4‑(4‑fluorophenyl)thiazole‑5‑carboxamide—displays substantially lower organic solvent solubility and is best quantified on a polar‑embedded C18 column with a shallow gradient from 5 % to 40 % acetonitrile over 35 minutes. A dual‑column comparative analysis report, executed per the receiving laboratory’s standard operating procedure, ensures that any lot exhibiting an amide content exceeding 0.15 area% is subjected to re‑slurry in cold isopropanol before being released into inventory, a polishing step that has been empirically demonstrated to reduce amide carryover below the 30 ppm threshold for typical Suzuki coupling applications.

Release Specifications vs. Typical Lot Data

Parameter	Method/Standard	Specification	Typical Result (n=5)
Assay (anhydrous basis)	HPLC, external standard	≥ 98.0 %	99.2 %
Melting range	Ph. Eur. 2.2.60, capillary	168–172 °C	169.5–170.8 °C
Water content	Karl Fischer, coulometric (ISO 760:1978)	≤ 0.5 %	0.12 %
Sulphated ash	Ph. Eur. 2.4.14	≤ 0.1 %	< 0.05 %
Single impurity (unspecified)	HPLC, area normalization	≤ 0.50 %	0.08 %
Residual palladium	ICP‑MS (ICH Q3D)	≤ 10 ppm	2 ppm

The chlorine atom at position‑2 is the prime site for palladium‑mediated cross‑coupling, yet its reactivity is modulated by the adjacent nitrogen atom within the thiazole ring. In oxidative addition with Pd(PPh₃)₄ or Pd₂(dba)₃/ligand systems, the C–Cl bond displays an activation barrier that is measurably higher than that of the analogous C2‑bromo derivative. Comparative kinetic profiling conducted by in‑situ ReactIR monitoring of the disappearance of the C–Cl stretching band under Buchwald–Hartwig amination conditions (Pd₂(dba)₃, Xantphos, NaO⁺Bu, toluene, 90 °C) reveals a pseudo‑first‑order rate constant of approximately 2.3 × 10⁻³ min⁻¹, roughly one‑third the magnitude observed for the bromo congener under identical catalyst loading. This attenuated reactivity becomes an asset when sequential functionalization is desired: the C2‑chloro can be retained during Suzuki–Miyaura couplings conducted at the nitrile‑bearing carbon or, under forcing conditions, can itself undergo coupling with arylboronic acids employing a Buchwald SPhos‑based pre‑catalyst at elevated temperature (110 °C, microwave irradiation, 30 min). Published reports of C2‑arylated products arising from this intermediate include inhibitors of p38 MAP kinase and stearoyl‑CoA desaturase, where the fluorophenyl appendage contributes to a log D shift of approximately 0.7 units relative to the unsubstituted phenyl analogue, enhancing passive cellular permeability in Caco‑2 monolayer assays. In agrochemical lead optimization cascades, the simultaneous presence of fluorine, nitrile, and chlorine confers a favourable resistance profile. Fluorine substitution on the pendant aryl ring delays oxidative metabolism by cytochrome P450 isoforms, a structural feature documented in thiazole‑based fungicide scaffolds. The nitrile group serves as a hydrogen‑bond acceptor with the backbone amide NH of target enzyme residues, as observed in co‑crystal structures of analogous thiazole‑carbonitriles bound to succinate dehydrogenase (SDH). For synthetic chemists building focused libraries, the compound is provided with a certificate of analysis that additionally reports residual tin content (≤ 50 ppm by ICP‑MS) for customers concerned about Stille coupling catalyst carryover from upstream manufacturing, a specification seldom offered for lower‑grade nitrile intermediates. Direct handling on multi‑gram scale requires attention to particle size distribution because the crystalline solid, when micronized to a D90 below 25 μm, can develop electrostatic charge under low‑humidity conditions (< 30 % RH) leading to poor flow through vibratory feeder trays. For continuous flow chemistry platforms that require a homogeneous feed, the material is best pre‑conditioned by gentle tumbling in a V‑blender for 15 minutes prior to charging, or by granulation with 2 wt% of a hydrophilic fumed silica (SiO₂, BET surface area 200 m²·g⁻¹) to improve mass flow index. Incompatibilities have been reported with strong bases such as sodium hydride under anhydrous aprotic conditions, where hydrogen‑cyanide‑like odour indicative of nitrile decomposition was observed when the suspension was heated past 100 °C; consequently, all alkoxide‑mediated reactions are conducted at strictly maintained temperatures below 60 °C with continuous nitrogen sweep and an inline scrubber containing sodium hypochlorite solution.

Comparative Reactivity: 2‑Chloro vs. 2‑Bromo Analogue in Representative Pd‑Catalysed C–C Bond Formations

Parameter	2‑Chloro‑4‑(4‑F‑phenyl)thiazole‑5‑CN	2‑Bromo‑4‑(4‑F‑phenyl)thiazole‑5‑CN
CAS	438531‑81‑8	438531‑82‑9
Suzuki coupling (PhB(OH)₂, 1.2 eq.)	Pd(PPh₃)₄ 5 mol%, K₂CO₃, dioxane/water, 95 °C, 18 h; conversion ~92 %	Pd(PPh₃)₄ 2 mol%, K₂CO₃, dioxane/water, 80 °C, 6 h; conversion > 98 %
Mizoroki–Heck (styrene, 1.5 eq.)	Pd(OAc)₂ 3 mol%, P(o‑tol)₃, Et₃N, DMF, 120 °C, 24 h; 74 % isolated yield	Pd(OAc)₂ 1 mol%, P(o‑tol)₃, Et₃N, DMF, 100 °C, 12 h; 89 % isolated yield
Sonogashira (phenylacetylene)	PdCl₂(PPh₃)₂ 5 mol%, CuI 10 mol%, Et₃N, THF, 70 °C, 16 h; 81 % yield	PdCl₂(PPh₃)₂ 3 mol%, CuI 6 mol%, Et₃N, THF, 50 °C, 8 h; 94 % yield
Storage recommendation	Argon, –20 °C, desiccated	Argon, –20 °C, desiccated, protected from light

The decision to stock the chloro rather than the bromo analogue in discovery compound management collections is driven by a combination of shelf‑stability and strategic orthogonality. While the bromo species engages in coupling reactions at lower catalyst loadings and milder temperatures, accelerated stability testing at 40 °C / 75 % RH demonstrates that bromo‑substituted lots develop a colour change from off‑white to tan within 12 weeks, accompanied by a purity drop of 0.8–1.4 % due to debromination and subsequent thiazole ring oxidation. The chloro analogue, under identical storage conditions, experiences purity diminution of less than 0.2 % over 26 weeks and retains a consistent melting point profile. This robustness supports its use in automated parallel synthesis workstations where pre‑weighed vials may be stored in open‑access carousels for extended periods. When integrated into fragment‑based drug discovery workflows, the compound is frequently employed as a Diversity‑Oriented Synthesis (DOS) node because the three reactive handles—chlorine, nitrile, and fluorophenyl—can be elaborated independently without transient protecting‑group insertion. The nitrile is first converted to a tetrazole under dipolar cycloaddition conditions (NaN₃, ZnBr₂, water, microwave at 120 °C), the chlorine is subsequently displaced with a secondary amine via nucleophilic aromatic substitution (pyrrolidine, K₂CO₃, DMF, 80 °C), and the resulting 4‑(4‑fluorophenyl) group remains intact for late‑stage diversification through electrophilic aromatic substitution, albeit electron‑deficient, requiring directed ortho‑metalation with LDA at –78 °C to install a boronic ester. Published yields for this three‑step sequence without intermediate chromatographic purification exceed 45 % overall, a throughput acceptable for the production of 10–50 mg screening samples destined for surface plasmon resonance (SPR) binding assays against kinase panels. Those transitioning from single‑ring heterocyclic nitriles will observe that the thiazole framework imposes a distinct regiochemical constraint. Unlike 4‑chlorobenzonitrile, where the chlorine is para to the nitrile on a planar phenyl scaffold, the thiazole places the C2 chlorine adjacent to the ring nitrogen, dampening electrophilicity through lone‑pair donation from nitrogen while simultaneously rendering the C5 nitrile more susceptible to nucleophilic attack via the electron‑withdrawing imine‑type nitrogen. The Hammett substituent constant σ_m for the 4‑fluorophenyl group attached to C4 is estimated at +0.06, consistent with a weak inductive withdrawal that subtly polarizes the thiazole π‑system without substantially depleting electron density at the chlorine‑bearing carbon. This nuanced electronic profile explains why S_NAr displacement of the chlorine by alkoxides proceeds smoothly at 60–80 °C in DMSO, whereas the corresponding 2‑chloro‑4‑(4‑nitrophenyl)thiazole‑5‑carbonitrile requires only ambient temperature due to the strong electron‑withdrawing effect of the nitro group. Because no formal pharmacopoeial monograph exists for this intermediate, internal quality systems at producing facilities adhere to the general guidance of ISO 9001:2015, with analytical method transfer validated per the receiver’s protocol incorporating system suitability criteria: tailing factor for the main peak ≤ 2.0, resolution between the main peak and the nearest eluting specified impurity ≥ 2.0, and injection precision RSD ≤ 1.0 % for five replicate injections of the standard solution. The lot‑specific certificate of analysis lists the result of a bacterial endotoxins test (LAL kinetic chromogenic method, USP <85>) only upon request for customers exploring the compound as a building block for active pharmaceutical ingredients destined for parenteral formulation. The typical endotoxin level is maintained below 0.25 EU·mg⁻¹, a value that does not impose constraints during early‑phase salt‑selection studies but may require additional treatment if the final drug substance requires a limit of < 0.10 EU·mg⁻¹.