4-Chloropyrimidine - ≥95% , CAS No.17180-93-7

CAS: 17180-93-7 Cat. No.: C1074163 EC Number: 845-733-4 PubChem CID: 642834

GRADE & PURITY ≥95%

Storage

Room temperature

Specifications

Specifications & Purity

≥95%

Storage

Room temperature

Purity

≥95%

Names and Identifiers

Canonical Smiles

C1=CN=CN=C1Cl

IUPAC Name

4-chloropyrimidine

InChIKey

DBPKMSBWOKAKLA-UHFFFAOYSA-N

INCHI

1S/C4H3ClN2/c5-4-1-2-6-3-7-4/h1-3H

Isomeric SMILES

C1=CN=CN=C1Cl

Alternate CAS

17180-93-7

PubChem CID

642834

Taxonomic Classification

Taxonomy Tree

• Kingdom Organic compounds
  • Superclass Organoheterocyclic compounds
    • Class Diazines
      • Subclass Pyrimidines and pyrimidine derivatives

• Kingdom: Organic compounds
• Superclass: Organoheterocyclic compounds
• Class: Diazines
• Subclass: Pyrimidines and pyrimidine derivatives
• Intermediate Tree Nodes: Not available
• Direct Parent: Halopyrimidines
• Alternative Parents: Aryl chlorides Heteroaromatic compounds Azacyclic compounds Organopnictogen compounds Organonitrogen compounds Organochlorides Hydrocarbon derivatives
• Molecular Framework: Aromatic heteromonocyclic compounds
• Substituents: Halopyrimidine - Aryl halide - Aryl chloride - Heteroaromatic compound - Azacycle - Organic nitrogen compound - Organopnictogen compound - Hydrocarbon derivative - Organonitrogen compound - Organochloride - Organohalogen compound - Aromatic heteromonocyclic compound
• Description: This compound belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
• External Descriptors: Not available

Data sources

1. Djoumbou Feunang Y, Eisner R, Knox C, Chepelev L, Hastings J, Owen G, Fahy E, Steinbeck C, Subramanian S, Bolton E, Greiner R, and Wishart DS. ClassyFire: Automated Chemical Classification With A Comprehensive, Computable Taxonomy. Journal of Cheminformatics, 2016, 8:61.

DOI: 10.1186/s13321-016-0174-y

Chemical and Physical Properties

• Molecular Weight: 114.530 g/mol
• XLogP3: 0.500
• Hydrogen Bond Donor Count: 0
• Hydrogen Bond Acceptor Count: 2
• Rotatable Bond Count: 0
• Exact Mass: 113.998 Da
• Monoisotopic Mass: 113.998 Da
• Topological Polar Surface Area: 25.800 Ų
• Heavy Atom Count: 7
• Formal Charge: 0
• Complexity: 57.700
• Isotope Atom Count: 0
• Defined Atom Stereocenter Count: 0
• Undefined Atom Stereocenter Count: 0
• Defined Bond Stereocenter Count: 0
• Undefined Bond Stereocenter Count: 0
• The total count of all stereochemical bonds: 0
• Covalently-Bonded Unit Count: 1

Application Protocols

Not applicable to this product type.

• There are no immunoassay or bioanalytical “tested applications” (e.g., WB, IHC, IF, FC) for a small-molecule reagent. For synthetic applications, see the Reaction Conditions and Synthetic Utility sections for representative procedures and guidance.

Biological Roles

Applicability to this product

• This item is supplied for research use only.

General biochemical context (literature; no clinical claims)

• Pyrimidine heterocycles are fundamental in biology as constituents of nucleobases (cytosine, thymine, uracil). While 4-chloropyrimidine itself is not a natural metabolite, it serves as a synthetic precursor to 4-substituted pyrimidines that can mimic or modulate interactions in nucleotide-binding enzymes in research settings.
• The electron-deficient ring engages in π–π stacking and hydrogen bonding when suitably substituted (e.g., 4-amino, 2- or 6-substitution), making the scaffold valuable in probe development.
• In enzymology studies, substituted pyrimidines are used to explore kinase active sites, dihydrofolate reductase ligands, and pyrimidine biosynthetic pathway enzymes (e.g., orotate-related chemistry), though 4-chloropyrimidine is typically only an intermediate to access those analogs.

Practical note

• If biological assays are intended, convert 4-chloropyrimidine to the target functionalized analog first, then remove residual aryl chloride through purification. Confirm identity/purity by NMR/LCMS and assay for endotoxin/biocompatibility if exposure to cells is planned.

Safety note

• No biological activity is implied for this product; handling should follow chemical safety protocols and institutional approval for use in biological laboratories.

Buffer Applications

Not typically applicable.

• 4-Chloropyrimidine is not a buffering agent and is not used to prepare biological or analytical buffers. It lacks the conjugate acid/base pair behavior in the physiological pH range needed for effective buffering.

Practical guidance

• For work in aqueous systems, 4-chloropyrimidine is usually transformed into more polar derivatives. If it must be handled in water, use organic cosolvents (e.g., MeCN, DMSO) and appropriate buffer systems unrelated to this reagent (e.g., phosphate, HEPES) chosen for your assay.

Green Alternatives

Solvent and process intensification strategies (general guidance)

• Replace dipolar aprotic solvents (DMF/DMAc/NMP) with greener options where feasible.
• Employ ligand/catalyst systems that enable lower temperature and shorter reaction times to reduce energy use.

Illustrative alternatives and trade-offs

• 1,4-Dioxane → 2-MeTHF or CPME: Similar boiling point and utility in Pd-catalyzed couplings; lower peroxide risk than ethers like THF, but still monitor. Better biorenewable profile for 2-MeTHF.
• DMF/DMSO → MeCN or propylene carbonate: MeCN is easier to remove and lower toxicity than DMF; propylene carbonate is green but viscous and high b.p.—best for SNAr with strong bases.
• Toluene → Bio-based solvents (Cyrene, limonene blends) for certain couplings; assess catalyst compatibility and solubility.

Work-up and waste minimization

• Favor aqueous K2CO3/K3PO4 bases over stronger, hazardous bases when compatible.
• Use high-activity Pd precatalysts with ppm-level loadings; enable catalyst recovery onto scavengers.
• Telescoping: Perform SNAr followed by in situ coupling when feasible to reduce isolations and solvent use.

Comparison snapshot (general)

• DMF: High SNAr rate; poor EHS profile; difficult to remove.
• MeCN: Moderate SNAr rate; good EHS profile; easy removal.
• 2-MeTHF: Good for couplings; partially renewable; lower polarity may slow SNAr.

Note: Selection should be guided by reaction performance and your organization’s green chemistry metrics (e.g., PMI, E-factor).

Pharmaceutical Uses

Formulation/excipient role

• Not an excipient. 4-Chloropyrimidine is a synthetic building block supplied for research use only.

Relevance to pharmaceutical R&D (general; no therapeutic claims)

• Valuable as a heteroaryl electrophile for rapid assembly of 4-substituted pyrimidine libraries during hit-to-lead campaigns.
• Intermediates derived from it (e.g., 4-aminopyrimidines, 4-arylpyrimidines) are common motifs in investigational APIs targeting kinases, ion channels, and metabolic enzymes.

CMC and process considerations

• Control of residual aryl chloride in drug substance intermediates is important to meet impurity guidelines (ICH Q3A/Q3B). Analytical methods typically include GC/HPLC assay and LCMS for identity of substituted products versus unreacted chloride.
• Halide displacement generates inorganic salts (e.g., KCl, CsCl) that may persist; robust work-up and washing are recommended.
• For scale-up, selection of lower-toxicity solvents and efficient Pd scavenging aligns with green and regulatory expectations.

Regulatory note

• No pharmacopeial monograph is expected for this fine chemical. Any use in GMP settings requires internal specification setting, vendor qualification, and full documentation (CoA, SDS, impurity profile).

Physical Properties

Item-specific properties (from Product Data)

• Appearance: Not specified for this item; refer to CoA/Spec Sheet.
• Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet.

Literature/general reference values (not Aladdin specifications)

• Physical state: Typically a low-melting solid or high-boiling liquid depending on purity; heteroaryl chlorides of this size are often liquids near ambient temperature (literature, qualitative).
• Boiling point: Reported in the literature in the low-to-mid 170 °C range at ambient pressure for 4-chloropyrimidine (literature; consult primary sources/SDS for exact values).
• Melting point: Reported near or below room temperature; many samples are liquids at 20–25 °C (literature, qualitative).
• Density: Expected >1.0 g/mL due to the chloro substituent (literature, qualitative).
• Solubility: Miscible with polar aprotic solvents (DMF, DMSO, NMP, MeCN) and chlorinated solvents; limited to moderate solubility in nonpolar hydrocarbons; modest solubility in water due to heteroaromatic nitrogens (literature, qualitative).
• Refractive index/logP/pKa: Not specified for this item; refer to CoA/Spec Sheet. For the pyrimidine core, conjugate-acid pKa is low (~1), and chloro substitution further reduces basicity (literature, qualitative trend).

Notes

• Use literature data only for method development and safety screening; for regulated or quantitative work, rely on the item’s CoA/SDS.

Quality & Grades

Item-specific quality information

• Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet for assay, impurity profile, and any stabilizers.

General notes on quality for heteroaryl chlorides

• Typical concerns: Hydrolytic or aminolysis byproducts (e.g., 4-hydroxypyrimidine, 4-aminopyrimidine), ring-opened traces, and residual halogenated solvents or bases from synthesis.
• If offered in multiple grades (analytical, synthetic, or “anhydrous” variants), higher grades may emphasize lower UV background (for photophysical studies), tighter GC purity, or controlled water content. For Pd-catalyzed cross-coupling or medicinal chemistry, low halide/metal contaminants and tight GC/HPLC assay are desirable.

What grade implies (general guidance)

• “Analytical reagent (AR)” grade: Purity suitable for routine analysis; impurity thresholds controlled.
• “Synthesis” or “reagent” grade: Suitable for general organic synthesis; may not control UV absorbance or trace ions.
• “HPLC grade solvents” concept does not directly apply here, but low-UV absorbance and particulate control can still matter if used as an LC reference or in photochemistry.

Documentation and verification

• Request CoA for: assay (GC/HPLC), identity (1H NMR/IR/MS), residual solvents, and if applicable, Karl Fischer water.
• For sensitive couplings, consider in-house verification (GC, 1H/13C NMR) and minimal pre-purification (short-path distillation under N2) if specifications are critical.

Reaction & Applications

Manufacturer applications

• Not specified in Product Data. The following expands on typical laboratory uses of 4-chloropyrimidine as a heteroaryl electrophile.

Key application domains (general/literature)

• Nucleophilic aromatic substitution (SNAr): The 4-position of pyrimidine is highly activated toward displacement by N-, O-, S-, and C-nucleophiles. Primary/secondary amines give 4-aminopyrimidines—common cores in kinase inhibitor discovery and agrochemicals.
• Pd-catalyzed cross-coupling: Aryl chloride participates in Suzuki–Miyaura (with boronic acids/esters), Buchwald–Hartwig amination, Negishi, Stille, and Sonogashira (after halide activation) to access diverse 4-substituted pyrimidines.
• Chalcogenation and etherification: Thiolates and alkoxides readily substitute Cl at moderate temperatures to form thioethers and ethers.
• Directed functionalization: The electron-deficient ring supports metallation at C5 (under very strong bases/low temperatures) enabling further elaboration.

Practical tips

• SNAr often succeeds under relatively mild conditions (50–100 °C) in polar aprotic solvents with inorganic base (K2CO3/Cs2CO3). Excess nucleophile can drive to completion.
• For couplings, aryl chlorides may require more active catalysts/ligands (e.g., Pd2(dba)3 with BrettPhos/XPhos or Pd-PEPPSI precatalysts). Add water (5–20%) in Suzuki to enhance transmetalation.
• Monitor for hydrolysis by LCMS/UPLC; 4-hydroxypyrimidine is a common side product, especially at high temperature in the presence of water.

Representative outcomes

• Access to libraries of 4-amino-, 4-alkoxy-, 4-thio-, and 4-aryl pyrimidines for SAR studies, materials motifs, and heterocycle scaffolds.

Reaction Conditions

General literature guidance (examples; adjust to your system)

• SNAr with amines: 4-chloropyrimidine (1.0 eq), amine (1.2–2.0 eq), K2CO3 or Cs2CO3 (2.0–3.0 eq) in DMF or MeCN (0.1–0.5 M). 60–100 °C, 2–16 h. Monitor by LCMS. Work-up by dilution with water and extraction (EtOAc). Typical isolated yields: moderate to high, depending on amine nucleophilicity.
• O-/S-substitution: Sodium alkoxide/thiolate generated in situ (NaH or NaOMe/NaSEt). Solvent: MeOH/EtOH (for O-), DMF/DMSO (for S-). 25–80 °C, 1–8 h. Avoid excess water.
• Suzuki–Miyaura: Aryl boronic acid (1.2–1.5 eq), Pd(PPh3)4 (1–3 mol%) or Pd2(dba)3 (1–2 mol% Pd) + XPhos/BrettPhos (2–4 mol%), base K2CO3/K3PO4 (2–3 eq), solvent 1,4-dioxane/H2O (4:1) or 2-MeTHF/H2O. 70–100 °C, 4–16 h. Inert atmosphere recommended.
• Buchwald–Hartwig amination: Amine (1.2–1.5 eq), Pd2(dba)3 (1–2 mol% Pd) with BrettPhos/DavePhos or precatalyst (e.g., XPhos Pd G2, 1–2 mol%), base NaOtBu or Cs2CO3, solvent toluene/dioxane/DMAc. 80–110 °C, 4–18 h.
• Sonogashira: Terminal alkyne (1.2–1.5 eq), Pd(PPh3)2Cl2 (1–2 mol%), CuI (5–10 mol%), Et3N or i-Pr2NH, solvent THF/MeCN. 50–80 °C, 4–12 h. Copper-free variants possible with modern ligands.

Notes

• Aryl chlorides can be less reactive; stronger ligands or higher temperatures may be required versus bromides/iodides.
• Water (5–20%) sometimes accelerates Suzuki but may promote hydrolysis—optimize balance.
• Always verify conditions on small scale and tailor ligands/bases to the nucleophile/electrophile pair.

Safety & Handling

Item-specific hazard classification

• GHS classification, signal word, H/P statements, and pictograms: Not specified for this item; consult the product SDS.

General safety considerations for 4-chloropyrimidine (literature/chemical-class guidance)

• Likely hazards: Irritation to skin/eyes/respiratory tract; harmful if swallowed; flammable combustible liquid/solid at elevated temperature. Avoid inhalation of vapors and aerosols.
• Peroxide formation: Not expected (not an ether). However, hydrolytic instability can form 4-hydroxypyrimidine under strongly basic aqueous conditions; store dry.
• Incompatibilities: Strong bases and nucleophiles can react by SNAr. Avoid contact with strong oxidizers. Moisture can promote slow hydrolysis.

Recommended PPE and engineering controls

• Wear lab coat, safety glasses or face shield, and appropriate chemical-resistant gloves (e.g., nitrile). Handle in a fume hood to control vapors/aerosols.

First-aid overview (consult SDS for full guidance)

• Inhalation: Move to fresh air; seek medical attention if symptoms persist.
• Skin/eyes: Rinse thoroughly with water for at least 15 minutes; remove contaminated clothing; obtain medical advice.
• Ingestion: Rinse mouth; seek medical attention; do not induce vomiting unless directed.

Spill/Fire response

• Small spills: Absorb with inert material (vermiculite), collect in compatible container. Prevent entry into drains.
• Fire: Use CO2, dry chemical, or foam. Combustion may produce NOx, HCl/HCl-containing fumes.

Always defer to the official SDS for authoritative safety and regulatory information.

Solvent Selection

Chemical class and polarity

• 4-Chloropyrimidine is a polar, electron-deficient heteroaromatic. It dissolves well in polar aprotic media and halogenated organics; solubility in nonpolar alkanes is limited (literature, qualitative).

Typical solvent choices by use-case

• SNAr with amines/alkoxides: DMF, DMSO, NMP, MeCN, or alcohols (EtOH/i-PrOH) as both solvent and nucleophile source. Add a base (K2CO3, Cs2CO3, DIPEA).
• Pd-catalyzed cross-coupling: 1,4-dioxane/H2O, toluene, CPME, Me-THF, or DMAc; base such as K2CO3, K3PO4, or Cs2CO3. For Buchwald–Hartwig amination, toluene or dioxane are common.
• Preparative work-up: Ethyl acetate, MTBE, or DCM for extraction; methanol or acetonitrile for analytical HPLC.

Selection tips

• Increase solvent polarity to favor SNAr rates and solubility of inorganic bases and byproducts. For protic nucleophiles, use the corresponding alcohol and an alkoxide base to drive substitution.
• For air/moisture-sensitive couplings, rigorously dry solvents and degas (sparge with N2/Ar or use freeze–pump–thaw). Water accelerates hydrolysis at elevated temperatures.

Small comparison (general)

• DMF/DMSO: Highest SNAr rates; harder to remove; DMSO malodor.
• MeCN: Good balance of polarity and ease of removal; may require stronger bases.
• 2-MeTHF/CPME: Greener options for couplings; lower polarity may limit SNAr but good for Pd catalysis.

Storage & Reconstitution

Item-specific storage

• Storage conditions: Room temperature (per Product Data).
• Shipped in: Not specified for this item; refer to CoA/Spec Sheet.

General handling and stability (heteroaryl chlorides)

• Store in a tightly closed, chemically compatible container (amber glass recommended) under dry, inert atmosphere (N2/Ar) to minimize hydrolysis to 4-hydroxypyrimidine.
• Avoid prolonged exposure to moisture and elevated temperatures. If frequent access is expected, consider aliquoting under dry nitrogen.

Preparation for use

• If solidified (near room temperature), gently warm to liquefy and homogenize, then verify purity by GC/NMR if critical.
• For solution preparation, use anhydrous solvents (e.g., MeCN, DMF, DMSO). Prepare stock solutions immediately before use when possible; store short-term stocks at 2–8 °C, protected from moisture, if required by your protocol.

Shelf-life and QC

• No item-specific shelf-life is provided; monitor by periodic GC/HPLC for formation of hydrolysis or substitution byproducts during extended storage.

Note

• All guidance above is general best practice. For definitive instructions, refer to the item’s label, CoA, and SDS.

Structure & Identity

Item-specific identifiers (from Product Data)

• SKU: C1074163
• Product name: 4-Chloropyrimidine
• CAS: 17180-93-7
• CID: 642834
• InChIKey: Not specified for this item; refer to CoA/Spec Sheet.
• SMILES: Not specified for this item; refer to CoA/Spec Sheet.

Literature/computed structural information (general reference for the chemical entity)

• Molecular formula (literature): C4H3ClN2
• Molecular weight (literature): ~114.53 g/mol
• IUPAC name (literature): 4-chloropyrimidine
• 2D structure description: A six-membered aromatic diazine ring (pyrimidine) with ring nitrogens at positions 1 and 3. A chlorine substituent occupies the 4-position (para to the N atoms across the ring), leaving ring hydrogens at C2, C5, and C6. The ring is planar and electron-deficient due to the two ring nitrogens and the electron-withdrawing chloro substituent.

Key structural features (general)

• Heteroaromatic diazine (pyrimidine) core; two ring nitrogens confer modest basicity and strong π-acceptor character.
• Aryl chloride at the 4-position provides an excellent handle for nucleophilic aromatic substitution (SNAr) and Pd-catalyzed cross-coupling.
• No stereocenters; achiral, planar heteroaromatic.

Notes

• Values labeled “literature” are reference values for the generic compound and are not item-specific specifications.

Synthetic Utility

Functional group and reactivity profile (general)

• Electrophile: The 4-chloro substituent on an electron-poor pyrimidine ring is highly activated toward SNAr by hard and soft nucleophiles.
• Cross-coupling handle: Functions as an aryl chloride in Pd/Ni catalysis for C–N, C–C, and C–S bond formation.
• Directing effects: Ring nitrogens modulate reactivity and can direct lithiation at C5 under strong bases.

Representative transformations

• SNAr with amines → 4-aminopyrimidines (key pharmacophores); bases such as K2CO3, Cs2CO3, or NaOtBu in DMF/DMSO/MeCN, 25–100 °C.
• O-/S-alkylation via substitution with alkoxides/thiolates → 4-alkoxy/4-arylthio pyrimidines.
• Suzuki–Miyaura → 4-aryl/heteroaryl pyrimidines using aryl boronic acids/esters; aqueous base facilitates transmetalation.
• Buchwald–Hartwig amination → 4-(arylamino/alkylamino)pyrimidines with Pd catalysts and tailored ligands (e.g., BrettPhos/XPhos/DavePhos).
• Sonogashira/Negishi/Stille → C(sp2)–C(sp), C(sp2)–C(sp3/sp2) linkages on the ring.

Retrosynthetic value

• Serves as a convergence point to access a wide range of 4-substituted pyrimidines from a single electrophilic core, enabling parallel synthesis and SAR diversification.

Operational insights

• Moisture control reduces hydrolysis to 4-hydroxypyrimidine. For sensitive nucleophiles, pre-form M–Nu species (e.g., NaSR, NaOR) to ensure clean substitution.
• For less reactive couplings, increase ligand electron richness, elevate temperature, or use micellar catalysis to enhance rates while reducing organic solvent load.

Target Specificity

Not applicable to this product type.

• 4-Chloropyrimidine is a small-molecule reagent and does not have biological target specificity parameters (e.g., antigen, clone, isotype). No item-specific target data are provided.