4-Chloro-6-(trifluoromethyl)quinoline: Properties & Uses
4-Chloro-6-(trifluoromethyl)quinoline: Properties & Uses
4-chloro-6-(trifluoromethyl)quinoline is a fluorinated heterocyclic building block widely employed in medicinal chemistry and pharmaceutical synthesis due to its electrophilic C-4 chloro substituent and the potent electron-withdrawing trifluoromethyl group at the 6-position.
- CAS Number
- 289686-70-0
- Molecular Formula
- C10H5ClF3N
- Molecular Weight
- 231.60 g/mol
- Core Scaffold
- Quinoline (bicyclic benzene-fused pyridine)
- Key Functional Groups
- 4-Chloro, 6-Trifluoromethyl
- Primary Application
- Pharmaceutical intermediate and medicinal chemistry building block
- SKU
- C135927
Chemical Structure and Key Properties
4-Chloro-6-(trifluoromethyl)quinoline belongs to the quinoline family of nitrogen-containing bicyclic aromatic heterocycles. Its structure consists of a benzene ring fused to a pyridine ring, with two strategically positioned substituents: a chlorine atom at the 4-position and a trifluoromethyl (–CF3) group at the 6-position.
The chlorine at the 4-position renders this carbon highly electrophilic, making it an excellent site for nucleophilic aromatic substitution (SNAr) reactions. This reactivity is further amplified by the strongly electron-withdrawing –CF3 group at the 6-position, which reduces the overall electron density of the aromatic ring system. The –CF3 group also imparts improved metabolic stability, enhanced lipophilicity, and favorable membrane permeability to derivatives—properties that are highly desirable in drug candidates.
Physically, 4-chloro-6-(trifluoromethyl)quinoline is typically a solid at ambient temperature. Its fluorinated character contributes to high chemical stability under standard laboratory conditions.
Synthesis and Reactivity
The primary synthetic utility of 4-chloro-6-(trifluoromethyl)quinoline stems from the highly activated C–Cl bond at the 4-position. This bond undergoes facile nucleophilic aromatic substitution (SNAr) with a broad range of nucleophiles including amines, thiols, alkoxides, and carbon nucleophiles, enabling efficient access to 4-substituted quinoline libraries.
Typical transformations include:
- Amination: Reaction with primary or secondary amines delivers 4-amino-6-(trifluoromethyl)quinoline derivatives, a privileged motif in kinase inhibitor design.
- Thioetherification: Reaction with thiolates affords 4-thioether quinolines relevant to antimicrobial research.
- Transition-metal-catalyzed cross-coupling: Palladium-catalyzed reactions (e.g., Suzuki, Buchwald–Hartwig) can be employed to install aryl, heteroaryl, or amino groups at the 4-position.
The trifluoromethyl group at the 6-position is generally stable under these conditions and can serve as an additional handle for further functionalization if required.
Applications in Pharmaceutical and Medicinal Chemistry
4-Chloro-6-(trifluoromethyl)quinoline is a valuable building block in the design and synthesis of bioactive molecules. The quinoline scaffold is found in numerous approved drugs and clinical candidates, encompassing antimalarial, antibacterial, antiviral, and anticancer agents.
The trifluoromethyl group is one of the most important fluorine-containing motifs in modern drug discovery. Its incorporation into drug candidates typically delivers: (1) enhanced metabolic stability by resisting oxidative metabolism, (2) improved binding affinity through favorable interactions with target proteins, and (3) tuned pharmacokinetic profiles including bioavailability and half-life.
Researchers commonly employ this compound as a starting material or intermediate to synthesize novel quinoline derivatives for biological screening. Its combination of an electrophilic leaving group and a bioisosteric –CF3 group makes it a strategically efficient scaffold for structure–activity relationship (SAR) studies targeting enzymes, receptors, and protein–protein interactions.
Handling, Storage, and Safety Considerations
As with all reactive halogenated heterocyclic compounds, appropriate safety precautions should be observed when working with 4-chloro-6-(trifluoromethyl)quinoline. Researchers should consult the current Safety Data Sheet (SDS) provided by Aladdin Scientific before use.
General handling guidelines:
- Use appropriate personal protective equipment (PPE) including nitrile gloves, safety glasses, and a laboratory coat.
- Handle in a well-ventilated fume hood to minimize inhalation exposure.
- Avoid contact with skin, eyes, and mucous membranes.
Storage recommendations:
- Store in a cool, dry, well-ventilated location away from incompatible materials such as strong bases, strong oxidizers, and moisture.
- Keep container tightly sealed when not in use to prevent moisture ingress and maintain product integrity.
- Recommended storage at 2–8 °C or as specified on the product label to ensure long-term stability.
Disposal should comply with applicable local, regional, and national regulations governing halogenated organic compounds.
Frequently asked questions
What makes the 4-position chlorine in this compound so reactive?
The 4-position of the quinoline ring is inherently electron-deficient due to the ring nitrogen. The additional –CF3 group at the 6-position further withdraws electron density, making the C-4 carbon strongly electrophilic and highly susceptible to nucleophilic aromatic substitution (SNAr) by amines, thiols, and other nucleophiles.
Why is the trifluoromethyl group important in drug discovery applications?
The trifluoromethyl group is a widely used bioisosteric modifier in medicinal chemistry. It enhances metabolic stability by resisting cytochrome P450-mediated oxidation, can improve binding affinity to biological targets through hydrophobic and electrostatic interactions, and modulates pharmacokinetic properties such as lipophilicity and membrane permeability.
What nucleophiles are compatible with SNAr reactions on this compound?
A wide range of nucleophiles can displace the 4-chloro group via SNAr, including primary and secondary aliphatic or aromatic amines, sodium or potassium thiolates, alkoxides, and in some cases, stabilized carbon nucleophiles. The reaction is typically conducted in polar aprotic solvents such as DMF, DMSO, or NMP, often with a base such as triethylamine or K2CO3.
How should I store 4-chloro-6-(trifluoromethyl)quinoline to maintain its quality?
Store the compound in a tightly sealed container in a cool, dry, and well-ventilated area, away from moisture and incompatible substances. Storage at 2–8 °C is generally recommended to ensure long-term stability, but always refer to the product label and SDS for specific guidance.
Can this compound be used in palladium-catalyzed cross-coupling reactions?
Yes, the C–Cl bond at the 4-position can participate in palladium-catalyzed cross-coupling reactions such as Suzuki–Miyaura and Buchwald–Hartwig amination. Appropriate ligand and catalyst selection is important for efficient reactivity with aryl chlorides, and standard conditions for electron-deficient aryl chlorides typically apply.
References
- Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. (General reference for nucleophilic aromatic substitution)
- Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881–1886. doi:10.1126/science.1131943
- Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822–5880. doi:10.1021/acs.jmedchem.7b01788
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