2-Chloro-5-(trifluoromethyl)-4-iodopyridine: Properties & Uses
2-Chloro-5-(trifluoromethyl)-4-iodopyridine: Properties & Uses
2-chloro-5-(trifluoromethyl)-4-iodopyridine is a multifunctional halogenated pyridine building block that combines a reactive C–I bond, a nucleofugal C–Cl bond, and an electron-withdrawing trifluoromethyl group on a single aromatic ring, making it exceptionally valuable for sequential cross-coupling and nucleophilic substitution strategies in medicinal and agrochemical synthesis.
- CAS Number
- Not specified in source material
- Molecular Formula
- C6H2ClF3IN
- Molecular Weight
- Approximately 307.44 g/mol
- Key Functional Groups
- Aryl iodide, aryl chloride, trifluoromethyl group, pyridine nitrogen
- Primary Application
- Sequential cross-coupling reactions (e.g., Suzuki, Negishi, Sonogashira) and nucleophilic aromatic substitution
- Storage Recommendation
- Store in a cool, dry place away from moisture and light, following supplier SDS guidelines
Chemical Identity and Structure
2-Chloro-5-(trifluoromethyl)-4-iodopyridine (SKU: C124047) is a trisubstituted pyridine featuring three distinct reactive or electronic elements: a chlorine atom at the 2-position, an iodine atom at the 4-position, and a trifluoromethyl (–CF3) group at the 5-position. The molecular formula is C6H2ClF3IN, with an approximate molecular weight of 307.44 g/mol.
The pyridine ring nitrogen and the flanking –CF3 group act cooperatively to render the ring highly electron-deficient. This electronic character profoundly influences the reactivity at each substituted carbon: the C–I bond at the 4-position is particularly activated toward oxidative addition into palladium(0) and other transition-metal catalysts, while the C–Cl bond at the 2-position is ortho to the ring nitrogen and thus susceptible to nucleophilic aromatic substitution (SNAr) under appropriate conditions.
The –CF3 substituent confers additional lipophilicity and metabolic stability to downstream molecules, properties that are highly sought after in drug discovery programs. The compound is typically a solid or low-melting crystalline material; consult the product SDS and specification sheet for precise physical data.
Reactivity and Synthetic Applications
The orthogonal reactivity of the two carbon–halogen bonds is the defining synthetic feature of this compound. Because aryl iodides undergo oxidative addition to Pd(0) significantly faster than aryl chlorides under standard mild conditions, chemists can selectively functionalize the C4–I position first using palladium-catalyzed cross-coupling reactions such as Suzuki–Miyaura (boronic acids/esters), Negishi (organozinc), Sonogashira (terminal alkynes), or Stille (organostannanes) couplings.
After selective functionalization at C4, the remaining C2–Cl bond can be engaged in a second cross-coupling step under more forcing conditions, or alternatively subjected to nucleophilic aromatic substitution with amines, alkoxides, or thiolates. The electron-withdrawing pyridine nitrogen and –CF3 group activate the C2–Cl bond toward SNAr, reducing the barrier to nucleophilic attack. This sequential two-step diversification strategy enables efficient construction of highly substituted fluorinated pyridine scaffolds from a single starting material.
Applications in the literature include the preparation of kinase inhibitor scaffolds, GPCR-targeted ligands, PET radiotracer precursors, and fluorinated agrochemical intermediates—all compound classes where the –CF3 group's metabolic and physicochemical benefits are exploited. Researchers should consult primary literature for specific reaction conditions, catalyst loadings, and substrate scope.
Role of the Trifluoromethyl Group in Drug Discovery
The incorporation of a trifluoromethyl group into bioactive molecules is one of the most widely practiced strategies in modern medicinal chemistry. The –CF3 group is strongly electron-withdrawing (Hammett σp ≈ +0.54) and increases the lipophilicity of aromatic systems (Hansch π ≈ +0.88), improving membrane permeability. Critically, the C–F bonds are highly resistant to metabolic oxidation by cytochrome P450 enzymes, thereby prolonging compound half-life in vivo.
When the –CF3 group is installed on a pyridine ring, these effects are amplified by the inherent polarity and aqueous solubility contribution of the ring nitrogen. The resulting trifluoromethylpyridine motif appears in numerous approved pharmaceuticals and agrochemicals. By providing 2-chloro-5-(trifluoromethyl)-4-iodopyridine as a ready-made building block, Aladdin Scientific enables researchers to rapidly access this privileged scaffold without requiring multi-step –CF3 introduction chemistries such as Ruppert–Prakash trifluoromethylation.
Researchers involved in fragment-based drug discovery or scaffold-hopping campaigns will find this compound particularly useful as a starting point for library synthesis, given its three points of diversification: C2 (halogen), C4 (halogen), and the –CF3 group itself (which can engage in specialized transformations under specific conditions).
Handling, Safety, and Storage
As with all halogenated aromatic compounds, 2-chloro-5-(trifluoromethyl)-4-iodopyridine should be handled in accordance with good laboratory practice (GLP). Always consult the Safety Data Sheet (SDS) supplied by Aladdin Scientific before use. General precautions include working in a well-ventilated fume hood, wearing appropriate personal protective equipment (nitrile gloves, safety glasses, and a lab coat), and avoiding inhalation of dust or vapors.
The compound should be stored in a tightly sealed container in a cool, dry location, away from moisture, heat sources, and direct light. Fluorinated aromatic compounds can release hydrogen fluoride or related fluorinated byproducts under harsh degradation conditions; therefore, waste disposal must comply with local regulations for halogenated organic waste. Do not pour down the drain.
For long-term storage stability, it is advisable to keep the compound under an inert atmosphere (nitrogen or argon) if repeated opening is anticipated. Upon receipt, verify purity by NMR or HPLC against the certificate of analysis (CoA) provided with each lot. Contact Aladdin Scientific's technical support team if purity falls below specification.
Frequently asked questions
What makes 2-chloro-5-(trifluoromethyl)-4-iodopyridine useful for sequential cross-coupling reactions?
The compound contains both an aryl iodide and an aryl chloride on the same ring, which exhibit markedly different reactivity toward palladium catalysts. Under mild standard conditions, Pd(0) selectively undergoes oxidative addition into the C–I bond, enabling chemoselective functionalization at C4 first. The C–Cl bond can then be engaged in a subsequent coupling or nucleophilic aromatic substitution step, allowing two independent diversification events from a single building block.
How does the trifluoromethyl group influence the physicochemical properties of compounds derived from this building block?
The –CF3 group is strongly electron-withdrawing and increases lipophilicity (log P contribution ≈ +0.88 by Hansch parameters), improving passive membrane permeability of the resulting compounds. It also confers high metabolic stability because C–F bonds resist cytochrome P450-mediated oxidation, which can translate to longer in vivo half-lives. These properties make trifluoromethylated pyridines privileged motifs in drug discovery and agrochemical development.
What purity grade is available for C124047, and how should I confirm it upon receipt?
Aladdin Scientific provides a certificate of analysis (CoA) with each lot of C124047 stating the purity as determined by analytical methods such as HPLC or GC. Upon receipt, you should cross-check your sample against the CoA using an appropriate in-house technique (e.g., 1H NMR, 19F NMR, or HPLC). If the purity does not meet the stated specification, please contact Aladdin Scientific's customer support for assistance or a replacement.
Are there any special disposal requirements for 2-chloro-5-(trifluoromethyl)-4-iodopyridine?
Yes. As a halogenated aromatic compound containing both iodine and fluorine, it must be treated as halogenated organic waste. Do not dispose of it via the sanitary sewer or general waste. Collect it in a designated halogenated organic waste container and arrange disposal through a licensed hazardous waste contractor in compliance with your local, national, and institutional regulations. Always consult the product SDS for specific hazard classification and disposal guidance.
References
- Hagmann, W. K. The Many Roles for Fluorine in Medicinal Chemistry. Journal of Medicinal Chemistry, 2008, 51(15), 4359–4369. doi:10.1021/jm800219f
- Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications. Wiley-VCH, 2004.
- Negishi, E. Handbook of Organopalladium Chemistry for Organic Synthesis. Wiley-Interscience, 2002.
- Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chemical Reviews, 1995, 95(7), 2457–2483. doi:10.1021/cr00039a007
- Aladdin Scientific Product Page, C124047: 2-chloro-5-(trifluoromethyl)-4-iodopyridine. https://www.aladdinscientific.com
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