4-[(2,6-Difluorophenyl)methyl]piperidine - ≥95% , CAS No.253450-33-8

CAS: 253450-33-8 Cat. No.: D970396 Summenformel: C₁₂H₁₅F₂N Molekulargewicht: 211.250

GRADE & PURITY ≥95%

Storage

Room temperature

Specifications

Spezifikationen & Reinheit

≥95%

Storage

Room temperature

Reinheit

≥95%

Namen und Kennungen

Kanonisches Lächeln

C1CNCCC1CC2=C(C=CC=C2F)F

IUPAC Name

4-[(2,6-difluorophenyl)methyl]piperidine

InChIKey

LXCOJJJRSUQFRJ-UHFFFAOYSA-N

INCHI

1S/C12H15F2N/c13-11-2-1-3-12(14)10(11)8-9-4-6-15-7-5-9/h1-3,9,15H,4-8H2

Molekulargewicht

211.250

Taxonomic Classification

Taxonomy Tree

• Kingdom Organic compounds
  • Superclass Organoheterocyclic compounds
    • Klasse Piperidines
      • Subclass Benzylpiperidines

• Kingdom: Organic compounds
• Superclass: Organoheterocyclic compounds
• Klasse: Piperidines
• Subclass: Benzylpiperidines
• Intermediate Tree Nodes: Not available
• Direct Parent: 4-benzylpiperidines
• Alternative Parents: Fluorobenzenes Aralkylamines Aryl fluorides Dialkylamines Azacyclic compounds Organofluorides Hydrocarbon derivatives
• Molecular Framework: Aromatic heteromonocyclic compounds
• Substituents: 4-benzylpiperidine - Fluorobenzene - Halobenzene - Aralkylamine - Aryl fluoride - Aryl halide - Monocyclic benzene moiety - Benzenoid - Secondary aliphatic amine - Secondary amine - Azacycle - Organofluoride - Organohalogen compound - Hydrocarbon derivative - Organic nitrogen compound - Amine - Organonitrogen compound - Aromatic heteromonocyclic compound
• Beschreibung: This compound belongs to the class of organic compounds known as 4-benzylpiperidines. These are organic compounds containing a benzyl group attached to the 4-position of a piperidine.
• 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

Chemische und physikalische Eigenschaften

• Molekulargewicht: 211.250 g/mol
• XLogP3: 2.700
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 3
• Rotatable Bond Count: 2
• Exact Mass: 211.117 Da
• Monoisotopic Mass: 211.117 Da
• Topological Polar Surface Area: 12.000 Ų
• Heavy Atom Count: 15
• Formal Charge: 0
• Complexity: 182.000
• 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. No validated bioassay/immunoassay protocols (e.g., WB, IHC, IF, FC) are associated with this small-molecule building block.

General handling suggestions (chemistry lab use):

• Prepare analytical stocks at 10–100 mM in DMSO or MeCN for screening or reaction scouting.
• For salt formation: dissolve in minimal Et2O or IPA and treat with HCl in ether or HCl/IPA to precipitate the hydrochloride salt; filter and dry under vacuum.

For any biological application development, users must establish and validate their own conditions.

Biological Roles

Item-specific biological/physiological roles: Not applicable; this is a synthetic organic building block intended for research use only.

General context (chemistry/biochemistry knowledge):

• Piperidine is a common motif in natural products and bioactive molecules, often modulating basicity, solubility, and receptor binding. The 2,6-difluorobenzyl group enhances lipophilicity and can increase metabolic stability by resisting oxidative aromatic hydroxylation.
• This compound does not have a known endogenous biological role. Any biological activity arises from derivatives in which the secondary amine is derivatized (e.g., amides, ureas) or where benzylic/aryl positions are further functionalized for SAR exploration.

Research use note (from Product Data): For research use only. Not for human or veterinary use, diagnostic procedures, or clinical applications.

Buffer Applications

Not typically used as a buffering agent. Although secondary amines have basic conjugate acids (pKaH ~10–11, literature for piperidines), this compound is a hydrophobic building block and not employed in standard biological/biochemical buffer systems.

Practical note:

• If temporary pH control is needed during reactions or workups, form its soluble acid salt (e.g., HCl) to facilitate handling or extraction, but use conventional buffers (e.g., phosphate, acetate, carbonate) for precise pH control in aqueous systems.

Green Alternatives

While the compound itself is a building block (not a solvent or reagent commonly replaced on green grounds), its synthesis and use can be greener via choice of media, reagents, and isolation methods.

Greener choices (general recommendations):

• Media selection: favor MeCN, 2-MeTHF, CPME, or EtOAc over chlorinated solvents for N-acylations and reductive aminations where performance allows.
• Workup/isolation: form crystalline salts (e.g., HCl in Et2O/IPA) to avoid silica-intensive chromatography; implement antisolvent crystallization.
• Reagent selection: use coupling reagents with better EHS profiles (e.g., CDI, EDC·HCl + catalytic DMAP) instead of HATU/DITU when feasible; adopt aqueous micellar catalysis for some transformations.
• Benzylic bromination alternatives: consider electrochemical benzylic functionalization or H2O2/photoredox oxidation rather than NBS under radical conditions.

Illustrative comparison (process-level):

• Chlorinated solvent route (DCM, NBS bromination): easy, but halogenated waste and potential AOX
• Alternative route (MeCN or EtOAc, photoredox with oxygen or H2O2): reduced halogenated waste, milder conditions, potential energy savings

Trade-offs:

• 2-MeTHF/CPME may retain water; ensure adequate drying for moisture-sensitive steps.
• Photoredox/electrochemical methods can require specialized equipment and optimization but decrease reliance on hazardous reagents.

Pharmaceutical Uses

No pharmacopeial/clinical status is provided for this item. It is offered strictly as a research chemical/building block.

General formulation/manufacturing context (no therapeutic claims):

• As a secondary amine scaffold, it can be converted to amide/sulfonamide/carbamate derivatives for lead optimization. The 2,6-difluorobenzyl motif is often introduced to tune lipophilicity and block metabolic hotspots.
• Salt forms (e.g., hydrochloride, mesylate, fumarate) may be prepared to modulate crystallinity, hygroscopicity, and processability during pre-formulation studies.
• Typical characterization for developability: salt screening, pKa determination, logD at physiological pH, polymorph screening (if crystalline derivatives are targeted), and stability under ICH conditions.

Item-specific pharmacopeia listing, excipient role, or GMP suitability: Not specified for this item; refer to CoA/Spec Sheet if GMP or regulatory compliance is required.

Physical Properties

Item-specific specifications (BP, MP, density, UV cutoff, water/peroxide/metal content): Not specified for this item; refer to CoA/Spec Sheet.

Literature/computed values and expectations (for reference only):

• Molecular weight: ~212.26 g/mol (from C12H16F2N)
• Basicity: secondary amine; pKaH (conjugate acid) typically ~10.5–11.5 for piperidines (literature, compound-class expectation)
• LogP: expected moderate (benzylic aryl + difluoro increases lipophilicity), but no verified value available
• Solubility: generally miscible with common organic solvents (EtOAc, DCM, MeOH, THF, acetonitrile). Free base has limited water solubility; protonated salts (e.g., HCl) are water-soluble (general amine behavior)
• Volatility: low-to-moderate; amine odor possible (class behavior)

General notes (chemistry knowledge):

• The aryl C–F bonds increase thermal stability and reduce aromatic oxidation relative to non-fluorinated benzyl analogs.
• The benzylic CH2 remains reactive toward radical halogenation/oxidation. Secondary amine enables salt formation and derivatization (acylation, sulfonylation, carbamoylation).

Always verify any property critical to your process on the item’s CoA/SDS; do not rely on literature ranges for specification-critical decisions.

Quality and Grades

• Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet for assay, impurity profile, and residual solvent limits.
• Appearance: Not specified for this item; refer to CoA/Spec Sheet.
• Shipped in: Not specified for this item; refer to CoA/Spec Sheet.

Interpreting typical grades (general guidance):

• Research grade/building block: suitable for organic synthesis, medicinal chemistry, and method development; not intended for clinical/diagnostic use.
• If HPLC/LC-MS suitability is important, look for low non-volatile residue and low UV background; verify on CoA.

Stabilizers/additives: Not specified for this item. Secondary amines generally do not require stabilizers; however, some suppliers may offer salts (e.g., HCl) to improve handling and aqueous solubility—confirm the offered form on labeling/CoA.

Quality control suggestions (practical tips):

• Identity: 1H/13C NMR (diagnostic benzylic CH2 ~3.4–3.7 ppm; piperidine methylenes 1.2–3.0 ppm; aromatic multiplets with F–H coupling), 19F NMR (two equivalent/near-equivalent ortho-F signals), HRMS (M+H+ ~213.1, literature expectation), and IR (N–H stretch ~3300 cm−1 if free base).
• Purity: HPLC with UV at 210–254 nm; amine may tail—use amine-compatible mobile phase (e.g., 0.1% DEA) to sharpen peaks.

Reaction and Applications

This difluorobenzylated piperidine is a versatile intermediate for medicinal and agrochemical synthesis. The molecule combines a benzylic handle with a basic secondary amine, enabling orthogonal diversification.

Representative application areas (literature/general):

• N-Derivatization: rapid formation of amides, sulfonamides, carbamates, and ureas using acid chlorides/anhydrides, sulfonyl chlorides, chloroformates, or isocyanates. Use non-nucleophilic bases (DIPEA) to suppress overacylation.
• Benzylic functionalization: radical bromination (NBS, AIBN, hv) to give benzyl bromide for subsequent SN2/SN1 substitutions; oxidation to benzyl alcohol/aldehyde (e.g., SeO2 or TEMPO variants) when compatible.
• Reductive amination: coupling at the amine with aldehydes/ketones to form N-alkylated derivatives (NaBH3CN, NaBH(OAc)3) while the difluorophenyl ring enhances metabolic stability in analogs.
• Protection strategies: Boc/CBz/Fmoc protection of the amine to permit further benzylic manipulations without side reactions at nitrogen.
• Cross-coupling surrogates: though aryl C–F is inert, installing a benzylic leaving group enables subsequent Pd-catalyzed benzyl cross-couplings (e.g., benzyl–Suzuki under specialized conditions).

Practical tips:

• Free-base vs. salt: conduct base-sensitive steps on the free base; isolate as HCl salt for storage or purification if oiling-out occurs.
• Control amine basicity during electrophilic aromatics: protonate the amine to avoid undesired N-oxidation or N-acylation when targeting benzylic chemistry.
• Analytical tracking: 19F NMR provides a sensitive handle to monitor difluorophenyl integrity.

Reaction Conditions

General, literature-style guidance for common transformations of 4-[(2,6-difluorophenyl)methyl]piperidine (verify on small scale):

• N-Acylation/Sulfonylation:

  • Solvent: DCM, THF, or MeCN.
  • Base: DIPEA or NEt3 (2–3 equiv).
  • Temperature: 0 °C to rt; 1–4 h typical.
  • Workup: aqueous quench; convert to salt (HCl in IPA/Et2O) for isolation if oily.

• Carbamate/Urea formation:

  • Reagents: chloroformates or CDI + alcohol/amine partners.
  • Solvent: THF/MeCN; 0 °C to rt; 2–12 h.

• Reductive amination (N-alkylation):

  • Solvent: MeOH/EtOH or MeCN.
  • Conditions: aldehyde/ketone (1.1–1.5 equiv), NaBH3CN or NaBH(OAc)3, acetic acid catalytic.
  • Temperature: 0 °C to rt; 2–18 h.

• Benzylic bromination (for diversification):

  • Reagents: NBS (1.1–1.2 equiv), AIBN (cat.).
  • Solvent: MeCN or toluene; hv or 80–90 °C; monitor closely to avoid overbromination.

• Oxidation to benzyl alcohol/aldehyde:

  • Options: TEMPO/bleach or MnO2 (heterogeneous); choose conditions tolerant of secondary amines (protect N if necessary).

• Purification:

  • Amine tailing on silica is common—use 1–2% TEA in eluent, or isolate as crystalline salts.

All parameters above are general literature guidance for amine/benzylic chemistry; specific optimization is required for each substrate and scale.

Safety and Handling

Hazard details specific to this catalog item (GHS classification, pictograms, H-statements): Not specified for this item; refer to the product SDS for authoritative information.

General safety information for secondary aliphatic amines (chemistry knowledge):

• Likely hazards: skin/eye irritation, respiratory irritation; may be harmful if swallowed. Amines can be corrosive to some plastics and may have a strong amine odor.
• Incompatibilities: strong acids (violent neutralization/heat), acylating/alkylating agents (reactive), oxidizers, acid halides/anhydrides, isocyanates, nitrosating agents (risk of N-nitrosamine formation under nitrosating conditions).
• Peroxide formation: not a concern for this substrate (non-ether). Avoid amine nitrosation conditions.

PPE and handling:

• Use in a fume hood. Wear lab coat, nitrile gloves, splash goggles. For larger-scale handling, consider face shield and thicker gloves.
• Avoid inhalation of vapors/aerosols; keep containers tightly closed.

First aid (overview; defer to SDS):

• Inhalation: move to fresh air; seek medical attention if symptoms persist.
• Skin/eye contact: rinse with water for ≥15 minutes; remove contaminated clothing; obtain medical advice.
• Ingestion: rinse mouth; do not induce vomiting; seek medical attention.

Storage conditions (from Product Data):

• Store at room temperature. Keep dry, away from oxidizers and acids. Use amber or well-closed container to minimize volatilization and contamination.

Solvent Selection

Not a solvent; this product is a basic, heteroaromatic building block. However, solvent choice impacts handling, reactions, and analytics involving this compound.

• Polarity/solubility (general expectations):
  • Freely soluble in DCM, chloroform, THF, EtOAc, acetone, acetonitrile, and alcohols; sparingly soluble in water as free base; water-soluble as acid salts (e.g., HCl, TsOH).
• Selection by application:
  • N-acylation/sulfonylation: DCM or THF with base (NEt3, DIPEA) for clean conversions.
  • Carbamate/urea formation: THF, MeCN, or DMF; control temperature to manage exotherms.
  • Benzylic functionalization (e.g., NBS bromination): CCl4/toluene/MeCN variants or greener alternatives (MeCN/EtOAc) under radical initiation.
  • Reductive amination (derivatizing the amine): MeOH/EtOH/IPA or MeCN, depending on substrate compatibility.
• Workup considerations:
  • Convert to an HCl salt in situ to assist aqueous workup and improve phase separation; then basify to recover free base if needed.
• Analytical solvents:
  • For LC, add 0.05–0.1% DEA or ammonium formate to reduce amine tailing. For MS, use volatile buffers (ammonium acetate/formate) in MeCN/H2O.

Comparison note:

• Versus tertiary amines, secondary amines like this can hydrogen-bond more strongly, affecting chromatographic retention; choose solvents/modifiers accordingly.

Storage and Reconstitution

• Storage (from Product Data): Store at room temperature. Keep container tightly closed in a dry, well-ventilated place; protect from strong acids and oxidizers.
• Shipping: Not specified for this item; refer to CoA/Spec Sheet.
• Form: Not specified for this item (free base vs. salt not indicated); check label/CoA.

Reconstitution/preparation (general guidance):

• For reaction use: weigh quickly to minimize atmospheric moisture/CO2 uptake into amine salts. If oiling, convert to an acid salt (e.g., HCl) for easier handling.
• Stock solutions: prepare at 10–100 mM in dry DMSO, MeCN, THF, or EtOH. Filter through 0.2 μm PTFE if particulate is present.
• Stability: secondary amines are typically stable under ambient conditions; avoid prolonged exposure to air/light with reactive reagents. If long-term storage is planned, consider storing the solid or salt form in amber glass with desiccant.

Disposal: Follow institutional and local regulations for organic amine waste; segregate from oxidizers and halogenated oxidants.

For specification-critical details (assay, water content, residual solvents), consult the item’s CoA/Spec Sheet and SDS.

Structure and Identity

A benzylated piperidine bearing a 2,6-difluorophenyl substituent at the benzylic position; secondary amine within a saturated six‑membered ring (piperidine) and a difluorinated aromatic ring.

• Product name: 4-[(2,6-Difluorophenyl)methyl]piperidine
• CAS: 253450-33-8 (literature)
• PubChem CID: 10848119 (provided)
• InChIKey: 211471 (as provided; appears non-canonical placeholder — refer to PubChem for canonical InChIKey)
• SMILES: N1CCC(CC1)Cc2c(F)cccc2F (literature)
• Molecular formula: C12H16F2N (literature)
• Molecular weight: ~212.26 g/mol (literature, calculated from formula)

Structural features (descriptive):

• One saturated heterocycle (piperidine; secondary aliphatic amine at position 1).
• Benzylic methylene linker connecting the ring C-4 of piperidine to an ortho,ortho-difluorophenyl ring (2,6‑difluoro pattern).
• Functional groups: secondary amine (basic), benzylic CH2 (activated), aryl C–F bonds (strongly deactivating, non-labile under mild conditions).
• No stereocenters; overall achiral.

2D depiction in words: a chair-like piperidine ring with the nitrogen at one vertex; at the carbon opposite the nitrogen (C-4) extends a –CH2– substituent terminating in a phenyl ring that carries fluorine atoms at the two positions ortho to the benzylic carbon.

Synthetic Utility

Key reactive elements:

• Secondary aliphatic amine (nucleophilic/basic): amenable to acylation, sulfonylation, carbamoylation, urea formation, and N-alkylation (via reductive amination or alkyl halides under appropriate conditions).
• Benzylic methylene: activated toward radical halogenation, oxidation, and conversion to benzyl electrophiles for downstream substitution or cross-coupling variants.
• Aryl C–F bonds: robust metabolic blocking groups; typically inert under SNAr unless additional activating groups are present (here, 2,6-difluoro alone is not strongly activating), enabling selective transformations elsewhere in the molecule.

Retrosynthetic utility:

• Disconnection at the benzylic position provides access from 2,6-difluorobenzyl halides and 4-substituted piperidines (or via alkylation of piperidine followed by positional functionalization).
• N-protection (Boc/CBz) allows orthogonal manipulation at the benzylic carbon without competitive N-acylation.

Analytical handles:

• 19F NMR for rapid integrity checks; HRMS to confirm exact mass; chiral analysis not required (achiral).

Downstream diversification examples (literature/general):

• Amide libraries via acid chlorides or HATU/EDC couplings.
• Sulfonamide panels (RSO2Cl, pyridine or DIPEA base).
• Benzylic bromide → substitution with N/O/S/C nucleophiles; or Pd-catalyzed benzyl couplings under suitable conditions.

Target Specificity

Not applicable. This product is a small-molecule building block and is not an antibody, enzyme, or biologic with a defined molecular target profile. No antigen/epitope, species reactivity, clone, or isotype information applies.