4-Methoxybenzylamine
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Product Description
4-Methoxybenzylamine (PMB-NH₂) is a valuable compound in organic synthesis, primarily used for its derivatization into a p-methoxybenzyl (PMB) protecting group, which selectively protects functional groups in alcohols, carboxylic acids, or amines. Compared to ordinary benzyl groups, the electronic effect of the methoxy group in the PMB protecting group allows for specific deprotection under mild conditions, especially when using oxidizing agents such as DDQ. This enables orthogonal selective deprotection compared to ordinary benzyl groups, playing a crucial role in the synthesis of complex multi-step molecules, such as the drug avanafil, natural products, and carbohydrates. This compound is a colorless to pale yellow liquid, corrosive, flammable, and highly irritating to skin and eyes; strict protective measures must be taken during handling in a fume hood.
Synthesis and Production
Synthesis Methods
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Reductive Amination (Most Common):
Reaction of 4-methoxybenzaldehyde with ammonia or ammonium salts to form an imine, followed by catalytic hydrogenation (Pd/C or Pd nanoparticles, 1–3 hours at room temperature, atmospheric pressure) in good yield. -
Nitrile Reduction:
4-Methoxybenzonitrile reduced with H₃N·BH₃ or NaBH₄/CoCl₂ systems in THF using Mo- or Ni-based catalysts (≈8 hours at room temperature). Suitable for substrates sensitive to aldehydes. -
Selective Hydrogenolysis:
Direct amination of 4-methoxybenzyl alcohol or the corresponding benzyl chloride with ammonia/ammonium salts in the presence of Pd/C.
Production Scale
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Laboratory synthesis: Widely used as a versatile intermediate in organic synthesis.
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Industrial production: Commercially available from multiple chemical suppliers in various purity grades (e.g., >97% GC).
Uses and Applications
Main Applications
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Organic Synthesis & Pharmaceutical Intermediates
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Protecting group precursor: Derivative para-methoxybenzyl (PMB) group used for reversible, selective protection of carboxylic acids, alcohols, amines, etc., especially crucial in the synthesis of complex natural products, peptides, nucleosides, and macrolide drugs.
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Key intermediate:
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Synthesis of the side chain for PDE‑5 inhibitor Avanafil.
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Building block for inosine analogs, complex purine derivatives, and other bioactive molecules.
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Multicomponent reactions: Participates in Ugi reactions, aza‑Michael additions, reductive aminations, etc., for constructing nitrogen‑containing compound libraries.
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Agrochemicals & Dyes
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Structural moiety in herbicides and fungicides to enhance lipophilicity or photostability.
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Intermediate for azo dyes and functional dyes.
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Materials & Industrial Chemicals
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Ligand & catalyst synthesis: Preparation of Schiff‑base ligands for coordination chemistry and catalysis.
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Specialty chemicals: Used as a basic additive or intermediate in electronic chemicals, specialty inks, textile auxiliaries, and corrosion inhibitors.
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Application Features
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Orthogonal protection strategy: PMB can be selectively removed with oxidants (e.g., DDQ, CAN) while leaving ordinary benzyl groups intact.
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Versatile building block: Combines aromatic and aliphatic amine reactivity, easily derivatized.
Chemical and Physical Properties
Physical Properties
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Appearance: Colorless to pale‑yellow clear liquid at room temperature (may darken on storage); can also be a low‑melting solid (m.p. ≈ 30–35 °C).
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Odor: Amine‑like (ammoniacal, fishy).
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Boiling point: 236–250 °C (at atmospheric pressure).
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Density: ≈1.05 g/mL at 25 °C.
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Refractive index: n²⁰/D ≈ 1.546.
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Solubility:
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Good solubility: Water, methanol, ethanol, acetone, diethyl ether, dichloromethane, chloroform, and most organic solvents.
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LogP: ≈0.8–1.15 (predicted), indicating moderate lipophilicity.
Chemical Properties
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Basicity: Aromatic primary amine; pKa (conjugate acid) ≈ 9.3, weak‑to‑moderate base.
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Reactivity:
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Nucleophilic reactions: Undergoes acylation (amide formation), alkylation, Schiff‑base (imine) formation with aldehydes/ketones.
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Salt formation: With inorganic or organic acids.
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Aromatic substitution: Methoxy group is electron‑donating, enhancing electrophilic substitution on the aromatic ring.
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Stability: Air‑ and light‑sensitive; prone to oxidation/discoloration; should be stored under inert atmosphere.
Spectroscopic Data
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Molecular formula: C₈H₁₁NO
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Molecular weight: 137.18 g/mol
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Hydrogen‑bond donors: 1
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Hydrogen‑bond acceptors: 2
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Rotatable bonds: 2
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Topological polar surface area: 35.3 Ų
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Mass spectrometry: GC‑MS main peaks m/z 136 (base), 137, 106, 121.
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NMR: ¹H and ¹³C NMR data available.
Safety and Handling
Hazard Identification
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Corrosive: Causes severe skin burns, eye damage, and corrosive injury to the respiratory tract.
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Toxicity: Harmful if swallowed; inhalation may cause toxic pneumonitis.
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Flammability: Combustible liquid.
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Environmental hazard: WGK Germany rating 3 (high water hazard).
Safe Handling Requirements
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Personal protective equipment (PPE): Wear chemical‑resistant gloves, safety goggles, face shield, and lab coat.
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Ventilation: Use only in a fume hood or well‑ventilated area.
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Incompatibilities: Keep away from strong oxidizers.
First Aid Measures
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Skin contact: Immediately remove contaminated clothing, wash thoroughly with plenty of water for at least 15 minutes, seek medical attention.
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Eye contact: Rinse immediately with flowing water for at least 15 minutes, seek medical attention.
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Inhalation: Move to fresh air; if breathing is difficult, administer oxygen; seek medical attention.
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Ingestion: Do NOT induce vomiting; seek immediate medical attention and bring the Safety Data Sheet (SDS).
Storage and Transport
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Storage conditions: Tightly sealed, protected from light, store at 2–8 °C preferably under inert gas (e.g., nitrogen).
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Transport classification:
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UN number: UN 2735
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Hazard class: 8 (Corrosive substances), Packing group II
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Shelf life: Air‑sensitive; use promptly after opening.