4-Carboxybenzaldehyde (CAS 619-66-9)

1、 Product Overview

2、 Basic Product Information

3、4-Carboxybenzaldehyde (CAS 619-66-9) — Q&A & Application Cases

Q1. What are the key quality control indicators, and how do HPLC purity, aldehyde residue, and moisture affect downstream synthesis?
Key QC indicators include:

• HPLC purity — typically ≥98% (industrial grade) or ≥99% (pharma/electronic grade); for pharma/electronic grades, single unspecified impurity is often controlled to ≤0.1% with specified total impurity limits. Related substances such as terephthalic acid (over-oxidation impurity), 4-(hydroxymethyl)benzoic acid (reduction impurity), and unreacted p-toluic acid must be controlled individually.

• Aldehyde content — determined by hydroxylamine hydrochloride titration or GC/HPLC; low aldehyde value indicates oxidation or degradation.

• Moisture (Karl Fischer) — typically ≤0.5%; excess moisture promotes hydrolysis of acid chlorides or anhydrides in downstream steps and interferes with anhydrous condensation reactions.

• Residue on ignition (sulfated ash) / heavy metals — critical for pharma and electronic-grade material.

• Melting point — 247–250 °C (decomp.), a quick identity/purity check.

Impact on downstream synthesis: low HPLC purity introduces competing functional groups; oxidized aldehyde (→ carboxyl) destroys the intended bifunctional reactivity; high moisture degrades moisture-sensitive reagents (e.g., SOCl₂, DCC, organometallics) and reduces yield in Schiff-base or reductive amination steps.

Q2. What are the solubility characteristics, which solvents are commonly used, and which should be avoided?

• Soluble in: DMSO, DMF, DMAc, methanol, ethanol (warm), acetone, THF (moderate), hot water, and dilute aqueous alkali (forms carboxylate salt).

• Slightly soluble in: cold water, diethyl ether, ethyl acetate.

• Practically insoluble in: n-hexane, heptane, toluene, petroleum ether.

Solvents to avoid:

• Primary amines / ammonia — react with the aldehyde to form Schiff bases/imines.

• Strongly basic alcoholic solutions — promote Cannizzaro-type disproportionation.

• Strong reducing media (e.g., LiAlH₄ in excess) — reduce both aldehyde and carboxyl groups.

• Solvents with high water content when the downstream step is anhydrous.

Q3. What is the synthesis/production method, and what precautions should be taken?
Main industrial routes:

• Liquid-phase oxidation of p-tolualdehyde — cobalt/manganese/bromide catalyst system, air/O₂ oxidation; the methyl group is oxidized to carboxyl while the aldehyde is retained.

• Oxidation of p-xylene — partial/selective oxidation to the monoaldehyde-acid; requires careful control to stop at 4-CBA rather than full oxidation to terephthalic acid.

• Hydrolysis of 4-cyanobenzaldehyde — acid or base hydrolysis of the nitrile to carboxyl; suitable for higher-purity small-batch production. (Note: aldehyde group generally requires protection (e.g., acetalization) prior to hydrolysis to prevent side reactions under harsh acidic/basic conditions).

Precautions:

• Control oxidation temperature and oxygen feed to avoid over-oxidation to terephthalic acid (the most common impurity).

• The aldehyde group is thermally sensitive; avoid prolonged high-temperature exposure.

• Use corrosion-resistant reactors (acidic conditions + bromide catalyst).

• Purify by recrystallization from ethanol/water or glacial acetic acid; vacuum drying to remove residual solvent and moisture.

Q4. What degradation occurs during storage, and how can product failure be identified?
Common degradation pathways:

• Aldehyde oxidation → terephthalic acid (exposure to air/oxygen, especially in moist conditions).

• Discoloration — yellowing or browning due to trace metal-catalyzed oxidation or condensation.

• Caking / moisture uptake — hygroscopic behavior in high-humidity environments.

• Cannizzaro reaction — in the presence of strong base, aldehyde disproportionates to alcohol + acid.

Failure indicators:

• Visual: yellow to brown discoloration, caking, or clumping.

• HPLC: emergence/increase of terephthalic acid peak; drop in main peak purity.

• Aldehyde titration: aldehyde value below specification.

• Acid value: elevated beyond the theoretical one carboxyl group (indicates over-oxidation).

• Melting point: deviation or broadening beyond 247–250 °C range.

Storage conditions: cool, dry, well-sealed container, under inert atmosphere (N₂) preferred, away from strong oxidizers, strong bases, and direct sunlight.

Q5. What downstream products can be generated from 4-Carboxybenzaldehyde?

• MOF / COF ligands — bifunctional linker (–COOH + –CHO) for metal-organic frameworks and covalent organic frameworks.

• Pharmaceutical intermediates — e.g., Bavisant (histamine H3 receptor antagonist); aldehyde undergoes reductive amination, carboxyl undergoes amidation/esterification.

• Schiff bases / imines — condensation with primary amines yields chelating ligands and fluorescent probes.

• Polymer monomers — aldehyde group enables condensation polymerization; carboxyl enables polyester/polyamide formation.

• Liquid crystal & fluorescent material intermediates — aromatic core for mesogenic units and optical brighteners.

• Corrosion inhibitors & epoxy curing agents — aldehyde-based condensation products for industrial coatings.

• Enzyme substrates — aromatic aldehyde substrate for transketolase and other biocatalytic studies.

4.Application Cases

1. MOF (Metal-Organic Framework) Ligand
4-Carboxybenzaldehyde serves as a bifunctional linker in NUIG4-series MOFs. The carboxyl group coordinates to metal nodes while the aldehyde group provides post-synthetic modification sites. The resulting MOFs are used for doxorubicin loading and pH-responsive controlled release in drug delivery research.

2. Pharmaceutical Intermediate Synthesis
Used as an aromatic building block in the synthesis of Bavisant (a histamine H3 receptor antagonist) and other drug candidates. The aldehyde group undergoes reductive amination to form amine linkages, while the carboxyl group is converted to amides or esters, constructing the drug’s core molecular structure.

3. pH-Responsive Hydrogel Preparation
4-CBA is used to modify polyvinyl alcohol (PVA) and other polymers. The aldehyde group reacts with hydroxyl or amine groups on the polymer chain to form dynamic covalent bonds (acetal/imine), producing hydrogels that respond to the acidic tumor microenvironment. These hydrogels can load anticancer drugs or serve as wound-dressing materials.

4. Enzyme Engineering Substrate
Used as an aromatic aldehyde substrate for transketolase mutants in directed evolution screening. By evaluating the enzyme’s activity and stereoselectivity toward 4-CBA, researchers develop asymmetric synthesis processes for chiral α,α-dihydroxy ketones, supporting green biocatalytic manufacturing.

5. Liquid Crystal & Fluorescent Brightener Intermediate
The aldehyde group participates in Knoevenagel or Schiff-base condensation to synthesize functional aromatic monomers. These monomers are incorporated into liquid crystal molecules and fluorescent brightener structures, finding small-batch use in optoelectronic materials and textile brightening agents.

5、Packaging, Storage and Transportation Requirements

6、 Product Manager Information

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