Introduction

4-Fluorobenzaldehyde, CAS 459-57-4, is a fluorinated aromatic aldehyde known for its versatility in chemical synthesis and industrial applications. Its structure includes a benzene ring substituted with a fluorine atom at the para position and an aldehyde group, making it an intermediate in the synthesis of fine chemicals, pharmaceuticals, and advanced materials. The incorporation of a fluorine atom into organic molecules imparts beneficial properties such as increased metabolic stability, increased lipophilicity, and improved binding capacity in biological systems. It is also involved in the development of advanced materials such as liquid crystals and high-performance polymers.

The reactivity of this compound is generated by the interaction between the electron-withdrawing fluorine atom and the electrophilic aldehyde group. This functionality allows 4-fluorobenzaldehyde to participate in a variety of chemical reactions including reduction, oxidation, aldol condensation, and Henry reaction. These reactions are used to build complex molecular structures and create new compounds for specific applications.

Physical and Chemical Properties of 4-Fluorobenzaldehyde

4-Fluorobenzaldehyde (C₇H₅FO) CAS 459-57-4 is a fluorinated aromatic aldehyde characterized by a benzene ring substituted with a fluorine atom in the para- position and an aldehyde group. Its molecular weight is 124.11 g/mol, and its appearance is typically as a colorless to pale yellow liquid with a faint, aromatic odor. The compound has a boiling point 181°C and a melting point −10°C. Its density at 25°C is 1.157 g/ml. This compound is immiscible with water but shows good miscibility with organic solvents such as chloroform, ethanol, ether and acetone.

Chemically, 4-fluorobenzaldehyde exhibits typical aldehyde reactivity, including nucleophilic addition and oxidation reactions. The electron-withdrawing effect of the fluorine atom deactivates the aromatic ring toward electrophilic aromatic substitution, directing further substitutions to meta positions relative to the aldehyde group.

4-Fluoroamphetamine (4-FA): What We Know

Synthesis of 4-Fluorobenzaldehyde

There are several methods for 4-fluorobenzaldehyde CAS 459-57-4 synthesis. Each of them uses specific reaction pathways to introduce both aldehyde and fluorine functionalities.

One of the classical methods for synthesizing 4-fluorobenzaldehyde involves a heating a mixture of 4-fluorobenzene and a strong Lewis acid in a carbon monoxide atmosphere at 100°C and 1 MPa. A reaction mass containing a complex of the Lewis acid and 4-fluorobenzaldehyde is formed, this complex is destroyed by quenching with a Lewis acid solvating liquid such as water to release 4-fluorobenzaldehyde.

Another popular synthetic route to 4-fluorobenzaldehyde is the reaction of 4-chlorobenzaldehyde, potassium fluoride, nitrobenzene, and tetrakis(diethylamino)phosphonium bromide (TDPB). The mixture is heated with constant stirring to 190°C and left to react for 20 hours.

Each of these synthetic routes leads to 4-fluorobenzaldehyde, with the choice of method depending on factors such as availability of starting materials, desired scale, and environmental considerations.

Chemical Reactions of 4-Fluorobenzaldehyde

4-Fluorobenzaldehyde, CAS 459-57-4, is a valuable intermediate in organic synthesis. The presence of both an electron-withdrawing fluorine atom and an aldehyde group influences its reactivity, allowing it to participate in a variety of reactions.

4-Fluorobenzaldehyde can undergo oxidation to form 4-fluorobenzoic acid. This conversion is typically achieved with oxidizing agents such as potassium permanganate (KMnO₄) or chromium trioxide (CrO₃). For example, treatment of 4-fluorobenzaldehyde with potassium permanganate under aqueous conditions yields 4-fluorobenzoic acid.

Reduction of 4-fluorobenzaldehyde typically targets the aldehyde group to form 4-fluorobenzyl alcohol. Sodium borohydride (NaBH₄) is a common reducing agent for this purpose, providing mild conditions and high selectivity. For example, reaction with sodium borohydride in methanol gives 4-fluorobenzyl alcohol.

4-Fluorobenzaldehyde is a candidate for aldol condensation reactions. When it’s reacted with acetone in the presence of a base such as sodium hydroxide, it forms α,β-unsaturated carbonyl compounds such as 4-(4-fluorophenyl)-3-buten-2-one, which can then be used to prepare an analogue of DBA (1,5-bis(4-fluorophenyl)-1,4-pentadien-3-one).

4-Fluorobenzaldehyde undergoes a Henry reaction with nitroethane, isopropanol, and n-butylamine upon heating for 5 h to give 4-fluorophenyl-2-nitropropene. This reaction is used as an intermediate for the preparation of 4-fluoroamphetamine.

4-Fluoramphetamine has been prepared by reacting lithium aluminium hydride in tetrahydrofuran(THF) with 4-fluorophenyl-2-nitropropene. The mixture is stirred at room temperature for 4 h, then the hydride excess is decomposed by a water addition. The hydrochloride salt can be prepared by dissolving the free base in petroleum ether and bubling through a dry HCl gas until no more crystals form.

Applications of 4-Fluorobenzaldehyde

4-Fluorobenzaldehyde, CAS 459-57-4 is a compound with a wide range of applications in pharmaceuticals, agrochemistry, materials science, and organic synthesis.

Pharmaceutical Applications

4-Fluorobenzaldehyde serves as an important building block in the synthesis of many biologically active molecules. It is commonly used in the preparation of fluorinated benzylamines, which are key intermediates in the development of anti-inflammatory, antifungal, and antitumor agents. For example, it is used in the synthesis of fluoroaromatic drugs such as UR-13756, where the substitution of fluorine enhances the pharmacokinetic properties and target specificity of the molecule.

Agrochemical Applications

In the agrochemical sector, 4-fluorobenzaldehyde is used as a precursor for the synthesis of fluorinated pesticides and herbicides. The strong electronegativity of the fluorine atom increases the metabolic stability of these compounds, providing long-term activity against pests and weeds. For example, the synthesis of fluorinated phenoxyacetic acids, which are used as herbicides in agricultural practice.

Materials Science and Industrial Applications

4-Fluorobenzaldehyde is used in materials science to obtain advanced polymers and coatings. Fluorinated aromatic aldehydes are part of the production of resins and films that demonstrate chemical resistance and thermal stability. For example, 4-fluorobenzaldehyde is used in the production of fluorinated polyimides and liquid crystal materials, which are necessary in electronic and display technologies.

Health Effects of 4-Fluorobenzaldehyde

4-Fluorobenzaldehyde, CAS 459-57-4 is classified as a hazardous substance due to its potential to cause irritation and other adverse health effects. Exposure can occur through inhalation, skin contact, or accidental ingestion. Inhalation of vapors or aerosols can lead to respiratory irritation, characterized by symptoms such as coughing, throat irritation, and shortness of breath. Long-term or severe exposure can lead to more severe respiratory distress.

Direct contact with skin or eyes may cause irritation, redness, or burning. Its aldehyde group makes it particularly reactive, posing a risk of sensitization or allergic reactions in some individuals. Accidental ingestion may result in gastrointestinal discomfort, nausea, or vomiting, and requires immediate medical attention. Although data on its long-term toxicological effects are limited, it is recommended to consider it as potentially hazardous upon repeated or prolonged exposure.

Safety Precautions

Handling 4-fluorobenzaldehyde, CAS 459-57-4 requires safety precautions. The use of appropriate personal protective equipment (PPE) is critical when handling 4-fluorobenzaldehyde. Personnel should wear lab coats, safety googles, and gloves made of chemical-resistant materials such as nitrile. Adequate ventilation must be provided to reduce the risk of inhalation. Fume hoods should be used for all handling of 4-fluorobenzaldehyde.

Handling Procedures

Care should be taken to avoid skin contact, inhalation, or ingestion of 4-fluorobenzaldehyde.

In case of accidental exposure, it is extremely important to take immediate action:

• Skin contact: Wash the affected area with soap and water for at least 15 minutes. Remove contaminated clothing and seek medical attention if irritation persists.
• Eye contact: Flush eyes with plenty of water for 15 minutes, keeping eyelids open. Seek medical attention.
• Inhalation: Remove victim to fresh air and administer oxygen if breathing is difficult. Seek immediate medical attention.
• Ingestion: Do not induce vomiting. Rinse mouth with water and seek immediate medical attention.

Storage

4-Fluorobenzaldehyde should be stored in tightly closed containers in a cool, dry and well-ventilated place. Keep away from incompatible materials such as strong oxidizing agents and bases.

Conclusion

4-Fluorobenzaldehyde, CAS 459-57-4 is a compound valued for its combination of physical and chemical properties. Its dual functionality, arising from the aldehyde group and fluorine substitution, underlies its usefulness in a wide range of applications. Incorporation of fluorine into molecular structures often improves desirable properties such as stability, reactivity, and biological activity.

Bibliography

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