Trifluoroacetamide
[CAS# 354-38-1]

Identification

• Classification: Chemical reagent >> Organic reagent >> Acid halide
• Name: Trifluoroacetamide
• Synonyms: 2,2,2-Trifluoroacetamide
• Molecular Formula: C₂H₂F₃NO
• Molecular Weight: 113.04
• CAS Registry Number: 354-38-1
• EC Number: 206-559-9
• SMILES: C(=O)(C(F)(F)F)N

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Melting point: 65 - 70 °C (Expl.)
• Boiling point: 162.5±35.0 °C 760 mmHg (Calc.)^*, 162.5 °C (Expl.)
• Flash point: 52.1±25.9 °C (Calc.)^*
• Solubility: water 460 g/L (20 °C) (Expl.)
• Index of refraction: 1.314 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	4	H302
Acute toxicity	Acute Tox.	3	H301
Eye irritation	Eye Irrit.	2A	H319

Discovery and Applications

Trifluoroacetamide is a simple organofluorine compound characterized by the presence of a trifluoromethyl group attached to an amide functional group, with the molecular formula CF₃CONH₂. Its discovery is linked to early studies in organofluorine chemistry in the mid-20th century, when chemists explored the effects of trifluoromethyl substitution on the reactivity, stability, and physical properties of amides and other functional groups. The electron-withdrawing trifluoromethyl group increases the electrophilicity of the carbonyl carbon and stabilizes the molecule, making trifluoroacetamide more resistant to hydrolysis and oxidative degradation compared with non-fluorinated acetamides. These properties make it a versatile intermediate in synthetic chemistry.

Trifluoroacetamide is primarily used as a building block in organic synthesis. It serves as a precursor for the introduction of the trifluoroacetyl group into organic molecules, which is valuable in both medicinal and agrochemical chemistry. The trifluoroacetyl group is known to enhance the metabolic stability, lipophilicity, and biological activity of target compounds, and trifluoroacetamide provides a convenient source for its incorporation. Reactions involving trifluoroacetamide include acylation, condensation, and nucleophilic substitution, which allow the synthesis of a variety of trifluoromethylated derivatives.

In pharmaceutical research, trifluoroacetamide is often used in the design and synthesis of drug candidates. Trifluoromethylated amides are recognized for their influence on the pharmacokinetic properties of compounds, improving absorption, distribution, and resistance to metabolic degradation. Trifluoroacetamide can be employed to prepare intermediates for small-molecule therapeutics, where the trifluoromethyl group enhances the chemical and metabolic stability of the active compounds. Its use is particularly common in medicinal chemistry programs focused on central nervous system agents, anti-inflammatory drugs, and enzyme inhibitors.

Beyond medicinal applications, trifluoroacetamide finds use in agrochemical synthesis. Fluorinated amides can serve as intermediates in the preparation of herbicides, fungicides, and insecticides, where the trifluoromethyl group provides both increased environmental stability and improved biological activity. Its chemical stability and solubility in polar organic solvents make it suitable for a range of synthetic procedures in these contexts.

Trifluoroacetamide has also been applied in materials science as a reagent in the synthesis of specialty polymers and fluorinated fine chemicals. The trifluoromethyl group contributes to the thermal stability, chemical resistance, and hydrophobicity of resulting materials, making it useful in the development of coatings, membranes, and other high-performance products. In analytical chemistry, trifluoroacetamide is sometimes used as a derivatizing agent in gas chromatography and mass spectrometry to improve the volatility and detectability of analytes containing polar functional groups.

The discovery and continued use of trifluoroacetamide highlight the importance of trifluoromethylated amides in modern chemistry. Its combination of chemical stability, reactivity, and the influence of the trifluoromethyl group has made it a valuable intermediate for synthesis in pharmaceuticals, agrochemicals, and specialty materials, supporting advances in both research and industrial applications.

References

2025. Novel Triazole Functionalized Quinazolinone Derivatives, Their Anticancer Activity, and Docking Interactions. Russian Journal of General Chemistry, 95(4).
DOI: 10.1134/s1070363224612729

2024. Crystallization of Aminium Salts and Amides of Trifluoroacetic Acid. Molecular Structure of Ethylenediamine N,N'-Bis(trifluoroacetyl). Crystallography Reports, 69(12).
DOI: 10.1134/s1063774524601692

2024. Supramolecular deep eutectic solvents in extraction processes: a review. Environmental Chemistry Letters, 22(11).
DOI: 10.1007/s10311-024-01795-3