Methyl 4,4,4-trifluoroacetoacetate
[CAS# 83643-84-9]

Identification

• Classification: Organic raw materials >> Carboxylic compounds and derivatives >> Carboxylic esters and their derivatives
• Name: Methyl 4,4,4-trifluoroacetoacetate
• Synonyms: Methyl 4,4,4-trifluoro-3-oxobutanoate; Methyl 4,4,4-trifluoroacetylacetonate
• Molecular Formula: C₅H₅F₃O₃
• Molecular Weight: 170.09
• CAS Registry Number: 83643-84-9
• EC Number: 672-601-1
• SMILES: COC(=O)CC(=O)C(F)(F)F

Properties

• Density: 1.3±0.1 g/cm³ Calc.^*, 1.34 g/mL (Expl.)
• Boiling point: 117.4±35.0 °C 760 mmHg (Calc.)^*, 117 - 118 °C (Expl.)
• Flash point: 25.1±20.8 °C (Calc.)^*, 40 °C (Expl.)
• Index of refraction: 1.349 (Calc.)^*, 1.372 (Expl.)

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

Safety Data

• Hazard Symbols: GHS02;GHS07 Warning
• Risk Statements: H226-H302-H315-H319-H335
• Safety Statements: P210-P233-P240-P241-P242-P243-P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P303+P361+P353-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P337+P317-P362+P364-P370+P378-P403+P233-P403+P235-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Flammable liquids	Flam. Liq.	3	H226
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335

Discovery and Applications

Methyl 4,4,4-trifluoroacetoacetate is a fluorinated β-ketoester with the molecular formula CF₃COCH₂COOCH₃. It is the methyl ester derivative of 4,4,4-trifluoroacetoacetic acid and is part of the class of fluorinated β-ketoesters, which are valued for their reactivity and utility in organic synthesis. The trifluoromethyl group at the 4-position is strongly electron-withdrawing, which increases the acidity of the methylene protons between the carbonyl groups and enhances the electrophilicity of the ketone carbonyl, making the compound a versatile building block for chemical transformations. Methyl 4,4,4-trifluoroacetoacetate is typically a colorless liquid and is soluble in organic solvents such as ether, dichloromethane, and alcohols.

The primary application of methyl 4,4,4-trifluoroacetoacetate is as a reagent in the synthesis of fluorinated compounds. Its β-ketoester structure allows it to undergo various condensation reactions, alkylation, Michael additions, and cyclization reactions, enabling the construction of complex molecules with trifluoromethyl groups. The trifluoromethyl group imparts chemical stability, lipophilicity, and electronic effects that are often desirable in pharmaceuticals, agrochemicals, and specialty chemicals.

In pharmaceutical chemistry, methyl 4,4,4-trifluoroacetoacetate is used to introduce trifluoromethylated motifs into drug candidates. The trifluoromethyl group can serve as a bioisostere for methyl or hydroxyl groups, enhancing metabolic stability, membrane permeability, and pharmacokinetic properties. It is used to synthesize heterocyclic scaffolds, fluorinated intermediates, and active pharmaceutical ingredients, particularly in the development of enzyme inhibitors, antiviral agents, and central nervous system drugs.

In agrochemical synthesis, methyl 4,4,4-trifluoroacetoacetate is employed to prepare fluorinated intermediates for herbicides, fungicides, and insecticides. Incorporation of the trifluoromethyl group increases chemical and thermal stability, lipophilicity, and bioactivity, which improves the performance and environmental persistence of agrochemical products. Its reactivity allows for efficient functionalization of precursor molecules and streamlined synthesis of bioactive compounds.

The compound is also used in the synthesis of functional materials and specialty chemicals. Fluorinated β-ketoesters derived from methyl 4,4,4-trifluoroacetoacetate are incorporated into polymers, resins, and coatings to enhance hydrophobicity, thermal stability, and chemical resistance. The reactive β-ketoester functionality allows selective incorporation into complex molecular architectures, contributing to the development of advanced materials.

The discovery and application of methyl 4,4,4-trifluoroacetoacetate highlight its importance as a versatile fluorinated building block. Its combination of electrophilicity, acidity, and chemical stability makes it a valuable intermediate in modern organic synthesis, supporting applications in pharmaceuticals, agrochemicals, and materials science. The compound exemplifies how selective fluorination of β-ketoesters can expand the functional utility of simple ester molecules in research and industrial processes.

References

2021. Domino Multicomponent Intramolecular Cyclization Strategy for the Multi Functionalized Imidazo[1,2-a]pyrimidin-5(1H)-one Derivatives. Russian Journal of General Chemistry, 91(6).
DOI: 10.1134/s1070363221060219

2009. Synthesis of Trifluoromethyl Pyrroles and Their Benzo Analogues. Synthesis, 2009(20).
DOI: 10.1055/s-0029-1217080

1999. Alpha-trifluoromethylated acyloins induce apoptosis in human oral tumor cell lines. Bioorganic & Medicinal Chemistry Letters, 9(20).
DOI: 10.1016/s0960-894x(99)00548-x