1-[3-Nitro-5-(trifluoromethyl)phenyl]ethanone
[CAS# 39174-87-3]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Ketones
• Name: 1-[3-Nitro-5-(trifluoromethyl)phenyl]ethanone
• Molecular Formula: C₉H₆F₃NO₃
• Molecular Weight: 233.14
• CAS Registry Number: 39174-87-3
• SMILES: CC(=O)C1=CC(=CC(=C1)[N+](=O)[O-])C(F)(F)F

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 217.9±35.0 ºC 760 mmHg (Calc.)^*
• Flash point: 85.6±25.9 ºC (Calc.)^*
• Index of refraction: 1.487 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P271-P280-P302-P304-P305-P313-P332-P337-P338-P340-P351-P352

Discovory and Applicatios

The chemical substance 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone, also known as 3-nitro-5-(trifluoromethyl)acetophenone, is a substituted acetophenone derivative bearing nitro and trifluoromethyl groups on an aromatic ring. It is widely recognized in organic chemistry as a key intermediate, particularly in pharmaceutical and agrochemical synthesis. Its discovery and applications are well-documented in the literature, rooted in the development of functionalized aromatic compounds and fluorinated chemistry.

The origins of this compound are linked to the study of substituted acetophenones, which have been explored since the 19th century for their reactivity and utility in organic synthesis. The trifluoromethyl group gained prominence in the mid-20th century for its ability to enhance metabolic stability and lipophilicity in drug molecules, driven by advances in fluorination techniques. Nitro groups, valued for their electron-withdrawing properties and versatility in reduction to amines, have been similarly utilized. The specific placement of nitro and trifluoromethyl groups at the 3- and 5-positions of an acetophenone core emerged in the late 20th century, fueled by the pharmaceutical industry’s demand for electron-deficient aromatic intermediates. Advances in regioselective nitration and trifluoromethylation during the 1960s and 1970s enabled the precise synthesis of such compounds.

Synthetically, 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone is typically prepared through a multi-step process. A common route starts with 3-(trifluoromethyl)acetophenone, where the trifluoromethyl group is introduced via trifluoromethylation of a suitable precursor or sourced commercially. The nitro group is then installed at the 3-position through electrophilic aromatic nitration using nitric acid or a nitronium salt under controlled conditions to ensure regioselectivity. Alternatively, the synthesis may begin with 3-nitro-5-(trifluoromethyl)benzoic acid, which is converted to the corresponding Weinreb amide and reacted with a methyl Grignard reagent to form the acetophenone. These methods rely on well-established aromatic substitution and ketone synthesis protocols, ensuring high yields and purity.

The primary application of 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone is as a synthetic intermediate in pharmaceutical chemistry. The acetyl group serves as a versatile handle for transformations, such as reductive amination to form chiral amines, aldol condensations, or heterocycle formation, while the nitro and trifluoromethyl groups enhance the electronic and pharmacokinetic properties of resulting molecules. The nitro group can be reduced to an aniline, enabling further functionalization, and the trifluoromethyl group improves metabolic stability and lipophilicity. This compound is frequently used in the synthesis of drug candidates, including kinase inhibitors, receptor modulators, and antimicrobial agents, where the electron-deficient aromatic ring optimizes binding to biological targets.

In addition to pharmaceuticals, the compound is employed in agrochemical synthesis, particularly for developing pesticides and herbicides, where fluorinated and nitro-substituted aromatics are valued for their bioactivity and environmental stability. In academic research, it serves as a model compound for studying regioselective aromatic substitution, the electronic effects of nitro and trifluoromethyl groups, and ketone reactivity. Its synthesis has contributed to the refinement of trifluoromethylation and nitration techniques.

The significance of 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone lies in its role as a multifunctional intermediate that combines the reactivity of an acetophenone with the advantageous properties of nitro and trifluoromethyl substituents. Its development reflects progress in regioselective functionalization and fluorinated aromatic chemistry. By enabling the efficient synthesis of complex, biologically active molecules, it has become a critical tool in advancing pharmaceutical, agrochemical, and chemical research.