2-Amino-4-fluorobenzonitrile: Properties, Synthesis & Applications
2-Amino-4-fluorobenzonitrile: Properties, Synthesis & Applications
2-Amino-4-fluorobenzonitrile is a difunctionally substituted fluorinated aromatic building block widely employed in pharmaceutical, agrochemical, and materials research as a versatile synthetic intermediate.
- IUPAC Name
- 2-amino-4-fluorobenzonitrile
- CAS Number
- 57948-95-5
- Molecular Formula
- C7H5FN2
- Molecular Weight
- 136.12 g/mol
- Key Functional Groups
- Primary amine (–NH2), nitrile (–CN), aryl fluoride (Ar–F)
- Typical Appearance
- Off-white to pale yellow crystalline solid
- SKU (Aladdin Scientific)
- A186701
Chemical Properties and Structure
2-Amino-4-fluorobenzonitrile (CAS 57948-95-5) is a benzene ring bearing three distinct substituents: an amino group (–NH2) at the 2-position (ortho), a fluorine atom at the 4-position (para), and a cyano group (–CN) at the 1-position. This arrangement creates a molecule with rich and complementary reactivity. The electron-withdrawing nitrile and fluorine substituents reduce the electron density of the ring, while the electron-donating amino group provides a nucleophilic handle. The molecular formula is C7H5FN2 with a molecular weight of approximately 136.12 g/mol.
The compound is typically encountered as an off-white to pale yellow crystalline solid. The aryl fluorine bond, while generally stable under mild conditions, is activated toward nucleophilic aromatic substitution (SNAr) by the flanking electron-withdrawing cyano group at the ortho position, making it a particularly reactive site for further functionalization. The primary amine group can participate in condensation, acylation, diazotization, and cyclization reactions, providing diverse entry points into complex molecular architectures.
Synthesis and Preparation Routes
2-Amino-4-fluorobenzonitrile can be accessed via several established synthetic strategies. One common approach involves the selective introduction of a cyano group onto a pre-formed fluoroaniline scaffold using the Sandmeyer reaction, whereby a 2-amino-4-fluoroaniline precursor is first diazotized and then treated with a copper(I) cyanide reagent to install the nitrile functionality. Alternatively, directed metalation of an appropriately protected fluoroaniline followed by quenching with a cyanating electrophile offers regioselective access to the target compound.
Another practical route involves the nucleophilic aromatic substitution of a suitable polyfluorinated benzonitrile with an amine nucleophile under controlled conditions, exploiting the differential reactivity of fluorine atoms activated by the cyano group. The amino group can also be introduced via reduction of a corresponding nitro precursor (e.g., 4-fluoro-2-nitrobenzonitrile) using catalytic hydrogenation or chemical reductants such as iron in acidic media. Researchers should consult the primary literature for optimized reaction conditions, yields, and purification protocols appropriate to their specific scale and facilities.
Research and Industrial Applications
The combination of an amino group, a nitrile, and an activated aryl fluoride in a single scaffold makes 2-Amino-4-fluorobenzonitrile a highly versatile building block in medicinal chemistry and drug discovery. It serves as a key precursor in the construction of heterocyclic ring systems, including benzimidazoles, quinazolines, benzothiazoles, and related N-containing bicyclics, which are privileged structural motifs found in numerous bioactive compounds and approved pharmaceuticals.
The activated aryl fluoride moiety is particularly valuable in SNAr reactions to introduce diverse nucleophiles (amines, thiols, alkoxides), enabling rapid diversification of chemical libraries for high-throughput screening. In agrochemical research, fluorinated nitrile-containing anilines are explored as building blocks for herbicides, fungicides, and insecticides. Additionally, the nitrile group can be further transformed into amides, carboxylic acids, amidines, tetrazoles, and primary amines via hydrolysis, cycloaddition, or reduction, providing broad downstream synthetic flexibility. The compound is also of interest in materials science for the preparation of functional polymers and ligands for coordination chemistry.
Handling, Storage, and Safety Considerations
As with all aromatic amine and nitrile-containing compounds, appropriate safety precautions must be observed when handling 2-Amino-4-fluorobenzonitrile. Users should consult the current Safety Data Sheet (SDS) supplied by Aladdin Scientific before use. Standard laboratory personal protective equipment (PPE), including nitrile gloves, safety glasses, and a laboratory coat, should be worn at all times. Operations that may generate dust or aerosols should be conducted in a well-ventilated fume hood.
The compound should be stored in a tightly sealed container, away from heat, direct sunlight, strong oxidizers, and strong acids or bases. Recommended storage is typically at room temperature or under cool, dry conditions. Waste disposal must comply with all applicable local, regional, and national regulations governing fluorinated aromatic and nitrogen-containing organic compounds. In the event of skin or eye contact, flush immediately with copious water and seek medical advice. The specific hazard classification and GHS pictograms are detailed in the product SDS.
Frequently asked questions
What is 2-Amino-4-fluorobenzonitrile used for in drug discovery?
2-Amino-4-fluorobenzonitrile is widely used as a bifunctional building block for the synthesis of heterocyclic scaffolds such as benzimidazoles, quinazolines, and benzothiazoles, which are common pharmacophores in medicinal chemistry. Its activated aryl fluoride also enables efficient SᴺAr reactions for library diversification, while the amino and nitrile groups can be further elaborated to access a broad range of analogs.
How should 2-Amino-4-fluorobenzonitrile be stored to maintain stability?
The compound should be stored in a tightly closed container under cool, dry conditions, away from direct sunlight, heat sources, and incompatible materials such as strong oxidizers and strong acids or bases. Always refer to the current Aladdin Scientific SDS for the most up-to-date storage recommendations specific to this product.
Can the nitrile group of 2-Amino-4-fluorobenzonitrile be converted to other functional groups?
Yes. The nitrile (–CN) group is a highly versatile functional group that can be transformed into primary amines (via reduction), amides or carboxylic acids (via hydrolysis), amidines (via reaction with amines), and tetrazoles (via [3+2] cycloaddition with azides), providing broad downstream synthetic utility.
Is the aryl fluoride in 2-Amino-4-fluorobenzonitrile reactive toward nucleophilic aromatic substitution?
Yes. The fluorine at the 4-position is activated toward nucleophilic aromatic substitution (SᴺAr) by the electron-withdrawing cyano group located ortho to the fluorine. This makes it a useful electrophilic partner for reaction with amine, thiol, and alkoxide nucleophiles under appropriate conditions.
What purity grade of 2-Amino-4-fluorobenzonitrile does Aladdin Scientific offer?
Aladdin Scientific offers 2-Amino-4-fluorobenzonitrile under SKU A186701. For specific purity grades, lot-specific certificates of analysis, and available pack sizes, please consult the product page on the Aladdin Scientific website or contact customer service directly.
References
- March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed.; Wiley-Interscience: New York, 1992. (General reference for SᴺAr and nitrile chemistry)
- Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. (Reference for functional group interconversions of nitriles and aromatic amines)
- Aladdin Scientific. Product page: 2-Amino-4-fluorobenzonitrile, SKU A186701. https://www.aladdin-e.com (accessed 2024).
Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.
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