What is it about?
NSAIDs in the Battle Against Discomfort: Flufenamic acid is a representative example of nonstereoidal anti-inflammatory drugs (NSAIDs), which are among the best-selling drugs worldwide (there is an estimate of more than 100 million prescriptions per year in the USA alone). The synthesis of best-selling pharmaceutical compounds is one of the most attractive laboratory experiences for chemistry students. This is especially appealing for those enrolled in organic chemistry courses in pharmacy faculties. This paper details an undergraduate organic chemistry experiment focusing on nitroso compounds and boronic acids. Students synthesize nitrosobenzenes, couple them with boronic acids without using transition-metals, and produce flufenamic acid by two different routes that they compare. [Some of the content on this page has been created by AI]
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Why is it important?
1. It introduces students to the chemistry of nitroso compounds, which is often overlooked in undergraduate organic chemistry courses. Nitroso compounds have gained importance in organic synthesis as an alternative to other nitrogen-containing reagents. 2. It allows students to expand their knowledge of the chemistry of boronic acids, showcasing their participation in reactions beyond the well-known transition-metal-catalyzed reactions. This aspect of boronic acid reactivity is currently an active area of research. 3. The experiment minimizes the generation of hazardous substances by using boronic acids and nitrosoarenes under transition-metal-free conditions. This is significant as it promotes environmentally friendly practices in chemical synthesis. 4. The synthesis provides students with an opportunity to compare different methods for the preparation of nitrosobenzenes and the yields of the coupling of nitrosobenzenes with boronic acids. This comparative analysis enhances their understanding of reaction mechanisms and experimental outcomes. 5. The approach is innovative and aligns with the current trends in organic synthesis, providing students with exposure to contemporary methods and reactions that are not typically covered in introductory organic chemistry courses. Overall, the transition-metal-free synthesis of flufenamic acid using boronic acids and nitrosoarenes is important for advancing students' understanding of organic synthesis, promoting sustainable chemistry practices, and familiarizing them with emerging areas of chemical research. An ample handout both for instructors and students is given as SI. This includes the following items: 1. Required Reagents: CAS Registry Numbers and Hazard Information 2. Safety and Waste Disposal Information 3. List of Chemicals and Equipment 4. Handout (Instructor´s version), that includes theoretical background on boronic acids, nitroso compounds, and other methods for the synthesis of diarylamines. 5. Questions (Instructor´s version) 6. Additional notes for instructors, including Experimental Notes, Reproducibility, and students´ results, Photos of the experiments, and Additional Experiments 7. Characterization data: Copies of spectra 8. Handout for students 9. Questions for students 10. Guide for the discussion sessions 11. Sample student report Enjoy!!
Perspectives
This paper is valuable for advanced undergraduate organic chemistry labs, introducing students to nitroso compounds and boronic acids, often overlooked in second-year courses. The experiment broadens knowledge beyond transition-metal-catalyzed reactions, allowing students to compare synthesis methods and coupling reactions. It provides practical experience in new concepts, enhancing experimental skills for multi-step synthesis. The students gain comfort in reading contemporary literature, understanding new reaction mechanisms, and interpreting spectral data, especially NMR spectra of fluorine-containing molecules.
Professor Aurelio G CSAKY
Universidad Complutense de Madrid. Instituto Pluridisciplinar
Read the Original
This page is a summary of: Synthesis of Flufenamic Acid: An Organic Chemistry Lab Sequence Using Boronic Acids and Nitrosoarenes under Transition-Metal-Free Conditions, Journal of Chemical Education, June 2019, American Chemical Society (ACS),
DOI: 10.1021/acs.jchemed.8b00824.
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Resources
Organic Synthesis and Bioevaluation
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Synthesis of Di(hetero)arylamines from Nitrosoarenes and Boronic Acids: A General, Mild, and Transition-Metal-Free Coupling
The synthesis of di(hetero)arylamines by a transition-metal-free cross-coupling between nitrosoarenes and boronic acids is reported. The procedure is experimentally simple, fast, mild, and scalable and has a wide functional group tolerance, including carbonyls, nitro, halogens, free OH and NH groups. It also permits the synthesis of sterically hindered compounds.
Synthesis of Mono‑N‑Methyl Aromatic Amines from Nitroso Compounds and Methylboronic Acid
The selective synthesis of mono-N-methyl aromatic amines was achieved by the reaction of aromatic nitroso compounds with methylboronic acid promoted by triethylphosphite under transition metal-free conditions. The target compounds are constructed efficiently without overmethylation, under environmentally benign reaction conditions that do not require bases or reductants and therefore are of interest in pharmaceutical, agricultural, and chemical industries.
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