Facile Amide Bond Formation with TCFH-NMI in an Organic Laboratory Course

A new undergraduate organic laboratory experiment has been developed for amide bond formation between biorenewable 2-furoic acid and either of two substituted piperazines to prepare medicinally relevant amide products using a procedure with industrial significance. The reactions proceeded smoothly under ambient conditions using the combination of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) in a minimal volume of acetonitrile with a direct crystallization upon addition of water. Students successfully collected their product by filtration and then characterized it by NMR ([superscript 1]H, [superscript 13]C, COSY, DEPT-135, HSQC), IR, MS, and melting point. Students also explored the reaction mechanism and compared green chemistry aspects of their procedure with literature routes. A virtual version of the experiment was adapted for remote instruction. [This paper was presented at the Spring 2022 American Chemical Society National Meeting and the 2022 National Organic Symposium.]