TCFH | CAS 94790-35-9 | ≥98%

TCFH — N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate — is a chloroformamidinium coupling reagent for amide, ester and thioester bond formation. Used with N-methylimidazole (NMI), it activates carboxylic acids through in situ N-acyl imidazolium formation, giving a highly reactive acylating intermediate that then acylates amines or alcohols; this species offers reactivity comparable to an acid chloride with the operational ease of a uronium reagent. The TCFH–NMI combination couples hindered carboxylic acids and weakly nucleophilic amines — including anilines and heteroaryl amines — under mild conditions, often with retention of adjacent stereocentres, and with examples run under air. TCFH is supplied as a white crystalline solid, soluble in acetonitrile, dichloromethane, DMF and THF; store cold and dry.

Common Scientific Applications

• Amide bond formation (TCFH–NMI): with N-methylimidazole, TCFH activates carboxylic acids through an N-acyl imidazolium intermediate for direct amide coupling.
• Hindered and weakly nucleophilic partners: effective for difficult couplings of sterically hindered acids with poorly nucleophilic amines such as anilines and heteroaryl amines, with examples run under air.
• Stereoretentive coupling: couples α-chiral acids with retention of the adjacent stereocentre in many cases, limiting epimerisation.
• Peptide coupling: activates carboxylic acids for peptide bond formation in solution-phase synthesis.
• Esterification and thioesterification: beyond amides, TCFH promotes esterification and thioesterification of carboxylic acids, expanding the same activation chemistry to alcohol and thiol nucleophiles.
• Bioconjugation and amide-linked RNA: reported in bioconjugation contexts, including difficult ester formation, and used in automated synthesis of amide-linked RNA.

Further Reading

For guidance on selecting between carbodiimides, aminium/uronium salts, phosphonium salts and other reagent classes for amide and peptide bond formation, see NorrChemica's Lab Journal guide: Choosing a Coupling Reagent for Amide and Peptide Bond Formation.