TFFH | CAS 164298-23-1 | ≥95%

TFFH — fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate — is a formamidinium coupling reagent that activates carboxylic acids as acyl fluorides in situ. In the presence of a tertiary amine base, the acid is converted to its acyl fluoride, which then acylates the amine to give the amide; the acyl fluoride is a reactive but comparatively selective acylating species. TFFH is a non-hygroscopic white crystalline solid, soluble in DMSO, DMF, acetonitrile and dichloromethane; the solid stores well, although solutions are moisture-sensitive and are best used freshly prepared.

Common Scientific Applications

• Amide and peptide bond formation: TFFH converts the carboxylic acid into its acyl fluoride in situ in the presence of a tertiary amine base; the acyl fluoride then acylates the amine to give the amide, in both solution- and solid-phase peptide synthesis.
• Hindered and electron-deficient couplings: through the in-situ acyl fluoride, TFFH couples sterically hindered carboxylic acids, α,α-disubstituted amino-acid derivatives and electron-deficient amines — difficult couplings where standard activation fails — typically at elevated temperature.
• Low-racemisation coupling: acyl fluoride activation proceeds with low racemisation in suitable cases, and is less prone to racemisation than the corresponding acyl chloride.
• Deoxofluorination of alcohols: activates alcohols toward deoxofluorination to the corresponding alkyl fluorides under mild conditions tolerant of carbonyl groups, in combination with a fluoride source.
• Isothiocyanates and acylhydrazides: also used to prepare isothiocyanates and acylhydrazides.
• Surface and bioconjugate chemistry: used on carboxyl-terminated self-assembled monolayers to form interchain carboxylic anhydrides, and separately reported in hydrazone-ligation bioconjugation.

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.