HCTU | CAS 330645-87-9 | ≥97%

HCTU (O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) is a benzotriazolium aminium/uronium-type coupling reagent developed as a faster-coupling alternative to HBTU for Fmoc solid-phase peptide synthesis. The chlorine at the 6-position of the benzotriazole ring lowers the pKa of the 6-chloro-1-hydroxybenzotriazole leaving group, giving a more reactive active ester than the HOBt-derived HBTU and TBTU and bringing its coupling efficiency close to that of HATU, while it remains considerably less costly. Couplings proceed with low racemisation. Like the related HBTU and HATU — which X-ray studies showed crystallise as the guanidinium (N-oxide) form rather than the uronium form their names imply — HCTU belongs to the aminium/guanidinium class, a point its systematic name reflects. It is an affordable, efficient activator for routine and demanding peptide couplings.

Common Scientific Applications

• Fast conventional Fmoc solid-phase peptide synthesis: HCTU enables markedly faster, shorter conventional Fmoc-SPPS cycles than HBTU while maintaining crude peptide purity, and requires no specialised reagents or techniques. It is suited to both manual and automated peptide synthesis.
• Difficult and amyloidogenic sequences: The more reactive 6-chloro active ester improves coupling efficiency in demanding sequences where HOBt-based reagents can be less effective. HCTU has been used to assemble difficult sequences such as the acyl-carrier-protein (65–74) fragment and amyloidogenic targets including human amylin(1–37) and β-amyloid(1–42).
• Macrolactamisation and cyclic-peptide synthesis: HCTU is an effective reagent for head-to-tail macrolactamisation, the intramolecular ring closure that converts linear precursors into cyclic peptides. It has been applied to on-resin cyclisation and to solution-phase closure of large rings, including giant β-sheet macrolactams.
• Carboxyl activation beyond peptide synthesis: As a carboxyl-activating reagent HCTU is used for amide-bond formation in general organic synthesis, and has also been reported as a catalyst for the synthesis of quinoxaline derivatives.

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.