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Cleavage from Resin

Typically, acid-liable groups are used to anchor the C terminus of the peptide to the resin, e.g., 2-chlorotrityl chloride. Once the desired peptide chain has been assembled, the product is leaved from the resin using trifluoroacetic acid in a chlorinated solvent. Solvents like1,2-dichloroethane and CHCl3 should be avoided. Dichloromethane is widely employed, but this solvent should be replaced where possible. Toluene, anisole, and dimethoxy anisole have been identified as possible alternatives to DCM.

Solvent Cleavage yield
DCM 98%
Anisole 100%
1,3-Dimethoxybenzene 94%
Toluene 100%
50% EtOAc–CH3CN  28%
GVL 8.2%
2-MeTHF 5.3%
Cyrene, Isoamyl acetate, Isobutyl acetate, NBP 0%
Alhassan, M.; Al Musaimi, O.; Collins, J. M.; Albericio, F.; de la Torre, B. G. Cleaving protected peptides from 2-chlorotrityl chloride resin. Moving away from dichloromethane. Green Chem. 2020, 22, 2840–2845.

King, D. S.; Fields, C. G.; Fields, G. B. A cleavage method which minimizes side reactions following Fmoc solid phase peptide synthesis. Int. J. Pept. Protein Res. 1990, 36(3), 255–66.