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Chemistry in Water

Amide bond formation has been shown to be amenable to chemistry in water (or water containing a small amount of organic solvent) in the presence of micellular catalysts or surfactants. A number of different micelle-forming reagents/surfactants have been reported to give high yields in essentially aqueous reaction media. These reactions are typically small peptides—two or three AA units. It is unclear if this approach can be used with SPPS / hybrid approaches or for longer peptide sequences.


Cortes-Clerget, M.; Berthon, J-Y.; Krolikiewicz-Renimel, I.; Chaisemartin, L.; Lipshutz, B. H. Tandem deprotection/coupling for peptide synthesis in water at room temperature. Green Chem. 2017, 19, 4263–4267.

Gallou, F.; Guo, P.; Parmentier, M.; Zhou, J. A General and Practical Alternative to Polar Aprotic Solvents Exemplified on an Amide Bond Formation. Org. Process Res. Dev. 2016, 20, 1388–1391.

Gabriel, C. M.; Keener, M.; Gallou, F.; Lipshutz, B. H. Amide and Peptide Bond Formation in Water at Room Temperature. Org. Lett. 2015, 17, 3968−3971.

Cortes-Clerget, M.; Lee, N. R.; Lipshutz, B. H. Synthetic chemistry in water: applications to peptide synthesis and nitro-group reductions. Nat. Protoc. 2019, 14, 1108–1129.

Cortes-Clerget, M.; Spink, S. E.; Gallagher, G. P.; Chaisemartin, L.; Filaire, E.; Berthon, J-Y.; Lipshutz, B. H. MC-1. MC-1. A “designer” surfactant engineered for peptide synthesis in water at room temperature. Green Chem. 2019, 21, 2610–2614.


Sharma, S.; Buchbinder, N. W.; Braje, W. M.; Handa, S. Fast Amide Couplings in Water: Extraction, Column Chromatography, and Crystallization Not Required. Org. Lett. 2020, 22, 5737–5740.

Hydroxypropylmethyl cellulose (HPMC)

Petkova, D.; Borlinghaus, N.; Sharma, S.; Kaschel, J.; Lindner, T.; Klee, J.; Jolit, A.; Haller, V.; Heitz, S.; Britze, K.; Dietrich, J.; Braje, W. M.; Handa, S. Hydrophobic Pockets of HPMC Enable Extremely Short Reaction Times in Water. ACS Sustainable Chem. Eng. 2020, 8, 12612−12617.