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Solid State Chemistry – Ball Milling, Twin Screw Mixing, Reactors

In common with a large number of reaction types, peptide synthesis has been demonstrated in mechanochemical reactors. Typically, solid reactants, or with a small amount of liquid, are ground together in a high energy mixer such as a ball mill. It is unclear if this methodology has been demonstrated on long peptide sequences. Unfortunately, it is not solvent free, as often reported, since at some point the final product and/or intermediates need to be dissolved and purified using conventional techniques.

Typical concerns regarding scale-up of mechanochemical reactions such as homogeneity, reproducibility and dealing with exothermic chemistry, could possibly be addressed by using twin screw extruders or reactors which work in a continuous feed mode.

Maurin, O.; Verdié, P.; Subra, G.; Lamaty, F.; Martinez, J. Métro, T.-X. Peptide synthesis: ball-milling, in solution, or on solid support, what is the best strategy? Beilstein J. Org. Chem. 2017, 13, 2087–2093.

Bolm, C.; Hernández, J. G. From Synthesis of Amino Acids and Peptides to Enzymatic Catalysis: A Bottom-Up Approach in Mechanochemistry. ChemSusChem 2018, 11, 1410–1420.

Hernández, J. G.; Ardila-Fierro, K. J.; Crawford, D.; James, S. L.; Bolm, C. Mechanoenzymatic peptide and amide bond formation. Green Chem. 2017, 19, 2620–2625.

Yeboue, Y.; Jean, M.; Subra, G.; Martinez, J.; Lamaty, F.; Métro, T.-X. Epimerization-Free C‑Term Activation of Peptide Fragments by Ball Milling. Org. Lett. 2021, 23(3), 631–635.

Naoum, J. N.; Alshanski, I.; Gitlin-Domagalska, A.; Bentolila, M.; Gilon, C.; Hurevich, M. Diffusion Enhanced Amide Bond Formation on Solid Support. Org. Process Res. Dev. 2019, 23, 2733–2739.

Alshanski, I.; Bentolila, M.; Gitlin-Domagalska, A.; Zamir, D.; Zorsky, S.; Joubran, S.; Hurevich, M.; Gilon, C. Enhancing the Efficiency of the Solid Phase Peptide Synthesis (SPPS) Process by High Shear Mixing. Org. Process Res. Dev. 2018, 22(9), 1318–1322.

Ying, P.; Yu, J.; Su, W. Liquid-Assisted Grinding Mechanochemistry in the Synthesis of Pharmaceuticals. Adv. Synth. Catal. 2021, 363, 1246–1271.

Further general references on chemistry in twin screw extruders

Stolle, A.; Schmidt, R.; Jacob, K. Scale-up of organic reactions in ball mills: process intensification with regard to energy efficiency and economy of scale. Faraday Discuss. 2014, 170, 267–286.

Crawford, D. E.; Miskimmin, C. K. G.; Albadarin, A. B.; Walker, G.; James, S. L. Organic synthesis by Twin Screw Extrusion (TSE): continuous, scalable and solvent-free. Green Chem. 2017, 19, 1507–1518.

Sharma, B. M.; Atapalkar, R. S.; Kulkarni, A. A. Continuous flow solvent free organic synthesis involving solids (reactants/products) using a screw Reactor. Green Chem. 2019, 21, 5639–5646.