Mechanochemistry: Fundamentals, applications and future

Miniaturisation of mechanochemical reactions for parallel synthesis Sarah E. Raby-Buck 1 , Katharine Ingram 2 and Dr Duncan L. Browne 1 1 Department of Pharmaceutical and Biological Chemistry, University College London (UCL), School of Pharmacy, UK, 2 Syngenta, Jealott’s Hill International Research Centre, UK One of the barriers to industrial use of mechanochemistry is the limited throughput. Typically, the number of simultaneous reactions is determined by the number of positions for milling jars to be accommodated on the milling device, this is most commonly two jars, however, six position mills have recently become available 1 . Parallel milling would open opportunities for faster and more efficient optimisation of reactions, and parallel library synthesis. There are some examples of medium throughput mechanochemistry in planetary mills enabled by adapters which fit different sizes of glass vial, allowing up to 48 samples to be processed simultaneously 2 . This was initially applied to co-crystallization studies 2,3 but has more recently been used for organic synthesis, in the parallel synthesis of benzoxazines and the optimisation of Buchwald-Hartwig coupling for difficult substrates 4,5 . Whilst adapters for mixer mills are commercially available, allowing 20 samples to be milled simultaneously in 2 mL Eppendorf tubes, exploration of the compatibility of this setup with organic synthesis has yet to be examined. Changing the material of the milling jar from stainless steel to plastic, altering the path length of the ball, and reducing the ball size could all have profound effects on the energy of collisions and therefore reactivity.

Figure 1 To investigate this, known mechanochemical reactions usually performed in 30-, 15-, or 10-mL stainless steel jars were chosen to scale down into the 2 mL Eppendorf tubes. We have demonstrated that a range of mechanochemical reactions can be scaled down to allow parallel milling, and we are beginning to investigate the use of Eppendorf’s for reaction optimisation, ligand screening and reaction kinetics before re-scaling up for use in synthetically relevant jar sizes. References 1. Mixer Mill MM 500 vario - for up to 50 samples - RETSCH, https://www.retsch.com/products/milling/ball-mills/mm-500-vario/ function-features/, (accessed July 4, 2022). 2. S. R. Bysouth, J. A. Bis and D. Igo, Int. J. Pharm., 2011, 411 , 169–171. 3. D. Hasa and W. Jones, Adv. Drug Deliv. Rev. , 2017, 117, 147–161. 4. K. Martina, L. Rotolo, A. Porcheddu, F. Delogu, S. R. Bysouth, G. Cravotto and E. Colacino, ChemComm , 2018, 54 , 551–554. 5. R. Li, / Greenchem, Q. Lemesre, T. Wiesner, R. Wiechert, E. Rodrigo, S. Triebel and H. Geneste, Green Chem , 2022, 00 , 1–3.

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