Mechanochemistry is becoming more widespread as a technique for molecular synthesis with new mechanochemical reactions being discovered at increasing frequency. This perspective explores what more it can offer, aside from the clear benefit of reduced solvent consumption.

We have identified an example of a mechanochemically milled organic reaction where liquid-assisted grinding controls the selectivity, such a phenomenon has not been reported/observed before.

A reaction manifold has been discovered in which the chemoselectivity can be altered by switching between neat milling and liquid assisted grinding (LAG) with polar additives. After investigation of the reaction mechanism, it has been established that this switching in reaction pathway is due to the neat mechanochemical conditions exhibiting different kinetics for a key step in the transformation. This proof of concept study demonstrates that mechanochemistry can be used to trap the kinetic product of a reaction. It is envisaged that, if this concept can be successfully applied to other transformations, novel synthetic processes could be discovered and known reaction pathways perturbed or diverted.

A form independent activation of zinc, concomitant generation of organozinc species and engagement in a Negishi cross‐coupling reaction via mechanochemical methods is reported. The reported method exhibits a broad substrate scope for both C(sp3)–C(sp2) and C(sp2)–C(sp2) couplings and is tolerant to many important functional groups. The method may offer broad reaching opportunities for the in situ generation organometallic compounds from base metals and their concomitant engagement in synthetic reactions via mechanochemical methods.

A study on the translation of a solid-state fluorination reaction from a mechanochemical mixer-mill to a continuous twin-screw extruder is discussed herein.

Solventless mechanochemical synthesis represents a technique with improved sustainability metrics compared to solvent-based processes. Herein, we describe a methodical process to run one solventless reaction directly into another through multistep mechanochemistry, effectively amplifying the solvent savings. The approach has to consider the solid form of the materials and compatibility of any auxiliary used. This has culminated in the development of a two-step, one-jar protocol for heterocycle formation and subsequent fluorination that has been successfully applied across a range of substrates, resulting in 12 difluorinated pyrazolones in moderate to excellent yields.

Efforts to generate organomanganese reagents under ball-milling conditions have led to the serendipitous discovery that manganese metal can mediate the reductive dimerization of arylidene malonates. The newly uncovered process has been optimized and its mechanism explored using CV measurements, radical trapping experiments, EPR spectroscopy, and solution control reactions. This unique reactivity can also be translated to solution whereupon pre-milling of the manganese is required.

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