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Over the last several years, chemists and engineers have identified the utility of using twin-screw extruders for performing large-scale organic chemistry mechanochemically. This equipment is convenient as it is familiar to several relevant industries for its use in formulation, and it is also well-equipped for temperature control and intense grinding of materials. However, the research and development scale of mechanochemistry is just like that of conventional synthesis: milligrams. These milligram-scale reactions are performed in batch-type reactors, often a ball mill. Commercially available ball mills do not have strict temperature control, limiting the information that can be obtained to inform the scale-up process reliably. This work uses an in-house modified, temperature-controlled, ball mill to bridge the knowledge gap regarding predictable, well-informed, economical, and reliable mechanochemical scale-ups. Included in this work is the first extrusion example of a nucleophilic aromatic substitution. 

A new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki–Miyaura couplings, enabled by an aqueous micellar reaction medium. A wide array of functionalized substrates including aryl/heteroaryl bromides are amenable, as are, notably, chlorides. The catalytic system is both general and highly effective at low palladium loadings (1000–2500 ppm or 0.10–0.25 mol%). Density functional theory calculations suggest that greater steric congestion in N 2 Phos induces increased steric crowding around the Pd center, helping to destabilize the 2 : 1 ligand–Pd(0) complex more for N 2 Phos than for EvanPhos (and less bulky ligands), and thereby favoring formation of the 1 : 1 ligand–Pd o complex that is more reactive in oxidative addition to aryl chlorides.