Challenges in quantifying how force affects bond formation have hindered the widespread adoption of mechanochemistry. We used parallel tip-based methods to determine reaction rates, activation energies, and activation volumes of force-accelerated [4+2] Diels-Alder cycloadditions between surface-immobilized anthracene and four dienophiles that differ in electronic and steric demand. The rate dependences on pressure were unexpectedly strong, and substantial differences were observed between the dienophiles. Multiscale modeling demonstrated that in proximity to a surface, mechanochemical trajectories ensued that were distinct from those observed solvothermally or under hydrostatic pressure. These results provide a framework for anticipating how experimental geometry, molecular confinement, and directed force contribute to mechanochemical kinetics.

Mechanical activation of reactions can reduce significantly the amounts of solvent and energy required to form covalent organic bonds.

Surface Cu is mechanically converted to Cu( ii )-OH species via water and oxygen to catalyse the mechanochemical synthesis of tolbutamide.

Using methods of DFT, we investigated the effect of electron withdrawing and electron donating groups on the relative stability of tentative glycosyl donor reaction intermediates. The calculation shows that by changing the stereoelectronic properties of the protecting group, we can influence the stability of the dioxolenium type of intermediates by up to 10 kcal mol⁻¹, and that by increasing nucleophillicity of the 4-O-Bz group, the dioxolenium intermediate becomes more stable than a triflate–donor pair. We exploited this mechanism to design galactosyl donors with custom protecting groups on O2 and O4, and investigated the outcome of the reaction with cyclohexanol. The reaction showed no change in the product distribution, which suggests that the neighboring group participation takes precedence over remote group participation due to kinetic barriers.

Here, we present a simple and efficient method for synthesizing substituted benzotriazoles under mechanochemical conditions. Under optimal conditions, the coupling between 1,2,3‐benzotriazole and benzyl bromide occurs with 99% conversion and 17:1 regioselectivity within 30 min of neat milling. Using density functional theory calculations, we demonstrate that this reaction proceeds through a concerted S _N 2 mechanism. Following this, various reaction environments were explored, which enable variable control over product regioselectivity. Notably, through the inclusion of tert ‐butoxide and phosphate salts, we were able to switch the reaction mechanism from this concerted pathway to a stepwise, S _N 1‐type mechanism. We attributed this change in mechanism to the sodium and potassium counter‐ions stabilizing the deprotonated imidazole ion intermediates. We were then able to influence the equilibrium between these intermediates, and by extension, the regioselective outcome of the reaction via liquid‐assisted grinding. These levers for reaction control are unique to mechanochemistry, and underscores its potential advantages over solvothermal synthesis.