Compliance Mismatch Drives Mechanochemical Reactivity in Diels-Alder Reactions

Mechanical forces can alter chemical reactivity by reshaping the potential energy surface landscape, but the relationships between force direction, molecular structure, and barrier structure remain poorly understood. Here, we develop a compliance-based framework for understanding primary mechanochemical activation by means of the compliance matrix and test it across a systematically designed chemical space of cyclopentadiene-based Diels-Alder reactions. Under the harmonic approximation, the force-induced change in a barrier height is determined by the difference in the compliances along the direction of force between the reactant complex and the transition state. We then evaluate this model across 233 Diels-Alder reactions, generating 1,271 reaction profiles and performing over 284,448 force-modified critical point calculations enabled by frontier machine-learned interatomic potentials. When deformation is restricted to a single coordinate, where the compliance matrix is effectively diagonal, the mechanochemical response depends strongly on the selected distortion, with dihedral motions providing a particularly effective mode of activation. However, upon optimizing in the presence of force, including the off-diagonal elements of the compliance matrix, the barrier-lowering behavior becomes widespread and is substantially less sensitive to the initial force direction. This behavior arises from the finding that reactant complexes are generally more compliant than their corresponding transition states. We show that a global reactant compliance descriptor captures this trend and identifies substituent-dependent differences in mechanochemical susceptibility, including candidate reactions for observing changes in stereoselectivity. These results show that mechanochemical activation for this reaction class does not require the force to be aligned with the traditional reaction coordinate. Instead, differential distortability across the reactant and transition states provides a general physical principle for understanding and potentially designing force-sensitive reactions. Finally, by extending this model to understand reactions under hydrostatic pressure conditions, this work provides insight into primary mechanochemistry across all distortion modes of molecular systems.