Orthogonal modulation of regiochemistry, electronics, and rigidity for programmable mechanochemical activation

The selective activation of mechanophores over non-specific backbone scission is critical for developing stress-responsive materials, yet a unified framework integrating molecular parameters remains elusive. Here, we systematically optimize cinnamate dimer mechanophores through the concerted modulation of three orthogonal structural dimensions: regiochemical attachment topology, electronic substituent effects, and scaffold rigidity. Using solution-state ultrasonication, NMR, UV-vis, GPC, and CoGEF calculations, we decouple the contributions of these parameters to activation efficiency. The para linkage minimizes geometric misalignment, enabling efficient force transduction. Electron-donating substituents stabilize the diradical intermediate, enabling a 2.3-fold variation in rate constants compared with its electron-withdrawing counterpart. Scaffold rigidity minimizes dissipative energy losses, with the biphenyl unit providing sufficient rigidity for near-optimal transduction. The orthogonal integration of these three dimensions enables continuous programming of activation extent from ~30% to 80% under identical sonication. This work establishes a molecular-level design paradigm for engineering cyclobutane-based mechanophores with programmable force thresholds.