Ultrasound activation of mechanophores embedded in polymer backbones has been extensively studied of late as a method for realizing chemical reactions using force. To date, however, there have been few attempts at systematically investigating the effects of mechanophore structure upon rates of activation by an acoustic field. Herein, we develop a method for comparing the relative reactivities of various cyclobutane mechanophores. Through the synthesis and ultrasonic irradiation of a molecular weight series of poly(methyl acrylate) polymers in which each macromolecule has a single chain-centered mechanophore, we find measurable and statistically significant shifts in molecular weight thresholds for mechanochemical activation that depend on the structure of the mechanophore. We also show that calculations based on the constrained geometries simulate external force method reliably predict the trends in mechanophore reactivity. These straightforward calculations and the experimental methods described herein may be useful in guiding the design and the development of new mechanophores for targeted applications.