In this work, we demonstrate that the estimation of the kp/ktr ratio using DFT calculations helps understand the effects of substituents on the reactivity of thionolactones, based on previously reported experimental results for a series of thionolactones (DOT-X-Y) substituted with electron-withdrawing and electron-donating groups. This improved understanding allowed us to design a new, more reactive thionolactone by adding electron-donating-donating and electron-withdrawing groups to a molecule previously described by our group, POT.