The synthesis of such functionalized POT thionolactones (POT-CF3 and POT-NO2) was only possible with electron-withdrawing groups since the thionation of the corresponding lactones containing electron-donating groups was not selective. Calculations predicted an increased reactivity of these POT-CF3 and POT-NO2 substituted thionolactone during copolymerization with styrene and isobornyl acrylate. An experimental study revealed a reactivity trend consistent with the calculations. The detailed kinetic analysis revealed reactivity ratios of rPOT-CF3 = 1.15 and rS = 0.29 for the POT-CF3-Styrene monomers, and rPOT-CF3 = 70 and rIBA = 0.25 for the POT-CF3-isobornyl acrylate monomers, for solution copolymerization at 80 °C in anisole (50 mol %) initiated with 0.5 mol % AIBN. In the case of POT-NO2, only copolymerization with initial fPOT-NO2,0 feed ratio of 0.05 was possible. In this condition, reactivity ratios of rPOT-NO2 = 8.0 and rS = 0.2 was determined. At higher feed ratios, the POT-NO2 acted as an inhibitor of the polymerization since the opened POT-NO2 derived radical selectively adds on the POT-NO2 thionolactone, but reversibly, impeding the polymerization. This work thus confirms the value of our approach combining theoretical and experimental studies to rationally identify the effects of substituents on the reactivity of thionolactones reported in the literature. In light of the challenges often encountered during the synthesis of the monomers, the utilization of a systematic design approach to identify the most appropriate substitution pattern emerges as a significant asset.