Comparative Study of Predicting Radical CH Functionalization Sites in Nitrogen Heteroarenes Using a Radical General-Purpose Reactivity Indicator and the Radical Fukui Function

The Radical General-Purpose Reactivity Indicator (R-GPRI) is a valuable new tool for discerning the most reactive atoms within a molecule undergoing radical attack. In this study, we apply the condensed R-GPRI and the condensed Radical Fukui Function (RFF) to identify the two most reactive atoms in 14 nitrogen heteroarenes subjected to radical attack by •CF₃ (trifluoromethyl radical) and •i-Pr (isopropyl radical). The results were compared with available experimental data and calculated activation barriers to comprehensively evaluate the reactivity of these molecules, especially in reactions without isolated products. The outcomes indicate that R-GPRI is a robust alternative for identifying the most reactive CH sites in disubstituted nitrogen heteroarenes, outperforming the RFF. We also found that for nitrogen heteroarenes, summing the charges of the hydrogen atoms into the heavier atoms to which they are bonded as computed with the Hirshfeld population scheme enhances the performance of the RFF compared to previous findings. As such, the R-GPRI appropriately incorporates both charge and RFF contributions. It is also observed that the atoms within molecules that have a small condensed RFF tend to be unreactive in these radical attack reactions. This is even observed in atoms with the largest charge in magnitude (with the appropriate sign) but a small condensed RFF.