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

Abstract

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.

Keywords: Fukui function; chemical reactivity; conceptual DFT; general‐purpose reactivity indicator; radical CH functionalization; radical addition reactions; radical chemistry.

SCHEME 1

Schematic representation of the radical C—H functionalization on nitrogen heteroarenes.

SCHEME 2

Molecular structure of nitrogen heteroarenes (1–14) and radicals •i‐Pr (R1) and •CF₃ (R2). The numbering scheme of the carbon atoms, shown in 1, is applied to all nitrogen heteroarenes, where C2, C3, and so forth, denote specific carbon positions. Atom colors: black (carbon), red (oxygen), light gray (hydrogen), blue (nitrogen), light green (fluorine), green (chlorine), and burgundy (bromine).

FIGURE 1

Mulliken electronegativity values in atomic units (au) for nitrogen heteroarenes (1−14), •i‐Pr (R1), and •CF₃ (R2). The color scale ranges from blue (lowest) to red (highest).

FIGURE 2

Transition state structures for the Reaction 3 (at C5) with •CF₃ (left‐hand side), and for the Reaction 3 (at C5) + •i‐Pr (right‐hand side), calculated at the B3LYP/6‐311++G** level of theory.

FIGURE 3

Performance of R‐GPRI, across three different reactivity situations: electron transfer, e⁻T, stronger electron transfer, Se⁻T, and the combination of both, ERRC, and RFF predicting the most reactive atoms in the reactions between the 14 nitrogen heteroarenes (1−14) and the two radicals for the Exp scenario. Rows (a) and (b) show model accuracy for the first and second most reactive atoms, respectively. Symbols: “✓” for correct regioselectivity, “✓*” for inverted regioselectivity, “!” when the most reactive atom appears at least in one cell but not the most prevalent atom, and a “⨯” is assigned when the most reactive atom is not predicted as reactive.

FIGURE 4

Performance of the R‐GPRI, across three different reactivity situations: electron transfer, e⁻T, stronger electron transfer, Se⁻T, and the combination of both, ERRC, and RFF predicting the most reactive atoms in the reactions between the 14 nitrogen heteroarenes (1–14) and the two radicals for the Cal scenario. Rows (a) and (b) show model accuracy for the first and second most reactive atoms, respectively. Symbols: “✓” for correct regioselectivity, “✓*” for inverted regioselectivity, “!” when the most reactive atom appears at least in one cell but not the most prevalent atom, and a “⨯” is assigned when the most reactive atom is not predicted as reactive.