Precise Introduction of the -CHX_3- (X = F, Cl, Br, I) Moiety to Target Molecules by a Radical Strategy: A Theoretical...

Addition of halomethyl radicals to form bioactive molecules has recently become an efficient strategy. The reaction has a bottleneck, however, which is the effective and selective generation of the proper halomethyl ^•CHX_3- radical by combining CHX_4- with a carbon radical. Understanding the reactivity and selectivity of carbon radicals in the hydrogen atom transfer (HAT) and halogen atom transfer (XAT) reactions of CHX_4- is key to the development of such an attractive method. With the help of the emerging data-driven strategy, DFT calculations were used to explore various correlations. For selectivity, the relative energy barriers between HAT and XAT reactions (ΔG^⧧_H - ΔG^⧧_X) correlate reasonably well with the three parameters ΔG_H, ΔG_X, and IP, and the correlation studies reveal that the calculated IP_inver and the experimental ΔBDE can be used to conveniently predict the selectivity. Predicted selectivities are consistent with experimental determinations. This work not only provides a possibility for selecting carbon radicals with the known or easily obtained physicochemical data but also demonstrates that the informatic workflow such as generating data and identifying correlations has potential applications in mining reaction rules.