Deciphering the Mechanistic Origin of Divergent Radical Annulation Reactions of ortho -Cyanoaryl Acrylamides

Abstract The divergent radical annulation reactions of ortho-cyanoaryl acrylamides involving cyanomethyl and α-oxyalkyl radicals were investigated using density functional theory (DFT) combined with DLPNO-CCSD(T) single-point computations. The calculations provide a detailed mechanistic comparison of the experimentally observed reaction pathways and reveal distinct downstream reactivity of the corresponding radical intermediates. Activation strain model (ASM) analyses show that the competing cyclization and C–C bond cleavage via β-scission pathways are characterized by different balances between structural distortion and interfragment interactions. For the cyanomethyl-radical-derived system, the cyclization pathway is associated with a substantially lower distortion energy, whereas for the α-oxyalkyl-radical-derived system, the cleavage pathway benefits from stronger stabilizing interfragment interactions that compensate for the larger distortion penalty. Noncovalent interaction (NCI) analyses provide qualitative structural support for these energetic trends. Overall, these computations provide a detailed mechanistic comparison of the competing downstream pathways of the cyanomethyl- and α-oxyalkyl-radical-derived intermediates.