Mechanistic Insights into the Propagation Cycle of the Hofmann–Löffler–Freytag Reaction: Halogen vs Hydrogen Atom Transfer

The Hofmann-Löffler-Freytag (HLF) reaction is a method that employs N-chlorinated precursors in radical-mediated rearrangement cycles to synthesize pyrrolidine rings and C-H functionalized products. This study aims to elucidate the mechanism of the propagation cycle, identify the rate-limiting step, and uncover the factors influencing the regioselectivity of the HLF reaction. Combining experimental techniques─laser flash photolysis (LFP), electron paramagnetic resonance (EPR), and nuclear magnetic resonance (NMR)─with computational density functional theory (DFT) calculations and kinetic modeling, we challenge the previous assumption that the hydrogen atom transfer (HAT) step was rate-limiting and regioselectivity was under both thermodynamic and kinetic control. We have identified that the halogen atom transfer (XAT) step in the propagation cycle of the HLF reaction follows pseudo-first-order kinetics and has the largest transition-state barrier. Additionally, we observed that regioselectivity is exclusively controlled by the intramolecular hydrogen atom transfer kinetics, while no thermodynamic preference exists in the formation of C₆- and C₅-chlorinated products. Our work predicts how to accelerate the HLF reaction and how we can control the regioselectivity by the smarter selection of substrates based on calculations, which could provide better control of the reaction when implemented in organic synthesis.