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

## TL;DR

This study reveals the mechanism of the Hofmann–Löffler–Freytag reaction, showing that halogen atom transfer is the rate-limiting step and that regioselectivity is controlled by hydrogen atom transfer kinetics.

## Contribution

The paper challenges previous assumptions by identifying the halogen atom transfer as the rate-limiting step and clarifying the kinetic control of regioselectivity.

## Key findings

- The halogen atom transfer step follows pseudo-first-order kinetics and has the largest transition-state barrier.
- Regioselectivity is exclusively controlled by intramolecular hydrogen atom transfer kinetics.
- No thermodynamic preference exists for the formation of C6- and C5-chlorinated products.

## Abstract

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.