Probing the Free Energy Landscape of Organophotoredox-Catalyzed Anti-Markovnikov Hydrofunctionalization of Alkenes

Experimental 13C kinetic isotope effects (KIEs)
provide
unprecedented mechanistic insight into three intermolecular anti-Markovnikov
alkene hydrofunctionalization reactionshydroesterification,
hydroamination, and hydroetherificationenabled by organophotoredox
catalysis. All three reactions are found to proceed via initial oxidation
of the model alkenes to form a radical cation intermediate, followed
by sequential nucleophilic attack and hydrogen-atom transfer to deliver
the hydrofunctionalized product. A normal 13C KIE on the
olefinic carbon that undergoes nucleophilic attack provides qualitative
evidence for rate-limiting nucleophilic attack in all three reactions.
Comparison to predicted 13C KIE values obtained from density
functional theory (DFT) calculations for this step reveals that alkene
oxidation has partial rate-limiting influence in hydroesterification
and hydroamination, while the nucleophilic attack is solely rate-limiting
in the hydroetherification reaction. The basic additive (2,6-lutidine)
activates the nucleophile via deprotonation and is an integral part
of the transition state for nucleophilic attack on the radical cation,
providing an important design principle for the development of asymmetric
versions of these reactions. A more electron-rich pyridine base (2,6-dimethoxypyridine)
exhibits considerable rate enhancements in both inter- and intramolecular
hydrofunctionalization reactions.