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 alkene (anethole) 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 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.