Quantitative Structure–Reactivity Relationship-Guided Mechanistic Study Enables the Optimization of Nitroxyl Radical-Catalyzed Alcohol Oxidation

Alcohol oxidation is a fundamental transformation in organic chemistry, playing a central role in the synthesis of valuable intermediates and products. Herein, the mechanism of alcohol oxidation using a nitroxyl radical catalyst and a hypervalent iodine reagent was investigated through kinetic isotope effect experiments and data-driven quantitative structure–reactivity relationship analyses to identify the rate-determining step and guide reaction optimization. Among the molecular representations evaluated, the percent buried volume: %Vbur at 2.5 Å centered on the α-carbon of the alcohol showed the strongest correlation with the initial reaction rate across a diverse substrate set, revealing a key structural factor governing the reaction rate of alcohols. These mechanistic insights, which suggested that the addition of the alcohol to the catalyst is likely the rate-determining step, motivated the investigation of potential additives. The addition of water was found to accelerate the reaction, leading to a more efficient catalytic system. This study offers mechanistic insights and predictive tools to guide the design of more efficient nitroxyl radical-catalyzed alcohol oxidations.