Revealing the Mechanism of TEMPO-Hypervalent Iodine(III) Oxidation of Alcohols

Experimental and computational studies on the mechanism of a well-known procedure for the oxidation of alcohols to carbonyl compounds using TEMPO and the hypervalent iodine(III) reagent (diacetoxyiodo)benzene (PIDA) are reported. Kinetic data show that the assumed classical oxoammonium-hydroxylamine mechanism requires modification due to zero-order behavior observed in TEMPO. Instead, a dual catalytic system is proposed featuring two rate-determining steps involving a combination of alcohol, hypervalent iodine species, and water, which is typically present in adventitious quantities and is necessary for the reaction to proceed. The use of different alcohols implies the mechanism to be general. Intramolecular radical trap probes rule out a radical mechanism, while an investigation of TEMPO derivatives suggests that TEMPO is involved prior to the rate-determining step. Kinetic isotope effect studies demonstrate that TEMPO is also involved after the rate-determining step. Electrochemical studies find that the oxoammonium form of TEMPO is reduced by PIDA, likely oxidizing iodine(III) to an iodine(V) species. Theoretical investigations support the feasibility of a pathway involving an iodine(V) species, demonstrate good agreement with the experimentally derived kinetics, and support an updated mechanism. Finally, the demonstration of oxidative kinetic resolution of a secondary alcohol using a chiral iodine(III) reagent rationally extends the reactivity of this system to new chemistry and lends further support toward our mechanistic proposals.