Catalytic Antioxidant Activity of Acyclic and Macrocyclic Selenides: Insights Into Structure–Activity Relationships and Mechanisms From Kinetic and Computational Studies

Diverse selenides were shown to act as potent catalytic antioxidants. This behavior was evaluated by measuring the rates of reduction of hydrogen peroxide with thiols in the presence of the catalysts in an NMR‐based assay. Structure–activity studies indicated that rates were enhanced with alkyl versus. aryl selenides and by the presence of OSe and SSe coordinating groups, while electron‐withdrawing para ‐substituents decreased rates. Benzenethiol generally resulted in zero‐order kinetics, while benzyl thiol produced faster rates and diverse behavior, including sigmoidal plots that suggested autocatalytic or acid‐catalyzed processes. Acyclic and macrocyclic bis(selenides), as well as macrocycles containing both selenide and sulfide groups afforded potent catalysts. Geometry optimization and transition state DFT computations revealed closer OSe and SSe contacts upon oxidation of the selenium atom. Transannular SSe or SeSe coordination in macrocyclic selenides was poorly accommodated in the conformations studied. Crystal structures of two macrocycles revealed no transannular coordination in the solid state. Remarkably, the use of macrocyclic selenides, as well as several acyclic analogs, resulted in consumption of >50% of benzyl thiol in less than 1 min. These rates were >100 times those obtained with the antioxidant ebselen, used for comparison in the same assay.