Attenuating N-oxyl Decomposition for Improved Hydrogen Atom Transfer Catalysts Design

The design of N-oxyl hydrogen atom transfer catalysts has proven challenging to date. Previous efforts have focused on the functionalization of the archetype phthalimide-N-oxyl. Driven in part by the limited options for modification of this structure, this strategy has provided only modest improvement in reactivity and/or solubility. Our previous mechanistic efforts have suggested that while the electron-withdrawing carbonyls of the phthalimide are necessary to maximize the O-H bond dissociation enthalpy of the HAT product hydroxylamine and thus overall reaction thermodynamics, they can undergo nucleophilic substitution leading to catalyst decomposition. In an attempt to minimize this vulnerability, this work replaces the aryl ring in PINO with the combination of a substituted heteroatom and quaternary carbon. By rendering one carbonyl carbon less electrophilic and the other less sterically accessible, the corresponding N1-aryl-hydantoin-N3-oxyl showed significantly higher stability than PINO as well as a modest improvement in reactivity. This proof-of-principle in new scaffold design may accelerate future HAT catalyst discovery and development.