Maximizing Driving Force in the Design of N-oxyl Hydrogen Atom Transfer Catalysts

Increasing the bond dissociation enthalpy (BDE) of potential hydrogen atom transfer (HAT) catalysts has the potential to un-lock a greater substrate scope for radical C-H functionalization reactions. For the archetype N-oxyl catalyst phthalimide-N-oxyl (PINO), tuning the BDEO-H of its precursor N-hydroxyphthalimide (NHPI) by substitution of the the aryl ring has minimal effects, limiting meaningful advances in catalyst development by modifications of PINO. Herein, we demonstrate that inserting a heteroatom between one of the carbonyl groups of PINO and the aryl ring significantly increases the BDEO-H. For example, an N-phenyl moiety, O-atom or S-atom raises the BDEO-H by 6.5, 6.9 and 8.1 kcal/mol, respectively, relative to NHPI – which translates to an increased kHAT of 4, 36.3 and 24.3, respectively. Our studies of these compounds and a panel of analogs thereof highlight three advantages of this strategy: 1) high synthetic accessibility of catalyst candidates; 2) simultaneous optimization across multiple parameters; and 3) effective activity tuning. These new scaffolds are promising for the development of next-generation HAT catalysts and C-H functionalization reactions.