Mechanism‐Based Approach to Reagent Selection for Oxidative Carbon−Hydrogen Bond Cleavage Reactions

Abstract

Numerous hydride-abstracting agents generate the same cationic intermediate, but substrate features such as intermediate cation stability, oxidation potential, and steric environment can influence reaction rates in an oxidantdependent manner. This manuscript provides experimental data to illustrate the role that structural features play in the kinetics of hydride abstraction reactions with commonly used quinone-, oxoammonium ion-, and carbocation-based oxidants. Computational studies of the transition state structures and energies explain these results and energy decomposition analysis calculations reveal unique sensitivities to electrostatic attraction and steric repulsions. Rigorous rate studies of select reactions validated the capacity of the calculations to predict reactivity trends. Additionally, kinetics studies demonstrate the potential for product inhibition in DDQ-mediated reactions. These studies provide a clear guide to select the optimal oxidant for structurally disparate substrates and lead to predictions of reactivity that were validated experimentally.

Synthetic applications of hydride abstraction reactions by organic oxidants

“…The activation free energies in this work were higher than expected, most likely as a result of the calculated products having the ( Z )-geometry for the oxocarbenium ion rather than the more favorable ( E )-geometry. A subsequent investigation by Miller, Zhou, and co-workers showed 42 that transition state free energies more closely match experimental results when the reaction pathway provides the ( E )-oxocarbenium ion, and that the rates of these reactions are generally much greater than those of corresponding oxidations by DDQ when both reactions are conducted in acetonitrile. This work also showed that, in contrast to DDQ reactions, oxidations by oxoammonium ions are not sensitive to substrate oxidation potential and cation stability is the defining factor in hydride abstraction rates.…”

“…41 The impact of steric effects on oxidation rate was established in an experimental and computational study by Miller, Zhou, and co-workers. 42…”

“…Miller reported that Bobbitt's salt can act as a faster and less sterically sensitive substitute for DDQ in oxidative cyclization reactions that are similar to those shown in Scheme 18. 42 Exposing sterically hindered allylic ether 296 to Bobbitt's salt resulted in the formation of 297 in excellent yield. This study also showed that acyclic acyliminium ions can be prepared from oxidizing allylic carbamates with Bobbitt's salt.…”

“…The authors observed a modest sensitivity to steric effects, with hydride transfer proceeding more rapidly from methylene groups than otherwise similarly substituted methine groups. Miller showed 42 that the trityl cation is significantly less sensitive than DDQ to steric effects distal to the reactive site. The calculated transition states for these reactions show that the aryl rings exist in a propeller arrangement that allows for remote steric effects to be avoided.…”

Recent advancements in the use of Bobbitt's salt and 4-acetamidoTEMPO

“…This selectivity is now understood to originate from the unique property that the oxidations occur via a hydride transfer from the substrate to the oxoammonium salt under acidic or neutral conditions (Scheme 2). 11,17–19…”