Computational Assessment of Verdazyl Derivatives for Electrochemical Generation of Carbon-Centered Radicals

Abstract

To expand the scope for carbon-centered radical generation by electrochemical activation of adducts based on stable free radicals, a test set of six simple electron-rich Kuhn verdazyl derivatives in conjunction with nine different alkyl leaving groups have been computationally assessed. Like triazinyls, adducts of simple verdazyl derivatives functionalized with electron donating substituents, favor mesolytic cleavage to carbon-centered radicals under mild electrochemical potentials (-0.7 to-0.2 V. vs Fc + /Fc). Electrochemical oxidation was found to reduce the bond-dissociation Gibbs free energy (298K in acetonitrile) by 70 kJ mol-1 on average, when comparing the homolytic cleavage pathway of the unoxidized adduct, to the preferred mesolytic pathway of the oxidized adduct (i.e. to form either a verdazyl radical and a carbocation, or a verdazyl cation and a carbon-centered radical). Considering the full thermochemical cycle, we illustrate that all the relevant free energy changes can be reduced to differences between the oxidation potentials of adducts and radicals, defining a series of criterion that govern the rational design of suitable candidates for oxidative carbon-centered radical cleavage. As a result of a trade-off between promoting the oxidation of the adduct and enhancing the net reduction in BDFE upon oxidation, the best verdazyl derivatives for carbon-centered radical generation are those substituted with t-Bu substituents.

Computational Optimization of Alkoxyamine-based Electrochemical Methylation

“…15 (C) Verdazyl and triazinyl R adducts examined previously. Their oxidation behavior is analogous to that of TEMPO−R, except that the strongly electron-donating substituents on the triazinyl or verdazyl moiety can convert them from a carbocation source to a carbon-centered radical source and vice versa for strongly electron-withdrawing groups 16,17 Gibbs free energies in solution. Improved single-point energies were subsequently calculated using the high-level composite ab initio method G3(MP2)-RAD, in combination with the ONIOM partitioning scheme.…”

“…While this suggests that the Me adducts of triazinyl and verdazyl radicals could be good candidates for methylation at low oxidation potentials, it is important to remember that it is the oxidation of the adduct that provides the energy required to activate it in the first place. 16,17 Thus, it is instructive to investigate whether or not reducing the activation potential compromises S N 2 reactivity.…”

“…(C) Verdazyl and triazinyl R adducts examined previously. Their oxidation behavior is analogous to that of TEMPO–R, except that the strongly electron-donating substituents on the triazinyl or verdazyl moiety can convert them from a carbocation source to a carbon-centered radical source and vice versa for strongly electron-withdrawing groups , …”

“…Previously, we have used theory and experiments to study the redox chemistry of TEMPO–R as a function of leaving group and reaction conditions, showing that when R is stable as a radical or carbocation, it undergoes oxidative cleavage, but poor leaving groups like Me only undergo cleavage via S N 2 reactions with nucleophiles (Scheme B). , It was this latter chemistry that led us to develop the aforementioned electrochemical methylation technique (Scheme A) . In following up these studies, we have used theory to evaluate triazinyl and verdazyl R adducts for oxidative cleavage reactions (Scheme C). , In the course of that work, we observed that the R adducts of both triazinyls and verdazyls undergo oxidation at considerably lower oxidation potentials than the TEMPO–R adducts (−0.3 to 0.4 V vs Fc/Fc + in acetonitrile for triazinyl adducts and −0.7 to −0.2 V for verdazyl adducts versus 0.79 V vs for TEMPO–Me itself). While this suggests that the Me adducts of triazinyl and verdazyl radicals could be good candidates for methylation at low oxidation potentials, it is important to remember that it is the oxidation of the adduct that provides the energy required to activate it in the first place. , Thus, it is instructive to investigate whether or not reducing the activation potential compromises S N 2 reactivity.…”

“…In following up these studies, we have used theory to evaluate triazinyl and verdazyl R adducts for oxidative cleavage reactions (Scheme C). , In the course of that work, we observed that the R adducts of both triazinyls and verdazyls undergo oxidation at considerably lower oxidation potentials than the TEMPO–R adducts (−0.3 to 0.4 V vs Fc/Fc + in acetonitrile for triazinyl adducts and −0.7 to −0.2 V for verdazyl adducts versus 0.79 V vs for TEMPO–Me itself). While this suggests that the Me adducts of triazinyl and verdazyl radicals could be good candidates for methylation at low oxidation potentials, it is important to remember that it is the oxidation of the adduct that provides the energy required to activate it in the first place. , Thus, it is instructive to investigate whether or not reducing the activation potential compromises S N 2 reactivity.…”