Understanding and Predicting Post H-Atom Abstraction Selectivity through Reactive Mode Composition Factor Analysis

Abstract

The selective functionalization of C–H bonds is one of the Grails of synthetic chemistry. In this work, we demonstrate that the selectivity toward fast hydroxylation or radical diffusion (known as the OH-rebound and dissociation mechanisms) following H-atom abstraction (HAA) from a substrate C–H bond by high-valent iron-oxo oxidants is already encoded in the HAA step when the post-HAA barriers are much lower than the preceding one. By applying the reactive mode composition factor (RMCF) analysis, which quantifies the kinetic energy distribution (KED) at the reactive mode (RM) of transition states, we show that reactions following the OH-rebound coordinate concentrate the RM kinetic energy on the motion of the reacting oxygen atom and the nascent substrate radical, whereas reactions following the dissociation channel localize most of their kinetic energy in H-atom motion. These motion signatures serve to predict the post-HAA selectivity, and since KED is affected by the free energy of reaction and asynchronicity (factor η) of HAA, we show that bimolecular HAA reactions in solution that are electron transfer-driven and highly exergonic have the lowest fraction of KED on the transferred H-atom and the highest chance to follow rebound hydroxylation. Finally, the RMCF analysis predicts that the H/D primary kinetic isotope effect can serve as a probe for these mechanisms, as confirmed in virtually all reported examples in the literature.

Bifurcating reactions: distribution of products from energy distribution in a shared reactive mode

“…Thus, it seems that a tight -CH 2 OCH 2 -tether outweighs this kinetic-energy propensity at TS 1 , which eventually leads to the (2+2) product. An analogous example was pointed out by us in the past in the context of 'rebound' hydroxylation vs dissociation in post H-atom abstraction reactivity, 27 where a reaction poised for dissociation in terms of KED follows the hydroxylation channel due to tethering. Such examples demonstrate the possibility to tilt the selectivity against the kinetic energy distribution at TS 1 .…”

“…Regarding the presence of shallow intermediates in branching PES and their influence on selectivity, we demonstrated in the past the successful application of the RMCF methodology to the rebound vs. dissociation dichotomous mechanism in C–H activation reactions by iron-oxo species. 27 In this context, a nascent carbon-centered radical can either (1) dissociate out of the solvent cage and become susceptible to trapping and further transformations, or (2) ‘ballistically’ recombine with the Fe–OH species in a nonequilibrium process. The kinetic energy distributions calculated using the RMCF protocol provided a clear and predictive rationalization of the selectivity observed in such cases.…”

“…Specifically, the presented method relies on the kinetic energy distribution within the reactive mode at TS 1 , as introduced by us and already applied to coupled electron-proton transfer (CEPT) reactivity and post-CEPT selectivity. 26,27 Here, we first concisely summarize the principles of the method (denoted as Reactive Mode Composition Factor -RMCF) and later assess its accuracy in the quantification of product ratios of bifurcating organic reactions and compare its performance with existing protocols. We also briefly discuss the chemical insight provided by the analysis and the limitations of the method.…”

A DFT study on the C–H oxidation reactivity of Fe(iv)–oxo species with N4/N5 ligands derived from l-proline

“…48 Beyond the rebound step, instead, the substrate radical may escape from the cage and go through the dissociation mechanism. 49,50 The non-rebound pathway has been observed in some non-haem Fe IV O complexes, such as [N 4 PyFe IV (O)] 2+ and [(Bn-TPEN)-Fe IV O] 2+ . 18,25 Based on experimental and theoretical studies, the dissociation of the substrate radical has been shown to be feasible.…”

From Synthetic to Biological Fe4S4 Complexes: Redox Properties Correlated to Function of Radical S‐Adenosylmethionine Enzymes

“…As demonstrated in Refs. [37][38][39][40][41][42][43][44], H-atom-abstraction (HAA) reactivity and selectivity are strongly influenced by the interplay of redox and acidobasic components of the HAA thermodynamic force, which are usually inter-dependent so that a lower E°is compensated to some extent by a higher pK a and vice versa. Thus, to probe the 5'-dAdo * properties relevant for enzymatic HAA reactivity, we first analyze electrochemical behavior of 5'-dAdo * in aqueous solution and then we compare it with its behavior in models of the [Fe 4…”