Direct Aerobic Generation of a Ferric Hydroperoxo Intermediate Via a Preorganized Secondary Coordination Sphere.

Kate A Jesse,Alexander S Filatov,Sophie W Anferov,Maia E Czaikowski,Kelsey A Collins,Juan A Valdez-Moreira,John S Anderson

doi:10.1021/jacs.1c06911

Abstract

Enzymes exert control over the reactivity of metal centers with precise tuning of the secondary coordination sphere of active sites. One particularly elegant illustration of this principle is in the controlled delivery of proton and electron equivalents in order to activate abundant but kinetically inert oxidants such as O2 for oxidative chemistry. Chemists have drawn inspiration from biology in designing molecular systems where the secondary coordination sphere can shuttle protons or electrons to substrates. However, a biomimetic activation of O2 requires the transfer of both protons and electrons, and molecular systems where ancillary ligands are designed to provide both of these equivalents are comparatively rare. Here, we report the use of a dihydrazonopyrrole (DHP) ligand complexed to Fe to perform exactly such a biomimetic activation of O2. In the presence of O2, this complex directly generates a high spin Fe(III)-hydroperoxo intermediate which features a DHP• ligand radical via ligand-based transfer of an H atom. This system displays oxidative reactivity and ultimately releases hydrogen peroxide, providing insight on how secondary coordination sphere interactions influence the evolution of oxidizing intermediates in Fe-mediated aerobic oxidations.

Highlights

Enzymatic systems and, in particular, metalloenzymes mediate a fascinating array of reactions via a carefully evolved secondary coordination sphere
Enzyme active sites leverage effects such as hydrogen bonding, electron transfer pathways, and electrostatic effects to precisely tune the reactivity of metallocofactors.[1,2,11,3−10] One example illustrating the importance of the secondary coordination sphere is in oxidase chemistry
Molecular chemists have drawn inspiration from these elegant biological examples, and the use of ancillary ligands with designed hydrogen bonding networks,[20−23] hydrogen shuttling functionalities,[24−30] or redox reservoirs have emerged as promising strategies in transition metal reactivity and catalysis.[31−40] While these strategies are effective individually, natural systems are not limited to one interaction type in the secondary coordination sphere but instead leverage all of these effects

Summary

Introduction

In particular, metalloenzymes mediate a fascinating array of reactions via a carefully evolved secondary coordination sphere. The terminal oxidant in cytochrome P450 enzymes, Compound I, consists of an Fe(IV)-oxo which is generated from O2 via the delivery of proton and electron equivalents from cofactors and the protein superstructure Other enzymes, such as cytochrome C oxidase, selectively reduce molecular O2 to water with the controlled addition of reducing equivalents mediated by an elaborate secondary coordination sphere.[12−16] While the reactivity and ultimate products of oxidases are varied, the initial steps in O2 activation can be quite general, proceeding through initial binding of O2 to generate an Fe superoxide intermediate before further activation to an Fe(III)-hydroperoxo intermediate by the addition of a formal H atom from the active site.[12−19]. Synthetic examples of Fe(III)-hydroperoxo intermediates are almost always generated with exogenous reducing or acid equivalents.[41,42,51,52,43−50] There are effectively no examples of welldefined Fe(III)-hydroperoxo intermediates generated via biomimetic H-atom transfer from a designed secondary coordination sphere, with one lone example arising from adventitious activation of a supporting ligand.[53]

Methods

Results

Conclusion