Abstract

Oxygenase metallo-enzymes are an inspiration for the development of one-step C-H bond hydroxylations reactions. Presented here are two synthetic models (cryptands LTEA and LTTA), that are inspired by the second-coordination sphere features of such enzymes. The reactivity of copper(II)- and iron(III)-hydroperoxo species with these cryptands were studied, as they are key intermediates proposed in the catalytic cycles of C-H bond hydroxylation performed by oxygenases. Ultimately, this work was developed to further our understanding of oxygenation reactions by guiding the reactivity of copper(II)- and iron(III)-hydroperoxo intermediates with second coordination sphere features.
The structure and the reactivity of copper(II) complexes of LTEA was influenced by the second coordination sphere. Reaction of the complexes with basic hydrogen peroxide in methanol led to the formation of copper(II)-hydroperoxo intermediates. The mechanism of the reaction was studied by low-temperature mass spectrometry, electron paramagnetic resonance and stopped-flow ultraviolet/visible spectroscopy. Both the starting complexes and intermediates were constrained by the cryptand to square-based geometries. The decomposition of the intermediates via self-oxidation was probed by deuterating select positions on the cryptand. A small kinetic isotope effect of 1.5, in conjunction with the analysis of the demetallated organic products, reveals that the cryptand steers the reactivity towards a direct oxygen-atom transfer to a tertiary amine on the cryptand, forming an N-oxide.
A novel cryptand, LTTA, was designed and synthesized in high-yields and was shown to be ditopic through X-ray crystallography and NMR spectroscopy. The reaction of iron(II)-triflate complexes of LTTA with hydrogen peroxide or iodosylbenzene led to an intramolecular aromatic C-H bond hydroxylation, to afford an iron(III)-phenolate species, which was characterized by mass spectrometry, electron paramagnetic resonance and stopped-flow ultraviolet/visible spectroscopy. The kinetic analysis from the reaction of the iron(II) complex with hydrogen peroxide led to the identification of an iron(III)-hydroperoxo intermediate, formed prior to the iron(III)-phenolate. The iron(III)-hydroperoxo is proposed to first undergo heterolytic cleavage to form a high-valent Fe(V)-oxo-hydroxo, a mechanism comparable to C-H bond activation in Rieske dioxygenases.