Synthetic models of dioxygen activation by mononuclear copper enzymes

Copper-containing proteins perform a wide range of important chemical reactions in biological systems. Many are involved in the activation of dioxygen for the functionalization of organic substrates. While the reactions these proteins carry out are well defined, the mechanisms of substrate oxidation are poorly understood. The goal of this research is to gain understanding of these reactions on a fundamental chemical level via the synthesis and characterization of small-molecule model complexes. Specifically, we aim to model the active sites and reactivities of the mononuclear copper enzymes dopamine beta-monooxygenase (DbetaM), peptidylglycine alpha-hydroxylating monooxygenase (PHM), and galactose oxidase (GAO). Generating 1:1 Cu-O2 adducts that serve as appropriate models for intermediates in these enzymes is challenging due to the tendency of copper complexes to dimerize in the presence of dioxygen. To target mononuclear adducts, a variety of sterically hindered copper(I) and copper (II) complexes have been synthesized and characterized.; Chapter 1 reviews relevant background literature on the biochemistry of DbetaM, PHM and GAO, as well as a summary of efforts in other laboratories to prepare mononuclear Cu-O2 adducts as models of these enzymes. Synthesis and characterization of Cu(II) complexes of bulky beta-diketiminate ligands, and their reactivity toward peroxides, are described in Chapter 2. Portions of this work have been reported previously.1,2 In Chapter 3, the synthesis, characterization and reactivity of a 1:1 copper-oxygen adduct supported by a bulky beta-diketiminate ligand are discussed; portions of the work have been communicated previously.1,3 The preparation and characterization of Cu(I) complexes of anilido-imine ligands is described in Chapter 4. These complexes react with O2 to form observable intermediates, one of which was structurally characterized. Portions of this work have been submitted for publication.4 The synthesis and characterization of Cu(I) complexes of sterically hindered alpha-diimine ligands is the focus of Chapter 5. Finally, the spectroscopic characterization of 1:1 and 2:1 copper-oxygen adducts supported by a tetradentate phenolate-based ligand are discussed in Chapter 6. Portions of this work were previously reported.5 We have also targeted new Cu(I)-phenolate complexes of tetradentate ligands, the synthesis and O2 reactivity of which will also be addressed in Chapter 6.; 1Spencer, D. J.; Aboelella, N. W.; Reynolds, A. M.; Holland, P. L.; Tolman, W. B. "beta-Diketiminate ligand backbone structural effects on Cu(I)/O2 reactivity: unique copper-superoxo and bis(mu-oxo) complexes." J. Am. Chem. Soc. 2002, 124, 2108--2109. 2Spencer, D. J.; Reynolds, A. M.; Holland, P. L.; Jazdzewski, B. A.; Duboc-Toia, C.; Le Pape, L.; Yokota, S.; Tachi, Y.; Itoh, S.; Tolman, W. B. "Copper chemistry of beta-diketiminate ligands: monomer/dimer equilibria and a new class of bis(mu-oxo)dicopper compounds." Inorg. Chem. 2002, 41, 6307--6321. 3Reynolds, A. M.; Lewis, E. A.; Aboelella, N. W.; Tolman, W. B. "Reactivity of a 1:1 copper-oxygen complex: isolation of a Cu(II)-o-iminosemiquinonato species." Chem. Commun. 2005, 2014--2016. 4Reynolds, A. M.; Gherman, B. F.; Cramer, C. J.; Tolman, W. B. "Characterization of a 1:1 Cu/O2 Adduct Supported by an Anilido-Imine Ligand." Inorg. Chem. Submitted. 5Jazdzewski, B. A.; Reynolds, A. M.; Holland, P. L.; Young, V. G., Jr.; Kaderli, S.; Zuberbuhler, A. D.; Tolman, W. B. "Copper(I)-phenolate complexes as models of the reduced active site of galactose oxidase: synthesis, characterization, and O 2 reactivity." J. Biol. Inorg. Chem. 2003, 8, 381--393.