Synthesis, Characterization and Oxidative Reactivity of Bio-inspired MnIII-Hydroxo and MnIII-Alkylperoxo Complexes

Abstract

Enzymes such as manganese lipoxygenase (MnLOX), manganese superoxide dismutase (MnSOD), and manganese-dependent homoprotocatechuate 2,3-dioxygenase (MnHPCD) employ the redox versatility of manganese to perform important biological reactions. The elementary steps in the catalytic cycles of some of these enzymes involve concerted-proton electron transfer (CPET) reactions featuring a mononuclear MnIII-hydroxo motif present in the enzyme active site. These MnIII-hydroxo motifs display hydrogen bonding with neighboring amino acid residues, but it is unclear how this hydrogen bonding interaction controls reactivity. This knowledge gap is addressed in this dissertation by the generation of synthetic MnIII-hydroxo complexes with and without intramolecular hydrogen bonding. Kinetic studies of these model complexes reveal the influence of this hydrogen bonding interaction on CPET reactions and offer insights into the potential role of the hydrogen-bonding interactions observed in the active sites of MnLOX and MnSOD.The driving force for CPET reactions depend fundamentally on the reduction potential and basicity of the MnIII-hydroxo unit. Therefore, the MnIII/II reduction potential and the pKa of the MnIII-hydroxo complexes can be modulated to control reactivity with substrates. This dissertation reports how steric perturbation was used to increase the MnIII/II reduction potential in an amide-containing N5- ligated MnIII-hydroxo complex. Using the 2-(bis((6-methylpyridin-2-yl)methyl)amino)-N-(quinolin-8-yl)acetamide (H6Medpaq) ligand, a sterically encumbered MnIII-hydroxo complex – [MnIII(OH)(6Medpaq)]+ was synthesized. The steric perturbation led to an elongated Mn-Npyridine bond, which causes the Lewis acidity of the Mn center to increase. The increased Lewis acidity consequentially increases the MnIII/II reduction potential. The increased MnIII/II reduction potential enhanced the CPET reactivity of the [MnIII(OH)(6Medpaq)]+ complex with O-H bond by three-fold relative to the complex without sterics – [MnIII(OH)(dpaq)]+ (dpaq = 2-[bis(pyridin-2ylmethyl)]amino-N-quinolin-8-yl-acetamidate). This show how structural perturbation can be employed to modulate thermodynamic parameters, which will eventually control reactivity. Alkylperoxomanganese(III) (MnIII-OOR) intermediates are proposed in the mechanisms of several manganese-dependent enzymes like MnLOX and MnHPCD. However, their characterization has been challenging due to their inherent thermal instability. Fundamental understanding of these important intermediates' structural and electronic properties is limited to a series of complexes with thiolate-containing N4S- ligands. These well-characterized complexes are metastable, yet unreactive in the direct oxidation of organic substrates. Because the stability and reactivity of MnIII-OOR complexes are likely to be highly dependent on their local coordination environment, we have generated two new MnIII-OOR complexes using an amide-containing N5- ligand. Using the H6Medpaq ligand, [MnIII(OOtBu)(6Medpaq)](OTf) and [MnIII(OOCm)(6Medpaq)](OTf) complexes were generated through the reaction of their MnII or MnIII precursors with stoichiometric amount of tBuOOH and CmOOH, respectively. Both new MnIII-OOR complexes are stable at room-temperature stable (t1/2 = 5 and 8 days, respectively, at 298 K in CH3CN) and capable of direct reactivity with phosphine substrates. These complexes are the most stable MnIII-alkylperoxo complexes reported thus far and the first MnIII-alkylperoxo complexes capable of direct oxidation of substrates. The stability of these MnIII-OOR adducts render them amenable for detailed characterization, including by X-ray crystallography for [MnIII(OOCm)(6Medpaq)](OTf), which allow obtaining metric information, like the MnIII-OOR O-O bond length for correlations with other MnIII-alkylperoxo complexes. Thermal decomposition studies support a decay pathway of the MnIII-OOR complexes by O-O bond homolysis. In contrast, direct reaction of [MnIII(OOCm)(6Medpaq)]+ with PPh3 provided evidence of heterolytic cleavage of the O-O bond. The MnIII-alkylperoxo adducts also undergo hydrolysis in the presence of water to generate the MnIII-hydroxo species, a reaction that mimics a step in the mechanism of MnLOX. These studies reveal that the local coordination sphere can tune both the stability and chemical reactivity of MnIII-OOR complexes.