Book Description

Copper-catalyzed aerobic C-H oxidation strategies are of great synthetic interest and are under active development. Cu(II) promotes a wide range of oxidative coupling reactions and these reactions can be linked to aerobic catalytic turnover due to the facile oxidation of Cu(I) to Cu(II) by O2. However, the mechanisms of these reactions are not well understood. Cu(II) can promote single-electron oxidation of electron-rich substrates, but new reactions have been developed featuring substrates that are electron-deficient or appear unlikely to undergo single-electron-transfer (SET). Evidence for organometallic intermediates has been obtained in some of these reactions. This thesis describes mechanistic studies of Cu(II)-mediated C-H oxidations that were carried out in order to gain further understanding of factors that promote organometallic or SET mechanisms. Procedures for Cu(II)-mediated C-H oxidation of an amidoquinoline substrate were developed and divergent regioselectivity of functionalization was observed depending on reaction conditions. Experimental and computational analysis is consistent with a switch between organometallic and SET-based C-H oxidation pathways upon changing from basic to acidic reaction conditions. The presence of a Bronsted basic ligand on the Cu(II) center facilitates C-H activation by an organometallic mechanism, while acidic conditions enhance the Cu(II) reduction potential, thereby favoring SET. The results of this study show that a macrocyclic chelate is not required to achieve organometallic C-H activation by Cu(II). Kinetic studies of Cu(II)-catalyzed oxidative halogenation of the electron-rich substrates 1,3-dimethoxybenzene and phenol were performed. Though chlorination and bromination occur under similar reaction conditions, the mechanisms are different. Experiments indicate the chlorination mechanism is consistent with a single-electron-transfer mechanism in which successive equivalents of Cu(II)-halide oxidize the arene to an aryl-radical-cation and deliver a chlorine atom. This mechanism is different than the commonly proposed mechanism in which a Cu(II)-phenoxide undergoes intramolecular electron-transfer to generate CuI and a phenoxyl radical. The bromination mechanism is more consistent with electrophilic bromination by Br2, which may be generated from disproportionation of CuBr2. Aryl-Pd(IV) triazamacrocyclic complexes were generated which are analogous to known aryl-Cu(III) triazamacrocyclic intermediates in Cu-mediated aerobic aryl-C-H bond oxidation.