UC Berkeley

The following dissertation discusses the development, mechanism, and computational studies of reactions involving transition metal complexes that form C–O and C–C bonds. These reactions include Ni-catalyzed oxidation of unactivated C(sp3)–H bonds, stereoselective synthesis of vicinal difluorides by the combination of Cu and Ir catalysts, and reductive elimination from Pd(aryl)(fluoroalkyl) complexes to form fluoroalkylarenes. Oxidative additions of C–H and C–Cl bonds to Ir and Pd complexes are also discussed.Chapter 1 is an overview of direct oxidations of unactivated, aliphatic C–H bonds involving metal-free organic oxidants, transition metal complexes, and enzymes. The synthetic applications and the mechanism of each oxidation are discussed in detail. Chapter 2 describes the mechanistic studies of Ni-catalyzed oxidation of unactivated C(sp3)–H bonds with meta-chloroperbenzoic acid (mCPBA) as the oxidant. Comparison of the selectivity of different oxidation reactions and deuterium-labelling experiments suggest that this Ni-catalyzed reaction occurs by a free-radical chain mechanism. Chapter 3 describes the development of a strategy to control the conformation of acyclic C(sp3)–C(sp3) bonds by synthesizing all four stereoisomers of vicinal difluorides with the combination of a chiral Cu catalyst and a chiral Ir catalyst. These vicinal difluoride products were synthesized in good yields and with high stereoselectivity. Due to the 1,2-gauche effect of the vicinal difluoride motif, each stereoisomer corresponds to a unique conformer of the acyclic C(sp3)–C(sp3) bond between the two C–F bonds. Chemical proteomic experiments suggest that biologically active molecules containing different stereoisomers of the vicinal difluorides bind differently to proteins. Chapter 4 describes the computational studies of reductive elimination from Pd(aryl)(fluoroalkyl) complexes to form fluoroalkylarenes. This work focuses on understanding the features of the fluoroalkyl ligand that affect the barriers to reductive elimination. Results from DFT calculations suggest that secondary orbital interactions between the Pd center and a π-acid or a hydrogen atom attached to the α-carbon of the fluoroalkyl ligand significantly stabilize the transition state for reductive elimination. In the absence of such orbital interactions, a more electron-withdrawing fluoroalkyl ligand leads to a higher barrier to reductive elimination than a less electron-withdrawing fluoroalkyl ligand. Chapter 5 explains the selectivity of Ir and Pd complexes for oxidative additions of aromatic C–H and C–Cl bonds. DFT calculations and energy decomposition analysis suggest that oxidative addition of a C–Cl bond to Ir and Pd complexes is more exergonic than that of a C–H bond whereas the barrier to oxidative addition of a C–H bond to Ir complexes is lower than that of a C–Cl bond. Palladium(0) complexes are highly selective for oxidative addition of C–Cl bonds over C–H bonds because oxidative addition of C–H bonds is endergonic. Such endergonicity is closely related to the weakness of Pd–H bonds. Iridium(I) complexes are highly selective for oxidative addition of C–H bonds over C–Cl bonds because charge transfer between Ir and the C–H bond in the transition state is more stabilizing than that between Ir and the C–Cl bond.