Mechanistic Investigation of Directed C-H Activation Reactions by Group 10 Metals
Creators: name: Milbauer, Michael
Publisher: name: My University
Year: 2023
Subjects: subject: organometallic chemistry
subject: C–H activation
subject: aminoquinoline
subject: palladium
subject: nickel
subject: Chemistry
subject: Science

description: Transition metal mediated C–H activation catalysis is a powerful tool for the regioselective introduction of functional groups that obviates the need for pre-functionalized starting materials. Among the most prevalent ways to achieve this type of reactivity, is by utilizing a group 10 metal, most commonly palladium and nickel, and a directing group. This thesis describes research efforts centered around mechanistic understanding of directed C–H activation catalysis, using aminoquinoline and related directing groups. Chapter 1 provides a detailed overview of aminoquinoline-directed C–H activation catalysis with group 10 metals. This chapter covers the major challenges associated with gaining mechanistic understanding from these reactions, as well as limitations in the scope of these transformations. Chapter 2 focuses on probing aminoquinoline-directed C(sp3)–H functionalization catalysis with nickel. The design, synthesis, and characterization of a NiIV complex that serves as a putative high-valent catalytic intermediate is described in detail. Key design features for stabilizing the NiIV complex include the incorporation of a sigma-fluoroalkyl substituent and a picolinate ligand. The reaction of an anionic Ni(II) precursor with a diaryliodonium oxidant affords a Ni(IV) sigma-aryl adduct, which was characterized by NMR spectroscopy, HRMS, elemental analysis and X-ray crystallography. C(sp3)–C(sp2) bond-forming reductive elimination from this complex is studied in situ by NMR spectroscopy. Chapter 3 explores enabling aminoquinoline-directed C2–H activation of bicyclo[1.1.1]pentanes (BCPs) as well as other strained cycloalkanes (cyclopropane and cyclobutane) as model systems. The reactivity of each substrate in stoichiometric cyclometallation reactions with Pd(OAc)2 is explored as a function of supporting ligands. These studies show that the cyclopropyl and cyclobutyl substrates undergo cyclometalation at ≤60 ºC, while the BCP forms a dimeric coordination complex. Computational investigations of the cyclometallation with each substrate revealed that C–H activation has comparable activation barrier for all three substrates but the resulting palladacycle is thermodynamically uphill for BCP but not cyclopropyl or cyclobutyl. Consistent with these computational data, the chapter culminates in the observation of facile H/D exchange between all three substrates and t-BuOD-d10 at 60 ºC. Chapter 4 discloses our work exploring different directing groups for the C2–H activation of BCPs. This led to the computational prediction that a pyridine N-oxide directing group and dimethyl sulfoxide as a stabilizing ligand would lead to isolable palladacycles. Using these predictions, a series of cyclometalated BCP containing palladacycles was isolated and characterized. The functionalization of these complexes was achieved with aryl iodides as well as with molecular iodine. Future directions for the introduction of additional functional groups are also discussed.