Electronic Theses and Dissertations

Angel Mercado

Date

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

Committee Chair

Timothy Brewster

Committee Member

Charles Garner

Committee Member

Michael Brown

Committee Member

Tomoko Fujiwara

Committee Member

Xuan Zhao

Abstract

C–H activation has become a pivotal strategy in organic synthesis, allowing for the direct transformation of inert carbon–hydrogen bonds into functionalized products without the need for pre-activated substrates. While directed C–H activation using coordinating directing groups (DGs) has enabled regioselective transformations, the installation and removal of DGs add extra steps and reduce synthetic efficiency. Traceless directing groups, which can be installed and removed in situ or transformed into part of the final product, offer a solution to this challenge. This dissertation explores the design, synthesis, and evaluation of novel triazole-pyridine (TriPy) ligands as potential traceless directing groups for palladium-catalyzed C–H activation. The initial strategy involved creating TriPy ligands with substrate docking functionalities, such as imines and diols, to facilitate meta-selective C–H functionalization of benzaldehyde derivatives. Kinetic and thermodynamic studies demonstrated that these docking groups are capable of reversible substrate binding under reaction conditions relevant to C–H activation, suggesting their suitability for traceless directing strategies. Despite the promising characteristics of the ligands, experimental results showed that the intended directed C–H functionalization did not occur. Instead, unintended C–H activation of the solvent was observed, indicating that the ligands were not effectively directing the palladium catalyst to the desired C–H bonds. This led to a shift in focus toward the palladium-catalyzed C–H olefination of difluoroarenes, a class of compounds typically resistant to such transformations due to the strong C–F bonds and electron-deficient aromatic rings. Optimization of reaction conditions for the olefination of 1,4-difluorobenzene was conducted, including the use of N-acetyl glycine as an additive and dimethylformamide as the solvent at elevated temperatures. These conditions resulted in modest yields of the olefinated products. A preliminary substrate scope revealed that this methodology could be applicable to a variety of difluoroarene substrates, providing a new avenue for the functionalization of fluorinated aromatics. Recognizing the limitations of the initial TriPy ligands, the study proposes modifications to enhance their effectiveness. Suggestions include introducing electron-donating substituents to increase metal coordination strength, optimizing steric factors to stabilize reactive intermediates, and enhancing ligand flexibility for better metal-ligand interactions. In conclusion, while the original goal of developing effective traceless directing groups based on TriPy ligands was not achieved, the research offers valuable insights into ligand design and palladium-catalyzed C–H activation. The discovery of olefination reactions with difluoroarenes contributes to the advancement of C–H functionalization methodologies and provides a foundation for future studies aimed at improving ligand performance and expanding the scope of accessible transformations.

Comments

Data is provided by the student.”

Library Comment

Dissertation or thesis originally submitted to ProQuest.

Notes

Open Access

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