Development of the cross-coupling of alcohols with olefins via positional tuning of the counterion in transition metal catalysis

Kaster, Sven Hermann Michael

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https://hdl.handle.net/2142/124627 Copy

Description

Title

Development of the cross-coupling of alcohols with olefins via positional tuning of the counterion in transition metal catalysis

Author(s)

Kaster, Sven Hermann Michael

Issue Date

2024-03-15

Director of Research (if dissertation) or Advisor (if thesis)

White, M. Christina

Doctoral Committee Chair(s)

White, M. Christina

Committee Member(s)

• Sarlah, David
• Mirica, Liviu M
• Hergenrother, Paul J

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Ether
• Palladium
• C-H activation
• Counteranion
• Ligand Control
• Cross-coupling

Abstract

The ether bond ranks among the most commonly occurring linkage in natural products and bioactive molecules. The Williamson ether synthesis has consistently ranked among the most common methods for synthesizing these linkages. The Williamson ether synthesis is the archetypical example of a SN2-type reaction, in which a nucleophile attacks an electrophile through a bimolecular mechanism. Due to the poor nucleophilicity of alcohols, the nucleophile requires activation through deprotonation to become able to perform the SN2 reaction. Owing to the deprotonation, the formed alkoxide also increases in basicity, this ultimately leads to significant side reactions. This nucleophile/base dichotomy persists throughout all etherification reactions, even in recent transition-metal mediated strategies. Modern methods have attempted to develop etherification protocols by utilizing the native alcohol species in tandem with an activated electrophilic species, often carbocations or charged metal complexes, but these methods have struggled to provide an efficient, cross-coupling approach to accessing linear ethers. These struggles underscore a persistent challenge in bimolecular reactions, bringing the two reactive species together in a manner which allows the reaction to occur. We reasoned that two key principles dictate the ability for bimolecular reactions to occur: proximity and orientation. A potential solution could be through utilizing ligand design in tandem with counterion design to generate a system in which a charged metal intermediate can undergo ligand positioned ion-pairing, while a counterion approximates the incoming nucleophile at the reactive site. Pd/SOX catalysis affords an efficient method by which to access a charged Pd/π-allyl intermediate. We envisioned that this intermediate could afford, through ligand controlled positional tuning of an appropriate counterion, a solution to the challenges with cross-coupling etherification. The first chapter of this thesis will discuss the mechanistic work that elucidated the effects of oxyphosphate counterions and ligand geometry in promoting reactivity. Herein, we demonstrate utilizing DFT calculations, rates studies, X-ray crystallography, and in depth Nuclear Magnetic Resonance spectroscopy that counterion and ligand design can afford a general procedure for cross-coupling etherification. The cis-SOX ligand geometry is shown to be necessary for affording a sterically accessible localization of positive charge for the anionic counterion to associate with. The phosphate counterion is determined to play a symbiotic role in promoting reactivity. It must coordinate at the location where the positive charge is localized to engage in productive hydrogen bonded delivery of the incoming alcohol nucleophile to the desired site of functionalization. The second chapter of this thesis will detail the substrate scope of the Pd/SOX catalyzed etherification. The development of this proximity catalyst allows for unprecedented access to sterically and electronically complex allylic ethers. Furthermore, due to the nature and conditions of this reaction, high chemo-selectivity for base sensitive functionality, catalyst promote site-selectivity, and truncation of synthetic sequences will be demonstrated. Collectively, these examples underscore the power of ligand and counterion design exploitation proximity in combination with orientation to enable reactivity.

Graduation Semester

2024-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2024 Sven Kaster

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