Manipulating Selectivity and Reactivity in Palladium-Catalyzed Oxidation Reactions

Citation

Wickens, Zachary Kimble (2015) Manipulating Selectivity and Reactivity in Palladium-Catalyzed Oxidation Reactions. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z97S7KS9. https://resolver.caltech.edu/CaltechTHESIS:06082015-101231805

Abstract

Since the initial discovery of the Wacker process over half a century ago, the Wacker oxidation has become a premier reaction for the oxidation of terminal alkenes to methyl ketones. This thesis describes strategies for manipulating selectivity and reactivity in Wacker-type oxidations to provide synthetically useful transformations.

Chapter 2 describes how nitrite co-catalysts can be exploited in Wacker oxidations to reverse their typically high Markovnikov selectivity. Using these aerobic oxidation conditions, alkenes can be oxidized to aldehydes in high yield and selectivity. Preliminary mechanistic experiments are presented that are consistent with oxygen atom transfer from the nitrite catalyst to the substrate. The influence of proximal functionality on the new reaction is explored, yielding both synthetically useful transformations and further mechanistic insight.

Chapter 3 investigates how minor modifications to the nitrite-modified Wacker can interrupt the Wacker oxidation pathway, providing dioxygenated products using molecular oxygen as the terminal oxidant. A variety of functional groups are tolerated and high yields of 1,2-diacetoxylated products are obtained with a range of substrates. Mechanistic experiments are presented that demonstrate the kinetic competency of nitrogen dioxide to mediate the reaction and probe the nature of the reductive elimination event.

Chapter 4 details the development of a highly active Wacker-type oxidation capable of efficiently oxidizing internal alkenes, which are unreactive under classical conditions. Under these simple and mild reaction conditions, a wide range of functional groups are tolerated and molecular oxygen can be employed as the terminal oxidant. Furthermore, the regioselectivity in unsymmetrical internal alkenes is investigated.

Chapter 5 explores the origins of innate regioselectivity in Wacker oxidations. Systematic investigations of both internal and terminal alkenes illustrate that inductive effects are sufficient to dramatically influence Wacker regioselectivity. These observations lead to the development of a simple set of reactions conditions that strongly enforces Markovnikov's rule, even with substrates that provide mixtures of aldehydes and ketones under classical conditions.

Thesis Files