Development of Group 10 Metal Catalyzed Decarbonylative Catalysis and Undergraduate Organic Chemistry 2 Lab Modules

Abstract

The development of novel methods to install fluoroalkyl groups into organic molecules is highly desirable due to the effects that fluorine atoms impart, such as metabolic stability and lipophilicity. Due to the commercial availability of fluorocarboxylic acid derivatives (RFC(O)X), we aimed to utilize these reagents and their derivatives in decarbonylative fluoroalkylative cross-coupling reactions. This works builds on literature examples of related decarbonylative reactions that form C–C bonds. Chapter 1 briefly introduces transition-metal catalyzed decarbonylative cross-coupling reactions and delineates the goal of this thesis, which is to use fluorocarboxylic acid derivatives to incorporate fluoroalkyl groups into molecules via decarbonylative coupling. The key considerations for reaction development (metal, ligand, RFC(O)X electrophile, aryl nucleophile) are discussed. Chapter 2 describes the development of a decarbonylative Pd-catalyzed aryl–difluoromethylation reaction that couples difluoroacetylfluoride (DFAF) with aryl boronate esters. This reaction was developed by interrogating the elementary steps of the catalytic cycle (oxidative addition, carbonyl de-insertion, transmetalation, and reductive elimination) to identify a pair of compatible coupling partners and a suitable Pd catalyst system, (SPhos)Pd0. Additionally, computational analysis established the presence of a stabilizing F2C–H---X electrostatic interaction that contributes to accelerating the key carbonyl de-insertion step of this transformation. Chapter 3 begins with the development of a decarbonylative C–H difluoromethylation reaction of azoles catalyzed by (XantPhos)Pd0. Stoichiometric syntheses revealed an unusual geometry of the putative catalytic intermediate, (XantPhos)Pd(CHF2)(OCOCHF2), which likely plays a role in the unique efficacy of Xantphos compared to other phosphine ligands for this reaction. Chapter 3 also details a systematic approach to building in complexity into the carboxylic acid coupling partner towards the ultimate goal of developing decarbonylative cross-coupling reactions of chiral acid derivatives. In this context, a (AdBu2P)Pd0-catalyzed difluorobenzylation is developed that is effective for a range of aryl organometallics with varying electronic properties. Chapter 4 details parallel investigations into the development of a Ni-catalyzed decarbonylative difluoromethylation reaction that couples DFAF with tributyl(aryl)stannanes. Thees studies reveal that tBuPPF is the optimal ligand for Ni0/II catalysis and that the Ni-catalyzed reaction exhibits a complementary substrate scope to the (SPhos)Pd0 one described in Chapter 2. Organometallic synthesis of model complexes was conducted and a catalytically-relevant Ni(CHF2)(F) complex was characterized by X-ray crystallography. These complexes will be used to elucidate the origins of the selectivity and electronic trends observed in our catalytic decarbonylative fluoroalkylation reactions. Chapter 5 shifts away from decarbonylative cross-coupling reactions and details the development of an organic chemistry 2 lab module for the CH216 course at the University of Michigan. The protocol was translated from a literature report that utilized deoxyfluorination of a carboxylic acid to access amide products. This project will be continued in a second FFGSI project with focus on developing an argument-based post-lab assignment to help students gain mechanistic insight from the experiment.