Ligand Design for Gold Catalysis

Abstract

The field of gold catalysis has undergone significant development over the past two decades. Once considered largely inert with limited applications in catalysis, the discovery of π-activation with Au(I) cations revolutionized the field, revealing gold's unique reactivity and potential applications. However, the linear geometry of Au(I) species presents a challenge in developing new complexes for Au(I) catalysis, as it is difficult to translate steric information from a ligand on one side of the Au(I) atom to the reaction site on the opposite side. One strategy to induce selectivity in gold-catalyzed reactions is the encapsulation of a gold atom in a sterically demanding area. However, previously developed confined complexes are often supramolecular compounds and suffer from lengthy synthesis. The first part of this thesis is dedicated to the synthesis of a new type of confined Au(I)-cationic catalysts. Upon comparing the performance of our complexes with the traditional Au(I) catalyst, it was discovered that the confinement and steric loading around the reactive site of the designed catalyst enabled us to alter and reverse the selectivity observed in standard benchmark Au(I) catalyzed cycloisomerization reactions. The new complexes were tested across a range of cycloisomerization reactions, where they demonstrated high selectivity between exo/endo and E/Z products. Furthermore, the synthesized catalysts displayed a high degree of substrate selectivity, reacting exclusively with one isomer of a compound, a characteristic reminiscent of enzymes. It was also demonstrated that the new complexes could catalyze the regioselective hydration of alkynes, offering superior selectivity compared to traditional phosphine-based Au(I) complexes. These findings were corroborated through X-ray studies and the calculation of various steric parameters, which revealed that the developed complexes exhibit a high degree of steric loading around the reaction site. The second part of the thesis discusses the work on understanding Au(I)/Au(III) catalytic processes and the subsequent development of a new family of potent and highly tunable hemilabile (P^N) catalysts. Less than a decade ago, the field of external oxidant-free Au(I)/Au(III) chemistry started to develop rapidly due to the discovery that properly designed hemilabile ligands can greatly facilitate the challenging oxidative addition step in the Au(I)/Au(III) catalytic cycle. However, the advancement of this field is severely hindered by the dependency on a limited number of reliable Au(I)/Au(III) catalysts, highlighting a requirement for deeper understanding on key parameters. This understanding could facilitate the development of new catalysts and broaden the horizons for their future applications. The study began with an investigation into the mechanism of Au(I)/Au(III)-catalyzed alkoxycyclization, which subsequently led to the elucidation and exploration of the so-called “silver effect” in such reactions. The mechanism and rate-limiting steps were determined, and the findings were supported through experimental and Density Functional Theory (DFT) studies. This understanding paved the way for the design of a new family of highly tunable Au(I)/Au(III) catalysts, whose efficacy was demonstrated in various reactions. Subsequently, a novel C–S coupling reaction was developed using readily available thiotosylate reagents and an Au(I)/Au(III) catalyst to prepare the corresponding ArSTs compounds. The reaction was validated with over 40 examples, and the versatility of this substrate class in a range of modifications was demonstarted. Importantly, this is the first instance of accessing this class of compounds using readily available reagents. It was also found that Pd(0)/Pd(II) is not an effective catalyst in this reaction. The mechanism of this reaction was studied both experimentally and via DFT. In summary, the research presented in this thesis introduces novel classes of potent catalysts for both Au(I) and Au(I)/Au(III) catalytic processes. It was demonstrated that the distinct properties of Au-complexes can be meticulously adjusted through thoughtful ligand design. Furthermore, we conducted an in-depth examination of the Au(I)/Au(III) catalytic cycles, providing valuable insights that could guide future studies in this field.