Dissertation committee:
Steven P. Nolan, Professor, Department of Chemistry, Ghent University
Georgios C. Vougioukalakis, Associate Professor, Department of Chemistry, National and Kapodistrian University of Athens
Andreas A. Danopoulos, Professor, Department of Chemistry, National and Kapodistrian University of Athens
Catherine S. J. Cazin, Professor, Department of Chemistry, Ghent University
Dimitrios Georgiadis, Professor, Department of Chemistry, National and Kapodistrian University of Athens
Thanasis Gimisis, Professor, Department of Chemistry, National and Kapodistrian University of Athens
A. Stephen K. Hashmi, Professor, Organic Chemistry Institute, Heidelberg University
Summary:
The remarkable properties of transition metals can be enhanced and tuned by appropriately designed ancillary ligands, such as phosphines and N-heterocyclic carbenes (NHCs), and this was a key discovery for the immense success of transition metal catalysis. The potential of NHCs as ancillary ligands has been thoroughly explored and undoubtedly, their most successful and well-known applications are in ruthenium-catalyzed olefin metathesis and palladium-catalyzed cross-coupling reactions, although their complexes with other transition metals have also been rapidly gaining popularity as efficient catalysts in an ever-growing multitude of organic transformations. In this thesis, the primary focus is on Au(I) catalysis, and, more specifically, on the development of sustainable and simple synthetic routes to Au(I)-NHC (pre-)catalysts and demonstrating their use in catalysis-relevant organometallic synthesis, mechanistic investigations into catalytic cycles, as well as the design of innovative catalytic systems for the synthesis of small organic molecules. Throughout this thesis, synthetic access to catalytically relevant species, an underappreciated aspect of catalysis, is highlighted. This concept encompasses the installation of NHC ligands on Au(I), and also the derivatization of the resulting [AuCl(NHC)] complexes with the purpose of also exploiting the anionic ligand. The identity of the anionic ligand dictates the applications of such complexes, ranging from catalysis/mechanistic studies and photonic applications to biological applications.
In Chapter 1, a general introduction regarding the synthetic methods towards Au(I)-NHC complexes is provided. The variety of methods for Au(I)-NHC bond formation is presented, and the development of the “weak base route” as the most versatile such method, is also described. Additionally, the definition of “golden synthons” is given, and the most historically important golden synthons of relevance to catalysis are presented.
In Chapter 2, our contribution to the establishment and mechanistic foundations of the weak base route is presented. Experimental and theoretical studies on the metallation of azolium salts lead to the proposal of a concerted metalation-deprotonation (CMD)-like mechanism, in which the intermediacy of metallate complexes appears to be relevant. This sheds light on the mechanistic principals behind the ability of weak bases to generate metal-NHC bonds. Additionally, the application of the weak base route on large-scale synthesis of [AuCl(NHC)] complexes is thoroughly described.
In Chapter 3, the development of a simple and sustainable route to Au(I)-Aryl complexes is described. These catalysis-relevant complexes are accessed using base-assisted transmetallation of aryl-boron reagents in desirable solvents. This route leads to an unprecedented variety of such complexes under mild conditions. One selected complex is synthesized on a multigram scale and utilized as a new golden synthon, providing access to catalytically active gold species, among others. Furthermore, the use of Au(I)-Aryls for C-H auration of terminal alkynes is presented and compared to the analogous reaction between terminal alkynes and the dinuclear derivatives of Au(I)-Aryls, leading to important insights into dual gold catalysis. Finally, the application of Au(I)-Aryls in dual gold catalysis is demonstrated.
In Chapter 4, the development of a sustainable route to Carbene-Metal-Amide (CMA) complexes of Au, Ag and Cu, is presented. This N-H metallation route provides access to various CMAs with applications in photochemistry and (photo)catalysis. Additionally, it provides a simple entryway into the application of CMAs in dual coinage metal catalysis, leading to efficient systems for alkyne hydrophenoxylation and hydrocarboxylation.
In Chapter 5, the synthesis of CMAs is further improved, focusing on the elimination of toxic organic solvents from the synthetic procedure. Additionally, an application of biorelevant, carboline-based CMAs beyond photochemistry and catalysis is shown, as they are screened as potential anticancer agents.
In Chapter 6, the complexes from the previous chapters are used as pre-catalysts in the hydrofluorination of alkynes with aqueous HF. The development of this innovative catalytic system led to unprecedented mechanistic insights regarding the effects of water and strong hydrogen bonds on gold catalysis. A new catalytic cycle for alkyne hydrofluorination is proposed, based on this unique system.
In Chapter 7, the development of catalytic systems which require no pre-functionalization or activation of [AuCl(L)] (L = ancillary ligand) complexes is described. Despite its inert character, the Au-Cl bond, which is ubiquitous in the most widely available gold complexes, can participate in hydrogen bonding. This feature provides a handle for activation, and we herein exploit the exceptional H-bonding ability of hexafluoroisopropanol (HFIP), to achieve this goal. The development of gold-catalyzed cycloisomerizations in HFIP provides a simple tool for the construction and functionalization of diverse organic molecules, while mechanistic investigations provide clear evidence for the hydrogen bonding interaction which permits catalysis.
In conclusion, this thesis demonstrates the importance of understanding and simplifying organometallic synthesis in gold chemistry, as well as implementing innovative designs in catalysis. The cutting-edge synthetic methods that were developed have already had an impact on the field of gold chemistry, while the use of various complexes as (pre-)catalysts, synthons, and tools for mechanistic studies as shown in catalytic systems developed herein, is expected to have a continuous impact on the field of gold catalysis in organic synthesis, be it in academia or in industry.
