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Title: Hydrogenation and hydrogen isotope exchange : novel, selective catalyst and process development
Author: Mudd, Richard J.
ISNI:       0000 0004 5991 6320
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2016
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The field of iridium(I)-mediated processes has expanded over the past 50 years, with new avenues of research constantly opening. To this end, the Kerr group has developed a series of cationic iridium(I) catalysts bearing a bulky NHC/phosphine ligand sphere that can effectively mediate mild hydrogen isotope exchange and olefin hydrogenation processes. Having said this, with the ever-expanding scope of NHCs and the increasing ease of access to phosphines, the possibility still exists to further improve upon these complexes with lower catalyst loadings, faster reaction times, and an improved substrate scope. To this end, this thesis details some of the work achieved throughout the last 3.5 years. Within the first chapter, progress towards more efficient olefin hydrogenation is discussed. In the first instance, highly selective hydrogenation, through the use of a directing group was targeted. Initial investigations focussed upon manipulating the counterion to the cationic iridium(I) complexes in question, and manipulating the ligand sphere through changing the nature of the phosphine and NHC. This process generated new methods for the synthesis of NHC/phosphine catalysts, and was applied to the production of a number of novel complexes. Following on from this, a highly efficient reduction process was optimised, and the selectivity therein investigated. Following on from this, the equivalent asymmetric reaction was then studied, thus entering a new field of research within the group, and therefore, requiring the development of a completely new catalyst system. This process was guided by the non-asymmetric system, and synthesis of a number of model non-chiral complexes. After thoroughly testing the newly synthesised complexes, greater understanding was gained of the requirements for a highly enantioselective reaction, and, through this, to propose a plausible selectivity model and mechanism. In chapter two, we discuss the development of NHC/phosphine catalysts in hydrogen isotope exchange, with a partiular focus on the selectivity of the exchange process. Following on from previous work in the group, this first targets the use of weakly coordinating acids as a directing group, and the impact that addition of base has upon the selectivity of the reaction. Furthermore, understanding that drug design is moving away from planar molecules, towards non-planar, sp³-rich compounds, we also investigated the possibility of exchange at positions in a molecule other than an sp² aryl ring. This was initially observed when developing the hydrogenation methods discussed in chapter one, enabling selective sp² exchange in conjugated olefins. This new, highly selective method of labelling was examined through a combined experimental and computational investigation, leading to a thorough understanding of the mechanism and factors governing reaction selectivity. Having progressed from sp²-aryl to sp²-non-aryl exchange, the logical progression was to next investigate sp³ exchange. Through a detailed study three protocols were developed, enabling exchange on a wide range of sp³ hybridised sites, in pharmaceutically relevant systems. These new processes were investigated mechanistically and computationally to ascertain the mechanism and selectivity of exchange.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral