Investigations into the selectivity of iridium catalysts in the hydrogen isotope exchange of aromatic aldehydes and in hydroxyl-directed stereoselective hydrogenation

Student thesis: Doctoral Thesis


Iridium catalysts have found many uses in recent years, such as Crabtree’s catalyst, which has found great utility for hydrogen isotope exchange and hydrogenation reactions. Isotopic labelling is an important tool in many areas of chemistry, such as drug discovery, mechanism elucidation and quantitative analysis; thus, it is important that effective methods are available which allow incorporation of the required isotopic label. There are numerous methods for incorporation of hydrogen isotopes into molecules, many of which employ transition metal catalysts. Iridium catalysts have proved highly effective in this transformation, and a wide variety of directing groups have been investigated in attempts to broaden the scope of this process. Within the Kerr group, iridium catalysts bearing a combination of bulky N-heterocyclic carbene and phosphine ligands have been developed which have proved highly effective at mediating the hydrogen isotope exchange process. These catalysts allow hydrogen isotope exchange reactions to be carried out under mild conditions, with low levels of catalyst loading required, and improved catalyst stability compared to Crabtree’s catalyst. These highly active catalytic species have been applied to deuteration of a wide variety of compounds bearing many different directing groups, however the labelling of aromatic aldehydes has yet to be fully investigated. There are two distinct sites available for deuteration in these substrates, and whilst a highly active and robust catalyst system has been developed within the research group for formyl C–H labelling, the area of selective aryl labelling requires further development. These studies describe the development of a highly selective aryl labelling of aromatic aldehydes, starting with an extensive catalyst and solvent screen, as well as a design of experiment approach to further optimise the conditions. This resulted in a system which could be successfully used to label a range of aromatic aldehydes bearing different substituents and substitution patterns, achieving high incorporation of the deuterium label. The utility of labelled aldehydes was shown through further diversification of the labelled material, allowing access to labelled molecules which may not be easily accessible through other methods. During the optimisation for an aryl-selective labelling process, a catalyst was discovered which allows concurrent labelling of both the aryl- and formyl positions. Further optimisation of this global labelling process provided access to a range of materials with isotope incorporation at both aryl- and formyl-sites and was successfully applied to a range of aromatic aldehydes. The products of the concurrent aryl and formyl labelling were also diversified to demonstrate the applicability of this methodology. The iridium catalysts developed within the Kerr group have also found use in hydrogenation protocols. Crabtree’s catalyst has previously been found to give good levels of conversion for many alkenes. In some cases where a facial bias for hydrogenation exists, Crabtree’s catalyst has also been seen to give high levels of selectivity. However, while the stereochemical outcome for hydrogenation with heterogeneous metal catalysts is usually governed by steric effects, Crabtree’s catalyst can coordinate to Lewis basic functional groups, which can direct the site for hydrogenation, leading to a highly diastereoselective process. This high selectivity has also been observed with other iridium catalysts, and as such, it was hypothesised that the N-heterocyclic carbene/phosphine containing catalysts developed within the Kerr group should also be able to hydrogenate C–C multiple bonds efficiently and selectively. Several of the catalysts developed in the Kerr group have been shown to be efficient in hydrogenation catalysts, and through the investigations reported herein, are shown to be able to perform hydrogenation directed by hydroxyl functional groups with excellent selectivity. However, the catalytic process seems to be sensitive to the substrate used, and it has been discovered that etherification of allylic alcohol substrates can also occur, and in some cases, become the dominating pathway. Further studies reveal that the bulky Kerr group catalysts can have complimentary selectivity to Crabtree’s catalyst, proposed to be due to the ligand conformation, and that their selectivity can be sensitive to different solvents. The hydrogenation of α-terpineol was studied in depth to assess the effect of reaction parameters and catalyst structure on selectivity. Density functional theory calculations were used to give a clearer understanding of the hydrogenation, as well as the related etherification, and investigated the conformation of the utilised catalyst species, as well as how the substrate species may bind to access different catalytic pathways. The computational calculations were also used to investigate the mechanism for hydrogenation directed by the hydroxyl group, again investigating possible species along the pathway, and which may lead to the highly selective hydrogenated product.
Date of Award2 Dec 2021
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council)
SupervisorWilliam Kerr (Supervisor) & Craig Jamieson (Supervisor)

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