Computationally Guided Ir(I) Catalyst Design for Hydrogen Isotope Exchange Reactions of Amino Acid and Peptide Molecules Computationally Guided Ir(I) Catalyst Design for Hydrogen Isotope Exchange Reactions of Amino Acid and Peptide Molecules Within the Kerr group there is considerable research into the development of novel Ir(I) catalysts for the introduction of heavy hydrogen isotopes into pharmaceutically-relevant drug molecules and motifs. Owing to the ~90% attrition rate within the drug discovery process throughout the pharmaceutical industry, early metabolism studies have become increasingly important to assess the properties of drug candidates. Indeed, isotopic labelling via hydrogen isotope exchange (HIE) has played a central role within these studies. Whilst a number of previously challenging functional groups within aromatic molecules can now be labelled using Ir(I) catalysts, directed HIE of sp3 C-H bonds of biologically relevant amino acid and peptide substrates remains relatively unstudied, with current methods displaying poor site selectivity and often loss of stereochemical integrity. Thus, an efficient and site selective labelling of amino acids and peptides is of great interest, and mild reaction conditions enabling retention of stereochemistry would constitute a significant advance within this area. Previous work within our laboratory has resulted in the development of a range of novel monodenate iridium(I)-based catalysts, and their activity has been understood through a combination of experimental and computational investigations. These complexes combine sterically encumbered N‑heterocyclic carbene and phosphine ligands. Within this project the amino acid substrates are more sterically encumbered around the site of activation, contain several Lewis-basic groups and, as such, a more bespoke ligand set may be required to deliver high levels of labelling. This could be achieved through the development of new monodentate ligand combinations or, indeed, novel chelated P-N ligand motifs. Whilst experimental work is ongoing, the use of DFT to investigate the energy of activation and, indeed, the energy of binding for several substrate and catalyst combinations would provide invaluable information to guide the targeting of specific ligands for synthesis and evaluation. Additionally, the reaction mechanism and transition state energies can be modelled using Gaussian09 to elucidate whether these more complex sp3 systems follow a similar mechanistic pathway to the previously studied sp2 C-H activation pathway. This will afford insight and aid both catalyst development and substrate choice. Computational support for our experimental observations is extremely attractive as this allows us to rationalise experimental findings, and to guide future catalyst design. In addition, our DFT results could aid us in predicting the outcome of more challenging substrates, or indeed the activity of more complex ligand systems which would otherwise require extensive synthetic investigation to access within the laboratory. For more information about the project contact William Kerr (email@example.com), Professor at the Department of Pure and Applied Chemistry at the University of Strathclyde, or Dr David Lindsay (firstname.lastname@example.org), Research Associate at the Department of Pure and Applied Chemistry at the University of Strathclyde. For a list of the research areas in which ARCHIE-WeSt users are active please click here.