The hydrogen isotope exchange reaction conditions that were used to collect isotopologue profiles are shown in Scheme 2. The loading of iridium catalyst Ir-1 was selected to ensure good levels of deuterium incorporation during the reaction, while limiting the rate to allow sufficient data density to be achieved by manual sampling of each reaction (full experimental details are described in the ESI). † All reactions were carried out under identical conditions in glassware of the same size and shape. Our catalyst Ir-1 was selected due to its widespread use in a range of labelling reactions, and its high turnover frequency. Additionally, we have previously assembled a comprehensive set of data related to directing group selectivity using complex 1. The selected substrates represent a diverse range of directing group ability. The directing group strength, quantified relative to 2-phenylpyridine, decreases in the order 1-methyl-2phenylimidazole (10.13) >> 2-phenyloxazoline (2.80) ≈ 2phenylpyrimidine (2.66) > 1-phenylpyrazole (1.77) > 2phenylpyridine (1.00) >> acetophenone (0.06) > nitrobenzene (0.03) > ethyl benzoate (0.01). The isotopologue time course data for the labelling of each substrate are presented in Figure . The same timescale was used throughout this Figure to allow for the ready comparison of directing groups, but full reaction profiles can be found in the ESI. † Samples from reactions with heterocyclic substrates were analysed by high-performance liquid chromatography coupled to electrospray ionisation mass spectrometry (LC-ESI-MS), while those from the reactions of acetophenone, nitrobenzene, and ethyl benzoate were analysed by gas chromatography coupled to electron impact ionisation mass spectrometry (GC-EI-MS). The relative concentration of each isotopologue was determined by integration of the mass spectra, after corrections to account for the C content of the starting material. † The levels of overall deuterium incorporation determined from mass spectrometry data agree well with data obtained for the same systems by integration of the 1 H NMR spectra of aliquots withdrawn at the same timepoints. Analysis of the HIE reactions of non-heterocyclic substrates reveals an initial spike in d1-isotopologue, peaking at ca. 50% of the total substrate, followed by the gradual conversion of the d1-into the d2-isotopologue. Acetophenone is the most strongly directing of this substrate sub-class and shows the most rapid formation of d2-isotopologue. Substrates with a five-membered heterocycle directing group also show a pronounced peak in d1isotopologue, again at ca. 50% of the total substrate, but notably earlier in the reaction than the non-heterocyclic directing groups. These trends are broadly consistent with our initial hypothesis, as the heterocyclic directing groups are stronger than the non-heterocyclic directing units. However, pyridine and pyrimidine directing groups behave somewhat differently to the other substrates that were studied, and show that the situation is rather more complex. The labelling reaction of 2-phenylpyrimidine proceeds with almost identical levels of d1-and d2-isotopologues as the reaction evolves; 2-phenylpyridine shows both the d1-and d2isotopologue levels increasing steadily as the reaction proceeds, with the d2-isotopologue growing slightly faster the d1isotopologue.