To further probe this distinct behaviour of 2-phenylpyridine, several substituted derivatives were prepared in order to finetune the Lewis basicity of the pyridine nitrogen: 2-phenyl-4methoxypyridine, 2-phenyl-4-(trifluoromethyl)pyridine, and 2phenyl-4-nitropyridine (prepared via palladium-catalysed crosscoupling reactions from the corresponding 2-chloropyridine analogue and phenylboronic acid). † The labelling reactions of these substrates were carried out in the same manner as those described above, with the data shown in Figure . LCMS analysis again allowed the isotopologue distribution in each reaction to be profiled over time. Our working hypothesis was that the more electron-rich congener (X = OMe, σp = -0.27) should lead to stronger binding to the metal centre, and therefore increase the proportion of d2-isotopologue relative to d1; while the opposite effect should be observed as electron density is withdrawn from the pyridine moiety (X = CF3, σp = 0.54; X = NO2, σp = 0.78). Indeed, the profiles from these reactions are qualitatively in agreement with this hypothesis. Most notably, there is a significant change in behaviour for the least electronrich substrate (X = NO2), which is consistent with weaker binding; an initial rapid increase of d1-isotopologue is observed, similar to the non-heterocyclic directing groups, with the d2isotopologue forming more slowly. However, the other two substrates (X = OMe, CF3) behave similarly to the parent 2phenylpyridine, with relatively small differences in rate and selectivity. No d3-or d4-isotopologue was detected for the nitrosubstituted analogue, suggesting negligible nitro-directed HIE; this is consistent with our previous observations regarding the kinetic behaviour of HIE reactions of substrates with multiple potential directing groups. DFT calculations were carried out to gain further insight into the processes occurring during the reaction. We have previously used DFT calculations to rationalise site-selectivity in several studies. As part of this investigation, only iridium protide complexes are considered in the calculations; in practice, the reactions involve iridium protide and deuteride complexes, but our focus here is on the events around substrate binding. Pathways proceeding via trans-dihydride complexes are not considered because these are likely to be considerably higher in energy than the corresponding cis-dihydride isomers due to the strong trans-effect of the hydride ligands. The model systems are considered in chloroform solution using the (implicit) SMD model and with explicit chloroform microsolvation where solvent binding to iridium is considered; additionally, data for DCM complexes and in DCM solvent can be found in the ESI, † with the same trends apparent in the DCM data as in the chloroform study. Free energies (at 323.15 K) with quasi-harmonic corrections (GoodVibes), at the M06-L/Def2-QZVP/SMD(chloroform)//M06-L/6-311G(d,p),SDD level of theory are used throughout. The possible mechanistic pathways are outlined in Figure , based on substantial previous experimental and computational work to understand the catalytic cycle and structure/reactivity relationships in these reactions. [IrD2(solvent)2(IMes)(PPh3)] + (I) is formed when Ir-1 is exposed to deuterium, and this species will then catalyse HIE of the substrate. Dissociation of solvent ligand would generate coordinatively unsaturated 16e species II, which can, in turn, bind dideuterium to form III, or bind substrate to form IV. Complex IV must then progresseither dissociatively via loss of solvent or associatively via V -to form agostic complex VI. Complex VI can then undergo C-H activation via TS1 to form the key iridacycle VII. The bound deuterium in complex VII would then exchange into the product via a 'hydrogen fluxionality' transition state and C-D bond formation, in the microscopic reverse of the C-H activation process. The resulting species VId might progress in two ways: