We elected to study three different scaffolds which each contain two chemically distinct C-H bonds capable of undergoing C-H activation to yield a 5-membered palladacycle (Fig. ). A wide range of picolinic acids are available commercially and we selected seven examples bearing both electrondonating (Me, MeO) and electron-withdrawing (CF3) substituents at a variety of positions around the ring, alongside the unsubstituted picolinic acid as a benchmark. In the case of the bornylamine scaffold, despite the proximity of the methyl C-H bond to the directing group, we had not observed C-H activation taking place at that site during our original study with an unsubstituted picolinamide directing group. Interestingly, in our evaluation of the substituted picolinic acid directing groups, it rapidly became apparent that the substituent on the directing group exerts a significant effect on the reactivity of the methyl group (Table ). As reported previously, the unsubstituted picolinamide 1a gives an excellent yield of monoarylated product 2a under our optimised reaction conditions, with no trace of methyl C-H activation. The 3-methylpicolinamide 1b also gives the monoarylated product 2b with complete selectivity and with the highest yield. Interestingly, upon changing the position of the methyl substituent to the 4 or 5 positions on the pyridine ring (1c/1d), a novel diarylated compound (3c/3d) was observed as a minor product, perhaps suggesting that the conformational or electronic effects of the substituent are able to facilitate C-H activation on the methyl group, although the C-H activation still evidently occurs preferentially at the CH2 in both substrates. Introduction of an electron withdrawing CF3 group at the 3-position (1e) increased the quantity of diarylated product formed, giving almost equal amounts of monoarylated product 2e and diarylated product 3e. The 5-CF3 derivative 1f gave the lowest overall conversion, with a mixture of monoarylated 2f and diarylated 3f products being generated. The 4-and 5methoxypicolinamides 1g and 1h gave similar overall yields of product, with small quantities of diarylated product in both cases. As a general rule, high overall yields were obtained with all of the picolinamides bearing the moderately electron-donating methyl group, with the 3methylpicolinamide giving the highest yield of monoarylated product 2b with no observable formation of the corresponding diarylated compound 3b. The 3-trifluoromethylpicolinamide 1e provided the largest quantity of diarylated product 3e as well as giving a high overall product yield. Control experiments (Scheme 1) demonstrated that the C-H insertion step for the initial methylene arylation reaction was not reversible as no deuterium exchange was observed at the methylene unit to give d1-1a upon heating 1a in the presence of Pd(OAc)2 and CsOAc in deuterated tert-butanol. Furthermore, the palladated complex 1a-Pd (L=CD3CN) generated from 1a and Pd(OAc)2/CsOAc in acetonitrile did not undergo deuteration upon treatment with either deuterated tert-butanol or deuterated acetic acid. In addition we observed that the monoarylated product 2e was not converted into the diarylated product 3e upon resubmission to the reaction conditions. This suggests that the selectivity in the Pd-catalysed C-H arylation is under kinetic control, and hence determined by the energy barriers of the C-H insertion steps. The diarylation product must be formed via two sequential C-H arylation processes, without dissociation of the palladium catalyst as dissociation of the palladium from the monoarylated product 2e seems to be irreversible.