From this complex, the free energy of activation for insertion into a C-H bond of the methyl group (transition state VIIIa) was found to be considerably lower than that for methyl group activation in the initial complex Ia via transition state IIIa (93.1 kJ mol -1 vs. 101.7 kJ mol -1 ). The corresponding calculations were repeated for the remaining picolinamide substrates 1b-1h. The free energy of activation for each of the C-H insertion steps is shown in Table For all compounds, the activation energy for initial CH3 insertion is considerably higher than for CH2 insertion (G ‡ = 15.9 kJ mol -1 on average), explaining why monoarylation at the CH3 is not observed. In all cases except for 1g, arylation of the CH2 leads to a lowering of the transition state energy for a subsequent CH3 insertion with this effect being most pronounced for substrates 1e and 1f (G ‡ = 10.3 kJ mol -1 and 11.0 kJ mol -1 respectively) which notably were the substrates which yielded the largest proportion of diarylated product. Given the fact that decomplexation of the monoarylated product 2 from the palladium appears to be irreversible (Scheme 1), the quantity of the diarylated product 3 obtained from each substrate probably reflects the relative rates of the CH3 insertion step and the decomplexation. In the case of substrate 1e, where the largest proportion of diarylated product was observed, the activation energy of the second CH3 insertion step (VIIIe) from the arylated palladium complex VIIe is comparable to that of the initial CH2 insertion (IIe) from complex Ie. In the case of substrates 1a and 1b, the decomplexation of the monoarylated product 2 from palladium is presumably much more rapid than C-H insertion into the methyl group so only monoarylated product is formed, even though the C-H insertion into the methyl group has a lower activation energy in the arylated product. To discover whether such calculations could be used to predict the selectivity for an untested directing group, we calculated the corresponding energy barriers for reactions of the 3-phenylpicolinamide derivative 1i (Scheme 4). Similar values (88.2, 103.0 and 94.0 kJ mol -1 respectively for the three C-H insertion transition states as shown in table 2) were obtained to the methyl derivatives 1c/1d so we expected that this substrate would provide ~10% of the diarylated product. 3-Phenylpicolinamide was synthesised according to a modified literature procedure, and coupled to bornylamine to give 1i. In the event, the arylation reaction of 1i gave 13% of diarylated product 3i alongside 65% of 2i (Scheme 4). We can conclude that the calculated energy barriers for the C-H insertion steps can only provide a qualitative guide to the likely reaction outcomes. This is a consequence of the difficulties of accurately modelling the decomplexation step which is in competition with the second C-H insertion reaction. Further work will be required to understand the complexation/decomplexation mechanisms in order to make more accurate predictions of the effect of different directing groups on the C-H insertion selectivity. We then set out to explore whether these directing group effects could be observed with other substrates. In contrast to the bornylamine framework, most acyclic scaffolds show a preference for methyl C-H activation over methylene C-H activation. The unsubstituted picolinamide 4a derived from (1-methylcyclohexyl)methylamine gives ~3:1 ratio of monoarylated product 5a and diarylated product 6a with the monoarylation occurring exclusively on the methyl group (Table ). Analysis of the 1 H and 13 C NMR spectra of 6a and comparison with calculated 1 H and C NMR shifts was used to assign the stereochemistry of the major isomer of 6a as the syn compound (Figure ). Interestingly, the 3-methylpicolinamide undergoes a more selective reaction with 57% of the monoarylated product 5b being isolated, alongside traces of diarylated compound 6b, with the balance of the material being unreacted starting material. The 4-and 5-methyl derivatives 4c and 4d give similar levels of selectivity with the former giving a high overall yield of arylated products (5c and 6c) which was comparable to the unsubstituted system 4a. On this amine scaffold, the trifluoromethyl derivatives (4e/4f) gave relatively low yields in the arylation reaction, as did the 4-methoxy derivative 4h. The 4-methoxy derivative 4g gave a good overall yield with reasonable selectivity for the monoarylated product.