Electronic differentiation competes with transition state sensitivity in palladium-catalyzed allylic substitutions

Electronic differentiations in Pd-catalyzed allylic substitutions are assessed computationally from transition structure models with electronically modified phospha-benzene-pyridine ligands. Although donor/acceptor substitutions at P and N ligand sites were expected to increase the site selectivity, i.e. the preference for "trans to P" attack at the allylic intermediate, acceptor/acceptor substitution yields the highest selectivity. Energetic and geometrical analyses of transition structures show that the sensitivity for electronic differentiation is crucial for this site selectivity. Early transition structures with acceptor substituted ligands give rise to more intensive Pd-allyl interactions, which transfer electronic P,N differentiation of the ligand more efficiently to the allyl termini and hence yield higher site selectivities.


Results and Discussion
Electron donating or withdrawing groups (i. e. X, Y = HNMe, H, NO 2 ) in para-positions of phosphabenzene (X) and pyridine (Y) units tune electronic characteristics of P,N-ligand models in Pd-catalyzed allylic substitutions (Scheme 1). The phosphabenzene and pyridine moieties are linked via C ar -C ar bonds and a methylene bridge retains planarity and limits conformational flexibility. NHMe rather than higher substituted NMe 2 was employed as donor group, to retain lp-aryl conjugation.
Ammonia serves as model nucleophile and attacks the Pd-η 3allylic intermediate cis or trans to phosphorus. This cis vs. trans site selectivity is employed as measure for electronic differentiation induced by the ligand system (Scheme 2). The lowest activation energies (E a , Table 1) for ammonia addition to the Pd-η3-allylic intermediate are apparent for strong electron withdrawing para-substituted phosphabenzene and pyridine units, i.e. X, Y = NO 2 ( Figure 1 and Figure 2, E a trans = 2.19, E a cis = 2.52 kcal mol -1 , Table 1). The highest activation energies result from electron donating amino groups X, Y = NHMe ( Figure 3 and Figure 4, E a trans = 10.67, E a cis = 10.47 kcal mol -1 , Table 1, Scheme 2). Such electronic tunings of the ligands strongly affect the reactivity and give rise to increased or decreased electrophilicity of Pd-allyl intermediates.
In agreement with the "trans to phosphorus" rule, [23][24][25][26][27][28] attack of ammonia is preferred for most X, Y combinations trans to P, due to the stronger π*/σ* acidity at P in phosphabenzene relative to N in pyridine (Table 1). [44] Surprisingly however, this electronic site selectivity, as it is measured from relative energies of the transition structures (∆E a TS ), is not largest for different X, Y donor-acceptor combinations ( Figure 5, Figure 6, Figure 7 and Figure 8), but is highest for X and Y = NO 2 (∆E a TS = 0.33 kcal mol -1 , Table 1). Likewise, the smallest electronic site "trans to P" selectivity is not found for X, Y donor-acceptor combinations, but for strong donating X and Y = NHMe. Here, the selectivity is so low, that it even inverts to "cis to P" (∆E a TS = -0.20 kcal mol -1 , Table 1   For each phosphabenzene moiety with X = H or NHMe or NO 2 , the "trans to P" site selectivity ∆EaTS increases for pyridine substituents Y in the order NHMe < H < NO 2 ( Figure 9, Table 1). Hence, there is apparently an additional effect, which controls the site selectivity ∆EaTS besides the electronic donor vs. acceptor properties of different ligand atoms, i.e. P vs. N. Via this effect; electron withdrawing groups (e.g. NO 2 ) give rise to the highest site-selectivities.
NO 2 -substituted ligands give rise to earlier transition structures with longer (forming) H 3 N-C α bonds ( Table 2, Figures 1 to 8), e.g. trans-TS with X = Y = NO 2 : H 3 N-C α = 2.04 Å (Figure 1). In contrast, amino-donor substitution leads to later transition structures with shorter H 3 N-C α distances, e.g. trans-TS with X = Y = NHMe: H 3 N-C α = 1.866 Å (Figure 3). This agrees with the more electrophilic properties of cationic Pd-allyl intermediates induced by electron withdrawing ligands.  Transition structures Pd-ene product complexes For each phosphabenzene moiety, the site selectivities ∆E a TS increase with more electron withdrawing pyridine substituents (Y) in the order HNMe < H < NO 2 (cf. Table 1)

Figure 9
For each phosphabenzene moiety, the site selectivities ∆EaTS increase with more electron withdrawing pyridine substituents (Y) in the order HNMe < H < NO 2 (cf. Table 1). The distance between Pd and the allylic systems decreases from early (allyl cation like) to late (ene like) positions on the reaction coordinate. A closer, more intense Pd-C α contact (e.g. 2.674 Å, Figure 2, Table 2) stronger delivers elec-tronic differentiation of the ligand, and hence "trans to P" selectivity. Hence, higher electronic site selectivity closely corresponds to intense Pd-allyl interactions with short Pd-C α distances ( Figure 11).
Apparently, the positions on the reaction coordinate influence the site selectivity even stronger than the electronic differentiation between P and N ligand atoms: No substitution (X = Y = H) gives rise to even higher ∆E a TS than more pronounced electronic differentiations with X, Higher site selectivities, i.e. larger ∆E a TS values, are found for transition structures with closer, more intense Pd-C α contacts     (Figure 11), due to higher TS-sensitivity originating from closer Pd-allyl contact.

Conclusion
In Pd-catalyzed allylic substitutions, the electronic site selectivity, i.e. the preference for "trans to P" addition, is affected by the intrinsic electronic differentiation of the ligand atoms, e.g. P vs. N. However, the sensitivity for this electronic differentiation depends on the intensity of the Pd-allyl interaction. A close Pdallyl distance in an early, allyl cation like transition structure delivers the electronic differentiation of the ligand system more efficiently to the allylic termini (C α ) than a more distant Pdallyl (more ene like) unit of a late transition structure. Electron withdrawing (e.g. NO 2 ) substituents in the ligand system generate earlier transition structures with more intense Pd-allyl interactions and higher sensitivity for electronic differentiations. Hence, both intrinsic electronic differentiation in the ligand and high TS-sensitivity appear to be crucial for high siteselectivity in Pd-catalyzed allylic substitutions.