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

Abstract

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.

Introduction

Palladium-catalyzed allylic substitutions allow very selective and mild allylations of C-,N- and O-nucleophiles. [1–13] The selectivity derives from steric and electronic properties of substrate and catalyst structures. "Side arm guidance" of nucleophiles with multifunctional phosphinoferrocenes [14–18] or "chiral pockets" in C₂-symmetric diphosphanes based on 2-(diphenyl-phosphino)benzoic acid amides [19–22] were applied especially successfully. Chiral P,N-ligands (e.g. phosphinooxazolines, phox) [23–27] provide in addition to steric control the possibility for "electronic differentiation", originating from the trans-influence [28] of different donor atoms. Nucleophiles (e.g. dimethylmalonate) normally favour addition to the "trans to phosphorus" position at the Pd-η³-allylic intermediate (Scheme 1). [29–42] This "trans to P" rule is supported by X-ray and computational analyses of Pd-η³-allylic intermediates, which exhibit longer and hence weaker Pd-C_allyl bonds trans to P (i.e. the stronger π-acceptor vs. N) and hence are more susceptible to nucleophilic attack (Scheme 1). [29–41] This electronic differentiation contributes to the high selectivity in Pd-catalyzed asymmetric allylic substitutions[19] and provides also an explanation for α-memory effects. [42–43] Computational model systems for P,N-ligands, i.e. PH₃ and para-substituted pyridines, have shown that cis-trans differentiations, i.e. the electronic site selectivity, of nucleophilic additions to Pd-η³-allylic intermediates is highest for electron poor pyridine ligands.[45]

Scheme 1.

Electronic and steric differentiations provide the basis for the high selectivity of P,N-ligands in Pd-catalyzed allylic substitutions. Effects are studied with P-N-model ligands with para-substituted, coplanar phosphabenzene and pyridine moieties.

To further explore origins of site selectivities based on electronic differentiations in Pd-catalyzed allylic substitutions, we here employ a more advanced model system with phosphabenzene, [45–48] and pyridine moieties for the crucial step of Pd-catalyzed allylic substitutions. Both P- and N-coordination sites are tuned electronically with para-substituents to reveal energetic and geometrical effects on cis- vs. trans- additions of nucleophiles to the Pd-η³-allylic intermediates (Scheme 1).

Results and Discussion

Electron donating or withdrawing groups (i. e. X, Y = HNMe, H, NO₂) 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 NMe₂ was employed as donor group, to retain lp-aryl conjugation. Ammonia serves as model nucleophile and attacks the Pd-η³-allylic 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).

Scheme 2.

Activation (ΔE_a) and reaction (ΔE_r) energies (kcal mol^-1), computed for the P,N-ligand model with tuneable electronic differentiation.

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 = NO₂ (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.

Table 1.

Activation (E_a) and reaction energies (E_r) reflecting electronic differentiations in transition structures (ΔE_a^cis-trans) and Pd-ene products relative to Pd-allyl and NH₃ reactands (pb = phosphabenzene; py = pyridine moieties)^[a]

pb-X	py-Y	Ea	TS	ΔEaTS	ErProd	ΔErProd
H	HNMe	cis	8.55	0.03	7.81	0.55
		trans	8.52		8.36
H	H	cis	6.38	0.17	5.14	0.52
		trans	6.21		5.67
H	NO2	cis	4.47	0.27	2.48	0.54
		trans	4.20		3.02
HNMe	HNMe	cis	10.47	-0.20 [b]	10.33	0.65
		trans	10.67		10.98
HNMe	H	cis	8.43	-0.03[b]	7.80	0.60
		trans	8.46		8.40
HNMe	NO2	cis	6.61	0.10	5.34	0.65
		trans	6.51		5.99
NO2	HNMe	cis	6.34	0.08	5.05	0.53
		trans	6.26		5.58
NO2	H	cis	4.24	0.23	2.26	0.43
		trans	4.01		2.70
NO2	NO2	cis	2.52	0.33	-0.25[c]	0.54
		trans	2.19		0.29

[a] B3LYP/6-31G* (C, H, N, P, O), /SDD (Pd) optimized structures. Energies include ZPE corrections scaled by 0.9806; [b] Negative ΔE_a^TS with E_a^cis < E_a^trans; [c] exothermic reaction energy.

Figure 1.

Transition structure for the energetically favored trans to phosphorus addition of ammonia at the Pd-η³-allylic intermediate (B3LYP/6-31G* (C, H, N, P, O), /SDD (Pd)). Bond distances are given in Å.

Figure 2.

Transition structure for the energetically disfavored cis to phosphorus addition of ammonia at the Pd-η³-allylic intermediate (B3LYP/6-31G* (C, H, N, P, O), /SDD (Pd)). Bond distances are given in Å.

Figure 3.

Transition structure for the energetically disfavored trans to phosphorus addition of ammonia at the Pd-η³-allylic intermediate (B3LYP/6-31G* (C, H, N, P, O), /SDD (Pd)). Bond distances are given in Å.

Figure 4.

Transition structure for the energetically favored cis to phosphorus addition of ammonia at the Pd-η³-allylic intermediate (B3LYP/6-31G* (C, H, N, P, O), /SDD (Pd)). Bond distances are given in Å.

The reaction energies (E_r) for ammonia addition to the Pd-η3-allylic intermediate show a similar preference: Pd-ene-adduct formation is favoured most for X, Y = NO₂ (E_r^trans = 0.29, E_r^cis = -0.25 kcal mol^-1) and becomes most unfavourable (i.e. endothermic) for X, Y = NHMe (E_r^trans = 10.98, E_r^cis = 10.33 kcal mol^-1, Table 1, Scheme 2). This points to a more π-donating character of the ene product relative to the allyl-cation reactant.

In agreement with the "trans to phosphorus" rule, [23–28] 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 (ΔE_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 = NO₂ (ΔE_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" (ΔE_a^TS = -0.20 kcal mol^-1, Table 1).

Figure 5.

Transition structure for the energetically favored trans to phosphorus addition of ammonia at the Pd-η³-allylic intermediate (B3LYP/6-31G* (C, H, N, P, O), /SDD (Pd)). Bond distances are given in Å.

Figure 6.

Transition structure for the energetically disfavored cis to phosphorus addition of ammonia at the Pd-η³-allylic intermediate (B3LYP/6-31G* (C, H, N, P, O), /SDD (Pd)). Bond distances are given in Å.

Figure 7.

Transition structure for the energetically disfavored cis to phosphorus addition of ammonia at the Pd-η³-allylic intermediate (B3LYP/6-31G* (C, H, N, P, O), /SDD (Pd)). Bond distances are given in Å.

Figure 8.

Transition structure for the energetically favored trans to phosphorus addition of ammonia at the Pd-η³-allylic intermediate (B3LYP/6-31G* (C, H, N, P, O), /SDD (Pd)). Bond distances are given in Å.

For each phosphabenzene moiety with X = H or NHMe or NO₂, the "trans to P" site selectivity ΔE_a^TS increases for pyridine substituents Y in the order NHMe < H < NO₂ (Figure 9, Table 1). Hence, there is apparently an additional effect, which controls the site selectivity ΔE_a^TS besides the electronic donor vs. acceptor properties of different ligand atoms, i.e. P vs. N. Via this effect; electron withdrawing groups (e.g. NO₂) give rise to the highest site-selectivities.

Figure 9.

For each phosphabenzene moiety, the site selectivities ΔE_a^TS increase with more electron withdrawing pyridine substituents (Y) in the order HNMe < H < NO₂ (cf. Table 1).

NO₂-substituted ligands give rise to earlier transition structures with longer (forming) H₃N-C_α bonds (Table 2, Figure 1 to Figure 8), e.g. trans-TS with X = Y = NO₂: H₃N-C_α = 2.04 Å (Figure 1). In contrast, amino-donor substitution leads to later transition structures with shorter H₃N-C_α distances, e.g. trans-TS with X = Y = NHMe: H₃N-C_α = 1.866 Å (Figure 3). This agrees with the more electrophilic properties of cationic Pd-allyl intermediates induced by electron withdrawing ligands.

Table 2.

H₃N-C_α, H₃N⁺-C_α and Pd-C_α distances (Å) of transition states and Pd-ene product complexes (pb = phosphabenzene; py = pyridine)^[a]

		Transition structures			Pd-ene product complexes
Pb-X	py-Y	Pd-Cα		H3N-Cα	H3N+-Cα
H	HNMe	cis	2.754	1.930	1.594
		trans	2.834	1.906	1.604
H	H	cis	2.728	1.968	1.588
		trans	2.815	1.947	1.598
H	NO2	cis	2.696	2.010	1.583
		trans	2.797	1.989	1.592
HNMe	HNMe	cis	2.767	1.898	1.598
		trans	2.850	1.866	1.611
HNMe	H	cis	2.745	1.932	1.593
		trans	2.840	1.902	1.603
HNMe	NO2	cis	2.718	1.969	1.588
		trans	2.824	1.940	1.598
NO2	HNMe	cis	2.733	1.970	1.587
		trans	2.805	1.957	1.596
NO2	H	cis	2.703	2.012	1.582
		trans	2.787	1.997	1.590
NO2	NO2	cis	2.674	2.051	1.578
		trans	2.765	2.040	1.586

[a] B3LYP/6-31G* (C, H, N, P, O), /SDD (Pd) optimized structures. Energies include ZPE corrections scaled by 0.9806.

These positions on the reaction coordinate indeed correspond to the site selectivity of the transition structures, i.e. ΔE_a^TS: earlier transition structures have higher, later transition structures exhibit lower "trans to P" selectivities (Figure 10).

Figure 10.

Higher site selectivities, i.e. larger ΔE_a^TS values, are found for earlier transition structures with larger H₃N-C_α distances.

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 electronic 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).

Figure 11.

Higher site selectivities, i.e. larger ΔE_a^TS values, are found for transition structures with closer, more intense Pd-C_α contacts.

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 ΔE_a^TS than more pronounced electronic differentiations with X, Y = NO₂ or NHMe (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 Pd-allyl 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 Pd-allyl (more ene like) unit of a late transition structure. Electron withdrawing (e.g. NO₂) 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 site-selectivity in Pd-catalyzed allylic substitutions.

Computational details

All structures were fully optimized and characterized by frequency computations as minima or transition structures using Gaussian 03[49] with standard basis sets [50–51] and the B3LYP [52–55] hybrid-DFT method. Zero point energies and thermochemical analysis were scaled by 0.9806.[56]