Energy Decomposition Analysis Reveals the Nature of Lone Pair-π Interactions with Cationic π Systems in Catalytic Acyl Transfer Reactions

Abstract

Lone pair-π (LP-π) interactions between Lewis basic heteroatoms, such as oxygen and sulfur, and electron-deficient π systems, are an important type of non-covalent interactions. However, they have been seldomly used to control catalyst-substrate interactions in catalysis. We performed density functional theory calculations to investigate the strengths of LP-π interactions between different lone pair donors and cationic π systems, and at different complexation geometries. Energy decomposition analysis calculations indicated that the dominant stabilizing force in LP-π complexes is electrostatic interactions and the electrostatic potential surface of the π system predicts the most favorable site to form LP-π complexes. Benzotetramisole (BTM) is revealed as a privileged acyl transfer catalyst that promotes LP-π interactions because the positive charge of the acylated BTM is delocalized onto the dihydroimidazole ring, which binds strongly with a variety of oxygen and sulfur lone pair donors.

Graphical Abstract

Through-space non-covalent interactions play a vital role in regio- and stereoselective catalytic transformations. Various types of non-covalent interactions with aromatic systems, including π-π, C─H-π, dipole-π, and ion-π interactions, have been exploited in transition metal catalysis, organocatalysis, and enzyme catalysis.^1,2 These interactions are crucial to anchor catalyst-substrate interactions to achieve desired reactivity and selectivity control. Lone pair-π (LP-π) interaction (Figure 1a) is another type of non-covalent interaction with π systems, which involves the stabilizing association with a lone pair of a Lewis basic atom such as oxygen and sulfur. LP-π interactions with electron-deficient π systems have been well recognized in structural biology.^3,4,5,6,7,8 However, the nature of LP-π interactions and their roles in catalysis are rarely explored.⁹

Figure 1.

a) Lone pair-π interactions and their applications in structural biology⁶ and catalysis.⁹ b) (R)-BTM-catalyzed site-selective acylation of glucosides.¹⁰

Recently, the Tang group developed a site-selective acylation of trans-1,2-diols in pyranoses^10,11 based on the LP-π interaction with the amidine-based catalysts, (R)- and (S)-benzotetramisole (BTM) (Figure 1b). This method has been further expanded by Wan et al. for the total synthesis of resin glycosides.¹² Because the intrinsic reactivities of the equatorial hydroxyl groups in trans-1,2-diols are similar, the non-covalent interactions between the acylated Ac-BTM catalyst and the pyranose substrate are the key to differentiate the hydroxyl groups and achieve high levels of selectivity. Density functional theory (DFT) calculations indicated that the site-selectivity is controlled by the LP-π interaction between the positively charged acylated BTM catalyst and the lone pair on an OH or OR group (named “anchoring oxygen”) adjacent to the hydroxyl group being functionalized. Because lone pairs are prevalent in carbohydrate substrates, understanding how different lone pairs interact with the π system of the catalyst will reveal factors controlling the selectivity of the catalytic acylation of carbohydrates and other transformations promoted by LP-π interactions. Here, we use DFT and energy decomposition analysis (EDA) calculations to explore the nature of LP-π interactions and factors affecting the strengths of such interactions with the acylated Ac-BTM catalyst and other cationic and neutral π systems.

We first studied the influence of geometrical parameters on the strengths of LP-π interaction. Using the intermolecular interaction between the lone pair of water and an unsubstituted Ac-BTM as a model, we evaluated how the LP-π binding energies (ΔE) are affected by the position of the oxygen atom (Figure 2a), the distance between the oxygen and the π system, and the orientations of the oxygen lone pair (Figure 2c). Favorable stabilizing LP-π interactions were observed when the oxygen atom is placed above either of the two five-membered rings in Ac-BTM (1-5). On the other hand, the LP-π interaction with the benzene ring of Ac-BTM is much weaker (6). To reveal the nature of the LP-π interactions and factors affecting their strengths, we performed EDA^13,14,15 calculations to separate the binding energy (ΔE) into several chemically meaningful energy terms, including: the distortion energies (ΔE_dist) of water and Ac-BTM to reach their geometries in the LP-π complex and various terms that contribute to the interaction energy (ΔE_int)—electrostatic interactions (ΔE_elstat), closed shell (Pauli) repulsions (ΔE_Pauli), London dispersion interactions (ΔE_disp), and orbital interactions (ΔE_orb), which include the polarization and charge transfer energies. The EDA calculations revealed that the electrostatic interaction (ΔE_elstat) is the largest component contributing to the stabilizing interactions in 1-5 (Figure 2b). In addition, ΔE_elstat is the dominant term that determines the different binding energies when the oxygen lone pair is placed at different positions above the Ac-BTM π system (see Figure S1). The relative strengths of the LP-π interactions in 1-6 also qualitatively agree with the electrostatic potential (ESP) surface of Ac-BTM. The strongest LP-π interactions occur when the oxygen is placed at the more positive regions on the ESP surface (i.e. above the dihydroimidazole ring, 1-4). On the other hand, the stabilizing LP-π interactions are diminished when the oxygen is placed above the benzene ring, which is the less positive region on the ESP surface. Dispersion (ΔE_disp), another important contributor to the stabilizing LP-π interactions, is generally weaker than ΔE_elstat and is not sensitive to the electronic properties of the π system. Orbital interactions (ΔE_orb) have small contributions to the LP-π interactions. The electrostatic nature of the LP-π interactions^16,17 indicates that these interactions are not directional and relatively less sensitive to distance because of the 1/r² relationship. Indeed, variations of the vertical distance (d_v) between the oxygen atom and the π system and the dihedral angle (θ) between the planes of H₂O and Ac-BTM (Figure 2c) led to relatively small changes in the binding energy. The LP-π interaction remains relatively strong (ΔE ≤ −4.5 kcal/mol) when d_v varies from 2.5 to 3.3 Å and when θ varies from 20° to 135°. EDA calculations indicated that electrostatic interactions are still the dominant factor at these geometries (Figures S3 and S4).

Figure 2.

(a) Binding energies (ΔE, in kcal/mol) of LP-π complexes of water with Ac-BTM calculated at the M06-2X/(O, S: 6-311+G(d,p); H, C, N: 6-311G(d,p))/SMD(chloroform)//M06-2X/6-31G(d) level of theory. (b) Energy decomposition analysis of the LP-π binding energy. (c) Effects of vertical distance (d_v) and dihedral angle (θ) on ΔE. (d) LP-π interactions in acylation transition states reported in Ref. 8.

The moderate sensitivity to the distance and dihedral angle between the LP heteroatom and the π system suggests that stabilizing LP-π interactions may exist in a variety of complexes with electron-deficient π systems. For example, in our previous work,¹⁰ we hypothesized that LP-π interactions are responsible for the stabilization of various acylation transition states with different pyranoses when an appropriate “anchoring oxygen” is present. Examination of these favorable transition state structures (Figures 2d and S6) indicated that the geometrical parameters of the LP-π complexes (d_v and θ) are all within the “strong interactions” range indicated in Figure 2c and the anchoring oxygen atoms are placed above the most positive regions on the ESP surface of Ac-BTM. On the other hand, when one of the parameters fall out of the favorable range (e.g. θ in TS2), the LP-π interaction is diminished, leading to an unfavorable transition state.

Next, we evaluated the LP-π interactions of Ac-BTM with different O and S lone pair donors (Table 1). The binding energies with dimethyl ether (8) and methanol (7) are slightly stronger than that with water (1). EDA calculations indicate that the electrostatic interactions only slightly increased from water to methanol and dimethyl ether while ΔE_disp increased by 2.3 and 6.0 kcal/mol, respectively. Consistent with the lower electronegativity of sulfur, the ΔE_elstat components of sulfur LP-π interactions are less negative than those with oxygen lone pairs. Nonetheless, the binding energies of complexes 9-11 are still relatively strong (−3.0 to −5.0 kcal/mol), as ΔE_disp becomes the dominant contributor. In both O and S LP-π complexes, methyl groups on the heteroatom increase the binding energy, indicating that the LP-π interactions with alkoxy and alkyl sulfide groups can be augmented by C─H-π interactions to provide greater stabilization. The strategy to combine LP-π and C─H-π interactions has been used experimentally in the BTM-catalyzed site-selective acylation of S-glucosides directed by the sterically encumbered adamantyl sulfide group.¹¹

Table 1.

LP-π interactions with different lone pair donors.^a

	1	7	8	9	10	11
ΔE	−6.1	−7.4	−8.6	−3.0	−4.4	−5.0
ΔEdist	0.3	0.3	0.3	0.7	0.8	0.9
ΔEint	−6.4	−7.7	−8.9	−3.7	−5.2	−5.9
ΔEelstat	−9.1	−9.5	−9.7	−3.9	−5.8	−6.6
ΔEdisp	−6.5	−8.9	−12.5	−6.4	−8.1	−8.6
ΔEorb	−1.6	−2.1	−2.8	−2.1	−2.7	−3.2
ΔEPauli	10.8	12.8	16.1	8.7	11.4	12.5
dv(Å)	2.66	2.66	2.66	3.13	3.13	3.13

^aAll energies are in kcal/mol.

Lastly, we investigated the magnitude and origin of LP-π interactions with other π systems (Table 2). Because DMAP was frequently used as an acyl transfer catalyst through a mechanism involving the acylated DMAP (Ac-DMAP) intermediate,^18,19 we considered two different geometries of the LP-π complex with the positively charged Ac-DMAP (12 and 13). In the most stable isomer (12), the oxygen atom of the LP donor is above the acyl group, a region with the most positive potential on the ESP surface of Ac-DMAP (Figure S7). When the LP donor is above the pyridine ring (13), the LP-π interaction becomes much weaker (−2.8 kcal/mol). This is in contrast to the LP-π interactions with Ac-BTM where the strongest interactions occur with the heterocycle adjacent to the acyl group. These results suggest that BTM is a more effective catalyst to promote LP-π interactions because of the better delocalization of the positive charge onto the heterocyclic π-system in Ac-BTM than to the pyridine ring in Ac-DMAP.

Table 2.

LP-π interactions with different π systems.^a

	1	12	13	14	15
ΔE	−6.1	−5.2	−2.8	−1.9	2.3
ΔEdist	0.3	0.1	0.1	0.3	0.0
ΔEint	−6.4	−5.3	−2.9	−2.2	2.3
ΔEelstat	−9.1	−8.2	−5.6	−3.4	1.9
ΔEdisp	−6.5	−5.3	−5.9	−4.5	−5.0
ΔEorb	−1.6	−1.7	−1.5	−0.8	−1.1
ΔEPauli	10.8	9.9	10.1	6.5	6.5
dv(Å)	2.66	2.63	2.63	2.81	2.81

^aAll energies are in kcal/mol.

The binding energy of LP-π complex with the neutral π system in C₆F₆ (14) is weaker than those in 1 and 12 and the LP-π interaction with benzene (15) becomes repulsive. Instead, the benzene/water complex favors a different geometry where the hydrogen atoms of water point towards the benzene ring.²⁰ EDA calculations corroborated the importance of electrostatic interactions on the strengths of the LP-π interactions with cationic π systems. Among the different LP-π complexes studied in Table 2, while ΔE_disp remains similar, ΔE_elstat values vary from negative (attractive) to positive (repulsive) and parallel the overall binding energies.

In conclusion, we have applied EDA calculations to study the nature of LP-π interactions between various O- and S-lone pair donors and positively charged aromatic systems that are relevant in catalytic acyl transfer reactions. The strengths of the LP-π interactions examined in this study are all mainly controlled by electrostatic interactions, which can be predicted by the ESP surface of the π-system²¹ and the electronegativity of the LP donor. Further investigations on the impacts of LP-π interactions in other catalytic acyl transfer reactions^22,23 are underway in our laboratories.