Mechanism and Origins of Selectivity for [Ga4L6]12- -Catalyzed SN2 Reaction with Benzylic Ether and Methanol: A Computational Mechanistic Study

doi:10.21203/rs.3.rs-4942851/v1

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Mechanism and Origins of Selectivity for [Ga4L6]12- -Catalyzed SN2 Reaction with Benzylic Ether and Methanol: A Computational Mechanistic Study

https://doi.org/10.21203/rs.3.rs-4942851/v1

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published 12 Nov, 2024

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Supramolecular catalysis often considered as the mimic of enzymatic catalysis, exhibits the properties of high reactivity and selectivity with various transformations. Bergman demonstrated that the reaction of chiral benzylic ester and methanol with Brønsted acid catalyst in bulk solution proceeded through an S_N2 mechanism and generate chirality-inversed product, while when the reaction occurred with the supramolecular [Ga₄L₆]^12- catalyst it formed the chirality-retained product. The detailed reaction mechanism as well as the origins of selectivity remains unclear. Therefore, in this work we have performed a comprehensive theoretical study on the nucleophilic substitution reaction catalyzed by both Brønsted acid and [Ga₄L₆]^12- catalyst. Our calculations are in agreement with experiment. Detailed analyses indicate that compared to that of a classical S_N2 reaction in bulk solution, after the encapsulation of the reactants in [Ga₄L₆]^12-, the same-side nucleophilic attack of the methanol with the leaving group is more favorable than the back-side attack, which is due to more favorable hydrogen bonding interactions and π-π stacking interaction between the reactants and the supramolecular cage. Understanding the mechanism and origins of the stereochemical outcome in the nucleophilic substitution reaction with the supramolecular host-guest catalysis would lead to the development of more efficient and selective transformations.

Enzymes could efficiently facilitate chemical reactions under mild conditions. It is thought that the hydrophobic cavity of enzymes plays a key role in capturing the substrate, stabilizing its conformation, creating a stable transition state, removing solvents, and releasing the product smoothly.^[1] This cavity also provides a specific microenvironment that promotes the occurrence of reactions.^[2] As a result, chemists are working on designing catalytic systems that mimic the unique environment found within enzyme pockets.^[3–4] Supramolecular coordination chemistry has the potential to be used as a material for creating mimic enzymes. By constructing a series of organic ligands with different sizes and shapes, it is possible to replicate the functioning of enzymes and host-guest interactions.

In recent decades, significant advancements have been made in the design and preparation of synthetic hosts, leading to a wide range of available supramolecules.^[5–6] Of these developments, metal-organic cages (MOCs) have emerged as particularly exciting. MOCs are formed by the self-assembly of metal ions and organic ligands, primarily driven by coordination rules. Certain MOCs possess enzyme-like cavities that can selectively recognize and en-capsulate guests.^[7–15] Upon encapsulation, substrates become separated from the reaction medium and are no longer within their solvation shells. The host possesses a specific cavity that restricts the guest’s movement, and this steric confinement can enhance the reaction rate or yield in the presence of host-guest interactions. One of the most remarkable MOCs to date is the tetrahedral host K₁₂[Ga₄L₆], where the ligand L is N,N-bis(2,3-dihydroxybenzoyl)-1,5-diaminonaphthalene, in initially developed by Raymond and co-workers.^[16] This MOC can function as an efficient catalyst for asymmetric synthesis in various organic transformations, including the photo addition of olefins,^[17] Aza-Cope rearrangement,^[18] Nazarov cyclization,^[19] carbonyl cyclization,^[20] hydroformylation,^[21] hydrolysis,^[22] and epoxi-dation of olefins.^[23] This type of MOCs can also facilitate unique reactions within their cavities, and the conformation and rotational freedom of the substrate are restricted, providing chances of leading to unusual regio- and stereo-selectivity. Additionally, when the active site has a chiral microenvironment, enantioselectivity can be effectively enhanced.^[24]

Raymond and colleagues have demonstrated that the inversed stereoselectivity of the nucleophilic substitution reaction of chiral 1-phenylethyl-2,2,2-trichloroacetimidate with methanol in bulk solution, can be influenced if it occurred within a confined supramolecular cage envir-onment, in which the stereoselectivity has been retented (Scheme 1).^[25] When enantiopure trichloroacetimidate (S)-1 was subjected to the [Ga₄L₆]^12- -Cage (2.5 mol%) in a buffered flood medium (CD₃OD/D₂O, pD = 8.0), the resulting benzyl ether exhibited 88% retention of stereo-chemistry. However, when 2.5 mol % of achiral phosphoric acid was used as the catalyst, the reaction underwent an S_N2 process and resulted in 84% stereo-inversion. Control experiments using either PEt₄-blocked cage or a small molecule as the catalyst yielded only modest inversion of the stereochemistry, confirming that the reaction occurred within the confined supra-molecular cavity. We propose that the reaction occurring in bulk solution undergoes classical back-side S_N2 nucleo-philic substitution process to provide the stereo-chemical inversed product. While in the supramolecular cage, it possibly proceeds via same-side nucleophilic substitution step (i.e., the methanol nucleo-philic approaches the carbon center from the same side with the leaving group) which results in retained stereo-selectivity. However, the detailed reaction mechanism and the origins of dramatically different selectivity remain uclear.

Although there is a growing interest in the catalytic and recognition capabilities of supramolecular hosts, a lack of complementary theoretical studies on their underlying reaction mechanisms persists. This may be due to the large size of metal-organic cages (MOCs) and their multiple metal centers. However, recent theoretical studies on MOCs have emerged, such as Ujaque^[26] and Head-Gordon’s^[27] computational investigations into the [Ga₄L₆]^12--catalyzed C-C reductive elimination reactions and Pavan’s characterization of the primary factors driving the trans to cis-isomerization of azobenzenes within a Pd(II)-based coordination cage.^[28] Additionally, Lusby, Duarte, and colleagues conducted computational study on the Diels-Alder reaction activity for two highly homologous metallo-cages, exploring binding and catalysis with multiple cage and substrate combinations.^[29] Recently, Xu group per-formed computational studies on the reactivity and selectivity of the Diels-Alder reaction of anthracene in [Pd₆L₄]¹²⁺ supramolecular cages.^[30] It is worth noting that other theoretical studies on supramolecular catalysis have primarily focused on organic systems without metal.^[31]

To enhance the understanding of the [Ga₄L₆]^12- cage-catalyzed stereoselectivity-retention S_N2 reaction, compre-hensive mechanistic studies are highly needed. Such studies not only have the potential to provide insights into this particular reaction, but also to other organic reactions catalyzed by the [Ga₄L₆]^12- cage, ultimately leading to the development of more efficient and selective MOC catalysis. In this regard, we employed computational studies using the ONIOM method,^[32] which was shown to be reliable and effective to provide accurate results with reasonable computational costs in recent study.^[30]

For calculation in bulk solution. All calculations were performed using the Gaussian 16 software.^[33] The structures were optimized using the B3LYP-D3(BJ)/6-31G(d,p) level of theory^[34], incorporating Grimme's empirical dispersion correction and BJ-damping (D3-BJ).^[35] Frequency calculations were carried out at the same level of theory to characterize each minimum (with no imaginary frequency) and transition state (with only one imaginary frequency), and intrinsic reaction coordinate calculations were conducted to ensure their accuracy. Single-point energy calculations were performed with 6-311 + + G(d,p) basis sets at the B3LYP-D3(BJ) optimized structures and with the SMD^[36] solvent model to account for solvent effects (water as solvent). The final free energies were calculated by summing the B3LYP-D3(BJ)/6-311 + + G(d,p) electronic energies and the B3LYP-D3(BJ)/6-31G(d,p) thermal corrections. It is well known that the entropic contribution estimated for 2-to-1 transformations in the gas phase is significantly overestimated compared to that in solution.^[37] Martin, Victuals, and Pratt (MHP)^[38] proposed a correction in which an additional 4.3 kcal/mol of entropic contribution is applied to a 2-to-1 transformation, and 8.6 kcal/mol to a 3-to-1 transformation. This correction has been used by other group to adjust for overestimation of the entropic contribution.^[39] In this study, we applied this correction to minimize the overestimation of the entropic contribution where there is applicable.

For calculation in supramolecular cage. The host-guest complexes were studied using the two-layer ONIOM (B3LYP-D3(BJ):PM6D3) method,^[40–41] in which B3LYP-D3(BJ)/6-31G(d,p) was employed as the high-layer method for guests and PM6D3 as the low-layer method for host. Single point energy calculations were performed using the 6-311 + + G(d,p) basis sets at the (B3LYP-D3(BJ):PM6D3) level. Solvent effects were considered in the single point energy calculations using the oniompcm = x solvent model, which was shown to be reliable in recent studies,^[42] with water as the solvent due to its much larger dielectric constant than methanol.^[43] The 3D geometry structures were created using CYLview software,^[44] and wave function analysis was carried out using Multiwfn 3.8.^[45] Weak interactions were investigated using the independent gradient model (IGM) method,^[46] and electrostatic potential (ESP) and transition state structure visualization were generated by Visual Molecular Dynamics (VMD) software.^[47] ΔGsol(ΔHsol) values are reported in kcal/mol in this study.

Brønsted Acid-catalyzed S _N 2 Reaction in Bulk Solution.

Firstly, we calculated the S_N2 reaction catalyzed by phosphoric acid in bulk solution. The S-enantiomer of the experimentally used 1-phenylethyl-2,2,2-trichloroacetimi-date (sub, Fig. 1) and the phosphoric acid (Cat) were chosen as the substrate and the catalyst in the calculations. The complexation of the trichloroacetimidate, methanol, and phosphoric acid leads to intermediate 1, which is slightly endergonic by 2.4 kcal/mol. In intermeidate 1, except the hydrogen bonding that between the methanol O-H bond and the catalyst’s oxygen atom, the O-H of the catalyst also forms a hydrogen bonding with the N atom of the trichloroacetimidate substrate. The methanol and the trichloroacetimidate group were located on opposite sites of the phenyl ring in 1. The phosphoric acid-assisted back-side nucleophilic substitution occurs via transition state 2-ts to produce intermediate 3, in which the chirality of the benzylic carbon has been inversed. This step has an activation free energy barrier of 7.9 kcal/mol and is exergonic by 11.7 kcal/mol with respect to sub. Finally, the release of the trichloroacetamide and regeneration of the phosphoric acid is exergonic by 4.7 kcal/mol to provide the ether product 8R, which has the opposite chirality compared to the starting reactant (sub).

Alternatively, the complexation of the three components could lead to intermediate 4, with the methanol and the trichloroacetimidate group locating on the same side of the benzylic carbon. Subsequently, the same-side nucleophilic attack takes place through 5-ts to generate 6, in which the chirality of the benzylic carbon has been retained. Similarly, the release of the trichloroacetamide and regeneration of acid catalyst lead to the production of the ether product 8S. This pathway has an activation free energy barrier of 9.2 kcal/mol, which is 1.3 kcal/mol higher than the pathway leading to 8R. Our calculations are consistent with experiment in which the chirality-inversed R-product was observed as the major product in bulk solution. We have also considered the other conformations of 1 and 4, in which the O-H of the catalyst forms hydrogen bondings with the O atom of the trichloroacetimidate (i.e., 1b and 4b, Fig. 1), however, calculations show that both are much more unfavorable in free energy and can be ruled out.

Distortion-interaction analysis^[48] were performed on the selectivity-determining transition states. It can be seen that the interaction energy (ΔE_int) between the substrate, methanol, and phosphoric acid is more favorable in 5-ts than in 2-ts. However, both the distortion of the substrate (ΔE_dist-sub) and the distortion of the catalyst (ΔE_dist-cat) is much larger in the former than the latter, which overcome the favorable interaction enengy and result in the unfavorable same-side attacking transition state 5-ts. Detailed geometric analysis shows that the larger distortion of the substrate in 5-ts comes from the more elongated C¹-O¹ bond (3.01 Å) compared to that in 2-ts (2.08 Å), which might be due to the more pronounced steric repulsion induced by the same-side methanol molecule with the leaving group. Similarly, the larger distortion of the phosphoric acid catalyst might be because of the elongated O³-H¹ bond in 5-ts (1.63 Å) than in 2-ts (1.57 Å).

Thus, the much larger unfavorable distortion of the substrate and catalyst in the same-side nucleophilic substitution transition state than in the back-side nucleophilic substitution transition state, mainly account for the selectivity of the S_N2 reaction between the 1-phenylethyl-2,2,2-trichloroacetimidate and methanol in bulk solution.

Supramolecular Cage-catalyzed S _N 2 Reaction.

Simplified Supramolecular Cage. The experimentally-used supramolecular cage is a chiral cage which is formed by the self-assembly of S-type chiral L ligands and Ga³⁺ (Fig. 3a and 3b). The R-type chiral ligand was also used to create supramolecular cage with different chirality.

It should be noted that different chiral cages provided same reaction results, indicating that the chirality of the product is independent to the chirality of the cages and the ligands. Based on this, we have simplified the tert-butyl group on the terminal substituent of the ligand to methyl group (Fig. 3c, Cage) to reduce the computational cost.

Conformation Search of the Host-substrate Complex. Firstly, we have performed conformational search for the substrate-encapsulated host-guest complex (see SI for details). Our calculations show that the phenyl ring on the substrate tends to be situated near the apex of [Ga₄L₆]^12-. This is also supported by the electrostatic potential (ESP) analysis and the non-covalent interaction (NCI) analysis. The ESP analysis shows that the electron-negative regions are located on the four apexes of the[Ga₄L₆]^12- molecule, which is due to the presence of the phenolic oxygen atoms (Fig. 4a). The ESP analysis on the substrate indicates that the hydrogen atoms on the phenyl ring posses positive electron densities (Fig. 4b). Therefore, it would tend to interact with the [Ga₄L₆]^12- cage at the electron-negative apex area. Importantly, such a conformation also brings stable π-π stacking interaction between the phenyl ring of substrate and the naphthalene ring of the ligand on the supramolecule, as shown by the NCI analysis (Fig. 4c, bottom left)

Reaction Pathway with One Methanol Molecule. After the determination of the most stable conformation of sub@C, the next step is the encapsulation of the the nucleophile, methanol, to proceed the nucleophilic substitution reaction. @@We have also calculated different conformations for the methanol encapsulated complex (i.e., sub@C with methanol) and the most stable one is given (1@C, Fig. 5) while all others are shown in Supporting Information (see SI for details).@@ Calculations show that the encapsulation of methanol is exergonic by 9.4 kcal/mol to form 1@C, in which the methanol forms hydrogen bonding interaction with the imine group of the substrate. Subsequently, the same-side nucleophlic substitution with the simutaneous proton transfer takes place via 2-ts@C to generate the chirality-rentention S-product 3@C. This step has an activation free energy barrier of 34.1 kcal/mol, which is dramatically high considering the reaction condition. It should be noted that the back-side nucleophilic substitution, which would lead to the chirality-reverse R-product, however, is unpractical because the proton transfer from methanol to imine during the nucleophilic attack is prohibited due to much longer distance (2-ts’@C). Overall, with one methanol molecule inside the [Ga₄L₆]^12- cage, the same-side nucleophilic substitution reaction occurs with quite high barrier and is unfavorable.

Encapsulation of Additional Solvent Molecule and Conformational search on the Adduct complex. Since the reaction with one methanol in the cage is unfavorable due to high activation barrier, we have further considered that whether additional solvent molecule encapsulated in the cavity that can promote the nucleophilic substitution process. Previously, there are studies that determine the number of solvents in supramolecular cages. Gregori Ujaque^[49] and coworkers used MD simulations to show that at maximum, two solvent molecules can be present inside the cavity of [Ga₄L₆]¹²⁻ with the encapsulated guest [(Et₃P)Au(I)(CH₃)₂]. The follow-up work by Gregori Ujaque^[50] also used MD simulations proved [Ga₄L₆]¹²⁻ encapsulated [R₃PAu(MeOH)(CH₃)₂] can accommodate additional MeOH, and the reaction rate is regulated by the presence of solvent molecule. In our system, mixed solvent (methanol:water = 1:1) were used. Given that in experiment the alcohol product, which was resulted by the nucleophilic attack of water, was observed as a side product, therefore, we considered an additional water present inside the cavity. That is, the starting intermediate for the nucleophilic substitution reaction is a host-guests complex, in which the substrate, one methanol, and one water are encapsulated inside the cage. It should be noted that the performed ab initio molecular dynamics simulation also supports that the metallocage host can encapsulate one methanol and one water together with the substrate (see SI for more details).

Reaction Pathway with Methanol and Water Inside the Cage. From 1@C, the encapsulation of one water into the cage leads to 4@C, which is slightly endergonic by 2.0 kcal/mol. It should be noted that we have also performed conformational search on this host-guests complex and 4@C is obtained as the most stable structure (Fig. 6, see also SI for more details).

In 4@C, water molecule forms hydrogen bonding interaction with both the imine group of the substrate and the methanol molecule, and methanol is placed on the same side with the leaving group. Subsequently, the same-side nucleophilic substitution occurs through 5-ts@C to provide the chirality-retained product 6@C. This step has an activation free energy barrier of 29.1 kcal/mol and is exergonic by 10.8 kcal/mol with respect to 1@C. The encapsulation of water could also lead to 7@C, in which the methanol is positioned at back-side with the leaving group. The following classical back-side nucleophilic substitution takes place via 8-ts@C to generate the chirality-reverse product 9@C. This pathway has a free energy barrier of 34.0 kcal/mol and is exergonic by 5.3 kcal/mol. By comparison, the pathway that leads to chirality-reversed product has 4.9 kca/mol higher free energy barrier than that leads to chirality-retained product, which is consistent with experiment.

Origins of Selectivity Inside the Metallocage. By detailed analysis of the selectivity-determining transition states, it is found that although both TSs have some steric repulsion between the substrates and the metallocage (shown in red dashed lines in Fig. 7), there are more favorable hydrogen bonding interactions in 9-ts@C than in 12-ts@C (shown in green dashed lines in Fig. 7). In addition, in transition state 9-ts@C, the methanol group and the leaving group position at the same side, making it possible for the back side of the phenyl ring of the substrate to approach the naphthalene ring of the cage in a parallel way. Indeed, there is a π-π stacking interaction between the phenyl ring of substrate and the naphthalene ring of the supramolecule in 9-ts@C (3.10 Å, shown in blue dashed line in Fig. 7). On the other hand, in 12-ts@C, the methanol attacks the benzylic carbon from the opposite side of the leaving group. Therefore, both sides of the phenyl ring were occupied, preventing the approach of the phenyl ring to the naphthalene ring of the supramolecule and resulting in no π-π stacking interaction. Thus, the more favorable hydrogen bonding interaction and π-π stacking interaction that favor the same-side nucleophilic substitution transition state inside the cage account for the enantioselectivity.

The Side Pathway Leading to Alcohol with Water as the Nucleophile. The side pathway that leads to the alcohol product has also been studied. In this reaction, water plays the role of nucleophile instead of methanol. As can be seen in Fig. 8, from 1@C, the encapsulation of water and rearrangement would generate 10@C or 13@C, which then proceed through same-side or back-side nucleophilic substitution transition states 11-ts@C or 14-ts@C, respectively, to produce the chirality-retained or chirality-reversed product complexes 12@C or 15@C. In agreement with experiment, the chirality-retained pathway (i.e. via 11-ts@C) is 1.1 kcal/mol more favorable compared to the chirality-reversed pathway (i.e., via 14-ts@C). More importantly, the pathway for formation of alcohol (i.e., 1@C → 10@C → 11-ts@C → 12@C) has a free energy barrier of 29.8 kcal/mol, which is 0.7 kcal/mol unfavorable compared to the formation of ether product (i.e., 1@C → 4@C → 5-ts@C → 6@C, Fig. 7), which is consistent with experimental observation that the ether is the major product.

In conclusion, we performed detailed computational studies on the phosphoric acid and [Ga₄L₆]^12-metallocage-catalyzed S_N2 reaction of 1-phenylethyl-2,2,2-trichloroacetimidate and methanol. Our calculations are consistent with the experiment. We found that:

For the phosphoric acid-catalyzed S_N2 reaction in bulk solution, the larger distortion of the substrate and catalyst in the same-side nucleophilic substitution transition state than in the classical back-side nucleophilic substitution transition state mainly account for the inversed stereoselectivity;
For the [Ga₄L₆]^12-metallocage-catalyzed S_N2 reaction, when only one methanol was encapsulated, the back-side nucleophilic substitution is unpractical because of the proton transfer from methanol to imine during the nucleophilic attack is prohibited due to much longer distance. However, the same-side nucleophilic substitution, which could generate the chirality-retained product, is also less likely due to high barrier (34.1 kcal/mol);
Water plays important roles in the [Ga₄L₆]^12-metallocage-catalyzed S_N2 reaction. It acts as a proton shuttle linking both the methanol nucleophile and the imine group of the substrate, making it possible for both the back-side and same-side nucleophilic attack. The existence of water also facilitates the same-side nucleophilic substitution process by lowering down the barrier to 29.1 kcal/mol;
The origins for the retained-chiralilty for the S_N2 reaction in the [Ga₄L₆]^12-metallocage are: (a) there are more favorable hydrogen bonding interactions between the reactants and the supramolecular cage in the same-side attack TS than in the back-side attack TS; and (b) in the same-side attack TS, the unoccupied side of the phenyl ring of the substrate forms favorable π-π stacking interaction with the naphathlene ring of the metallocage, which also stabilizes the transition state structure.

We believe that this work would shed light on the understanding of the mechanism and origins of selectivity in the [Ga₄L₆]^12--catalyzed organic reactions and provide a detailed mechanistic overview that may be difficult to obtain from experiments. We hope the findings of this research could also facilitate the development of more efficient and selective supramolecular catalysis.

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge at https://

Additional computational results, energies, and Cartesian coordinates of all reported structures, Figure S1-S7, and Table S1-S5 (PDF)

FUNDING

This work was supported by the Natural Science Foundation of China 21702126 and 21801155..

AUTHOR INFORMATION

Corresponding Author

Zheng-Xu Zhang - School of Chemistry and Chemical Engineering, Shandong University of Technology, Zibo 255049, People’s Republic of China; Email: [email protected]

Author

Ze-Hua-Sun - School of Chemistry and Chemical Engineering, Shandong University of Technology, Zibo 255049, People’s Republic of China

Author Contributions

The manuscript was written through contributions of Zhengxu-Zhang and Zehua-Sun. Zhang and Sun wrote the main manuscript text. Zhang prepared all figures and Sun prepared the supporting materials. All authors have given approval to the final version of the manuscript.

Notes
The authors declare no competing financial interests.

ACKNOWLEDGEMENT

We would like to thank the School of Chemistry and Chemical Engineering, Shandong University of Technology for providing computing resources and Dr. Liping Xu for his computational guidance.

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Scheme 1 is available in the Supplementary Files section.

No competing interests reported.

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Scheme1.tif
Scheme 1. The Nucleophilic Substitution Reaction of 1-Phenylethyl-2,2,2-Trichloroacetimidate and Methanol Cata-lyzed by Phosphoric Acid in Bulk Solution and by the [Ga₄L₆]^12- Metallocage Catalyst.

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Mechanism and Origins of Selectivity for [Ga4L6]12- -Catalyzed SN2 Reaction with Benzylic Ether and Methanol: A Computational Mechanistic Study

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