Theoretical Study on Asymmetric [2 + 2] Cycloaddition of an Alkynone

Article Cite This: Organometallics XXXX, XXX, XXX−XXX

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Theoretical Study on Asymmetric [2 + 2] Cycloaddition of an Alkynone with a Cyclic Enol Silyl Ether Catalyzed by a Chiral N,N′‑Dioxide-Zn(II) Complex Xiangxiang Meng, Jing Li, Yini Zuo, Changwei Hu, and Zhishan Su* Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, People’s Republic of China Downloaded via NOTTINGHAM TRENT UNIV on August 16, 2019 at 12:31:56 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: The reaction mechanism and enantioselectivity of the asymmetric [2 + 2] cycloaddition between an alkynone (R1) and a cyclic enol silyl ether (R2) were studied theoretically by the DFT method at the B3LYP-D3(BJ)/6311G**(CH2Cl2,SMD)//B3LYP-D3(BJ)/def2-SVP(CH2Cl2,SMD) theoretical level. The noncatalytic reaction occurred via a stepwise mechanism. The first C− C bond was constructed by coupling two pseudo radical centers generated at the most nucleophilic C2 atom in the cyclic enol silyl ether and the most electrophilic terminal Cβ atom in the alkynone, which was responsible for the regioselectivity of the reaction. The counterion NTf2− could stabilize the Zn(II) complex by coordinating to the center metal, forming a high-reactivity hexacoordinate Zn(II)complex intermediate. The bulky CF3 group in the NTf2− ion adjusted the blocking effect of o-iPr in aniline of the ligand toward the reactive site (that is, the Cβ atom in the alkynone) and induced the si face of the cyclic enol silyl ether to approach the alkynone from its less hindered re face, achieving a high enanotioselectivity of products. The Pauli repulsion between the Zn(II)-associated moiety and cyclic enol silyl ether fragment was the main contributor to the stereodifference of the two competing pathways in chiral N,N′-dioxide-Zn(II)-catalyzed [2 + 2] cycloaddition. The unfavorable steric repulsion between the o-iPr group of aniline in the ligand and tert-butyldimethylsilyl (TBS) in the cyclic enol silyl ether along the re face path translated into a more destabilizing ΔEPauli value, leading to the predominant cycloaddition product (P-RR) observed in experiments. Variation of the linkage and chiral backbone could affect the repulsion among the o-iPr in the ligand, the counterion NTf2−, and substrates, leading to different stereochemical outcomes. These results are in good agreement with experimental observations.

1. INTRODUCTION [2 + 2] cycloaddition is one of the most powerful synthetic methods to prepare strained cyclobutenes, which are important structural motifs for the synthesis of numerous natural products and bioactive compounds.1−4 In this transformation, the transition-metal complexes exhibit good catalytic behaviors.4 According to the electronic nature of the substrates, Lewis acid promoted [2 + 2] cycloadditions can be classified into three types: that is, (i) cycloaddition of electron-deficient alkenes and electron-rich alkynes,5 (ii) a Ficini reaction,6 and (iii) cycloaddition between polarized electron-rich alkenes and electron-poor alkynes.7 Metal complexes containing Cu(II),5b,7 Ti(IV),5a and Ru(II)4d,6a have been the most popular catalysts in [2 + 2] cycloaddition. In addition, other Lewis acids with Ir(I),4b Co(II),4i Ni(0),4k Au(I),4l,8 In(III),9 Pd(II),10 and Sn(IV)11 were also found to be efficient for the [2 + 2] cycloaddition reactions. Shao and co-workers developed Ir(I)-catalyzed asymmetric [2 + 2] cycloaddition of oxabicyclic alkenes and a terminal alkyne.4b The combination of [Ir(COD)Cl]2 with the chiral ligand (R)-xylyl-PHANEPHOS afforded the desired product in excellent enantioselectivity (94−98% ee). The © XXXX American Chemical Society

experimental investigations on the cycloaddition of propiolamides catalyzed by a Cu(II)-3-(2-naphthyl)-L-alanine amide complex indicated that the reaction occurred via a stepwise mechanism through a Michael aldol process. The propiolamide enantiofacially approached the re face of the silyl enol ether, achieving a bicyclic [2 + 2] reaction with 80% ee.7 Loh et al. found that an In(III) salt and trimethylsilyl halide could form a combined Lewis acid complex for [2 + 2] cycloaddition, affording cyclobutenes bearing aryl and carbonyl substituents with high chemo- and stereoselectivity. DFT calculations indicated that InBr3 initially abstracted a Br− ion from TMSBr to form TMS+ species, which in turn coordinated to methyl acrylate to lower the energy barrier of cycloaddition.9 In the nickel-catalyzed intermolecular [2 + 2] cycloaddition of conjugated enynes with alkenes, η3-butadienyl coordination was the key for the selective formation of cyclobutene.4k Zhang and co-workers assumed that the terminal chloral group in chloroalkynes could make the alkyne-gold complex more polarized toward the vinyl cation mesoisomer and hence more Received: May 5, 2019

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DOI: 10.1021/acs.organomet.9b00299 Organometallics XXXX, XXX, XXX−XXX

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Scheme 1. Asymmetric Cycloaddition of an Alkynone (R1) with a Cyclic Enol Silyl Ether (R2, Si = tert-Butyldimethylsilyl, TBS) Catalyzed by a Zn(II) Complex Formed by a Chiral N,N′-Dioxide Ligand (L1−L4) and Zn(NTf2)2

Scheme 2. Global Electrophilic Index (ω, eV) of an Alkynone (R1), the Global Nucleophilic Index of a Cyclic Enol Silyl Ether (R2) (N, eV), and Their Corresponding Local Reactivity Indices for Possible Reacting Sitesa

a

Two reaction pathways associated with the re face of R1 attacked by the si face of R2 are shown representatively. The activation energy barriers (ΔG⧧) are given in kcal mol−1 (Si = TBS).

1-indanone-derived cyclic enol silyl ether (R2). The key structural units in the chiral ligand and reactants affecting enantioselectivity were explored. In addition, the role of the counterion NTf2− in the catalytic reaction is revealed. These results are expected to explain the stereochemical outcome, providing useful information for the rational design and synthesis of new chiral N,N′-dioxide-Zn(II) catalysts.

reactive and capable of interacting with unactivated alkenes in intermolecular [2 + 2] cycloadditions.8 In addition, the cycloaddition could also be achieved by Brønsted acid catalysis,12 metal salt catalysis assisted by a chiral propiolic acid auxiliary,13 or even a photochemical reaction.14 Recently, Feng’s group developed a chiral N,N′-dioxide/ Zn(NTf2)2 catalyst for the asymmetric cycloaddition of alkynones with cyclic enol silyl ethers (see Scheme 1), affording the corresponding cyclobutenes with high yield and excellent enantioselectivity (up to 99% yield and 97% ee).15 Experimental results indicated that both the chiral backbone and the linker of the ligands significantly affected the selectivity and reactivity of the process. An L-ramipril-derived ligand with two −CH2 units in the linkage exhibited the best asymmetric induction. In comparison to other chiral N,N′-dioxide-metal salt catalysts,16 reports on Zn(II)-catalyzed asymmetric reaction have been limited.15,17,18 Furthermore, the reaction mechanism of asymmetric [2 + 2] cycloaddition of an alkynone mediated by N,N′-dioxide/Zn(NTf2)2 is still unclear. Herein, we adopted the DFT method to study the reaction mechanism of cycloaddition between an alkynone (R1) and a

2. COMPUTATIONAL DETAILS All calculations in this work were performed using the Gaussian 09 program package.19 Geometries were optimized in dichloromethane (CH2Cl2) solvent at the B3LYP-D3(BJ)/def2-SVP level. Frequency analysis was performed to verify the characteristics of all optimized structures as minima or transition states and to derive the thermochemical corrections for the free energies at 263 K.15 The self-consistent reaction field (SCRF) method based on the universal solvation model SMD was adopted to evaluate the effect of the solvent.20 Dispersion corrections were considered with Grimme’s D3(BJ) method in optimization.21 The intrinsic reaction coordinate (IRC) path was traced to check the energy profiles connecting each transition state (TS) to the two associated minima of the proposed mechanism.22 To gain insight into the electronic property of B


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Figure 1. Energy profiles for noncatalytic cycloadditions between alkynone (R1) and cyclic enol silyl ether (R2). Relative Gibbs free energies are given in kcal mol−1 (Si = TBS).

Figure 2. Optimized geometry (a) and the ELF attractors (V(Cβ) and V(C2)) and the corresponding average electron populations (b) of transition state 1-TS1 associated with the formation of the C2−Cβ bond along path 1. stationary points, the electrostatic potential (ESP) on the molecular van der Waals (vdW) surface,23 natural bond orbitals (NBOs),24 and reactivity index analysis (electrophilicity index ω and nucleophilicity index N) of the reactants were performed at the B3LYP-D3(BJ)/6311G**(SMD,CH2Cl2) level.25,26 The corresponding local reactivity indices (ωk and Nk) were obtained by the equations ωk = ωPk +

Nk = NPk

molecular orbital (KS-MO) model. EDA calculations were performed using the Amsterdam density functional (ADF) program35 at the B3LYP-D3(BJ)/TZP level. Unless specified, the Gibbs free energies corrected by both solvation and zero-point vibrational effects at the B3LYP-D3(BJ)/6-311G**(SMD,CH2Cl2)//B3LYP-D3(BJ)/def2SVP(SMD,CH2Cl2) level at 263 K15 are used in the discussion.

(1)

−

3. RESULTS AND DISCUSSION 3.1. Mechanism of the Noncatalytic Reaction. First, the cycloaddition between an alkynone (R1) and a cyclic enol silyl ether (R2) in the absence of catalyst was studied (see Schemes 1 and 2). Four transition states associated with different orientations of aromatic rings in the two reactants were located (see Figure 1 and Figure S1). Two enantiomers (P-RR and P-SS) were produced via a stepwise mechanism along path 1 (or 1a) and path 2 (or 2a), respectively. As shown in Figure S2, suffering from the repulsion of tert-butyldimethylsilyl (TBS), the phenyl group in the alkynone (R1) tended to be positioned on the same side with the aromatic ring of cyclic enol silyl ether (R2). Accordingly, the energy barriers along path 1 (or 1a) were lower than those along path 2 (or 2a) by 6.4 kcal mol−1 (C2−Cβ bond formation) and 7.7 kcal mol−1 (C1−Cα bond formation). An electron localization function (ELF) topological analysis indicated that the formation of a C−C bond involved the coupling of two

(2) Pk+

and nucleophilic Parr where the electrophilic Parr functions functions Pk− were obtained by Mulliken atomic spin density (ASD) at the radical anion and the radical cation of the corresponding reagents. The topological analysis of the electron localization function (ELF)27 obtained by the Multiwfn program28 was used to rationalize the electron behavior of reactants. Activation strain analysis (ASM)29,30 (or distortion/interaction model31) was performed by the Gaussian 09 program to gain insight into the physical factors controlling the height of the activation barriers and reactivity trends upon changing the structure of the reactants.32 The energy barrier (ΔE) was decomposed into the distortion energy (ΔEstrain) and the interaction energy (ΔEint) along the reaction coordinate ζ. Moreover, ΔEint between reacting species was further divided into the electrostatic interaction (ΔVelstat), Pauli repulsion (ΔEPauli), orbital interaction (ΔEoi), and dispersion effect (ΔEdisp) (i.e., ΔEint = ΔVelstat + ΔEPauli + ΔEoi + ΔEdisp) by energy decomposition analysis (EDA)33,34 according to the Kohn−Sham C


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Figure 3. Hexacoordinate Zn(II) complex (L2-COM). The hydrogen atoms of the ligand are omitted for clarity.

Scheme 3. Catalytic [2 + 2] Cycloaddition between an Alkynone (R1) and a Cyclic Enol Silyl Ether (R2) Mediated by an L2Zn(II) Catalyst (CAT)a

a

The schematic mechanisms involving a hexacoordinate Zn(II) complex (L2-COM) and a pentacoordinate Zn(II) complex (L2-COM-P) along the si face path are shown as representatives.

3.2. Mechanism of the Catalytic Reaction. The mechanism of cycloaddition between an alkynone (R1) and a cyclic enol silyl ether (R2) mediated by a chiral N,N′dioxide-Zn(II) complex (CAT) was further studied at the same theoretical level. On the basis of the X-ray crystal structure of the N,N′-dioxide-Zn(II)17,18 complex and our previous works,37−39 a hexacoordinate Zn(II) complex was considered to be an active species. We first focused on the Zn(II) complex containing a chiral N,N′-dioxide ligand L2 with two CH2 groups in the linkage (see Scheme 1, m = 1), which was reported in experiments.15 The electrostatic potential (ESP) analysis in Figure S4 indicates that more electronic density accumulated on the oxygen atom in the carboxyl group (not the alkynyl moiety) of the alkynone than on the oxygen of the cyclic enol silyl in R2. These results suggested that the alkynone could easily interact with Zn2+ by the oxygen atom via model II (see Figure S5), contributing to the lowest Gibbs free energies of formation (ΔG) of hexacoordinate Zn(II) complexes (see Table S1). Considering the fact that there existed different conformations of the counterion NTf2− as well as orientations of the indene moiety in R1, four possible hexacoordinate Zn(II) complexes were optimized, and their low-energy geometries were located (L2COM−L2-COM-c, see Figure S6). Furthermore, the corresponding catalytic [2 + 2] cycloaddition of the alkynone with the cyclic enol silyl ether were studied. The calculations indicated that the reaction mechanisms starting from the four

pseudo radical centers generated at the most nucleophilic terminal C2 center (Nk = 1.78 eV) in R2 and the most electrophilic Cβ center (ωk = 0.61 eV) in R1 (see Scheme 2). The average electron populations accumulated on the two monosynaptic basins (V(Cβ) and V(C2)) in 1-TS1 were predicted to be 0.30 and 0.48 e, respectively (see Figure 2). The C2−Cβ bond formation occurred accompanied by electron density flowing from the cyclic enol silyl ether (R2) to the alkynone (R1), with a global electron density transfer (GEDT) of 0.39 e.36 To understand the regioselectivity of the cycloaddition reaction, the reaction mechanism involving the C2−Cα (not C2−Cβ) bond formation for the regioselective product P-RR-1 was also studied. Path 3 corresponding to the attack of the re face of the alkynone by the si face of the enol silyl ether was analyzed as a representative case (Scheme 2). From the viewpoint of energy, the relative Gibbs free energies of the two transition states (3-TS1 and 3-TS2) along path 3 were higher than those along path 1 by 17.5 and 18.5 kcal mol−1 respectively, indicating that it was difficult to form the product P-RR-1 (see Figure 1). ASM analysis indicated that the high activation barrier via transition state 3-TS1 could be mainly attributed to a more destabilizing deformation energy (ΔEstrain) of the two reactants in the construction of the C2−Cα bond along path 3, which was responsible for the good regioselectivity result observed in experiment (see Figure S3 in the Supporting Information). D


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Figure 4. Energy profiles of asymmetric cycloaddition between an alkynone (R1) and a cyclic enol silyl ether (R2) catalyzed by the L2-Zn(II) catalyst (CAT) along the L2-si and L2-re paths. Relative Gibbs energies are given in kcal mol−1. The reaction pathways involving the pentacoordinate Zn(II) complex (L2-COM-P) without a NTf2− anion are denoted as L2-re-P and L2-si-P paths, respectively.

Figure 5. Optimized geometries of transition states along the L2-si and L2-re paths. The relative Gibbs energies are given in kcal mol−1.

E


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Figure 6. (a) ASM of catalytic [2 + 2] cycloaddition between an alkynone (R1) and a cyclic enol silyl ether (R2) along the reaction coordinate projected onto the C2···Cβ distance along the two competing paths (L2-si path and L2-re path). (b) Evolution of the Pauli repulsion (ΔEPauli), electrostatic interaction (ΔVelstat), orbital interaction (ΔEoi) and dispersion effect (ΔEdisp) along the reaction coordinate.

Zn(II) complexes were very similar. Moreover, the ΔG value of the transition state L2-si-TS1 in the first C−C bond formation starting from L2-COM was the lowest among the four TSs (Figure S7 in the Supporting Information). Therefore, the pathway involving L2-COM is discussed as a representative case. The optimized geometry of L2-COM is shown in Figure 3. NBO analysis indicated that the Wiberg bond indices of C3− O4 and Cα−Cβ in the alkynone (R1) were decreased by 0.169 (from 1.706 to 1.537) and 0.045 (from 2.794 to 2.839), respectively. Moreover, the global electrophilic index of L2COM as well as the local electrophilic index at Cβ of alkynone increased to 3.26 and 0.92 eV, respectively. These results indicated that the alkynone substrate in L2-COM was significantly activated. As shown in Figure 3, when cyclic enol silyl ethers (R2) approached the re or si face of the alkynone (R1) in L2-COM by its si or re face, two enantiomers (P-RR and P-SS) with R,R′ and S,S′ configurations would be afforded along the four pathways. Due to the significant steric repulsion between the indene moiety of R2 and the ligand, we failed to locate the two transition states involving the indene moiety of R2 on an opposite side with the Ph group of R1. Instead, we just focused on the two pathways L2-si and L2-re, in which the indene moiety of R2 was placed away from the chiral cavity. That is, the si face of R2 approached the re face of R1 along the L2-si path for P-RR and the re face of R2 approached the si face of R1 along the L2-re path for P-SS. Similar to the case for the noncatalytic reaction, the cycloaddition mediated by the L2-Zn(II) complex also occurred via a stepwise mechanism (see Scheme 3). The first C−C bond formation step (C2−Cβ) was predicted to be the chiral-controlling step as well as the rate-determining step (RDS). As shown in Figure 4, the relative Gibbs free energies of the two C−C bond formation transition states (L2-si-TS1 and L2-si-TS2) along the L2-si path (−18.5 and −20.7 kcal mol−1) were lower than those along the L2-re path (−16.0 and −18.5 kcal mol−1), indicating that the enantiomer P-RR with

R,R′ configuration was predominantly produced. According to the Curtin−Hammett principle,40 the predicted selectivity (ee %) was 98%, which is close to the experimental observation (81%). 3.3. Origin of Stereoselectivity. Structural analysis allowed us to understand the preferred si face over re face attack pathway in the asymmetric cycloaddition between an alkynone (R1) and a cyclic enol silyl ether (R2) catalyzed by the L2-Zn(II) catalyst. As shown in Figure 3, two CF3 groups in the counterion NTf− exhibited a trans arrangement in L2COM. Suffering from the steric repulsion of the bulky SO2CF3 in NTf2− ion, the left aniline in ligand L2 rotated by a C−N13 single bond. Consequently, the neighboring o-iPr group shielded the si face of the alkynone well, with an iPr···Cβ distance as short as ∼3.616 Å. In contrast, the blocking effect from the o-iPr group in the right aniline was less significant since the brachial aniline was placed to be far away from the alkynone, with the angle (θ) between the alkynone and right aniline of 58.8° (see Figure 3). This favorable spatial arrangement provided enough space for the cyclic enol silyl ether to attack the alkynone along the L2-si pathway. The geometries of the two competing transition states (L2si-TS1 and L2-re-TS1) in the chiral-controlling step (C2−Cβ bond formation) along the L2-si and L2-re pathways are shown in Figure 5. When the re face of the cyclic enol silyl ether (R2) approached the si face of the alkynone (R1), the steric repulsion between the tert-butyldimethylsilyl (TBS) and adjacent o-iPr of aniline distorted the Zn(II) complex significantly, with an increased Zn−O6 distance of 2.285 Å. This structural deformation could also be verified by te small G parameter41,42 (G(L2)) of 64.6% (that is, a percentage of the metal coordination sphere shielded by the ligand) in L2-reTS1, in comparison to L2-COM (65.3%). Accordingly, the active barrier (ΔG⧧) via transition state L2-re-TS1 was 2.7 kcal mol−1 higher than that via L2-si-TS1 (9.6 vs. 6.9 kcal mol−1). In comparison to L2-re-TS1, this unfavorable steric hindrance could be efficiently avoided in transition state L2-si-TS1, since the bulky TBS was placed in the center of the aniline. Thus, F


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Figure 7. Schematic molecular orbital interaction diagram for transition states (L2-si-TS1), constructed from a Zn(II)-associated fragment (Frag.1) and a cyclic enol silyl ether (Frag. 2), obtained by the ADF program.

ΔVelstat) could overwhelm the unfavorable repulsion term in the L2-si path. As a result, ΔEint along the L2-si pathway was more stabilizing than that along the L2-re pathway, leading to the low energy barrier (ΔE) in the L2-si path. Therefore, the Pauli repulsion was the main contributor to the stereodifference of the two pathways. The unfavorable steric repulsion between the o-iPr group of aniline in the ligand and tert-butyldimethylsilyl (TBS) in the cyclic enol silyl ether in the L2-re path translated into a more destabilizing ΔEPauli, leading to the predominant cycloaddition product P-RR observed in experiments.15 To understand the orbital interaction between the alkynone (R1) and the cyclic enol silyl ether (R2) in the construction of a C2−Cβ bond, the geometries of transition states L2-si-TS1 and L2-re-TS1 were decomposed into a Zn-associated fragment (Frag.1) and a cyclic enol silyl ether fragment (Frag.2). The corresponding schematic orbital interactions are visualized in Figure 7 and Figure S8. As shown in Figure 7, the HOMO orbital of L2-si-TS1 is mainly formed by a mixture of the highest occupied fragment orbital (HOFO) of the cyclic enol silyl ether fragment (Frag.2, 52.51%) and lowest unoccupied fragment orbital (LUFO) of the Zn(II)-associated fragment (Frag.1, 17.70%). The electronic density transfer from the π orbital of C1−C2 double bonds in the cyclic enol silyl ether to the unoccupied π* orbital of the Cα−Cβ bond in the Zn(II)-associated fragment facilitated the formation of a C2−Cβ bond. A similar orbital interaction was also observed in transition state L2-re-TS1 (see Figure S8). The energy gap of the frontier molecular orbital (FMO) between two fragments in L2-re-TS1 was smaller than that in L2-si-TS1 (0.261 vs 0.306 eV), contributing to its more stabilizing orbital interaction energy (ΔE⧧oi = −54.6 kcal mol−1). However, the closed-shell interaction from the filled orbital in L2-re-TS1 was stronger than that of L2-si-TS1 (see Table S4 in the

the relative Gibbs free energy of L2-si-TS1 was lower than that of L2-re-TS1 by 2.5 kcal mol−1. We then performed ASM analysis to explore further the origin of the stereoselectivity of the reaction and chiral induction of the catalyst. The complete diagram of activation strain analysis along the reaction coordinate (C2−Cβ bond formation process) is shown in Figure 6. When R2 approached the alkynone substrate along either the si face (L2-si path) or re face (L2-re path) pathways, the total deformation energy (ΔEstrain) along the two pathways increased monotonously. Moreover, the ΔE⧧strain at transition state L2-re-TS1 in the unfavorable re face pathway was more destabilizing than that at L2-si-TS1 along the si face pathway by 0.8 kcal mol−1 (see Table S2 in the Supporting Information). In comparison to the deformation energy, the main difference in the energy barrier (ΔΔE) along the two competing pathways came from the interaction energy term (ΔEint). As shown in Figure 6a, ΔEint in the si face attack pathway (L2-si path) along the reaction coordinate was more stabilizing than that along the re face attack pathway (L2-re path) at any given point in the curve, contributing to its low energy barrier. The interaction energies (ΔEint) between the reacting species along the two competing paths was further decomposed into four contributors, that is, the electrostatic interaction (ΔVelstat), Pauli repulsion (ΔEPauli), orbital interaction (ΔEoi), and dispersion effect (ΔEdisp), at the B3LYP-D3(BJ)/TZP theoretical level by ADF program calculations. As shown in Figure 6b and Table S3, the dispersion terms (ΔEdisp) along the two competing pathways were comparable. Although ΔEoi and ΔVelstat along the L2-si path were less stabilizing than those along the L2-re path, the Pauli repulsion (ΔEPauli) along the L2-si path was significantly less destabilizing than that along the L2-re path at any given point in the curve. Moreover, the attractive terms (ΔEoi and G


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Figure 8. ASM of [2 + 2] cycloaddition between an alkynone (R1) and a cyclic enol silyl ether (R2) involving the pentacoordinate Zn(II) complex L2-Zn(II)-P without the counterion NTf2−: (a) evolution of ΔE, ΔEstrain, and ΔEint along the reaction coordinate; (b) evolution of ΔEstrain of two energy components (ΔEstrain‑L2‑COM‑P and ΔEstrain‑R2) along the reaction coordinate.

the product P-SS (not P-RR for L2-COM) would be produced predominantly (see Figure 4) when a pentacoordinate Zn(II) complex (L2-COM-P) was involved in the catalytic reaction. As shown in Figures S10 and S11, L2-COM-P exhibited an ideal triangular-bipyramidal geometry. In comparison to L2COM, a “contracted” chiral pocket was observed, with a shorter Zn−O(C) distance (RZn−O(C)) of 2.057 Å as well as a larger G parameter G(L2) of 71.7%. Most importantly, removing the bulky counterion NTf2− from L2-COM decreased the torsion angle DC11−O5···C12−O6 (86.8° vs 54.8°) in the Zn(II) complex. As a result, the ortho-substituted iPr groups on the left aniline of the ligand were far from the reacting site (Cβ atom) in the alkynone, with iPr···Cβ distances of 4.054 and 4.993 Å, respectively. This orientation significantly weakened the steric repulsion between the TBS group of R2 and the aniline moiety of ligand L2 in the transition state L2-re-TS1-P. Accordingly, the distortion energy (ΔEstrain) along the L2-re-P pathway was less destabilizing than that along L2-si-P pathway, especially for the Zn(II)-associated fragment (L2-COM-P, Figure 8). As expected, the energy barrier along the re face pathway was lower than that of the si face pathway in the chiral-controlling step, contributing to the inverse stereoselectivity results. From the viewpoint of energy, the relative energies of the transition states along the two competing pathways (L2-si-P and L2-re-P) for enantiomers PSS and P-RR were higher than those along L2-si and L2-re paths by 5.3−15.3 kcal mol−1, indicating that the [2 + 2] cycloaddition tended to occur through the hexacoordinate Zn(II) complex (L2-COM). Thus, the coordination of NTf2− to the metal center of the catalyst was helpful in forming a highly active hexacoordinate Zn(II) complex, lowering the relative energy of the species along the reaction pathway. Most importantly, it adjusted the chiral environment of the Zn(II) complex by raising the blocking effect of the ortho-substituted group toward the reacting site (Cβ atom of alkynone) in the L2-re path, enhancing the chiral induction of N,N′-dioxide-Zn(II) catalyst for the R,R′ configuration product observed in experiments.

Supporting Information), which raised the unfavorable Pauli interaction in L2-re-TS1 (ΔE⧧Pauli = 98.7 kcal mol−1). Thus, the net result was that the relative Gibbs free energy of L2-reTS1 was higher than that of L2-si-TS1. To get insight into the effect of the bulkiness of the silyl group in the cyclic enol silyl ether on the stereoselectivity, we replaced TBS in R2 by the small trimethylsilyl (TMS) group and optimized the corresponding transition states (L2-si-TS1m and L2-re-TS1-m) in the chiral-controlling step (Figure S9). As expected, the difference in relative Gibbs free energy (ΔΔG) of the two competing TSs decreased to 0.4 kcal mol−1, indicating that inferior stereoselectivity would be obtained. As shown in Table S3, the ΔΔE⧧Pauli value at the TSs decreased to 2.4 kcal mol−1, which was smaller than that of R2 (7.1 kcal mol−1). Therefore, the bulky TBS in R2 played an important role in strengthening the chiral induction of the catalyst in asymmetric cycloaddition between the alkynone (R1) and cyclic enol allyl ether (R2). 3.4. Role of Counterion NTf2−. Our previous studies indicated that a counterion could coordinate to the metal center of a chiral N,N′-dioxide-metal complex, stabilizing the active species,38 adjusting the Lewis acidity of the metal center,39 and even taking part in reactions.43 The positive effect of the counterion NTf2− in alkenylsilylation reactions was also studied by Xia and co-workers.44,45 To understand the role of the counterion NTf2− in [2 + 2] cycloaddition reactions, we also optimized the geometry of a pentacoordinate Zn(II) complex without an NTf2− anion (L2-COM-P). For comparison, the reaction mechanism between an alkynone (R1) and a cyclic enol silyl ether (R2) involving a pentacoordinate Zn(II) complex (L2-COM-P) was also studied at the same theoretical level. As shown in Figure 4, the relative Gibbs free energy of L2-COM-P was higher than that of the corresponding hexacoordinate Zn(II) complex (L2COM) by 12.4 kcal mol−1, indicating that the counterion NTf2− could stabilize the Zn(II) complex well. Moreover, the ΔG value of the transition state L2-si-TS1-P along the si face pathway (L2-si-P) was higher than that of L2-re-TS1-P along the re face pathway (L2-re-P) by 3.3 kcal mol−1, suggesting that H


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Scheme 4. Hexacoordinate Zn(II) Complex (L-COM, m = 0−2)

3.5. Turnover Frequency (TOF) Analysis. The theoretical turnover frequency (TOF)46,47 was determined to evaluate the efficiency of the L2-Zn(II) catalyst along the two competing pathways, on the basis of the transition state theory and energetic span model,48 using eqs 3 and 4.49,50 δE (the energetic span) is defined as the energy difference between the summit and the trough of the catalytic cycle. G(TDTS) and G(TDI) are the Gibbs free energies of the TOF-determining transition state (TDTS) and the TOF-determining intermediate (TDI), and ΔGr is the global free energy of the whole cycle. TOF ≈

KBT −δE / RT e h

(3)

δE = E(TDTS) − E(TDI)

if TDTS appears after TDI (4a)

δE = E(TDTS) − E(TDI) + ΔGr if TDTS appears before TDI

in the counterion NTf2− and the ortho-substituted aniline in the Zn(II) complex significantly affected the spatial orientation of the alkynone as well as the blocking effect of the ligand, consequently leading to different stereochemical outcomes. For L1-COM, the average of Zn−O(C) distances was 2.082 Å, which was shorter than that of L2-COM. To avoid the repulsion from the ortho-substituted aniline, the counterion NTf2− rotated by the Zn−N15 bond, with a dihedral angle S17− N15−Zn−O4 of 149.7°. As a result, the right (not the left) aniline moiety shielded the reacting site Cβ in the alkynone (R1) well, directing the cyclic enol silyl ether (R2) to approach preferentially the alkynone (R1) along the L1-re pathway. As shown in Figure 10, the strain energy (ΔEstrain), especially for the Zn-associated fragment (ΔEstrain‑L1‑COM), became a decisive factor for the ΔΔE values of the two competing pathways. The calculations indicated that the relative energy of transition state L1-si-TS1 (Figure S12) was higher than that of L1-re-TS1 by 2.4 kcal mol−1, leading to the revised stereoselectivity results (Table 2). For L3-COM, the dihedral angle DS17−N15−Zn−O4 was 78.9°, which was smaller than that of L2-COM (100.5°). The right CF3 group in the counterion NTf2− was parallel to the alkynone and partially blocked the Cβ atom in the alkynone. This unfavorable steric effect raised the strain energy in the L3si pathway. However, the interaction energy was more stabilizing than that along the re face attack pathway at any given point in the curve (Figure 10), affording P-RR predominantly in the presence of L3-COM. As shown in Figure S13, the calculated ΔΔG valeus of transition states in the C2−Cβ and C1−Ca bond formation steps along the two competing pathways (L3-si and L3-re) were 1.2 and 1.4 kcal mol−1, respectively, which were lower than those of L2-COM (2.5 and 2.3 kcal mol−1). 3.6.2. Changing the Chiral Backbone. When the chiral ligand L2 in L2-COM was replaced by the bulky L4 (Figure S14), the chiral cavity of the Zn(II) complex (L4-COM) became contracted, with a G(L4) value of 65.8%. This effect increased the steric repulsion between the ligand and the bulky TBS of R2 in TSs along either the si face pathway or the re face pathway. As a result, the relative Gibbs free energies for the two competing transition states (L4-si-TS1 and L4-re-TS1) in the formation of the C2−Cβ bond became comparable (−17.6 vs −16.9 kcal mol−1). However, the introduction of a second five-membered ring significantly raised the repulsion between the chiral backbone of the ligand and the Ph group of the alkynone in the second C−C bond formation step (C1−Cα) in

(4b)

kB is the Boltzmann constant, T is the absolute temperature, and h is Planck’s constant. As shown in Table 1, the intermediate L2-si-IM1 was predicted to be the TDI and L2-si-TS2 was predicted to be the Table 1. Turnover Frequency (TOF) of the Catalytic Cycle for Asymmetric [2 + 2] Cycloaddition Reactions between an Alkynone (R1) and a Cyclic Enol Silyl Ether (R2) Catalyzed by L2-Zn(II) Complexes along L2-si and L2-re Pathsa path

TDI

TDTS

L2-si L2-re L2-si-P L2-re-P

L2-si-IM1 L2-COM L2-COM L2-COM

L2-si-TS2 L2-re-TS1 L2-si-TS2-P L2-re-TS2-P

TOF (s−1)

product

× × × ×

P-RR (major) P-SS P-RR P-SS

3.33 5.69 3.43 1.89

106 104 10−4 10−1

a

TDI and TDTS denote the TOF-determining intermediate and TOF-determining transition state, respectively.

TDTS in the cycloaddition between R1 and R2 catalyzed by the L2-Zn(II) complex. The TOF for the reaction along the L2-si pathway was 3.33 × 106 s−1, which was higher than those of the other three pathways. These results indicated that the catalyst L2-Zn(II) exhibited a good catalytic efficiency along the L2-si pathway. In addition, the TOF values for the pathways (L2-si-P and L2-re-P) involving the pentacoordinate Zn(II) complex (L2-COM-P) were lower than those involving the hexacoordinate Zn(II) complex (L2-COM), which indicated that the catalytic cycles might be easy to accomplish with the assistance of the counterion NTf2−. 3.6. Effect of Ligand on Enantioselectivity. 3.6.1. Changing the Linkage between Two N-Oxide Units in the Ligand. To understand the effect of the ligand on the reaction barrier as well as the enantioselectivity of the [2 + 2] cycloaddition reaction, we first changed the number of CH2 units (that is, m in Scheme 4) in the linkage of L2 (m = 1), giving two more chiral N,N′-dioxide ligands, L1 (m = 0) and L3 (m = 2), respectively. The corresponding hexacoordinate Zn(II) complexes (L1-COM and L3-COM) are shown in Figure 9. As shown in Table S5, the variation of the linkage between two N-oxide units adjusted the chiral cavity of the Zn(II) complex. Both the G parameter G(L) and torsion angle DC11−O5···O6−C12 increased as the alkyl chain was lengthened in the linkage, which reached 69.4% and 133.1° at L3-COM. Most importantly, the steric repulsion between the CF3 group I


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Organometallics

Figure 9. Optimized geometries of L1-COM (a) and L3-COM (b).

Figure 10. ASM results of the catalytic [2 + 2] cycloaddition between an alkynone (R1) and a cyclic enol silyl ether (R2) catalyzed by L1-Zn(II) (a, b) and L3-Zn(II) (c, d): (a, c) evolution of ΔE, ΔEstrain, and ΔEint along the reaction coordinate; (b, d) evolution of ΔEstrain of the two energy components along the reaction coordinate.

the L4-re pathway. As a result, the energy difference ΔΔG of TSs (L4-si-TS2 and L4-re-TS2) increased to 3.3 kcal mol−1. These results indicated that it was the second C−C bond formation step (not the first) which became decisive for the

enantiodifference of the two competing pathways. Moreover, superior stereochemical outcomes could be obtained because of a larger ΔΔG value (3.3 vs 2.2 kcal mol−1 for L2-COM) when L4-Zn(II) was used as the catalyst for the [2 + 2] J


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Organometallics

competing pathways in [2 + 2] cycloaddition catalyzed by the Zn(II) complex with two CH2 units in the linkage. The unfavorable steric repulsion between the oiPr group of aniline in the ligand and tert-butyldimethylsilyl (TBS) in the cyclic enol silyl ether in the L2-re path raised the closed-shell interactions between the alkynone and cyclic enol silyl ether in the L2-re path, leading to the predominant cycloaddition product (PRR) observed in experiments. (4) The o-iPr group in the aniline and the chiral backbone were the two key structural units in the Zn(II) catalyst for the enantioselectivity control of the asymmetric [2 + 2] cycloaddition. Variation of the linkage and chiral backbone of the ligand could adjust the repulsion among the ligand, the counterion NTf2− and the substrates, leading to different stereochemical outcomes.

Table 2. Relative Gibbs Free Energies (ΔG) and Differences (ΔΔG) of the Two Competing Transition States in the Chiral-Controlling Stepa catalyst

path

ΔG

ΔΔGb

L1-Zn(II)

si face re face si face re face si face re face si face re face

−14.2 −16.6 −18.5 −16.0 −9.5 −8.3 −20.9 −17.6

−2.4

98

2.5

98 (81)

1.2

83

3.3

>99 (90)

L2-Zn(II) L3-Zn(II) L4-Zn(II)d

eec (%)

product P-SS P-RR P-RR P-SS P-RR P-SS P-RR P-SS

(major) (major) (major) (major)

a The Gibbs free energies are given in kcal mol−1. bThe relative Gibbs free energy of the transition state in the si face path was set to zero. c The theoretical ee was obtained according to ref 40, and the ee obtained in experiment is given in parentheses. dThe relative Gibbs free energies of transition states in the C1−Cα bond formation step.

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ASSOCIATED CONTENT

S Supporting Information *

cycloaddtion reaction between R1 and R2. A higher ee % (90%) was also obtained in experimental investigations.15 Therefore, the [2 + 2] cycloaddtion reaction catalyzed by the Zn(II) complex exhibited a ligand-dependent stereochemical outcome, and the bulky counterion NTf2− could act as an important regulator to adjust the chiral induction of the N,N′-dioxide-Zn(II) complex catalyst, in which the repulsion between the CF3 group in NTf2− and the o-iPr group in aniline, combined with the backbone of the ligand, adjusted the spatial orientation of the alkynone as well as the blocking effect of aniline toward the reacting site (Cβ atom) in the alkynone, leading to different stereochemical outcomes. For L2 and L4 with two CH2 units in the linkage, the cooperation of the ligand and the counterion NTf2− constructed a good chiral environment and directed the cyclic enol silyl ether with bulky TBS to approach the coordinated alkynone along the less hindered si face pathway, consequently, achieving excellent ee in the asymmetric [2 + 2] cycloaddtion reaction.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.9b00299. Optimized geometries of transition states in the noncatalytic reaction and catalytic reaction mediated by Zn(II) complexes L1-Zn(II), L3-Zn(II,) and L4Zn(II), results of activation strain analysis of [2 + 2] cycloaddition between an alkynone and a cyclic enol silyl ether without catalyst, results of ESP surface for the substrates alkynone and cyclic enol silyl ether, results of activation strain analysis of [2 + 2] cycloaddition between an alkynone and a cyclic enol silyl ether catalyzed by chiral N,N′-dioxide-Zn(II) complexes L1Zn(II)−L3-Zn(II). (PDF) Cartesian coordinates for the calculated structures (XYZ)

■

4. CONCLUSION Theoretical investigations on the mechanism and enantioselectivity of an asymmetric [2 + 2] cycloaddition between an alkynone (R1) and a cyclic enol silyl ether (R2) catalyzed by chiral N,N′-dioxide-Zn(II) revealed the following results. (1) The noncatalytic reaction occurred via a stepwise mechanism, and the C1−Cα bond formation step was predicted to be the rate-determining step (RDS). The first C−C bond was formed by coupling two pseudo radical centers generated at the most nucleophilic C2 center in the cyclic enol silyl ether (R2) and the most electrophilic terminal Cβ center in the alkynone (R1), which was responsible for the regioselectivity of the reaction. (2) The counterion NTf2− coordinated to the metal center, forming a hexacoordinate Zn(II) complex with high reactivity. Most importantly, the bulky CF3 group in the NTf2− ion could adjust the blocking effect of o-iPr in aniline of the ligand toward the reactive site (that is, the Cβ atom) of the alkynone and induced the cyclic enol silyl ether to approach the alkynone from a less hindered direction to achieve a high enantioselectivity of products. (3) The Pauli repulsion between the Zn(II)-associated moiety and the cyclic enol silyl ether fragment was the main contributor to the stereodifference of the two

AUTHOR INFORMATION

Corresponding Author

*E-mail for Z. S. Su: [email protected]. ORCID

Changwei Hu: 0000-0002-4094-6605 Zhishan Su: 0000-0001-5168-3823 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Nos. 21290182 and 21572141), the Fundamental Research Funds for the Central Universities, and the 111 project (B17030) for financial support.

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REFERENCES

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Theoretical Study on Asymmetric [2 + 2] Cycloaddition of an Alkynone

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