Mechanism and Origins of Stereoinduction in Asymmetric Friedel

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Mechanism and Origins of Stereoinduction in Asymmetric Friedel-Crafts Alkylation Reaction of Chalcone Catalyzed by Chiral N, N'-Dioxide-Sc(III) Complex Yini Zuo, Na Yang, Xunkun Huang, Changwei Hu, and Zhishan Su J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00387 • Publication Date (Web): 30 Mar 2018 Downloaded from http://pubs.acs.org on March 30, 2018

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The Journal of Organic Chemistry

Mechanism and Origins of Stereoinduction in Asymmetric Friedel-Crafts Alkylation Reaction of Chalcone Catalyzed by Chiral N, N'-Dioxide-Sc(III) Complex Yini Zuo, Na Yang, Xunkun Huang, Changwei Hu, Zhishan Su* Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, Sichuan, 610064, P. R. China [email protected]

Abstract: The mechanism and selectivity of asymmetric Friedel–Crafts (F-C) alkylation reaction between indole and chalcone catalyzed by chiral N, N'-dioxide-Sc(III) complexes were investigated at the M06/6-311+G(d,p)//M06/[LANL2DZ, 6-31G(d)](SMD,CH2Cl2) level. The reaction occurred via a three-step mechanism: (i) the C3-Cβ bond formation by interacting the most mucleophilic C3 centre of indole with the most electrophilic Cβ centre of chalcone; (ii) the abstraction of the proton at C3 atom of indole by counterion OTf-; (iii) proton transfer from HOTf to Cα atom of chalcone, generating F-C alkylation product. The reaction preferred to occur along favorable re-face attack pathway, producing the dominant R-product. The turnover frequency (TOF) of catalysis was predicted to be 1.59×10-7 s-1, with the rate constant of K(T) = 1.58×10-7exp(-29057/RT) dm6· mol-2·s−1 over 248 K~368 K temperature range. Activation strain model(ASM), energy decomposition analysis (EDA) as well as Noncovalent interaction(NCI) analysis for the stereocontrolling transition state revealed that the substituent attached to the N atom of amide subunits as well as amino acid backbone of ligand played an important role in chiral inductivity. The benzyl group with structural flexibility tended to form strong π-π stacking with substrate as well as terminal phenyl group of chalcone, stabilizing re-face attack transition state.

Keywords: Friedel–Crafts alkylation reaction; mechanism; enantioselectivity; chiral N,N'-dioxides; counterion

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Introduction The Friedel–Crafts (F-C) alkylation reaction is one of the most powerful tools for carbon–carbon bond formation1,2, which has been widely used to generate important building blocks for organic transformations3-7. Since the first case of catalytic asymmetric F-C alkylation reaction was reported in the middle of 80s8, it has received much attention. Some organocatalysts (such as chiral amines9,10, thiourea11, phosphoric acid12, ureas13,14, cinchona alkaloids15, or bissulfonamide16), Lewis acidic transition-metal complexes3,4,17,18 as well as supramolecular metal-complexes/DNA catalysts6,19 have been proved to be efficient for catalytic asymmetric F-C alkylation reactions. In these successful cases, the reports involving chalcone derivatives as electrophiles were very limited, owing to their low reactivity and the difficulty in controlling of enantiofacial differentiation20,21. The generally accepted mechanism of F-C alkylation reaction involves two continuous 22 steps , i.e. C-C bond formation between the most electrophilic centre and the most nucleophilic centre of two reactants, followed by proton transfer step. Some experimental and theoretical investigations have been performed to explore the mechanism as well as the selectivity of asymmetric F-C alkylation reactions23-28. Herrera et al. studied the F-C alkylation reaction between indole and nitroalkene catalyzed by a chiral amino indanol-derived thiourea at the PCM(CH2Cl2)/M06-2X/6-311G(d,p) theoretically level. The -OH group of the catalyst was assumed to activate the nitroalkene as well as indole substrates by hydrogen bonding and orientated the preferential attack of the indole over the nitroalkene23. In chiral phosphoric acid-catalyzed asymmetric F-C reactions, the good reactivity of 4,7-dihydroindoles substrate was attributed to its high HOMO energy and suitable trajectory to attack the nitroolefin in the transition state29. A nine-membered transition state formed by hydrogen bonding between N-H group of indole with the phosphoryl O atom of catalyst was proposed, to explain the controlling step of the enantioselecivity for excellent ee30. When ketimines generated in situ acted as electrophiles for F-C reaction of 2-methoxyfuran mediated by BINOL-derived phosphoric acid, the excellent enantiochemical outcomes arose from the suitable hydrogen bonding network as well as the steric repulsion between the phenanthryl substituent of phosphoric acid and the methoxy group of 2-methoxyfuran31. Electron localization function (ELF) bonding analysis by Domingo et al. indicated that C-C bond formation between indoles and the electrophilically activated nitroethylene occurred via C-to-C coupling of two pseudoradical centers located at the most reactive centers of indoles and nitroethylene, producing a zwitterionic intermediate22. Transition-metal complexes containing zirconium32, aluminum33, copper34,35, nickel36, Zinc3,17,37 and platinum38,39 or palladium40 have been successfully applied in asymmetric F-C reactions. In these Lewis acid-catalyzed transformations, coordination of the bidentate organic substrates (such as N-sulfonyl aldimine35 and nitroalkene37) to the metal center in chelating fashion enhanced stereochemical outcomes. A 1,3-metal binding model of N-sulfonyl aldimine or nitroalkene substrates to a metal center was assumed to the key point for enantiocontrol in M(II)-bisoxazoline complexes (M = Cu35, Zn37 and Ni36) catalyzed asymmetric F-C reactions. In Trost’s dinuclear zinc complexes-catalyzed asymmetric F-C reactions, the deprotonated indole and ethyl glyoxylate imine coordinated to Zn center simultaneously, to form the key reactive species3. Carmona and co-workers studied the Rhodium-catalyzed F-C reaction at the B3LYP-D3/def2-SVP level. The zwitterionic intermediate was generated by nucleophilic attack of the N-methyl-2-methylindole carbon on the trans-β-nitrostyrene. The participation of water 2


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molecules decreased the energy barrier of 1,3-prototropic shift for final adducts17. In addition, the π-π stacking between the phenyl group of the ligands (4R,5S)-DiPh-BOX or Bis(sulfonamide)-diamine and substrates were supposed to stabilize the key species in Cu(II)-complex catalyzed F-C alkylation of indoles, contributing to high ee41,42. Recently, the chiral N, N'-dioxide-Sc(III) catalyst developed by Feng's group have shown excellent performance on asymmetric F-C alkylation reactions4,21. The β-heteroaryl-substituted dihydrochalcones were obtained with high yield(99%) and excellent stereoselectivity (85~92% ee) in the presence of Sc(III)-complexes21. A transition state model was proposed, in which the chalcone and counterion OTf- coordinated to scandium center simultaneously. The incoming indole preferred to attack the re-face rather than si face of chalcone because of the shielding effect of nearby anthracenyl ring in ligand for R-configuration product. Interestingly, the aforementioned complex could also catalyze the asymmetric F-C reaction of ortho-hydroxybenzyl alcohols with C3-substitutend N-protected indoles, providing diarylindol-2-ylmethanes up to 99% yield and 99% ee. With the aid of LiBr, the OTf- anion might capture the proton to cleavage the O-H bond of phenyl hydroxyl group of alcohol, generating key intermediate4. Although the experimental results provide valuable information for beginning the mechanistic analysis of the asymmetric F-C reaction catalyzed by N, N'-dioxide-Sc(III) catalyst, the characteristic of chiral environment and the major factors contributing to the chiral discrimination process were still unclear. Furthermore, the theoretical studies of the Lewis acid catalyzed asymmetric F-C reaction were very limited17,23. Herein, reaction mechanism and enantioselectivity of asymmetric F-C alkylation reaction between chalcones and indole were investigated by using DFT method. The key structural units in the chiral ligand affecting on activation barriers as well as enantioselectivity were explored in details. These results are expected to suggest a model to explain the stereochemical outcome, providing useful information for the rational design and synthesis of new chiral N, N'-dioxide-Sc(III) catalyst complex catalysts.

Scheme1. Asymmetric F-C alkylation reactions between indole (R1) and chalcone (R2) catalyzed by chiral N, N'-dioxide-Sc(III) complexes.

Computational details All structures were full optimized using the Gaussian 09 software program43, employing the M0644 functional, with the LANL2DZ basis set with an effective core potential for scandium ion and the 6-31G(d) basis set for other atoms. The solvation effect was considered in optimization, 3



using the SMD45 solvation model. Frequency calculations were carried out at the same level of theory as those for the structural optimization to characterize the nature of the stationary points on the potential energy surface. The intrinsic reaction coordinate (IRC) calculations was used to confirm the connectivity between each transition state (TS)and two associated minima of the proposed mechanism46. Natural Bond Orbital (NBO)47,48 and reactivity indices analysis (electrophilicity index ω and nucleophilicity index N)49,50 of the reactants were performed to obtain further insight into the electronic properties of stationary points at the M06/6-311+G(d,p)(SMD, CH2Cl2) level. The corresponding local reactive indices (ɷk and Nk) of reactants or molecular complexes were calculated using the following equations: ɷk = ɷPk+, Nk = NPk-, where the electrophilic Parr functions Pk+ and nucleophilic Parr functions Pk- were obtained from ASD at the radical cation and the radical anion of the corresponding reagents. Unless specified, the Gibbs free energies corrected by both solvation and zero-point vibrational effects at the M06/6-311+G(d,p) (SMD, CH2Cl2) level at 308K21 were used in the discussions. To explore the origin of selectivity of the reaction, we employed activation strain model analysis (ASM)51,52 (or distortion/strain model calculation53) to decompose bonding energy or activation barrier into the distortion energy (∆Estrain) and interaction energy (∆Eint) at the B3LYP/6-311+G(d,p) (SMD, CH2Cl2) level by using Gaussion 09 program. Furthermore, the interaction ∆Eint between reacting species was further decomposed into electrostatic interaction ∆Velstat, Pauli repulsion ∆EPauli as well as orbital interaction ∆Eoi (i.e., ∆Eint = ∆EPauli+∆Velstat + ∆Eoi) based on the conceptual framework provided by the Kohn-Sham molecular orbital (KS-MO) model54. Energy decomposition analysis55 (EDA) as well as the extended transition state-natural orbitals for chemical valence analysis (ETS-NOCV)56,57 were performed by single-point calculations using the Amsterdam Density Functional (ADF) program55,58,59 at the M06/TZP level.

Results and discussion Activation of chalcone substrate X-ray structural analysis60 and our previous calculations61 indicate that chiral N, N'-dioxide ligand interacts with Sc3+ metal center, forming a tetracoodinate-Sc(III) complex (CAT) with 'pocket-like' chiral environment61-63. The chalcone substrate and counter anion OTf- from metal salt Sc(OTf)3 could interact with central metal Sc3+ ion of tetradentate-Sc(III) catalyst simultaneously, forming a hexacoordinate chiral N, N'-dioxide-Sc(III) complex (L-COM)59b. Considering that there exist two possible conformations (s-cis and s-trans) for free chalcone substrate, s-cis-chalcone and s-trans-chalcone as well as their corresponding Sc(III) complexes were optimized firstly. As shown in Table S1, s-cis-chalcone was more stable than of s-trans-chalcone by 2.1 kcal mol-1. In addition, the relative energy of hexacoordinate-Sc(III) complex with s-cis chalcone (s-cis-L1-COM) was also slightly lower than that of s-trans-chalcone-Sc(III) complex (s-trans-L1-COM) by 0.6 kcal mol-1. Thus, unless otherwise specified, s-cis-chalcone was used in the following discussions. The geometry and electronic properties of L1-COM formed by the interaction of chalcone with [L1-Sc(OTf)]2+ are analyzed as a representative (Figure 1). The calculations indicate that the coordination processes is exothermic by 35.3 kcal mol-1. Compared to free chalcone (R2), the Cα=Cβ double bond in L1-COM is lengthened by 0.015 Å. Moreover, the corresponding Wiberg bond index (WBI) is decreased from 1.743 to 1.630. These results indicate that Cα=Cβ double 4


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bond of chalcone in L1-COM is significantly weakened. The formation of L1-COM also leads to electron density flowing from chalcone substrate to [L1-Sc(OTf)]2+ moiety and redistribution in the complex. To quantify the electron-transfer process, we visualized the deformation density (∆ρ), and the corresponding orbital interaction energies by ETS-NOCV analysis are shown in Figure S1. ∆ρ(2) represents the σ-donation from O atom of chalcone to unoccupied dx2-y2 orbital of Sc(III) centre, with orbital interaction energy ∆Eorb(2) of -18.7 kcal mol-1. For ∆ρ(3), the electronic density depletion in C=O π orbital of chalcone indicates the weakening of C=O bond. Accordingly, the electrophilicity (ω) of chalcone in L1-COM is enhanced, with larger global electrophilic index (3.75 eV vs. 2.35 eV in free chalcone) and local electrophilic index at Cβ atom (ωk = 1.75 eV vs. 0.63 eV in free chalcone).

OTf

Cβ HN

O

O Ph

Sc O

N

N O NH

≡

O

Figure 1. Optimized geometry of hexacoordinate-Sc(III) complex (L1-COM). The bond lengths are in Å. We also performed conformation search and located another possible complex L1-COM-1, in which the phenyl group of chalcone attached to C=O bond is placed to be the same side with coordinated OTf- anion (Figure S2). Although L1-COM-1 exhibits the similar global electrophilic index as L1-COM, the local electrophilic index of Cβ atom in L1-COM-1 is lower than that in L1-COM (1.25 eV vs. 1.75 eV). Moreover, the corresponding WBI of Cα=Cβ double bond in L1-COM-1 is larger than that of L1-COM (1.653 vs. 1.30). These results indicate that Cα=Cβ double bond in L1-COM-1 is less activated, compared to L1-COM. Thus, we just focus on the reaction pathways using L1-COM as staring complex. Mechanism of catalytic reaction The reaction mechanism and catalytic cycle for the F-C alkylation reaction of indole (R1) with chalcone (R2) is further investigated at the same theoretical level. The calculations indicate that the reaction occurs along a stepwise mechanism, namely, C3-Cβ bond formation followed by H-transfer from indole to the activated chalcone (Scheme 2). Considering the orientation of indole to metal-activated chalcone, four possible pathways (si-a, si-b, re-a and re-b) are studied (Scheme 3), in which two re-face approach pathways (re-a and re-b) and two si-face approach pathways (si-a and si-b) produce the R-product and S-product, respectively. As shown in Figure 2, the C3-Cβ bond formation step is predicted to be the chirality-controlling step, with energy barriers of 19.8~22.4 kcal mol-1. The relative energies of L1-re-a-TS1 and L1-re-b-TS1 along re-face attack pathways in chiral-controlling step are lower than those of L1-si-a-TS1 and L1-si-b-TS1 along si-face pathways by 1.4~2.2 kcal mol-1. In the view point of energy, the energy barriers for intramolecular H transfer step are as high as 40.0~49.6 kcal mol-1, indicating that it is difficult for 5



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reaction to occur via intramolecular H transfer step. H Ph L-Sc

N H

H

H Ph

OTf-assisted H-transfer

∗ Ph

N H

L1-COM Ph

L-Sc O

L-Sc O

L-Sc O

O

Ph

OTf -

Ph

Ph

N H

L1-IM1

L1-TS1

O

OTf

H

∗ Ph

Ph

NH

OTf-L1-IM2

intramolecular H-transfer

Ph

L1-Sc(III) catalyst

L-Sc O

L-Sc O

H

H

OTf H

∗

∗

R-product

Ph

Ph

Ph L-Sc O

L-Sc

Ph N H

N H

L1-IM2

L1-TS2

NH

OTf-L1-TS2

Ph -

OTf

∗ Ph

Ph

L-Sc O

Ph OTf

H

L-Sc O

OTf H

∗

∗ Ph

Ph N H

OTf-L1-TS3

NH

OTf-L1-IM3

Scheme 2. Reaction mechanism of F-C alkylation reactions between indole (R1) and chalcone (R2) catalyzed by chiral L-Sc(III) catalyst via intramolecular H-transfer and OTf-assisted H-transfer processes, respectively (L = chiral N, N'-dioxide ligand).

Scheme 3. Four possible reaction pathways corresponding to the formation of products with S and R-configuration, respectively.

6


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Figure 2. Energy profile associated with a intramolecular H-transfer mechanism in F-C alkylation reactionbetween indole (R1) and chalcone (R2) catalyzed by chiral L1-Sc(III) catalyst. Relative Gibbs free energies are shown in parentheses (kcal mol-1). Role of counter ion OTfThe presence of an anion (counterion) in the proton transfer step has been found to be important in several reaction processes64,65. Base on experimental assumption4, a possible H-transfer mechanism assisted by counter anion was studied, in which basic OTf- anion generated from metal salt precursor (Sc(OTf)3) abstracts H atom from indole substrate and transfers the proton to the C atom at α position of chalcone via intermolecular H transfer process along OTf-L1-re-a~OTf-L1-si-b pathways (Figure S3). As shown in Figure 3 and Figure S4, the energy barriers for the OTf-assisted intermolecular H-transfer process are decreased by 8.6~19.8 kcal mol-1, suggesting that the counter ion OTf- could accelerate reaction process. For OTf-L1-re-b pathway, the relative Gibbs free energies of the two H-transfer transition states (OTf-L1-re-b-TS2 and OTf-L1-re-b-TS3) are predicted to be 26.6 and 19.7 kcal mol-1 respectively, which are significantly lower than those along other three pathways (OTf-L1-re-a, OTf-L1-si-a and OTf-L1-si-b). As a result, the product with R-configuration is produced predominantly21. As shown in Figure 4, the distances between H and OTf- are 1.301 Å for transition state OTf-L1-re-b-TS2 and 1.063 Å for transition state OTf-L1-re-b-TS3, respectively. The negative Laplacian of electronic densities ∇2ρ at (3, -1) bonding critical points (a, Figure 4) by AIM analysis indicates covalent interaction between OTf- and H atom in OTf-L1-re-b-TS2 and OTf-L1-re-b-TS3. These results suggest OTf- takes part in proton transfer acting as proton shuttle in the reaction. Thus, counterion OTf- is crucial for F-C reaction between indole and chalcone, which takes part in proton transfer and decrease reaction barrier. The role of proton transfer agent and the OTf-assisted H-transfer process were also addressed by Ujaque and co-workers in gold(I)-catalyzed addition of phenols to olefins64.

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L1-si-a-TS1

∆G kcal mol-1

L1-si-a pathway

(49.6)

OTf-L1-si-a pathway

∆∆G ∆∆ = 19.8 (27.7) OTf-L1-si-a-TS2 (22.0) L1-si-a-TS1

OTf-L1-si-a-TS3 (29.8)

OTf (17.5) L1-si-a-IM1

(16.3)

(18.0)

OTf-L1-si-a-IM2

OTf-L1-si-a-IM3

(11.2) OTf-L1-si-a-IM4

(0.0) L1-COM+R1

R2

(-2.2)

(-3.0)

L1-si-a-IM2

S-product+L1-COM

R2

(a)

L1-re-b-TS1

∆G kcal mol-1

(45.9)

L1-re-b pathway ∆∆G ∆∆ = 19.3

OTf-L1-re-bTS2 (19.8) L1-re-b-TS1 (15.8) L1-re-b-IM1

OTf-L1-re-b pathway

(26.6) (19.7) OTf-L1-re-bTS3

OTf-L1-re-b-IM2 (23.1) OTf -

(15.6) OTf-L1-re-b-IM3 R2

(0.0)

R2

L1-re-b-IM2(4.3)

L1-COM+R1

(-4.0) OTf-L1-re-b-IM4

(-3.1) R-product+L1-COM

(b) Figure 3. Comparison of energy profiles associated with intramolecular H-transfer (red line) and OTf-assisted H-transfer (blue line) along si-a (a) and re-b pathways (b) for catalytic F-C alkylation reaction between indole (R1) and chalcone (R2) mediated by L1-Sc(III) complex. Relative Gibbs free energies are shown in parentheses (kcal mol-1).

Figure 4. Laplacian (∇2ρ) and electronic density (ρ, in parenthesis) of selected bond critical points (BCP) for transition states were obtained by AIM analysis. 8


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Origin of stereoselectivity The optimized geometries of the four competing transition states (L1-si-a-TS1, L1-si-b-TS1, L1-re-a-TS1 and L1-re-a-TS1) in C-C bond formation step are shown in Figure 5. For transition states L1-re-TS1-a and OTf-L1-re-b along re-face pathway, the terminal Ph group of chalcone is placed away from the bulky chiral backbone of ligand, avoiding the unfavorable steric repulsion. As a result, the relative energies of L1-re-a-TS1 and L1-re-b-TS1 are slightly lower than those of L1-si-a-TS1 and L1-si-b-TS1 by 1.0~2.2 kcal mol-1. Compared to transition state L1-re-b-TS1, the repulsion between aromatic ring of indole and OTf- anion increases the instability of L1-re-a-TS1, leading to slightly higher relative energy (19.8 vs. 21.0 kcal mol-1). In contrast to L1-re-b-TS1, the terminal phenyl group in chalcone becomes closer to the six-membered aliphatic ring in ligand when indole approaches to chalcone from si-face via transition state L1-si-a-TS1. Accordingly, more significantly structural deformation of chiral pocket is observed, accompanying with slightly larger variance in the G-parameter66 (from 70.2% to 67.1%). As shown in Figure 3 and Figure S4, the energy barrier corresponding to the re-face attack along OTf-L1-re-b pathway is the lowest among the four pathways either in chiral-controlling step (C-C bond formation step) or in intermolecular H transfer step, producing the predominant R-product observed in experiment (Figure 3b). The corresponding low energy competing pathway for enantioselectivity is predicted to be OTf-L1-si-a, with energy barrier of 22.0 kcal mol-1 in chiral-controlling step via transition state L1-si-a-TS1 (Figure 3a). The difference of energy barriers (∆∆G) along two competing pathways (L1-si-a-TS1 and L1-re-b-TS1) is 2.2 kcal mol-1. According to the Curtin−Hammett principle67, the predicted enantioselectivity is 94% ee (Table 1), which is close to the experimental result (87% ee). As expected, similar selectivity result (93% ee) is also obtained when L4-Sc(III) catalyst with 9-anthracenylmethyl groups at amino moiety is used for F-C alkylation reaction between indole (R1) and chalcone (R2) Figure S5). These results are in good agreement with experimental observations.

L1-si-a-TS1

L1-si-b-TS1

S-product

(22.4)

(22.0)

9


S-product


11 2.0 β

1.427

1.429 3.3 49 pa ra lle l

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

3 O5 O1 Sc 2.152 O3

L1-re-a-TS1

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11 2.0 β 3

O5 O1 Sc 2.149

O2 2.116 O4

O3

R-product

O6 O2 2.118

O4

L1-re-b-TS1

R-product

(19.8)

(major)

(21.0)

Figure5. Optimized geometries of four competing transition states in C3-Cβ bond formation step (chiral-controlling step) and their relative Gibbs free energies (kcal mol-1) in the F-C alkylation reactionbetween indole (R1) and chalcone (R2) catalyzed by chiral L1-Sc(III)complex. To gain insight into the origin of stereoselectivity of reaction and explore the key factor contributing to the favorable re-face attack pathway, activation-strain model (ASM) analysis is adopted to study the evolution of energy components in formation of L1-si-a-TS1 and L1-re-b-TS1 in chirality-controlling step. As shown in Figure 6a, two competing pathways presented similar tendency in strain energy curve, although the deformation energy of catalyst moiety ([L1-Sc(OTf)]2+) along favorable re-face pathway is more destabilizing than that along si-face pathway (Figure 6b). The main difference of energy barrier along two competing pathways arises from the interaction energy term (∆Eint). Moreover, ∆Eint corresponding to the re-face attack along OTf-L1-re-b pathway is more stabilizing at any given point along the reaction coordinate than along si-face attack one, which is responsible for the lower reaction barrier of the favorable re-face attack pathway.

(a)

10


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(b) Figure 6. Activation strain analysis (ASM) of the catalytic F-C reaction between indole (R1) and chalcone (R2) along the reaction coordinate projected onto the C3···Cβ distance in two competing pathways (L1-si-a and L1-re-b). (a) Evolution of ∆E, ∆Eint, and ∆Estrain along the reaction coordinate; (b) Evolution of the three components of ∆Estrain along the reaction coordinate. Then, the interaction energies (∆Eint) of reacting fragments along two competing pathways are decomposed into the electrostatic interaction ∆Velstat, Pauli repulsion ∆EPauli as well as orbital interaction ∆Eoi. As shown in Figure 7 and Table 2, EDA analysis suggests that the orbital energy ∆E≠oi and electrostatic energy ∆V≠elstat for L1-si-a-TS1 are -119.1 and -116.0 kcal mol-1, respectively, which are less stabilizing than those of L1-re-b-TS1 (-123.8 and -127.3 kcal mol-1). In the formation of transition state L1-re-b-TS1, the orbital energy term ∆Eoi of chalcone fragment and Sc-based fragment is less stabilizing than that of ∆Velstat by 3.5~17.0 kcal mol-1 (Figure 7b). Although the Pauli repulsion ∆E≠Pauli in L1-re-b-TS1 is slightly more destabilizing than that of L1-si-a-TS1 by 11.7 kcal mol-1, the stronger attractive terms, especially electrostatic energy term (∆V≠elstat), overwhelm the unfavorable Pauli repulsion ∆E≠Pauli. As a result, the interaction energy (∆E≠int) in L1-re-b-TS1 is stronger than that of L1-si-a-TS1 by 4.1 kcal mol-1. As shown in Figure 5, structural analysis of transition state L1-re-b-TS1 suggests that the planar indole substrate is parallel to the left benzyl group of ligand, with the distance of 3.349 Å. Noncovalent interaction(NCI) analysis indicates that there exists a strong π-π stacking effects for these three sub-parallel π-conjugated aromatic rings (Figure 8). This effect stabilizes the transition state L1-re-b-TS1 well and contributes to strong electrostatic interaction of reacting fragments (∆V≠elstat = -127.3 kcal mol-1). The similar π-π stacking effect between conjugated 9-anthracenylmethyl group and indole substrate is also observed for transition states L4-re-b-TS1 in L4-Sc(III)-catalyzed F-C alkylation reaction between indole (R1) and chalcone (R2) (Figure S6) . Therefore, the combination of steric repulsion of chiral backbone with strong π-π stacking effect between chiral ligand and substrates enhances the difference of interaction energy of reacting fragments along two competing pathways, attributing to high enantioselectivity.

11



Page 12 of 23

(a)

(b) Figure7. Energy decomposition analysis (EDA) of the catalytic F-C reaction between indole (R1) and chalcone (R2) along the reaction coordinate projected onto the C3··· Cβ distance in two competing pathways (L1-si-a and L1-re-b). (a) Evolution of Pauli repulsion (∆Epauli) along the reaction coordinate; (b) Evolution of electrostatic interaction (∆V≠elstat) and orbital energy (∆Eoi) along the reaction coordinate. Table 1. Results of activation strain analysis (ASM) for competing transition states for catalytic F-C alkylation reaction between indole (R1) and chalcone (R2) catalyzed by L-Sc(III)catalysts (L = chiral N, N'-dioxide liagnd) (Energies in kcal mol-1). G(L) is the percentage of metal center coordination sphere shielded by the chiral N,N'-dioxide ligands (L1~L3),obtained by Solid-G program66. ∆E≠strain TSs

∆E≠

∆E≠int

indole

chalcone

(R1)

(R2)

G(L)

[L-Sc(OTf)]2+

Sum

(%)

L1-si-a-TS1

14.9

-6.9

6.9

15.5

0.3

21.8

67.1

L1-re-b-TS1

11.8

-12.7

7.1

16.4

1.0

24.5

67.9

L2-si-b-TS1

12.6

-12.6

6.9

17.6

0.7

25.2

61.7

L2-re-a-TS1

15.9

-8.7

6.5

17.2

0.9

24.6

62.6

12


∆∆G≠

eea (%)

2.2

94.4

0.9

62.3

Page 13 of 23

a

L3-si-b-TS1

17.2

-8.9

6.2

16.2

3.7

17.2

65.4

L3-re-a-TS1

23.5

-6.7

6.7

17.7

5.7

30.2

66.1

-4.0

99.7

Theoretical enantioselectivity excess (ee) obtained by the Curtin−Hammett principle67.

Table 2. Results of Energy Decomposition Analysis (EDA) for two competing transition states in chirality-controlling step (C-C bond formation step) in asymmetric F-C alkylation reaction between indole (R1) and chalcone (R2) mediated by chiral N, N'-dioxide-Sc(III) catalysts. (Energies in kcal mol-1). TSs

∆E≠int

∆E≠Pauli

∆V≠elstat

∆E≠oi

L1-si-a-TS1

-85.4 -89.5

149.7 161.4

-116.0 -127.3

-119.1 -123.8

-92.3 -87.7

160.4 160.4

-125.1 -125.3

-127.5 -122.8

-90.2 -92.8

150.1 165.3

-119.8 -129.9

-120.4 -128.2

L1-re-b-TS1 L2-si-b-TS1 L2-re-a-TS1 L3-si-b-TS1 L3-re-a-TS1

n ki ac st

g

s ta ck ing

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 8. The π-π stacking interaction between indole, phenyl group of chalcone and benzyl group of chiral N, N'-dioxide ligand (L1) in transition state L1-re-b-TS1, visualized by Multiwfn software (isovalue = 0.70). The Friedel-Crafts alkylation reactions of chalcone with pyrrole (R3) or N-Methylindole (R4) , respectively, catalyzed by chiral L1-Sc(III) catalyst were further studied (Scheme 4). Four possible transition states in chiral-controlling step(C-C bond formation step) were located at the same theoretical level. As shown Figure S7 and Figure S8, the reaction barriers were 20.6~24.0 kcal mol-1 for N-methylindole, and 22.6~27.6 kcal mol-1 for pyrrole, respectively, indicating that the Friedel-Crafts reaction of chalcone with N-methylindole or pyrrole could also occur under the mild experimental condition. Similar to indol(R1), the relative energies of transition states L1-pyrrole-re-b-TS1 or L1-N-methyl-re-b-TS1 in re-face attack pathway were lower than those of L1-pyrrole-si-b-TS1 or L1-N-methyl-si-a-TS1 in si-face attack pathway in chiral-controlling step. These results indicated that the re-face attack pathway were more favorable than si-face attack pathway either for N-methylindole or pyrrole substrates. These results were in good agreement with the experimental observations.[21] 13



Page 14 of 23

Similar to indole substrate, the π-π stacking effect between substrates (pyrrole and N-methyl indole) and benzyl group of chiral ligand were also observed in the favorable transition states L1-pyrrole-re-b-TS1 or L1-N-methyl-re-b-TS1 (Figure S9 in supporting information). These results indicated that removing the phenyl ring from indole (R3, pyrrole) or introduction N-methyl group to indole (R4, N-methyl indole) didn't break completely π-π stacking between substrate and ligand in re-face attack transition states (L1-pyrrole-re-b-TS1 for pyrrole and L1-N-methyl-re-b-TS1 for N-methyl indole), although this stabilizing effect were weakened to some extent (the electrostatic interaction energy ∆V≠elstat between reaction fragments for pyrrole and N-methylindole (-120.2 and -126.0 kcal mol-1) were lower than that of indole (-127.3 kcal mol-1, see Table 2 and S2 in supporting information).

NH

(a)

O

β

2 Ph

R3: pyrrole

Ph CH2Cl2, 308K

α

H α * 2 N

Ph O

Product

R2: chalcone

Ph β

H 3 (b)

L1-Sc(III)

Ph β

O

β 2

Ph

N R4: N-methylindole

α

L1-Sc(III) Ph CH2Cl2, 308K

R2: chalcone

H α * 3

Ph 2

O

N Product

Scheme 4. Asymmetric F-C alkylation reactions between pyrole (R3) or N-methylindole (R4) and chalcone (R2) catalyzed by chiral L1-Sc(III) catalyst.

Analysis of turnover frequency (TOF) and rate constant in catalytic cycle Based on the transition state theory and energetic span model68, we evaluated the theoretical turnover frequency (TOF) of catalytic cycles via intramolecular and OTf-assisted H-transfer mechanism catalyzed by L1-Sc(III) catalyst. In equation (1) and (2)69-71, the δE (the energetic span) is the energy difference between the summit and the trough of the catalytic cycle. GTDTS and GTDI are defined as the Gibbs free energies of the TOF-determining transition state (TDTS) and the TOF-determining intermediate (TDI), and ∆Gr is the global free energy of the whole cycle72. TOF ≈

௄ಳ் ௛

షഃಶ

݁ ೃ೅

(1)

δE = E (TDTS) −E (TDI) δE = E (TDTS) −E (TDI) + ∆Gr

if TDTS appears after TDI (2a) if TDTS appears before TDI (2b)

Where kBis Boltzmann’s constant, T is the absolute temperature, and h is Plank’s constant. As shown in Table 3, the intermediate L1-COM+R1 orL1-COM+R1+OTf- are predicated to be TDI, and the H-transfer transition states are TDTS for the whole cycle of the F-C reaction between R1 and R2 catalyzed by L1-Sc(III) catalyst. As expected, the TOF of catalytic cycles involving OTf-assisted H-transfer pathways (OTf-L1-si-a~OTf-L1-re-b) are significantly higher than that of the intramolecular H-transfer pathways. Moreover, L1-Sc(III) exhibits better catalytic performance when the catalytic reaction occurs along path OTf-L1-re-b, with TOF of 1.59×10-7 s-1. 14


Page 15 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 3. The turnover frequency (TOF) of the catalytic cycle for F-C reaction catalyzed by L1-Sc(III) complex along eight pathways. TDIs sand TDTSs are TOF-determining intermediate and TOF-determining transition state, respectively. Path L1-si-a L1-si-b

TDI

TDTS

TOF

L1-si-a-TS2 L1-si-b-TS2

3.21×10 s 8.40×10-17 s-1

L1-re-a-TS2

2.03×10-20 s-1

L1-re-b

L1-re-b-TS2

1.72×10-20 s-1

OTf-L1-si-a OTf-L1-si-b

OTf-L1-si-a-TS3 OTf-L1-si-b-TS2

4.42×10-9 s-1 1.01×10-10 s-1

OTf-L1-re-a-TS2

1.03×10-8 s-1

OTf-L1-re-b-TS2

1.59×10-7 s-1

L1-re-a

OTf-L1-re-a OTf-L1-re-b

L1-COM+R1

L1-COM+ R1+OTf-1

product

-23 -1

S-product R-product S-product R-product (major)

The rate constants K(T) along two low energy competing pathways OTf-L1-si-a and OTf-L1-re-b) were further evaluated according to conventional transition state theory (TST) and the following Winger’s formulations73,74:

k (T ) =

k B T −∆G ≠ / kB T e hc 0

κ (T ) = 1 +

1 hν ≠ 24 k BT

Where kB is Boltzmann’s constant, T is the absolute temperature, h is Plank’s constant, c0 is the standard concentration (1 mol dm−3). ∆G≠ is the activation Gibbs free energy barrier (kJ mol-1) between TDI and TDTS in catalytic cycle, and ν≠ is imaginary frequency of TS, obtained at M06/(6-31G(d), LanL2DZ) level. Then, the Winger's tunneling effect corrected rate constants K(T) is calculated by the expression of k(T)×κ(T).At the 348 K~368 K temperature range, the rate constants K(T) for OTf-L1-si-a pathway (si-a) and OTf-L1-re-b pathway (re-b) can be fitted by the following expressions (in dm6·mol-2· s−1):

K si -a (T ) = 3.78 × 10 −8 exp(44189 / RT ) Kre -b (T ) = 1.58 ×10−7 exp(29057 / RT ) Namely, the rate constants Ksi-a is two to three orders of magnitude smaller than Kre-b at the 348 K~368 K temperature range, suggesting that OTf-L1-re-b pathway is more favorable kinetically than OTf-L1-si-a pathway.

Effect of ligand on enantioselectivity The influence of substitute (R group in Scheme 1) of amide moiety in ligand on energy barrier as well as enantioselectivity are further explored. When benzyl groups of ligand in L1 are replaced by phenyl groups (L2), an opening chiral pocket is constructed75. NBO analysis indicates that the Wiberg bond index of Cα=Cβ bond in L2-COM is slightly larger than that in L1-COM (1.644 vs. 1.630). As expected, the energy barriers of C3-Cβ bond formation step for four pathways are higher than those of L1-Sc(III) catalyst (22.1~25.9 kcal mol-1 vs. 19.8~22.0 kcal mol-1) (Figure 9). Different from L1, two low energy competing transition states are L2-si-b-TS1 and L2-re-a-TS1, 15



Page 16 of 23

respectively, with aromatic ring of indole being at the same side with phenyl group of chalcone. ≠ Compared to L1-Sc(III) catalyst, the ∆∆G decreased from 2.2 kcal mol-1 to 0.9 kcal mol-1, with theoretical enantioselectivity of 62% ee. Lacking of methylene linkage between N atom of amide and phenyl group in ligand, it is difficult for aromatic group to reach and overlap with indole substrate well for π-π stacking along re-face attack pathways, although they still look like parallel in geometry (the distance between phenyl group of ligand and indole is about 3.627 Å). Consequently, the stabilizing effect along in transition state L2-re-a-TS1 is significantly weakened, with comparable electrostatic energy (-125.1 vs. -125.3 kcal mol-1) as well as orbital interaction energy (-127.5 vs. -122.8 kcal mol-1) with L2-si-b-TS1 (Table 2). The inferior enantioselectivity for L2-Sc(III) catalyst was also obtained in experiment21.

2.0 1.430

27

3

O5 O6 O1 2.141 O3

L2-si-a-TS1

L2-si-b-TS1

S-product

Sc O 2.155 2 O4

S-product

(23.0)

(25.7)

L2-re-a-TS1

R-product

L2-re-b-TS1

(22.1)

(major)

(25.9)

R-product

Figure 9. Optimized geometries of four competing transition states in C3-Cβ bond formation step (chiral-controlling step) and their relative Gibbs free energies (kcal mol-1) in the F-C alkylation reaction between indole (R1) and chalcone (R2) catalyzed by chiral L2-Sc(III) complex. When L3 with ortho-diisopropylphenyl groups is used to form the key reactive species (L3-COM), a contracted chiral pocket is observed with G-parameter G(L3) of 68.0%. As shown in Figure 10, the ortho-isopropyl groups in left amide of ligand blocks the reacting site Cβ atom of chalcone. Accordingly, the indole is preferred to approach the chalcone substrate from the less hindrance si-face (not re-face). This repulsion effect increases the deformation energy of reacting 16


Page 17 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


fragments, especially for [L3-Sc(OTf)]2+ fragment in transition states L3-re-a-TS1 (∆E≠strain= 30.2 kcal mol-1). As a result, the relative energy of L3-si-b-TS1 is lower than that of L3-re-a-TS1 by 4.0 kcal mol-1 (Figure S7), giving the predominant product with S-configuration. The inversed enantioselectivity results is also obtained in experiment21.

si-face

re-face ing block s ite ing react

1.359

O5 O1

Sc 2.109

O3

O6 O2 2.108 O4

Figure 10. Optimized geometry of hexacoordinate-Sc(III) complex L3-COM. The bond lengths are in Å Therefore, the R group attached to N atom of amide subunits in ligand plays an important role for asymmetric inductivity of chiral N, N'-dioxide-Sc(III) catalyst. The benzyl group with suitable linker and structural flexibility in L1 ligand make π-π stacking between indole, phenyl group of chalcone and benzyl group feasible. This favorable effect translates into more stabilizing interaction energy (∆Eint) of reacting fragments, facilitating re-face pathway for R-product. When benzyl group is replaced by phenyl group, the stabilizing interaction along re-face pathway disappears, leading to low ee. The additional bulky ortho-iPr in anline reverses the enantioselectivity of F-C reaction by shielding the reacting site from re-face and increasing the deformation energy of [L3-Sc(OTf)]2+ fragment. These results are in good agreement with experimental observations.

Conclusion The mechanism and selectivity of F-C alkylation reaction between indole (R1) and chalcone (R2) catalyzed by chiral N, N'-dioxide-Sc(III) complexes are investigated theoretically, revealing the following results: (1) Chalcone substrate and counterion OTf- coordinate to Sc(III) center of chiral N, N'-dioxide -Sc(III) complex to form hexacoordinate reactive species, in which chalcone is significantly activated with higher electrophilic reactivity index and weaker Wiberg bond index of Cα=Cβ double bond. (2) The catalytic asymmetric F-C alkylation reaction occurs via a three-step mechanism, i.e. the C3-Cβ bond formation between the most nucleophilic C3 centre of indole and the most electrophilic Cβ centre, followed by OTf-assisted intermoleculer H-transfer. The counter OTf- anion accelerates the reaction rate by taking part in proton shift process. The TOF-determining transition state is characteristic of H-transfer for catalytic cycle. The TOF of most favorable pathway (OTf-L1-re-b) 17



is predicted to be 1.59×10-7 s-1, with the rate constant of K(T) = 1.58×10-7exp(-29057/RT) dm6·mol-2·s−1 over 248 K~368 K temperature range. (3) The strong π-π stacking effect between indole, phenyl group of chalcone and benzyl group at amide moiety translates into more stabilizing interaction which favors re-face pathway. Lacking of CH2 group between N atom and phenyl group, the stabilizing interaction of re-face pathway is significantly weakened, even the additional bulky ortho-iPr in anline reverses the enantioselectivity by shielding the re-face reacting site.

Supporting Information Comparison of relative energies (kcal mol-1) for chalcone with s-cis or s-trans conformations; deformation density ∆ρ associating with the coordination interaction in L1-COM; optimized geometry of the key intermediates and transitions states; energy profiles of OTf-assisted intermolecular H-transfer mechanism; visualization of π-π stacking interaction of L4-re-b-TS1, L1-pyrrole-re-b-TS1 and L1-N-methyl-re-b-TS1; results of Energy Decomposition Analysis (EDA) for F-C reactions of chalcone with pyrrole or N-methylindole; the cartesian coordinates, the 3D structures and energies of all stationary points . (PDF)

Acknowledgement We thank the National Natural Science Foundation of China (Nos. 21290182 and 21572141), and the 111 project (B17030) for financial support.

18


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Mechanism and Origins of Stereoinduction in Asymmetric Friedel

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