Insights into the DielsâAlder Reaction between 3-Vinylindoles and

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Insights into the Diels-Alder Reaction between 3-Vinylindoles and Methyleneindolinone without and with the Assistance of Hydrogen-Bonding Catalyst Bisthiourea: Mechanism, Origin of Stereoselectivity, Role of Catalyst Chao-Xian Yan, Fan Yang, Xing Yang, Da-Gang Zhou, and Pan-Pan Zhou J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00026 • Publication Date (Web): 22 Feb 2017 Downloaded from http://pubs.acs.org on February 24, 2017

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The Journal of Organic Chemistry

Insights into the Diels-Alder Reaction between 3Vinylindoles and Methyleneindolinone without and with the Assistance of Hydrogen-Bonding Catalyst Bisthiourea: Mechanism, Origin of Stereoselectivity, Role of Catalyst Chao-Xian Yan, Fan Yang, Xing Yang, Da-Gang Zhou, Pan-Pan Zhou* State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, 222 South Tianshui Road, 730000, Lanzhou, P. R. China. Fax: +86-931-8912582; Tel: +86 931 8912862; *E-mail: [email protected]

ACS Paragon Plus Environment

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ABSTRACT: The Diels-Alder reaction between 3-vinylindoles and methyleneindolinone can proceed both with catalyst-free and bisthiourea catalyst, the reaction with bisthiourea is much faster and yields product with even higher stereoselectivity. The reaction mechanisms, origin of stereoselectivity and role of catalyst were elaborated based on quantum mechanical calculations and theoretical methods of reactivity indexes, NCI, QTAIM and distortion/interaction models. In uncatalyzed reaction, the two C-C bonds formed undergo the conversion from noncovalent to covalent bonding via concerted asynchronous mechanism. The weak intermolecular interactions formed in the transition state play important roles. The difference between the interaction and distortion energies is responsible for the stereoselectivity. In catalyzed reaction, bisthiourea induces both the diene and the dienophile to approach it via weak intermolecular interactions which greatly lower the reaction energy barrier and lead to the product with excellent stereoselectivity. The possible pathways were explored which suggested that the formations of two C-C bonds go through either stepwise or concerted asynchronous mechanism. These results would shed light on the detailed reaction mechanisms and the significant role of the bisthiourea catalyst and the origin of stereoselectivity for this type of Diels-Alder reactions and the related ones. KEYWORDS:

Diels-Alder

reaction,

bisthiourea,

hydrogen

bonding,

QTAIM,

the

distortion/interaction model, stereoselectivity


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1. INTRODUCTION Chiral (thio)urea as asymmetric organocatalyst was developed by Jacobsen and coworkers in 1998,1,2 and it has been widely applied into organic transformations3-6 because it is low-cost, environmental friendly, hypotoxic and easy to work-up and regenerate7 compared to Lewis acid catalyst (e.g., transition metals, BF3, etc.). Additionally, thiourea exhibits excellent compatiblity with aqueous solution8,9 and acid sensitive reactants.10 These advantages enable thiourea and its derivatives to serve as efficient catalysts in various reactions including acyl Pictet-Spengler reaction,11 Cope-type Hydroamination,12 Claisen rearrangement,13 cycloaddition,14,15 Henry reaction,16 Mannich reaction,17,18 Michael addition,19-27 Morita-Baylis-Hillman reaction,28,29 Strecker reaction,1,2,30,31 oxirane ring-opening reaction,32 lactide ring-opening polymerization reaction33 and nucleophilic addition reaction34 etc. The highly catalytic reactivity of thiourea can be attributed to the fact that thiourea can interact with the substrate via hydrogen-bonding interaction which significantly affects the reaction process.6,35,36 As a consequence, various thiourea organocatalysts have been synthesized and applied into different organic reactions.6,37-40 Diels-Alder (D-A) reactions have been considered as one of the most powerful routes in the synthesis of complicated molecules, and the applications of efficient organocatalysts like thiourea and its derivatives in D-A reactions have been a booming field in the past decades. Schreiner and Wittkopp reported the thiourea catalyzed D-A reaction between enone and cyclopentadiene.8,9,35 Mao et al. suggested that the chiral tertiary amine thiourea can catalyze the inverse-electron-demand D-A reaction between chromone heterodiene and 3-vinylindole.41 Jacobsen and coworkers reported that the primary aminothiourea can catalyze the formal azaDiels-Alder reaction between enone and cyclic imine,37 while Hu et al. applied the primary amine-thiourea bifunctional catalyst into the formal aza-Diels-Alder reaction between enone and


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3-H indole.42 Li et al. employed the chiral secondary amine-urea bifunctional catalyst to catalyze the [4+2] cycloaddition between 3-nitroindole and (E)-5-methylhexa-2,4-dienal.43 Besides these experimental work, theoretical investigations in understanding the detailed reaction mechanisms of (thio)urea catalyzed D-A reactions are also underway. For instance, Schreiner and Wittkopp,8,35 Fu and Thiel44 investigated the mechanisms of D-A reactions between enones and cyclopentadiene catalyzed by thiourea. By using density functional theory at the different levels, Linder and Brinck explored the detailed mechanisms of thiourea catalyzed acrolein–butadiene [4+2] cycloaddition.45 Recently, the [4+2] cycloaddition between Danishefsky's diene and 3nitroindole was studied by Andreini and coworkers at the B3LYP/6-31G(d,p) level of theory.10 These results indicate that thiourea as well as its derivative plays an important role in D-A reaction. Scheme 1. D-A reaction of 3-vinylindoles and methyleneindolinone catalyzed (a) by bisthiourea catalyst I; (b) with catalyst-free.


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The aforementioned work which used thiourea catalyst in D-A reactions inspired the development of bisthiourea HB catalysts and their applications,6,28,29,46,47 especially

in the

syntheses of complicated compounds. Carbazolespirooxindoles can be considered as a merge between the two privileged structures of spirooxindoles and tetrahydrocarbazoles which possess noteworthy biological activities. In the past years, a vast number of cycloaddition reactions between

2-

and

3-vinylindoles

and

methyleneindolinones

for

the

synthesis

of

carbazolespirooxindoles have been developed especially in their enantioselective versions which involve the use of chiral Ni(II) complexes or are performed with suitable organocatalysts (e.g., bisthiourea and cinchonidine-squaramide based catalysts and chiral phosphoric acids).48-52 In particular, an important work aiming at constructing the bioactive carbazolespirooxindole derivatives with multiple stereocenters has been reported (Scheme 1), in which a bisthiourea catalyst I was applied into the asymmetric D-A reactions between 3-vinylindoles and methyleneindolinones.48 Interestingly, with the help of the bisthiourea catalyst I, the reaction can be readily achieved within 8 min (Scheme 1a), which provided the product in almost quantitative yield with excellent stereoselectivity (>99:1 dr, up to 96% ee). While the reaction proceeded smoothly and required about 2 hours to reach completion in the absence of the bisthiourea catalyst I (Scheme 1b), resulting in quantitative yield with poor stereoselectivity (ca. 3:1 dr, 0% ee). Their experiments further suggested that (1) the catalyst forms hydrogen bonding with the methyleneindolinone; (2) the N-H group of 3-vinylindole is essential in leading to the stereocontrol; (3) additional interactions between the catalyst and substrates play roles in the stereoselectivity; (4) the bulky Boc-protecting group is very important in providing a stereocontrolled product. They hypothesized that the π-π and hydrogen-bonding interactions might form between N-H group of 3-vinylindole and the Boc group of methyleneindolinone,


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which exert an orientation effect for 3-vinylindole prior to the C-C bond formation in the D-A reaction. These experimental results and their speculation stimulate our great interest to have a better understanding of these reactions. Accordingly, computational investigations for the uncatalyzed and catalyzed reactions of 3-vinylindoles and methyleneindolinone were carried out for comparison, we aim at uncovering the mechanisms and origins of the stereoselectivity for the D-A reactions with and without the bisthiourea catalyst I, the role of the catalyst, the intermolecular interactions formed in the reaction with and without the catalyst and their different roles, and moreover, the effects of N-H and Boc groups will be elaborated in detail. We expect the studies would provide valuable insights into these types of interactions.

2.COMPUTATIONAL DETAILS All the calculations were performed with the Gaussian 09 suite of program.53 Geometry optimizations of the reactants, transition states, intermediates and products were carried out using the M06-2X functional54 with 6-31G(d,p) basis set, and the PCM using the Integral Equation Formalism model (IEFPCM)55 was adopted to simulate the solvation effect. Vibrational frequency calculations were carried out at the same level to ensure that the optimized structures are energy minima without imaginary frequencies and the transition states have only one imaginary frequency. Intrinsic reaction coordinate (IRC)56,57 calculations were also performed at this level to verify that the transition state structures lead to the expected reactants and products. Single point calculations of all the optimized structures were further performed at the M062X/Def2-TZVP level of theory with IEFPCM model to obtain their accurate energies because the basis set superposition error (BSSE) becomes insignificant for the TZVP basis.58 The optimized


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structures were displayed with GaussView (Version 559) and CYLview (version 1.0b60) softwares. The reactivity indexes within the framework of conceptual density functional theory (CDFT61,62) were employed to evaluate the reactivity tendency of a molecule in response to the attack of different types of reagents. In order to measure the weak noncovalent interactions appearing in the D-A reactions, we further used noncovalent interaction (NCI63,64) analysis and quantum theory of atoms in molecules (QTAIM65,66) to uncover the reaction mechanisms. QTAIM analyses were performed with AIMAll67 (Version 08.11.06) program, which is efficient in reflecting the topology characteristics at the bond critical points(BCPs) for hydrogen bond, van der Waals, and π-π interactions.68-75 NCI analyses were carried out by Multiwfn76 (version 3.3.8) software with the wave functions obtained at the M06-2X/Def2-TZVP level of theory. In addition, the powerful theory of distortion/interaction analyses developed by Ess and Houk77,78 were applied into the investigated systems to explain the activation energy barriers and the influencing factors. 3. RESULTS AND DISCUSSION The D-A reaction between 3-vinylindole (denoted as R1) and methyleneindolinone (denoted as R2) in Scheme 1 could proceed via eight different modes (Figure 1), in which R1 can attack R2 from both Si- and Re-faces. Accordingly, eight possible isomers ((±)-A, (±)-B, (±)C and (±)-D) may be produced (Figure 1). With regard to these isomers, A, B, C and D are diastereoisomers obtained via the attack of the Si-face of R2 by R1 from different directions, and each of them has one enantiomer (ent-A, ent-B, ent-C, ent-D, obtained via the attack of the Reface of R2 by R1 from different directions). The isomers A and C (or B and D) are regioisomers


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in which they have different C-C bonding manners (i.e., C1-C6 and C4-C5 for A or B, C1-C5 and C4-C6 for C or D) in the formed six-membered rings, while A and B (or C and D) are epimers because they have only one different stereocenter. It is shown that the D-A reaction in Scheme 1 can occur with and without the bisthiourea catalyst I but go through different reaction times, leading to the products in excellent and poor stereoselectivity, respectively. Evidently, such D-A reaction is strongly affected by the bisthiourea catalyst I. Thereby, in the following sections, we will discuss the mechanisms of the uncatalyzed reaction and the catalyzed reaction with the bisthiourea catalyst I in detail.

Figure 1. Eight modes for the reaction between 3-vinylindole (R1) and methyleneindolinone (R2) and the resulted products (isomers (A, B, C, D) and their enantiomers (ent-A, ent-B, ent-C, ent-D) are obtained via the attack of the Si- and Re-faces of R2 by R1 from different directions, respectively).


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3.1 Uncatalyzed Reactions For the uncatalyzed reaction, without the participation of catalyst as the chiral environment, there is no enantioselectivity and the enantiomeric excess (ee) is zero, leading to the equivalent yields of isomers and their enantiomers. Therefore, we only need to consider the reaction pathways resulting in the four diastereoisomers A, B, C and D. Their enantiomers (ent-A, ent-B, ent-C, ent-D) have the same the reaction pathways.

Figure 2. Optimized geometries of reactant R1 and four conformations (R2C1, R2C2, R2C3, R2C4) at the local minima on the potential energy surface for reactant R2. The value in the parenthesis is the relative Gibbs free energy compared to that of R2C2.

Reactivity of the reactants. Because the Boc and CO2Me groups of R2 are rotatable, a conformation scan was done in order to obtain the local minima, and four conformations (R2C1, R2C2, R2C3, R2C4) at local minima were found, which are different from each other in the orientations of the Boc and CO2Me groups. The two groups tend to form coplanar structure with the methyleneindolinone moiety in these conformations, and R2C2 has the lowest conformation


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energy. The optimized structures of reactant R1 and the four conformations of R2 were shown in Figure 2. Table 1. The HOMO (EHOMO) and LUMO (ELUMO) Energies (in eV), Electronic Chemical Potential (µ, in eV), Chemical Hardness (η, in eV), Electrophilicity (ω, in eV) and Nucleophilicity (N, in eV) Indexes for the Reactants R1 and R2 (R2C1, R2C2, R2C3, R2C4). EHOMO

ELUMO

µ

η

ω

N

R1

-6.474

0.445

-3.014

6.919

0.657

3.997

R2C1

-7.667

-1.738

-4.702

5.929

1.865

2.804

R2C2

-7.647

-1.741

-4.694

5.906

1.865

2.824

R2C3

-7.714

-1.723

-4.718

5.991

1.858

2.757

R2C4

-7.690

-1.722

-4.706

5.968

1.856

2.780

Based on these optimized structures, the reactivity of the reactants was examined by employing the global reactivity indexes. The electronic chemical potential µ and chemical hardness η of a molecule are approximately calculated in terms of the highest occupied molecular orbital (HOMO) energy (EHOMO) and the lowest unoccupied molecular orbital (LUMO) energy (ELUMO), that is, µ=(EHOMO + ELUMO)/2, η=ELUMO−EHOMO. The global electrophilicity index ω is obtained by the equation ω=(µ2/2η), while the global nucleophilicity index N is calculated by the definition of Domingo and coworkers79-82 based on the HOMO energies obtained within the Kohn-Sham scheme,83 N=EHOMO(R)−EHOMO(TCE). Here, the HOMO energy of tetracyanoethylene (TCE) is taken as a reference because its HOMO energy is the lowest in a large series of molecules investigated in the polar cycloadditions, and EHOMO(R) is the HOMO energy of the related reactant. Table 1 shows their HOMO and LUMO orbital energies, electronic chemical potential (µ), chemical hardness (η), electrophilicity (ω) and nucleophilicity (N). Evidently, the electrophilicity of R2 (R2C1, R2C2, R2C3, R2C4) is stronger than that of R1, whereas the nucleophilicity of R1 is stronger than that of R2 (R2C1, R2C2, R2C3, R2C4), so it can


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be expected that R2 (R2C1, R2C2, R2C3, R2C4) as dienophile could be susceptible to nucleophilic attack while R1 as diene could be susceptible to electrophilic attack in the D-A reaction.

Figure 3. The pathways for the reactions between R1 and four conformations of R2 (R2C1, R2C2, R2C3, R2C4) in leading to the products (a) (AC1, AC2, AC3, AC4), (b) (BC1, BC2, BC3, BC4), (c) (CC1, CC2, CC3, CC4), (d) (DC1, DC2, DC3, DC4) and the relative Gibbs free energy profiles (∆G, the Gibbs free energies of [R1+R2C2] were set to 0.0 kcal/mol as a reference).

Reaction Mechanism.

Geometrically, R1 can attack each conformation from four

directions, so sixteen transition states might form. The pathways for the reactions between R1 and four conformations of R2 (R2C1, R2C2, R2C3, R2C4) and relative Gibbs free energy profiles were displayed in Figure 3, in which the Gibbs free energies of [R1+R2C2] were set to 0.0 kcal/mol as a reference. The complexations of R1 and four conformations of R2 (R2C1, R2C2,


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R2C3, R2C4) proceed via four different transition states in leading to four different forms of the corresponding products (A, B, C, D). The reaction pathways of [R1+R2C2]→TSAC2→AC2, [R1+R2C2]→TSBC2→BC2,

[R1+R2C2]→[R1+R2C4]→TSCC4→CC4,

[R1+R2C2]→[R1+R2C4]→TSDC4→DC4 are more favorable due to their lower energy barriers of 16.2, 18.6, 26.9, 26.2 kcal/mol, respectively. To ascertain the preference of transition state, a comparison of the distortion/interaction energies of these transition states was made. Herein, each of the transition states (TSAC2, TSBC2, TSCC4, TSDC4) was divided into two fragments (distorted R1 and distorted R2), and then single point calculations were performed on the two fragments. The energy differences between the fully optimized ground state structures of the reactants (R1 and R2 with R2C2 conformation) and their distorted structures (distorted R1 and distorted R2) are their respective distortion energies (∆E⧧distR1 and ∆E⧧distR2), and the total distortion energy (∆E⧧[distR1+ distR2]) is the sum of ∆E⧧distR1 and ∆E⧧distR2. The interaction energy (∆E⧧int) is calculated by the difference between the activation energy (∆E⧧act) and the total distortion energy (∆E⧧[distR1+ distR2]). The calculated distortion, interaction, and activation energies for transition states of reactions between the reactants R1 and R2 (R2C1, R2C2, R2C3, R2C4) with different conformations are summarized in Table S1. Because only one transition state appears in the process from reactants to product, so the step from reactants to transition state is ratedetermining step. The transition state TSAC2 has the lowest activation energy compared to other three ones (TSAC1, TSAC3, TSAC4), so the [R1+R2C2]→TSAC2→AC2 reaction proceeds faster than other three reactions in generating the product A. Therefore, it can be concluded that TSAC2 is the preferential transition state. Similarly, TSBC2, TSCC4, TSDC4 possessing the lowest activation energies are the preferential transition states in the processes leading to the


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corresponding products (B, C, D), respectively. The optimized structures of the transition states (TSAC2, TSBC2, TSCC4, TSDC4) and products (AC2, BC2, CC4, DC4) were depicted in Figure 4 (see supporting information for other transition states and products in Figures S1 and S2, respectively.).

Figure 4. Optimized geometries of the transition states (TSAC2, TSBC2, TSCC4, TSDC4) and products (AC2, BC2, CC4, DC4). The distances are in Å. The hydrogen not involved in the reaction was omitted.

The forming bonds in the transition states TSAC2 and TSBC2 are C1-C6 and C4-C5 bonds while those in TSCC4 and TSDC4 are C1-C5 and C4-C6 bonds. Their bonding distances are


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summarized in Table 2, which are longer than the normal C-C bond (1.54 Å) by 0.40~1.40Å. It suggests that these forming bonds are still of noncovalent rather than covalent characters. It is well established that the D-A reactions of unsymmetrical dienes and dienophiles usually go through the concerted asynchronous mechanisms, in which the stretch and twist modes84-86 are used to identify the asynchronicity. The stretch mode reveals the difference of the two forming C-C bonding distances in the transition state, and the twist mode which is measured by a twistasynchronicity parameter (θ) reflects the change of the diene and dienophile backbones from being parallel. With regard to the three transition states (TSAC2, TSBC2, TSDC4), the forming two C-C bonds go through asynchronicity processes because their bond length differences are 0.88, 0.70 and 0.77 Å for TSAC2, TSBC2 and TSDC4, respectively. However, for the transition state TSCC4, the difference of the forming two C-C bond lengths is even smaller (0.08 Å), meaning that the two C-C bonds almost simultaneously form which could be a synchronicity process. Meanwhile, we noted that TSAC2 and TSCC4 are much less twisted because their twistasynchronicity parameter θ values are -1.2 and -2.8º, respectively. While TSBC2 and TSDC4 are highly twisted with θ=-14.5 and 7.9º, respectively. Obviously, the different twists experienced by the transition states should be related to the attack directions as well as the interactions between the groups of R1 and R2 (i.e., R2C2 and R2C4). For uncatalyzed reaction, the step from reactants to transition state is also the stereoselectivity-determining step. By contrast, the [R1+R2C2]→TSAC2→AC2 and [R1+R2C2] →TSBC2→BC2

processes

have

energy

barriers

considerably

lower

than

the

[R1+R2C2]→[R1+R2C4]→TSCC4→CC4 and [R1+R2C2]→[R1+R2C4]→TSDC4→DC4 processes by 7.0-11.0 kcal/mol, so the [R1+R2C2]→TSAC2→AC2 and [R1+R2C2] →TSBC2→BC2 processes are more likely to occur. The experimental results obtained a 3:1 dr value, so we


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speculated that (±)-A and (±)-B could be the major and minor products which take up 75% and 25%, respectively. To prove it, the lowest-energy transition state TSAC2 will be made a comparison with its counterparts (TSBC2, TSCC4, TSDC4), and the distortion/interaction analyses will be used to understand the stereocontrolling factors in these transition states. Table 2. The Bonding Distances (r, in Å) for the Forming Two C-C Bonds and Their Distance Difference (∆r, in Å), and the Twist-Asynchronicity Parameter (θ, in degree) at the Transition States (TSAC2, TSBC2, TSCC4, TSDC4). Transition state

Bonding

r

∆ra

θb

TSAC2

C1-C6

2.84

0.88

-1.2

C4-C5

1.96

C1-C6

2.68

0.70

-14.5

C4-C5

1.98

C1-C5

2.20

0.08

-2.8

C4-C6

2.12

C1-C5

1.92

0.77

7.9

C4-C6

2.69

TSBC2 TSCC4 TSDC4 a

∆r=|rC1-C6− rC4-C5| for TSAC2, TSBC2; ∆r=|rC1-C5− rC4-C6| for TSCC4, TSDC4.

b

θ is the dihedral angle of C1-C4-C5-C6 for TSAC2, TSBC2, where C4-C5 is the shorter one of the

forming two C-C bonds; θ is the dihedral angle of C1-C4-C6-C5 for TSCC4, where C4-C6 is the shorter one of the forming two C-C bonds; θ is the dihedral angle of C1-C4-C6-C5 for TSDC4, where C1-C5 is the shorter one of the forming two C-C bonds.

The detailed analyses of the distortion, interaction, and activation energies for transition states (TSAC2, TSBC2, TSCC4, TSDC4) are displayed in Figure 5. The lower activation energies for

the

[R1+R2C2]→TSAC2

and

[R1+R2C2]→TSBC2

for[R1+R2C2]→[R1+R2C4]→TSCC4 and

processes

relative

to

[R1+R2C2]→[R1+R2C4]→TSDC4 processes

those are

resulted from the different distortion energies of R1 and R2 and their interaction energies. The energies to distort R1 and R2 to their transition states for the [R1+R2C2]→TSAC2 process are smaller, while their interaction energy is larger, leading to the lowest activation energy of 2.2


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kcal/mol, so it can be concluded that this process is the most favorable stereoselectivitydetermining step in yielding the major product A. By contrast, the larger energy to distort R1 and the smaller interaction energy for the [R1+R2C2]→TSBC2 process make this process has a lower activation energy of 4.2 kcal/mol, so it is a less favorable stereoselectivity-determining step which generates the minor product B. The larger energies to distort R1 and R2 to their transition states and the smaller interaction energy for R1 and R2 in the [R1+R2C2]→[R1+R2C4]→TSCC4 and [R1+R2C2]→[R1+R2C4]→TSDC4 processes result in their higher activation energies, so these processes are less possible to occur. Clearly, the stronger interaction energies and the smaller distortion energies play the dominant factor in determining the stereoselectivity of uncatalyzed reaction, making the [R1+R2C2]→TSAC2 and [R1+R2C2]→TSBC2 processes in leading to the major product A and minor product B achievable at room temperature.

Figure 5. The relationships between distortion, interaction, and activation energies for transition states of reactions between the reactants R1 and R2 with different conformation (blue: distortion energy of R1; red: distortion energy of R2 with different conformation; green: interaction energy; black: activation energy, units are in kcal/mol). The energies were obtained at M06-2X/Def2TZVP-IEFPCM(nhexane)//M06-2X/6-31G(d,p)-IEFPCM(n-hexane) level of theory.


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The total distortion energy in these processes comes from the respective distortion energies of R1 and R2 (∆E⧧distR1 and ∆E⧧distR2), so we further assessed the distortion extents of R1 and R2 through comparing their optimized geometries at the ground state and the distorted ones in the transition states. The superposition results suggest that the distortion energy of R1 is mainly caused by the distortion of its vinyl group. This group in the transition state (TSAC2, TSBC2, TSCC4, TSDC4) distorts to a distinctive extent and deviates from the coplanar structure of R1 at the ground state (Figure S3). The vinyl group of R1 in TSAC2 seems to distort much more but the distortion energy is the smallest one (∆E⧧distR1=12.9 kcal/mol, Figure 5). The superposition of the optimized geometry of R2C2 with the lowest conformation energy at the ground state with the corresponding R2 fragment in the transition state (TSAC2, TSBC2, TSCC4, TSDC4) was displayed in Figure S4. Besides the distortion of the Boc group, the CO2Me group of R2 also distorts in the transition state. We noted that the CO2Me groups of R2 in TSAC2 and TSBC2 have the similar directions to that of the ground state R2C2, but those in TSCC4 and TSDC4 have the opposite directions. As a result, the ground state R2C2 can convert into the corresponding R2 fragments in TSAC2 and TSBC2 with a smaller distortion energy, while the distortion energy (∆E⧧distR2) is larger for the conversion of R2C2 to TSCC4 and TSDC4 (Figure 5). Both the distortions of Boc and CO2Me groups contribute to the distortion energy of R2 (∆E⧧distR2) in the transition state. The different distortions of groups in the transition state usually facilitates the formation of attractive interaction73 and thus the subsequent bonding reaction process. Furthermore, the interaction between R1 and R2 in the transition state (TSAC2, TSBC2, TSCC4, TSDC4) was elaborated. From Figure 5, we knew that the interaction energy in the transition state has the order: TSAC2>TSBC2>TSCC4>TSDC4, suggesting that the relative orientations of R1 and R2C2 in TSAC2 are the most favorable. Structurally, R1 is located above


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R2C2 in TSAC2 which tends to form weak intermolecular noncovalent interactions like π-π and hydrogen-bonding interactions, as shown in Figure 4. These intermolecular interactions strongly affect the bonding reaction process. To understand their roles in these transition states, NCI and QTAIM analyses were employed to identify strong intermolecular interactions, weak van der Waals interactions and steric interactions. Figures 6 and S5 show the NCI and QTAIM analyses of transition states TSAC2, TSBC2, TSCC4, TSDC4. Clearly, both TSAC2 and TSBC2 have a large green cloud between the π-systems of R1 and R2 fragments, in addition, a green cloud for NH···O interaction is observed in TSAC2. However, these features are not observed in TSCC4 and TSDC4.

Figure 6. NCI analyses of the interactions for (a) TSAC2 and (b) TSBC2 (The blue, green and red surfaces are indicative of strong attraction, weak interaction and steric effect, respectively. The isosurface value is set to 0.40 a.u.). QTAIM analyses of the intermolecular BCPs with the numbered points between atoms along the bond paths for (c) TSAC2 and (d) TSBC2.

QTAIM analyses further suggested that a number of intermolecular contacts were found between R1 and R2 fragments in these transition states (Figure 6). The orientations of R1 and


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R2C2 in TSAC2 render them to interact with each other via many π···π interactions, strong NH···O hydrogen bond and lp···π interaction (Figure 6 and Table S2). Also, π···π, lp···π, C-H···π interactions and C-H···π hydrogen bond are found in TSBC2. In contrast, fewer intermolecular BCPs corresponding to intermolecular interactions (e.g, π···π, lp···π, etc) are observed in TSCC4 and TSDC4 (Table S2 and Figure S5). The intermolecular interactions significantly contribute to the stability of more favorable transition state TSAC2 and are responsible for the smaller activation energy of the [R1+R2C2]→TSAC2→AC2 process, and they also play a significant role in determining the stereoselectivity. In addition, the two forming C4-C5 and C1-C6 bonds in TSAC2 are of covalent and electrostatic features, respectively. It indicates that the forming C4C5 bond belongs to a covalent-bonding interaction while the forming C1-C6 bond is a noncovalent bonding interaction. Evidently, the two forming C4-C5 and C1-C6 bonds are indeed asynchronous which go through the conversion from noncovalent bonding to covalent bonding. The similar phenomena are also observed in TSBC2, the two forming C-C bonds are asynchronous which undergo from the noncovalent to covalent bonding processes. 3.2 Catalyzed Reactions Compared to the uncatalyzed reaction, the [R1+R2] D-A reaction catalyzed by bisthiourea catalyst I (denoted as Cat) yields the products with excellent stereoselectivity (>99:1 dr, up to 96% ee). The experimental diastereoselective ratio (>99:1 dr) means that the yielded product is almost isomer A without the formation of any other diastereoisomers, while the enantiomeric excess (96% ee) suggests that only trace amount of ent-A is obtained. In this section, we further investigated the mechanisms of the reactions occurred in the modes of yielding products A and ent-A (Figure 1) with bisthiourea catalyst I and discussed the possible reaction pathways.


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Moreover, the role of bisthiourea catalyst I and the origin of stereoselectivity were also elaborated.

Figure 7. Optimized geometries of two conformations (CatC1 and CatC2) at the local minima on the potential energy surface for bisthiourea catalyst I. The value in the parenthesis is the relative Gibbs free energy compared to that of CatC2.

According to the experimental results of Tan and coworkers,48 the downfield shift in

13

C

NMR spectra for oxindole-carbonyl of methyleneoxindole is indicative of the formation of hydrogen bonding between bisthiourea catalyst I and methyleneindolinone (R2). On the other hand, the control experiment with the help of bisthiourea catalyst I further suggested that the Boc group in methyleneoxindole which affects the ee value plays a crucial role in generating the stereocontrolled product. In addition, the CO2Me substituent had little effect on the yields and stereoselectivities.48 These results indicate that both the oxindole-carbonyl and Boc groups of methyleneoxindole interact with bisthiourea catalyst I and thus lead to the product with excellent stereoselectivity. With respect to bisthiourea catalyst I (Cat), two possible conformations (CatC1 and CatC2) exist, in which the two thiourea functional groups in CatC1 are on the same side while those in CatC2 are on the opposite side, as depicted in Figure 7. The conformation CatC1 has a Gibbs free energy higher than CatC2. As a result, the interaction of Cat (CatC1 and CatC2) with reactant R2 (R2C1, R2C2, R2C3, R2C4) would lead to many possible dimeric complexes.


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Figure 8. Optimized structures for the 18 dimeric complexes formed between Cat (CatC1 and CatC2) and the four conformations (R2C1, R2C2, R2C3, R2C4). The distances are in Å.


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Based on the above analyses, a series of possible interaction models of the dimeric complexes formed between Cat (CatC1 and CatC2) and R2 (R2C1, R2C2, R2C3, R2C4) were constructed for optimization. Meanwhile, in view of the fact that the dimeric complexes will interact with reactant R1 to generate product A or ent-A in the subsequent D-A reaction, we further checked all the optimized structures to see whether the R2 fragments in these structures pose an appropriate position because the R2 fragment should expose its C=C bond to facilitate the approaching of reactant R1. A large group around the C=C bond of R2 fragment in the optimized structure would result in the steric hindrance which is unfavorable for the D-A reaction, so such optimized structure will not be considered. Finally, 18 dimeric complexes without imaginary frequencies were found (Figure 8), which enable reactant R1 to approach in yielding the major product A. There are 15 dimeric complexes without imaginary frequencies (Figure S6), which enable R1 to approach in yielding the trace product ent-A. They were taken into account in the catalyzed reactions. It is known that the intermolecular interactions between R1 and R2C2 in TSAC2 of uncatalyzed reaction play crucial roles in determining the stereoselectivity. Analogously, with regard to catalyzed reaction, besides the intermolecular interactions between R2 (R2C1, R2C2, R2C3, R2C4) and Cat (CatC1 and CatC2) in their dimeric complex, R1 could also tend to form intermolecular interactions with R2 (R2C1, R2C2, R2C3, R2C4) as well as Cat (CatC1 and CatC2) in their trimeric complex, these interactions would certainly promote the reaction procedure. The dimeric and trimeric complexes could be resulted from the interactions between the higher energy conformations of R2 and Cat, so the procedure from the mixed lowest energy conformations (CatC2 and R2C2) to the higher ones is termed as "conformation conversion processes (step 1)". Due to the flexible conformation of reactant R2, R2 could adopt a


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conformation with a higher conformation energy to react with catalyst (Cat) and reactant R1, so it is not necessary that the reaction occurs via the "conformation conversion" process. For comparison, we considered this process for all possible pathways. The procedure from the mixed single monomers (R2C1, R2C2, R2C3, R2C4, CatC1, CatC2, R1) to the trimeric complex is termed as "complexation processes (step 2)". Subsequently, the trimeric complex formed between R2 (R2C1, R2C2, R2C3, R2C4), Cat (CatC1 and CatC2) and R1 would go through a transition state in which two C-C bonding process would take place. The procedure starting from this point to the final product A or ent-A is termed as "reaction processes (step 3)". Thereby, the detailed reaction mechanisms were elaborated in the following section. For the reaction process leading to the major product A, there are 18 dimeric complexes formed between R2 (R2C1, R2C2, R2C3, R2C4) and Cat (CatC1 and CatC2), so the reactant R1 could interact with these complexes via 18 pathways. But which one is more possible and favorable? To identify, a screening was made based on the relative Gibbs free energies (∆G). The positive ∆G means the dimeric complex cannot form spontaneously at room temperature, so the pathway associated with this dimeric complex is not considered because the reactions occur quickly at room temperature. On the other hand, the approaching of R1 to R2 (R2C1, R2C2, R2C3, R2C4) in the dimeric complex should be an energetically favorable process due to the strong intermolecular interactions between them, so the trimeric complex formed would be more stable than the dimeric complex (i.e., with a more negative ∆G value). The relative Gibbs free energies (∆G) for the 18 dimeric and trimeric complexes, the subsequent transition states are summarized in Table 3, and the free energy profiles for the "conformation conversion and complexation processes" are shown in Figures S7-14, in which the Gibbs free energies of [CatC2+R2C2+R1]


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were set to 0.0 kcal/mol as a reference. In terms of the aforementioned analyses, seven possible pathways (1-7) were selected out (see the pathway screening in Table 3).

Table 3. The relative Gibbs free energies (in kcal/mol) for the sum of monomers ((Cat+R2+R1) with two conformations of Cat (CatC1 and CatC2) and four conformations of R2 (R2C1, R2C2, R2C3, R2C4)), for the sum of R1 and dimeric complex between Cat and R2, for the trimeric complex between Cat, R2 and R1, and for the corresponding transition state (TS).a Sum of monomers

∆G

Dimer+R1

∆G

Trimer

∆G

TS

∆G

CatC1+R2C1+R1

7.0

(CatC1•R2C1)-I+R1

-4.0

(CatC1•R2C1)-I•R1

5.0

TSC1C1I

9.0

-5.9

(CatC1•R2C1)-II•R1

-3.9

TSC1C1II

4.1

-3.7

(CatC1•R2C1)-III•R1

-5.7

TSC1C1III

3.9

(CatC1•R2C1)-II+R1 (CatC1•R2C1)-III+R1 CatC1+R2C2+R1

4.7

-2.0


-1.0

TSC1C2I

7.5

c

-2.2


-3.2

TSC1C2II

7.8

(CatC1•R2C2)-III+R1

-0.8


-0.7

TSC1C2III

10.3

d

(CatC1•R2C2)-I+R1 (CatC1•R2C2)-II+R1

CatC1+R2C3+R1

9.2

b

-1.6


-1.8

TSC1C3I

9.7

e

-1.4


-5.4

TSC1C3II

8.1

f

-2.3


-2.7

TSC1C3III

7.2

(CatC1•R2C4)-I+R1

0.8


-3.0

TSC1C4I

8.3

(CatC1•R2C4)-II+R1

1.2


0.1

TSC1C4II

12.9

(CatC2•R2C1)-I+R1

0.6


-2.3

TSC2C1I

8.6


-9.6


-5.6

TSC2C1II

7.6

(CatC1•R2C3)-I+R1


(CatC1•R2C3)-III+R1 CatC1+R2C4+R1

CatC2+R2C1+R1

CatC2+R2C2+R1 CatC2+R2C3+R1

CatC2+R2C4+R1

6.5

2.3

0.0 4.6

1.8

g

-0.6

(CatC2•R2C2)•R1

-2.6

TSC2C2

8.8

h

-5.2


-6.3

TSC2C3I

2.4


-3.2


-2.7

TSC2C3II

10.2

(CatC2•R2C3)-III+R1

-5.3


-2.3

TSC2C3III

10.4

(CatC2•R2C4)+R1

0.5

(CatC2•R2C4)•R1

-0.6

TSC2C4

10.8

(CatC2•R2C2)+R1

(CatC2•R2C3)-I+R1

a c

b

The Gibbs free energies of [CatC2+R2C2+R1] were set to 0.0 kcal/mol as a reference. pathway 1; pathway 2; dpathway 3; epathway 4; fpathway 5; gpathway 6; hpathway 7.

Similarly, the processes in generating the trace product ent-A were also divided into three steps (i.e., conformation conversion, complexation and reaction processes). Although 15 dimeric complexes are suitable for the approaching of the reactant R1 to form the trimeric complexes, a screening based on the relative Gibbs free energies (∆G) suggests that only two pathways (1′ and 2′) are energetically favorable. The relative Gibbs free energies (∆G) for the 15 dimeric and


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trimeric complexes, the subsequent transition states are summarized in Table S3, and the free energy profiles for the "conformation conversion and complexation processes" are shown in Figures S15-21 with the Gibbs free energies of [CatC2+R2C2+R1] to be 0.0 kcal/mol as a reference. The experimentally excellent enantioselectivity (up to 96% ee) in the catalyzed reaction indicates that the process leading to the major product A is far superior to that leading to the trace product ent-A. Based on the screening, we knew that the enantioselectivity is dependent upon the trimeric complex obtained via the attack of the Si- or Re-face of R2 by R1 from a certain direction, so the stability of the trimeric complex will determine the enantioselectivity. The more stable trimeric complex will result in the preferential product, and vice versa. From Tables 3 and S3, it can be seen that the trimeric complexes in pathways (2, 3, 5 and 6) have the higher Gibbs free energies (i.e., -3.2, -1.8, -2.7, -2.6 kcal/mol, respectively.) than those (i.e., -4.8, -3.9 kcal/mol) in pathways (1′ and 2′), meaning that these trimeric complexes are less stable. Thereby, the pathways (2, 3, 5 and 6) are less competitive which will not take place. In contrast, the trimeric complexes formed in pathways (1, 4, and 7) are more stable than those in pathways (1′ and 2′), their concentrations in equilibrium will be larger than those in pathways (1′ and 2′), so they are much more competitive which are responsible for the high ee value (96%). The whole free energy profiles for the three pathways (1, 4, and 7) leading to the major product A and two pathways (1′ and 2′) leading to the trace product ent-A were elaborated, as shown in Figures 9-13.


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Figure 9. The pathway for the reactions between CatC1, R2C1 and R1 of the whole process (pathway 1) and the free energy profile (∆G, the Gibbs free energies of [CatC2+R2C2+R1] were set to 0.0 kcal/mol as a reference. The distances are in Å.).

With respect to the "conformation conversion and complexation processes (steps 1 and 2)" of pathway 1 (Figure 9), the reactions occur between CatC1, R2C1 and R1, so the lowest energy conformations CatC2 and R2C2 may change their conformations to CatC1 and R2C1, respectively. An energy of 7.0 kcal/mol is needed to realize the step 1. Then CatC1 and R2C1 interact with each other, leading to the dimeric (CatC1•R2C1)-III complex (Figure 8). QTAIM analyses show that three N-H groups and one C-H group of CatC1 interact with oxindole-carbonyl of R2C1, and also three N-H groups and one C-H group interact with the carbonyl of Boc group (Figure S22a and Table S4), so CatC1 and R2C1 act as electron acceptor and donor, respectively. In addition, the intermolecular interactions between C-H bonds of Boc group in R2C1 and the F atoms of CF3 group in CatC1 were also observed. The electron donation from R2C1 to CatC1 through hydrogen


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bonding and van der Waals interactions would make R2C1 more susceptible to nucleophilic attack. To verify it, the variations of HOMO and LUMO orbital energies of the R2C1 fragment in (CatC1•R2C1)-III were evaluated, and the electrophilicity (ω) and nucleophilicity (N) were calculated. As shown in Table 4, the electrophilicity of R2C1 fragment (ω=2.600) in (CatC1•R2C1)-III complex becomes larger compared to the R2C1 monomer (ω=1.865, Table 1), indicating that the R2C1 fragment becomes more susceptible to nucleophilic attack by R1. Obviously, CatC1 plays an important role in the activation of R2C1, which favors the D-A reaction of R2C1 and R1. The subsequent complexation of (CatC1•R2C1)-III and R1 with a negative ∆G value (-5.7 kcal/mol) suggests that this process is energetically favorable. QTAIM analyses of (CatC1•R2C1)-III•R1 complex suggest that R1 interacts with CatC1 via hydrogen bonding and van der Waals interactions (Figure S22b and Table S4), while it interacts with R2C1 mainly via π···π interactions (Figure S22c and Table S4). The intermolecular distances for the C1···C6 and C4···C5 contacts in (CatC1•R2C1)-III•R1 are 3.18 and 3.03 Å, respectively (Figure 9). Table 4. The HOMO (EHOMO) and LUMO (ELUMO) Energies (in eV), Electronic Chemical Potential (µ, in eV), Chemical Hardness (η, in eV), Electrophilicity (ω, in eV) and Nucleophilicity (N, in eV) Indexes for the R2 fragments in the dimeric complexes in pathways (1, 4, 7, 1′, 2′). Pathway

R2 fragment

EHOMO

ELUMO

µ

η

ω

N

1

R2C1-(CatC1•R2C1)-III

-8.470

-2.590

-5.530

5.881

2.600

2.000

4

R2C3-(CatC1•R2C3)-II

-8.451

-2.323

-5.387

6.128

2.368

2.020

7

R2C3-(CatC2•R2C3)-I

-7.957

-1.985

-4.971

5.972

2.069

2.513

1′

R2C1-(CatC1•R2C1)-I′

-8.319

-2.439

-5.379

5.880

2.460

2.151

2′

R2C2-(CatC1•R2C2)-I′

-8.422

-2.617

-5.519

5.805

2.624

2.049

Subsequently, in the "reaction process" (step 3), (CatC1•R2C1)-III•R1 first goes through a transition state (TSC1C1III) to generate an intermediate (IMC1C1III), which needs to overcome an


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energy barrier of 9.6 kcal/mol (Figure 9). In TSC1C1III, the distances for the forming C1-C6 and C4-C5 bonds are 2.92 and 2.10 Å, respectively (Figure 9). Their distance difference of 0.82 Å reveals that the forming two C-C bonds cannot go through synchronicity processes, while the small value of twist-asynchronicity parameter (θ=3.8º) means that the backbones of R1 and R2C1 are almost parallel. The C4-C5 bond forms in IMC1C1III with a length of 1.59 Å, but the forming C1-C6 bond is shortened (2.55 Å). The TSC1C1III→IMC1C1III process is an exothermic process which releases an energy of 11.2 kcal/mol. Then IMC1C1III undergoes a transition state (TS′C1C1III) to form the C1-C6 bond, yielding the CatC1•AC1III complex. The energy barrier for IMC1C1III→TS′C1C1III→CatC1•AC1III is very small (1.0 kcal/mol). In TS′C1C1III, both the C4C5 bond and the forming C1-C6 bond are contracted. The C1-C6 and C4-C5 bonds form later with respective bond lengths of 1.55 and 1.54 Å in CatC1•AC1III. Evidently, the processes to form the two C-C bonds need to undergo two transition states which are stepwise rather than concerted. The exothermic process from TS′C1C1III to CatC1•AC1III releases an energy of 15.3 kcal/mol, which facilitates the broken of intermolecular interactions in the CatC1•AC1III complex. Finally, the separate CatC1 and AC1 from the CatC1•AC1III complex convert into their most favorable conformations CatC2 and AC2. In pathway 1, the process from (CatC1•R2C1)III•R1 to TSC1C1III is the rate-determining step, this pathway can readily occur because the energy barrier of 9.6 kcal/mol in the rate-determining step is much smaller than that in uncatalyzed reaction (16.2 kcal/mol). Meanwhile, the process from (CatC1•R2C1)-III•R1 to TSC1C1III is also the stereoselectivity-determining step in which the attack of the Si-face of R2 by R1 from the direction leading to the product A corresponds to the major product observed experimentally.


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Noticeably, in the section of catalyst screening of Tan and coworkers' work,48 the catalyst (Cat, CatC1 and CatC2) with the CF3 groups exhibits much better performance than that without the CF3 groups (catalyst II) in both the stereoselectivity and yield, clearly telling us that the CF3 groups in Cat (CatC1 and CatC2) are crucial in determining the stereoselectivity. In pathway 1, it is known from QTAIM analyses that the C-H bonds of Boc group in R2C1 and the N-H bond in R1 interact with the CF3 group via hydrogen bonding or van der Waals interactions, which demonstrates the important roles of CF3 groups in Cat (CatC1 and CatC2).



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Figure 10 shows the free energy profile for pathway 4 of the reactions between CatC1, R2C3 and R1. The conformation conversion processes from the lowest energy conformations CatC2 and R2C2 to CatC1 and R2C3 need a high energy of 9.2 kcal/mol. Then CatC1 can interact with R2C3 via the mode of (CatC1•R2C3)-II (Figure 8). For (CatC1•R2C3)-II, the oxindole-carbonyl, Boc and C-H groups of R2C3 interact with the N-H, C-H and CF3 groups of CatC1 (Figure S23a and Table S5), while the interactions between the groups (oxindole-carbonyl, Boc) of R2C3 and the N-H, C-H and CF3 groups of CatC1 are observed in (CatC1•R2C3)-III (Figure S23a and Table S5). Compared to the R2C3 monomer (ω=1.858, Table 1), the electrophilicity value of R2C3 fragment in the complex (CatC1•R2C3)-II increases (Table 4), reflecting that the R2C3 fragment is more susceptible to nucleophilic attack. Thereby, the interaction of R2C3 with CatC1 activates R2C3 which will promote the subsequent reaction between R2C3 and R1. QTAIM analyses of (CatC1•R2C3)-II•R1 indicate that R1 interacts with CatC1 via hydrogen bonding and van der Waals interactions while it interacts with R2C3 mainly via π···π interactions (Figure S23b and c, Table S5), there are no intermolecular BCPs for C1···C6 and C4···C5 contacts due to the large distances of 4.25 and 4.04 Å, respectively (Figure 10). For the "reaction processes" (step 3) in pathway 4 (Figure 10), without forming any intermediate, the trimeric complex (CatC1•R2C3)-II•R1 goes through only one transition state (TSC1C3II) to generate the CatC1•AC3II complex. The distance difference for the forming C1-C6 and C4-C5 bonds in TSC1C3II is 0.86 Å, and the backbones of R1 and R2C3 in TSC1C3II are in parallel arrangement because of the very small twist-asynchronicity parameters (θ=-0.7º). It tells us that the two C-C bonds formed in pathway 4 are concerted asynchronous. The energy barriers of 13.5 kcal/mol for the (CatC1•R2C3)-II•R1→TSC1C3II→CatC1•AC3II process is observed, and the energy release for TSC1C3II→CatC1•AC3II is 30.4 kcal/mol. The exothermic processes will


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drive the broken of intermolecular interactions in CatC1•AC3II, and then the separate CatC1 and AC3 undergo the conformation conversions to yield CatC2 and AC2. For pathway 4, the ratedetermining step is the process from the trimeric (CatC1•R2C3)-II•R1 complex to the transition state TSC1C3II. The energy barriers in these processes are smaller than 16.2 kcal/mol, so this pathway could also occur. This processes is also the step determining the stereoselectivity which is associated with the major product A in experiment. With respect to pathway 7 (Figure 11), an energy of 4.6 kcal/mol is needed to accomplish the conformation conversion from R2C2 to R2C3, then R2C3 interacts with CatC2 to form the dimeric (CatC2•R2C3)-I complex via numerous intermolecular interactions (Figure 8). QTAIM analyses show that the interactions occur between the oxindole-carbonyl, Boc and CO2Me groups of R2C3 and the N-H, C-H and CF3 groups of CatC2 (Figure S24a and Table S6). The R2C3 fragment in (CatC2•R2C3)-I is activated and is more susceptible to nucleophilic attack by R1 because of the increased electrophilicity (ω=2.069, Table 4). The attack of R1 on (CatC2•R2C3)-I results in the trimeric (CatC2•R2C3)-I•R1 complex with a ∆G value of -6.3 kcal/mol, smaller than that of (CatC2•R2C3)-I (-5.2 kcal/mol). The N-H and C-H groups of R1 strongly interact with the CF3 group and benzene ring of CatC2 by forming N-H···F and C-H···π hydrogen bonding and van der Waals interactions (Figure S24b and Table S6), while R1 interacts with R2C3 mainly via π···π interactions (Figure S24c and Table S6). In (CatC2•R2C3)I•R1, the intermolecular BCPs for C1···C6 and C4···C5 contacts are found with intermolecular distances of 3.12 and 3.04 Å, respectively (Figure 11 and Table S6). After going through a transition state (TSC2C3I) with an energy barrier of 8.7 kcal/mol, the CatC2•AC3I complex is generated. In TSC2C3I, the distance difference for the forming C1-C6 and C4-C5 bonds is of 0.70 Å, and the twist-asynchronicity parameter (θ) for the backbones of R1 and R2C3 is 2.5º. Hence,


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the two C-C bonds formed are concerted asynchronous in this pathway. The intermolecular interactions in CatC2•AC3I can be readily broken to yield CatC2 and AC3 with the help of the energy release (27.8 kcal/mol) of the TSC2C3I→CatC2•AC3I process. Finally, a conformation conversion of AC3 gives out AC2. Pathway 7 with an energy barrier of 8.7 kcal/mol in the ratedetermining step from (CatC2•R2C3)-I•R1 to TSC2C3I could be the most favorable one compared to other pathways. In TSC2C3I, the attack of the Si-face of R2 by R1 determines the stereoselectivity in generating the product A.



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Figure 12. The pathway for the reactions between CatC1, R2C1 and R1 of the whole process (pathway 1′) and the free energy profile (∆G, the Gibbs free energies of [CatC2+R2C2+R1] were set to 0.0 kcal/mol as a reference. The distances are in Å.).

For pathway 1′ (Figure 12), CatC1 interacts with R2C1 via numerous intermolecular interactions in the dimeric (CatC1•R2C1)-I′ complex (Figure S6). The oxindole-carbonyl, Boc and CO2Me groups of R2C1 interact with the N-H, C-H and CF3 groups of CatC1 in terms of QTAIM analyses (Figure S25a and Table S7). The electrophilicity of R2C1 fragment (ω=2.460, Table 4) in (CatC1•R2C1)-I′ complex increases relative to that of the R2C2 monomer (ω=1.865, Table 1), so the R2C1 fragment is activated and it has a stronger tendency to react with R1. The resulted ent-(CatC1•R2C1)-I′•R1 complex from the interaction between (CatC1•R2C1)-I′ and R1 has a ∆G value (-4.8 kcal/mol) smaller than (CatC1•R2C1)-I′. QTAIM analyses indicate that there is no interaction between R1 and CatC1, while R1 interacts with R2C1 via π···π and lp···lp


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interactions and a N-H···O hydrogen bonding. In ent-(CatC1•R2C1)-I′•R1, the C1···C6 and C4···C5 contacts have intermolecular distances of 3.23 and 3.16 Å, respectively (Figure 12). In the "reaction process" (step 3), an energy barrier of 10.2 kcal/mol is needed to overcome for the ent-(CatC1•R2C1)-I′•R1→ent-TSC1C1I′ process. The distances for the forming C1-C6 and C4-C5 bonds in ent-TSC1C1I′ are 2.94 and 2.10 Å, respectively (Figure 12). A difference of 0.84 Å was observed, meaning the asynchronicity processes to form two C-C bonds. The arrangement of the backbones of R1 and R2C1 was seen from a large twist-asynchronicity parameter (θ=-9.4º). These results suggest the two C-C bonds formed in this pathway are stepwise. The C4-C5 bond formed in ent-IMC1C2I′ with a distance of 1.59 Å. The process of ent-IMC1C2I′→ent-TS′C1C2I′ needs to overcome an energy barrier of 1.3 kcal/mol, resulting in the CatC1•ent-AC1-I′ complex. The formed C4-C5 bond and the forming C1-C6 bond in ent-TS′C1C2I′ are contracted. In CatC1•ent-AC2-I′, the formed C1-C6 and C4-C5 bonds are 1.58 and 1.55 Å, respectively. The energy release (15.4 kcal/mol) for the ent-TS′C1C1I′→CatC1•ent-AC1-I′ process will promote the broken of intermolecular interactions in CatC1•ent-AC1-I′ to generate CatC2 and ent-AC2. This pathway could take place because of the smaller energy barrier in its rate-determining step of the ent-(CatC1•R2C1)-I′•R1→ent-TSC1C1I′ process compared to that in uncatalyzed reaction (16.2 kcal/mol). The trimeric ent-(CatC1•R2C1)-I′•R1 complex has a Gibbs free energy smaller than those in the three pathways leading to the product A, so the concentration of ent-(CatC1•R2C1)-I′•R1 is

smaller. Because the ent-(CatC1•R2C1)-I′•R1→ent-TSC1C1I′ process is also the stereoselectivitydetermining step, the attack of the Re-face of R2 by R1 in ent-TSC1C1I′ in leading to the product ent-A is a small amount.


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Figure 13. The pathway for the reactions between CatC1, R2C2 and R1 of the whole process (pathway 2′) and the free energy profile (∆G, the Gibbs free energies of [CatC2+R2C2+R1] were set to 0.0 kcal/mol as a reference. The distances are in Å.).

The free energy profile for pathway 2′ is shown in Figure 13, the interaction between CatC1 and R2C2 is spontaneous due to the negative ∆G value (∆G=-2.2 kcal/mol). The oxindolecarbonyl, Boc and CO2Me groups of R2C2 interact with the N-H, C-H and CF3 groups of CatC1 in terms of QTAIM analyses (Figure S26a and Table S8). The larger electrophilicity value of R2C2 fragment (ω=2.624, Table 4) in (CatC1•R2C2)-I′ relative to the R2C2 monomer (ω=1.865, Table 1) reveals that the R2C2 fragment is activated by CatC1 and is more susceptible to nucleophilic attack by R1. Compared to (CatC1•R2C2)-I′, a much negative ∆G value (∆G=-3.9 kcal/mol) of the trimeric ent-(CatC1•R2C2)-I′•R1 complex is observed, so R1 interacts with (CatC1•R2C2)-I′ and forms the trimeric complex with a stronger intermolecular interaction. According to QTAIM analyses, the C-H groups of R1 strongly interact with the N atom of CatC2


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while R1 interacts with R2C2 mainly via π···π interactions and a N-H···O hydrogen bonding (Figure S26b and Table S8). In ent-(CatC1•R2C2)-I′•R1, the intermolecular BCPs for C1···C6 and C4···C5 contacts with respective distances of 3.23 and 3.07 Å were found (Figure S26c and Table S8). The complex ent-(CatC1•R2C2)-I′•R1 goes through a transition state (ent-TSC1C2I′) to yield the intermediate (ent-IMC1C2I′) with an energy barriers of 9.6 kcal/mol. The distance difference for the forming C1-C6 and C4-C5 bonds in ent-TSC1C2I′ is 0.86 Å, and the backbones of R1 and R2C2 have a small twist-asynchronicity parameter (θ=-2.7º). Therefore, the two C-C bonds formed in this pathway are stepwise. The C4-C5 bond with a distance of 1.60 Å formed in ent-IMC1C2I′. Then IMC1C2I′ undergoes a transition state (ent-TS′C1C2I′) to form the C1-C6 bond, yielding the CatC1•ent-AC2-I′ complex. The energy barrier for ent-IMC1C2I′→entTS′C1C2I′→CatC1•ent-AC2-I′ is very small (0.2 kcal/mol). In ent-TS′C1C2I′, both the formed C4C5 bond and the forming C1-C6 bond are contracted. The formed C1-C6 and C4-C5 bonds in CatC1•ent-AC2-I′ are 1.57 and 1.55 Å, respectively. Clearly, the formations of two C-C bonds which need to undergo two transition states are stepwise. An energy release of 15.6 kcal/mol is found for the ent-TS′C1C2I′→CatC1•ent-AC2-I′ process, which facilitates the broken of intermolecular interactions in CatC1•ent-AC2-I′ to generate CatC2 and ent-AC2. This pathway could take place because of the rate-determining step of the ent-(CatC1•R2C2)-I′•R1→entTSC1C2I′ process has a smaller energy barrier relatively. The ent-(CatC1•R2C2)-I′•R1→entTSC1C2I′ process is also the stereoselectivity-determining step, the attack of the Re-face of R2 by R1 in ent-TSC1C2I′ leads to the experimental trace product ent-A. But the small concentration of trimeric ent-(CatC1•R2C2)-I′•R1 complex only results in a trace amount of ent-A. In terms of the aforementioned analyses and discussion of three possible pathways in generating the major product A and two possible pathways in generating the trace product ent-A


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for catalyzed reaction, we can know the reactants 3-vinylindole (R1) and methyleneindolinone (R2 with four conformations of R2C1, R2C2, R2C3, R2C4) can interact with each other much better in yield and stereoselectivity due to the presence of bisthiourea catalyst I (Cat with two conformations CatC1 and CatC2). Compared to the uncatalyzed reaction, it is clear that the bisthiourea catalyst I plays a crucial role in determining the stereoselectivity in the catalyzed reaction. It is well known that the chiral catalyst usually provides a "chiral pocket" to make the reactants interact with each other in a certain way, leading to the stereospecific product.87-89 With respect to the bisthiourea catalyst I, on one hand, its combination with R1 and R2 through weak intermolecular interactions activates the substrates and thus accelerates the reaction, which can be derived from the lower energy barrier in the catalyzed reaction relative to the uncatalyzed reaction. On the other hand, the "chiral pocket" of the bisthiourea catalyst I would induce the substrates to draw close to each other in a certain way and thus control the stereroselectivity. It can be seen that different steric hindrance and weak intermolecular interactions form in the transition states, and these effects strongly affect the stereroselectivity. For instance, trifluoromethyl groups in the bisthiourea catalyst I not only increase the catalytic activity by electron-withdrawing effect, but serve as hydrogen-bonding acceptor (e.g., N-H···F hydrogen bonding with diene and C-H···F hydrogen bonding with dienophile) which plays a crucial role in improving the stereoselectivity. The experimental result shows that the reaction rate, yield, stereoselectivity decrease after the remove of trifluoromethyl groups from the bisthiourea catalyst I,48 indicating the importance of trifluoromethyl groups in the "chiral pocket". In addition, the weak intermolecular interactions between the bisthiourea catalyst I and the substrates (R1 and R2) should contribute to the stereroselectivity. With respect to the three possible pathways in generating the major product A for catalyzed reaction, the formation of two


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C-C bonds proceeds via either stepwise or concerted asynchronous mechanism, but essentially, they form through the conversion from noncovalent bonding to covalent bonding.

4. CONCLUSION The Diels-Alder reactions of 3-vinylindoles and methyleneindolinone with catalyst-free and the bisthiourea catalyst have been investigated using density functional theory. The reactivity of the reactants and their active sites were assessed by the global reactivity indexes, and the computational predictions are consistent with the experimental results. In terms of the twistasynchronicity model, the Diels-Alder reaction with catalyst-free undergoes the asynchronous mechanisms, in which the diene and the dienophile first approach to each other by forming weak intermolecular interactions, and then the connections between C atoms go through a conversion from noncovalent bonding to covalent bonding processes. The bisthiourea catalyst plays an important role in the Diels-Alder reaction by inducing both the diene and the dienophile to approach it via weak intermolecular interactions, these interactions greatly lower the reaction energy barrier and cause the product obtained with excellent stereoselectivity, and the asynchronous formations of two C-C bonds also undergo the conversions from noncovalent to covalent bonding. The N-H group of 3-vinylindole, the carbonyl and Boc groups of methyleneindolinone take part in the formation of these weak intermolecular interactions. The bisthiourea catalyst provides a stereospecific room to accommodate and interact with the diene and the dienophile, so the stereoselectivity is even higher in the catalyzed reaction. This work would be helpful for us to understand the detailed reaction mechanisms, the role of the bisthiourea catalyst, and the origin of stereoselectivity for these types of Diels-Alder reactions.


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Acknowledgment The work was financially supported by the National Natural Science Foundation of China (Grant No. 21403097) and the Fundamental Research Funds for the Central Universities (lzujbky-201645). Supporting Information The optimized structures and cartesian coordinates of the reactants, transition states and products, NCI and QTAIM analyses in uncatalyzed reactions; The cartesian coordinates of the dimeric and trimeric complexes, intermediates, transition states and products, favorable pathway screening and QTAIM analyses in catalyzed reactions. References (1) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (2) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. (3) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138. (4) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520. (5) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (6) Pihko, P. M. Hydrogen Bonding in Organic Synthesis; WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim, 2009. (7) Hollmann, K.; Oppermann, A.; Amen, M.; Flörke, U.; Egold, H.; Hoffmann, A.; Herres-Pawlis, S.; Henkel, G. Z. Anorg. Allg. Chem. 2016, 642, 660. (8) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289. (9) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407. (10) Andreini, M.; Paolis, M. D.; Chataigner, I. Catal. Commun. 2015, 63, 15. (11) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558. (12) Brown, A. R.; Uyeda, C.; Brotherton, C. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2013, 135, 6747. (13) Kirsten, M.; Rehbein, J.; Hiersemann, M.; Strassner, T. J. Org. Chem. 2007, 72, 4001. (14) Lykke, L.; Carlsen, B. D.; Rambo, R. S.; Jørgensen, K. A. J. Am. Chem. Soc. 2014, 136, 11296. (15) Mayr, F.; Brimioulle, R.; Bach, T. J. Org. Chem. 2016, 81, 6965. (16) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem. Eur. J. 2006, 12, 466.


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