Ka
Lu
a,
Peng-Yu
Liang
a,
Chao-Xian
Yan
a,
Fang-Ling
Yang
a,
Xing
Yang
a,
Wei
Dou
a,
Qinwei
Yu
b,
Jianming
Yang
b and
Pan-Pan
Zhou
*a
aState Key Laboratory of Applied Organic Chemistry, Key Laboratory of Special Function Materials and Structure Design of Ministry of Education, Advanced Catalysis Center, College of Chemistry and Chemical Engineering, Lanzhou University, 222 South Tianshui Road, 730000, Lanzhou, P. R. China. E-mail: zhoupp@lzu.edu.cn; Fax: +86-931-8912582; Tel: +86 931 8912862
bState Key Laboratory of Fluorine & Nitrogen Chemicals, Xi'an Modern Chemistry Research Institute, Xi'an, 710065, P. R. China
First published on 3rd November 2020
The amination reaction between azonaphthalene and carbazole to achieve the C–H amination of an arene can be effectively accomplished by the usage of a chiral phosphoric acid catalyst, which can generate the important N-arylcarbazole framework compound with high yield and excellent enantioselectivity. To figure out the reaction mechanism, origin and influencing factors of enantioselectivity, quantum mechanical calculations were carried out. The results indicate that two pathways lead to the experimental desired major product while other two pathways lead to the enantiomeric minor product. The theoretical ee value is 90% which is in agreement with the experimental 96% ee value. Quantum theory of atoms in molecules was employed to illustrate the roles of weak intermolecular interactions in the reaction process. A detailed analysis of the types of chiral phosphoric acids was performed to elaborate on what factors affect the enantioselectivity and how they cause the effect, and a statistical analysis of the performances of different types of chiral phosphoric acids in the C–N and C–C bond formation reactions was conducted. It is expected that the present work would be insightful for understanding the chiral phosphoric acid catalyzed C–N cross-coupling reaction and thus can guide the selection of chiral phosphoric acids for the asymmetry reaction.
In recent years, organocatalysis28–34 has been rapidly developed and has become a very promising field in organic synthesis, especially for the reactions catalyzed by chiral phosphoric acids (CPAs) through hydrogen-bonding (HB) interactions.33–35 Organocatalytic C–H arylation of arenes with CPAs has been successively accomplished by Tan et al.36,37 in which the C nucleophile has been applied in the aromatic nucleophilic substitution. Inspired by this intriguing work, a more interesting and challenging idea was proposed by Tan's group, that is, how to use the N nucleophile to realize C–H amination of arenes to synthesize N-arylcarbazole frameworks in an organocatalytic way? Excitingly, for the first time, an efficient organocatalytic strategy has been elegantly developed by Tan and coworkers,27 and they utilized a CPA (i.e., the catalyst (S)-C6) to catalyze the C–H amination of an azonaphthalene derivative with 2-tert-butyl-9H-carbazole via C–N cross-coupling and obtained the N-arylcarbazole compound in good yield with excellent enantiocontrol, as shown in Scheme 1. The reactants azonaphthalene derivative and 2-tert-butyl-9H-carbazole are denoted as R1 and R2, respectively. It can be seen that the axially chiral N-arylcarbazole product (denoted as P) with a high yield of 96% and an excellent enantioselectivity of 96% ee is achieved. The proton-donating and accepting abilities of the CPA enable it to act as an efficient bifunctional catalyst.38,39 Thereby, the dual HB activation mode38,40–45 can be expected to be applicable to the reaction system in Scheme 1 in which both R1 and R2 would simultaneously interact with (S)-C6 through HBs and thus would be activated. This significant success in organocatalytic C–C and C–N cross-couplings achieved with CPAs greatly stimulates our interest, because the C–C cross-coupling reaction between an azobenzene derivative and indole has been theoretically investigated by us recently;46 thus in the present work we aim at figuring out the reaction mechanism, origin of enantioselectivity and role of the catalyst in the C–N cross-coupling reaction between 2-tert-butyl-9H-carbazole and the azonaphthalene derivative catalyzed by (S)-C6, and meanwhile, a comparison of organocatalytic C–C and C–N cross-couplings achieved by the CPA will be made to explore and elucidate their similarity and difference. It is expected that the results would be insightful for the organocatalytic C–C and C–N cross-couplings.
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Scheme 1 (S)-C6 catalyzed C–H amination reaction of an azonaphthalene derivative with 2-tert-butyl-9H-carbazole via C–N cross-coupling. |
Based on the optimized structures of the reactants, the global and local reactivity indexes within the framework of conceptual density functional theory (CDFT)55,56 were applied in assessing the reactivity tendency and the reactive sites. The electronic chemical potential (μ) and chemical hardness (η) can be calculated based on the energies of the highest occupied molecular orbital (EHOMO) and the lowest unoccupied molecular orbital (ELUMO) using the equations μ = (EHOMO + ELUMO)/2 and η = ELUMO − EHOMO. The global electrophilicity index (ω) can be calculated in terms of μ and η using ω = (μ2/2η). The global nucleophilicity index (N) can be calculated according to the definition by Domingo and coworkers,57–60 which can be defined as the HOMO energy difference between the reactant (R) and tetracyanoethylene (TCE): N = EHOMO(R) − EHOMO(TCE). The molecule tetracyanoethylene (TCE) has the lowest EHOMO compared to a large series of molecules,61 so it is taken as a reference. Herein, the HOMO energies are obtained within the Kohn–Sham scheme.62 Additionally, to evaluate the reactivity of an atom k in each reactant, the local reactivity indexes like the condensed-to-atom versions of the Fukui functions56,63–67 were employed:
Herein, qk is the electronic charge of an atom k and N is the number of electrons. When the value of fk+ is positive and large, it means that atom k in a molecule is susceptible to nucleophilic attack (electron-accepting). But when the value of fk− is positive and large, it indicates that atom k in a molecule is susceptible to electrophilic attack (electron-donating). The negative Fukui function will not be taken into account because it is usually obtained from the inability of a molecule to accommodate orbital relaxation due to a change in the number of electrons and/or improper charge partitioning techniques68–70 or distorted molecular structures.67,71–73
The powerful theoretical tools including quantum theory of atoms in molecules (QTAIM)74–76 analyses were utilized to illustrate the roles of intermolecular interactions formed in the complexes, transition states and intermediates. QTAIM analyses can be used to reveal the topological properties at the bond critical points (BCPs) of HB, van der Waals, and π–π interactions.61,77–85 Natural bond orbital (NBO)86,87 analyses were used to obtain the natural atomic charge. The plots were obtained using Multiwfn (Version 3.588) software.
E HOMO | E LUMO | μ | η | ω | N | |
---|---|---|---|---|---|---|
R1 | −7.449 | −1.996 | −4.723 | 5.453 | 2.045 | 3.058 |
R2 | −6.911 | −0.124 | −3.518 | 6.788 | 0.911 | 3.596 |
Reactant | Atom | f + | f − |
---|---|---|---|
a The atomic numbers of the selected C and N atoms in the reactants R1 and R2 are shown in Scheme 1. | |||
R1 | C1 | 0.133 | 0.117 |
C2 | −0.032 | 0.025 | |
C3 | 0.016 | 0.081 | |
C4 | 0.026 | 0.151 | |
C5 | 0.048 | −0.040 | |
C6 | 0.003 | 0.156 | |
C7 | 0.059 | 0.031 | |
C8 | 0.011 | 0.073 | |
C9 | 0.034 | 0.136 | |
C10 | −0.017 | −0.024 | |
R2 | C1 | 0.087 | 0.102 |
C2 | 0.000 | −0.024 | |
N3 | 0.020 | 0.190 | |
C4 | 0.007 | −0.004 | |
C5 | 0.073 | 0.093 | |
C6 | 0.106 | −0.003 | |
C7 | −0.003 | 0.136 | |
C8 | 0.114 | 0.023 | |
C9 | 0.039 | 0.064 | |
C10 | 0.048 | 0.034 | |
C11 | 0.126 | 0.041 | |
C12 | −0.003 | 0.105 | |
C13 | 0.113 | 0.000 |
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Fig. 1 Four modes of the reaction between R1 and R2 catalyzed by (S)-C6 and the resultant products P and ent-P. |
As depicted in Fig. 2, the Gibbs free energy profile for path I indicates that the overall reaction leading to the product P goes through the dimeric and trimeric complexes (i.e., DI and COMI), two transition states (i.e., TSI-1 and TSI-2) and four intermediates (i.e., IMI-1–IMI-4). The optimized geometries of the reactants, catalyst, complexes, transition states, intermediates and product are shown in Fig. 3. Both the reactants (R1 and R2) can interact with the catalyst (S)-C6 to form the dimeric complex, but the calculation results suggest that the dimeric complex formed between R1 and (S)-C6 (i.e., DI) has a lower Gibbs free energy than that between R2 and (S)-C6 (see Table S1 in the ESI† for details), meaning that the complex DI is more favorable. An energy of 4.2 kcal mol−1 is needed in the formation of DI. In DI, the O2–H2⋯N2 HB forms between the N1N2R group of R1 and the O2–H2 group of (S)-C6 (see Fig. S2 and Table S2 in the ESI†). The subsequent interaction between DI and R2 forms the trimeric complex COMI in which the O1⋯H3–N3 HB between the N3–H3 group of R2 and the P
O1 group of (S)-C6 (see Fig. S3 and Table S3 in the ESI†), and an energy of 2.1 kcal mol−1 are needed for DI to COMI. The H2⋯N2 distance increases after the formation of COMI (i.e., 1.72 Å in DI and 1.73 Å in COMI). From Table 3, it can be seen that the O2–H2⋯N2 HB in COMI has a shorter H2⋯N2 distance than the O1⋯H3 distance of O1⋯H3–N3 HB, and the O2–H2⋯N2 HB strength is stronger than O1⋯H3–N3 HB strength. The natural atomic charge of the C1 atom in COMI becomes less negative than that in R1, indicating that the C1 atom of R1 is electrophilic, while the natural atomic charge of the N3 atom in COMI becomes more negative than that in R2, suggesting that the N3 atom of R2 is nucleophilic. Then the proton transfer occurs from (S)-C6 to R1 which leads to the conversion of the O2–H2⋯N2 HB into O2⋯H2–N2 HB in TSI-1 (see Fig. S4 and Table S4 in the ESI†). Meanwhile, the nucleophilic attack of the N3 atom on the C1 atom also takes places, as can be seen from the decreased C1⋯N3 distance (i.e., 2.08 Å) relative to that in COMI (i.e., 3.12 Å). The C1–N3 bond with a bond length of 1.55 Å forms in IMI-1 (Fig. 3), and an energy release of 7.0 kcal mol−1 is observed for the process from TSI-1 to IMI-1. Due to the proton transfer of the H3 atom to O1 atom, one new O1–H3⋯N3 HB also forms in IMI-1 (see Fig. S5 and Table S5 in the ESI†). From COMI to IMI-1, the tautomerization of (S)-C6 finishes the conversions of the phosphorus–oxygen bond from a single bond (i.e., P–O2 in COMI) to a double bond (i.e., P
O2 in IMI-1) and from the double bond (i.e., P
O1 in COMI) to a single bond (i.e., P–O1 in IMI-1), and (S)-C6 is converted into its tautomer in IMI-1. But then the O1–H3⋯N3 HB breaks in IMI-2 (see Fig. S6 and Table S6 in the ESI†), and the N3 atom recovers back to the sp2 hybridized state. In the process of conversion from IMI-1 to IMI-2, the tendency of the axial chirality along the C1–N3 bond appears. The ionization of the tautomerized (S)-C6 in IMI-2 makes the protonation of the N1 atom possible which leads to the formation of the N1–H3 bond. After this, the left O1− group is able to approach the H1 atom of the H1–C1 group and forms the O1−⋯H1 interaction with a distance of 2.03 Å in IMI-3 (see Fig. S7 and Table S7 in the ESI†). The processes from IMI-1 to IMI-3 have a total energy release of 9.8 kcal mol−1. The H1 atom gradually shifts to the O1− anion which goes through the transition state TSI-2, and the O1−⋯H1 and C1⋯H1 distances in TSI-2 are 1.38 and 1.29 Å, respectively (Fig. 3 and S8, Table S8†). An energy of 6.2 kcal mol−1 is absorbed (Fig. 2) from IMI-3 to TSI-2. The O2⋯H2 distance of O2⋯H2–N2 HB becomes longer (i.e., 1.96 Å) in TSI-2. The O1–H1 bond finally forms in the intermediate IMI-4 and thus the catalyst (S)-C6 is recovered which releases an energy of 28.1 kcal mol−1 (Fig. 2). In IMI-4, (S)-C6 interacts with the experimental favorable axially chiral product Pvia O2⋯H2–N2 and O1–H1⋯N1 HBs (see Fig. S9 and Table S9 in the ESI†). After the breakage of the O2⋯H2–N2 and O1–H1⋯N1 HBs, the catalyst is separated from IMI-4 and the major product P is finally generated.
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Fig. 3 The optimized geometries of the reactants, catalyst, complexes, transition states, intermediates and product in path I. The distances are in Å. Some hydrogen atoms are omitted for clarity. |
Complex | HBb | Natural atomic chargec | ||
---|---|---|---|---|
O1⋯H3–N3 | O2–H2⋯N2 | q C1 | q N3 | |
a The atomic number is shown in Scheme 1. b The HB strength can be calculated using EHB = −0.429GBCP, in which GBCP is the local electronic kinetic energy density at the bond critical point (BCP) of HB. c The natural atomic charge on the C1 atom in R1 (qC1) is −0.1352 electrons, and that on the N3 atom in R2 (qN3) is −0.5261 electrons. | ||||
COMI | d (O1⋯H1) = 2.07 | d (H2⋯N2) = 1.73 | −0.1036 | −0.5438 |
E HB = −4.2 | E HB = −7.9 | |||
COMII | d (O1⋯H1) = 1.95 | d (H2⋯N2) = 1.68 | −0.1041 | −0.5459 |
E HB = −5.4 | E HB = −9.0 | |||
COMIII | d (O1⋯H1) = 1.99 | d (H2⋯N2) = 1.71 | −0.1247 | −0.5415 |
E HB = −4.6 | E HB = −8.5 | |||
COMIV | d (O1⋯H1) = 2.06 | d (H2⋯N2) = 1.68 | −0.0841 | −0.5459 |
E HB = −4.4 | E HB = −9.3 |
Path II is the most favorable pathway in generating the product ent-P (Fig. 1). The Gibbs free energy profile for the whole reaction processes of path II is shown in Fig. 4, and the optimized geometries of the complexes, transition states, intermediates and product are shown in Fig. 5. Similar to the reaction processes occurring in path I, the catalyst (S)-C6 firstly interacts with R1 and forms the dimeric complex DIIvia the O2–H2⋯N2 HB (see Fig. S10 and Table S10 in the ESI†) which needs an energy of 4.2 kcal mol−1. Then R2 participates in the interaction and its H3–N3 group interacts with the PO1 group of (S)-C6via the O1⋯H3–N3 HB (see Fig. S11 and Table S11 in the ESI†), resulting in the trimeric complex COMII. This process is endothermic and needs an energy of 4.8 kcal mol−1. In COMII, the H2⋯N2 distance of the O2–H2⋯N2 HB is 1.68 Å which becomes shorter than that in DII (i.e., 1.72 Å), while the O1⋯H3–N3 HB has an intermolecular O1⋯H3 distance of 1.95 Å (Fig. 5). Also, it can be seen from Table 3 that the H2⋯N2 distance of the O2–H2⋯N2 HB in COMII is shorter and the O2–H2⋯N2 HB is stronger. The variation of the natural atomic charge of the C1 (or N3) atom in COMI relative to that in R1 (or R2) indicates that the C1 atom of R1 is electrophilic, while the N3 atom of R2 is nucleophilic. Then the proton transfer takes place in which the H2 atom in the O2–H2 group of (S)-C6 is shifted to the N2 atom of R1 and forms a new O2−⋯H2–N2 HB with an O2−⋯H2 distance of 1.76 Å in TSII-1. As shown in Fig. 5, the O1⋯H3 distance of the O1⋯H3–N3 HB in TSII-1 is contracted (i.e., 1.86 Å). The nucleophilic attack of the N3 atom on the C1 atom is observed in TSII-1, and the C1⋯N3 distance is 2.05 Å (Fig. 5 and S12, Table S12†). The process of conversion from COMII to TSII-1 needs to overcome an energy barrier of 19.1 kcal mol−1 (Fig. 4). Due to the tautomerization of (S)-C6 in TSII-1, the original P–O2 single bond is converted into a P
O2 double bond in IMII-1, while the original P
O1 double bond is converted into a P–O1 single bond, and thus (S)-C6 is converted into its tautomer in IMII-1. In IMII-1, the H3 atom is abstracted from the H3–N3 group and is shifted to the O1 atom, leading to the O1–H3 bond. Two intermolecular HBs (i.e., O2⋯H2–N2 and O1–H3⋯N3 HBs) exist in IMII-1 (see Fig. S13 and Table S13 in the ESI†), and the C1–N3 bond forms with a bond length of 1.54 Å. After the breakage of the O1–H3⋯N3 HB (see Fig. S14 and Table S14 in the ESI†), the N3 atom is recovered to the sp2 hybridization state and the axial chirality along C1–N3 bond tends to appear in IMII-2. The acidity of IMII-2 enables it to give its proton in the O1–H3 group to the N1 atom leaving the O1− anion which tends to approach the H1 atom in the C1–H1 group in the intermediate IMII-3. QTAIM analyses of IMII-2 and IMII-3 are shown in Fig. S14, S15 and Tables S14, S15.† The process from IMII-1 to IMII-3 is exothermic. Due to the strong attraction between the O1− anion and H1 atom, the H1 atom gradually shifts to the O1− anion in the transition state TSII-2. QTAIM analyses of TSII-2 are shown in Fig. S16 and Table S16.† As shown in Fig. 5, the interaction distance between the O1− anion and H1 atom is 1.33 Å, while the distance between C1 and H1 atoms is 1.31 Å. The energy barrier for the process from IMII-3 to TSII-2 is 5.4 kcal mol−1. The O1–H1 bond forms in IMII-4, in which the O2⋯H2–N2 HB remains (see Fig. S17 and Table S17 in the ESI†). After the breakage of the O2⋯H2–N2 HB, the catalyst (S)-C6 is regenerated and the minor product ent-P is yielded.
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Fig. 5 The optimized geometries of the complexes, transition states and intermediates in path II. The distances are in Å. Some hydrogen atoms are omitted for clarity. |
Both the reaction paths I and III result in the experimental desired product P, while both the reaction paths II and IV lead to the minor product as ent-P, so the mechanism of path III (or IV) is similar to that of path I (or II), and therefore, the detailed reaction mechanisms for paths III and IV are presented in the ESI† for simplicity.
A comparison of the energy barriers in paths I–IV suggests that the enantioselectivity-determining steps correspond to the rate-determining steps in which the transition states TSI-1, TSII-1, TSIII-1, and TSIV-1 in paths I–IV with the highest energies determine the enantioselectivity of (S)-C6-catalyzed amination reaction. From Fig. 2, 4, S18 and S19,† we can see that the energies of TSI-1, TSII-1, TSIII-1, and TSIV-1 in paths I–IV follow an order of TSI-1 (26.2 kcal mol−1) < TSII-1 (28.1 kcal mol−1) < TSIV-1 (38.5 kcal mol−1) < TSIII-1 (39.5 kcal mol−1), indicating that path I is the most favorable pathway leading to the experimental desired product P and path II is the most favorable pathway leading to the product ent-P. In addition, we found that the trimeric complex COMI (or COMII) with a lower energy is more favorable than COMIII (or COMIV) in converting into the corresponding transition state.
The calculated ee value (see the ESI† for details) matches well with the experimental one (96% ee, Scheme 1). The results show that the amination reaction between R1 and R2 catalyzed by (S)-C6 proceeds through path I which leads to the major product P, while the minor product ent-P is achieved through path II.
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Fig. 6 The orientations of the reactants and catalyst in the optimized structures of TSI-1 and TSII-1. |
Accordingly, in the following sections, the size of the chiral pocket of the CPA which affects the enantioselectivity will be elaborated in detail. To gain a good understanding of the relationship between the sizes of chiral pockets of CPA catalysts and their enantioselective performance, the amination reactions between 2-(naphthalen-2-yl)diazenecarboxylate (denoted as R1a) and 2-tBu-9H-carbazole (R2) catalyzed by a series of CPA catalysts with different –R and –Ar groups were selected and investigated, as outlined in Table 4. From the previous analysis of the (S)-C6 catalyzed amination reaction between R1 and R2, it can be found that paths I and II are more favorable and they mainly lead to the respective products P and ent-P, while paths III and IV are less favorable and they make a small contribution in leading to the respective products P and ent-P, so the final ee value is determined by paths I and II. Because the transition state with the highest energy determines the enantioselectivity of the amination reaction, the transition states of the two favorable pathways resulting in the main product and its enantiomer for the amination reactions (Table 4) were taken into account to explain the influence of the structures of CPAs on the ee values. As shown in Fig. 7, the theoretical ee value is in agreement with the experimental ee value, and the result indicates that the catalytic performance in the stereocontrol of BINOL-derived CPAs (i.e., (R)-C8, (R)-C10) is inferior to that of SPINOL-derived CPAs (i.e., (S)-C1, (S)-C2, (S)-C3, (S)-C6) in the amination reactions between R1a and R2 (Table 4).
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Fig. 7 The relationship between the experimental and theoretical ee values for the amination reactions catalyzed by CPA catalysts. |
CPA | Solvent | T | ΔΔGTS![]() |
Exper. ee | Theor. ee |
---|---|---|---|---|---|
a 10 mol% of (S)-C6 was used, and 3 Å molecular sieves (MS) were added, DCE = 1,2-dichlorethane. b ΔΔGTS is the energy difference between the Gibbs free energies of the transition states in the two favorable pathways resulting in the main product and its enantiomer for the amination reactions. | |||||
(S)-C1 | CH2Cl2 | 40 | 1.3 | 65 | 78 |
(S)-C2 | CH2Cl2 | 40 | 1.6 | 74 | 87 |
(S)-C3 | CH2Cl2 | 40 | 2.7 | 87 | 98 |
(S)-C6 | CH2Cl2 | 40 | 3.0 | 90 | 98 |
(R)-C7 | CH2Cl2 | 40 | −1.2 | −88 | −76 |
(R)-C8 | CH2Cl2 | 40 | −0.6 | −25 | −46 |
(R)-C10 | CH2Cl2 | 40 | −0.4 | −24 | −31 |
(S)-C6a | CHCl3 | 50 | 4.1 | 93 | 100 |
To assess the role of the –Ar group in the CPA catalyst, a comparison was made. Herein, the –Ar group of (S)-C6 is replaced by a H atom to obtain a new catalyst (denoted as (S)-C6H), and then the interactions of (S)-C6H, R1a and R2 were optimized and they are similar to the previous paths I and II. Accordingly, the two transition states TSIH-1 and TSIIH-1 corresponding to two paths IH and IIH for the (S)-C6H catalyzed reaction between R1a and R2 can be obtained, and TSIH-1 has a higher Gibbs free energy than TSIIH-1 by 1.2 kcal mol−1. It can be seen from their optimized geometries displayed in Fig. 8 that the C1⋯N3 distance in TSIIH-1 is longer than that in TSIH-1 by 0.05 Å (i.e., 2.09 Å in TSIH-1 and 2.14 Å in TSIIH-1), which can be attributed to the intermolecular repulsion between the –tBu group of R2 and the azo group of R1a. The relatively lower Gibbs free energy of TSIIH-1 compared to that of TSIH-1 indicates that the smaller chiral pocket of (S)-C6H cannot cause significant steric hindrance for the interaction between R2 and R1a. Similarly, the reaction between R1a and R2 catalyzed by (S)-C6 with the –Ar group also occurs following paths IAr and IIAr, and the C1⋯N3 distance of TSIIAr-1 is 0.06 Å longer than that in TSIAr-1 (i.e., 2.03 Å in TSIAr-1 and 2.09 Å in TSIIAr-1). It can be seen that the protonated R1a interacts with R2 with an appropriate C1⋯N3 distance in TSIAr-1, and the –tBu group of R2 is out of the chiral pocket of the (S)-C6 anion, and these arrangements make the complex between the protonated R1a and R2 match well with the chiral pocket of the (S)-C6 anion. In contrast, the interaction between the protonated R1a and R2 in TSIIAr-1 has a different arrangement in which the –tBu group of R2 is located in the chiral pocket of the (S)-C6 anion, causing a longer C1⋯N3 distance. Clearly, such an arrangement results in a stronger steric repulsion between the aromatic ring of the protonated R1a (or R2) and the –Ar group of the (S)-C6 anion, so a relatively higher Gibbs free energy (ca. 3.0 kcal mol−1) of TSIIAr-1 compared to that of TSIAr-1 is observed.
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Fig. 8 The transition states (a) TSIH-1 and TSIIH-1 for (S)-C6H catalyzed and (b) TSIAr-1 and TSIIAr-1 for (S)-C6 catalyzed reactions between R1a and R2. The C1⋯N1 distances are in Å. |
To further illustrate the effect of the chiral pocket of the CPA catalyst, a comparison between (S)-C6 and (R)-C10 was made, as shown in Fig. 9. The chiral pocket is measured from the distance between the C atoms of –Ar groups connected to the main skeleton of the CPA. Compared to (S)-C6, (R)-C10 provides a similar chiral environment, but the (R)-C10 catalyzed reaction between R1a and R2 offers the opposite axially chiral product with a lower ee value. The reason can be the fact that (R)-C10 provides a larger chiral pocket which can effectively reduce the steric repulsion between the –tBu group of R2 and the –Ar group of the (R)-C10 anion in the transition state which is denoted as TSI(R)-C10-1 or TSII(R)-C10-1. Consequently, the Gibbs free energies for the transition states TSI(R)-C10-1 and TSII(R)-C10-1 have a few differences (ca. 0.4 kcal mol−1, Table 4), so a lower enantioselectivity (i.e., −24% ee) is observed.
In terms of the above analyses, for the amination reaction in which the C–N bond forms, it appears that the BINOL-derived CPA catalyst possessing the larger size of the chiral pocket like (R)-C10 shows poor performance while the SPINOL-derived CPA catalyst with the smaller size of the chiral pocket like (S)-C6 shows good performance. In the transition states, given that the C–N bond is shorter than the C–C bond, it can be hypothesized and expected that the BINOL-derived CPA catalyst could catalyze the reaction system in which the C–C bond forms because the C⋯C distance in the transition state for C–C bond formation reaction is usually longer than the C⋯N distance in the transition state for C–N bond formation reaction. To verify this, the BINOL-derived CPA (i.e., (R)-C10) catalyzed C–C bond formation reaction between 2-(naphthalen-2-yl)diazenecarboxylate (denoted as R1a) and 2-tBu-indole (R3) was investigated, as shown in Fig. 10a. It can be seen from Fig. 10 that the C⋯C distances in the transition states (i.e., TSI′(R)-C10-1 and TSII′(R)-C10-1) for (R)-C10 catalyzed reactions are longer than the C⋯N distances in the transition states (i.e., TSIAr-1, TSIIAr-1) for the (S)-C6 catalyzed reaction between R1a and R2 by about 0.23 or 0.14 Å. Note that the size of the chiral pocket of BINOL-derived CPAs like (R)-C10 (i.e., the C⋯C distance between the C atoms of –Ar groups connected to the main skeletons of (R)-C10 shown in Fig. 9) is larger than that of SPINOL-derived CPAs like (S)-C6 (i.e., the C⋯C distance between the C atoms of –Ar groups connected to the main skeletons of (S)-C6 shown in Fig. 9) by about 0.17 Å. Therefore, the size of the chiral pocket of BINOL-derived CPAs seems to be suitable for catalyzing the C–C bond formation reaction, but actually the catalytic performance of BINOL-derived CPAs is also related to the sizes of substrates.
Furthermore, a statistical analysis of the previous experimental work37,89–99 was conducted to assess the tendencies of SPINOL- and BINOL-derived CPAs in catalyzing C–C and C–N bond formation reactions. The reactions catalyzed by CPAs including SPINOL- and BINOL-derived catalysts to form the C–N and C–C bonds are summarized in Tables 5 and 6, respectively. As shown in Fig. 11, the C–N bond formation reaction systems catalyzed by the SPINOL-derived CPAs provide higher ee values and better yields than those catalyzed by the BINOL-derived CPAs. In contrast, the C–C bond formation reaction systems catalyzed by the BINOL-derived CPAs lead to higher ee values and better yields than those catalyzed by the SPINOL-derived CPAs. Thereby, it can be concluded that the type of CPA does significantly affect the experimental results in terms of both the ee value and yield, and to a certain extent the SPINOL-derived CPA possessing a moderate chiral pocket functions more efficiently for the C–N bond formation reaction system while the BINOL-derived CPA possessing a larger chiral pocket functions more efficiently for the C–C bond formation reaction system, and the reason is that the sizes of substrates match well with the chiral pocket of these CPAs. Further analyses suggest that the SPINOL-derived CPA can function excellently in catalyzing not only the C–N bond formation reaction but also the C–C bond formation reaction,100 or even better than the BINOL-derived CPA,101 while the BINOL-derived CPA can also catalyze the C–N bond formation reaction with good performance.102 Obviously, the good performance of either the SPINOL- or BINOL-derived CPA is significantly dependent upon the precondition that the sizes of substrates should match well with the chiral pocket of CPA. In addition, it should be noted that the chiral pocket of the CPA catalyst is decided not only by the backbone but also by the substituent on the –Ar group. The bigger hindrance the substituent provides, the smaller pocket the CPA catalyst has. The relationship between the substituent on the –Ar group and the size of the chiral pocket of the CPA will be taken into account in future work.
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Fig. 11 The experimental yield (%) and ee (%) value for (a) the C–N and (b) C–C bond formation reactions catalyzed by SPINOL- and BINOL-derived CPAs. |
Reaction | CPA | Yield | ee | Refa |
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a Ref.: The reaction, yield (%) and ee (%) value are taken from the previous experimental work. | ||||
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CA6 | 33 | −90 | 37 |
CB4 | 99 | 92 | ||
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CA7 | 88 | −41 | 93 |
CB5 | 90 | 57 | ||
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CA7 | 75 | −86 | 94 |
CB5 | 91 | −89 | ||
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CA8 | 41 | 12 | 95 |
CB6 | 99 | 96 | ||
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CA3 | 17 | 44 | 96 |
CB1 | 33 | 89 | ||
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CA7 | Traces | — | 97 |
CB3 | 18 | 88 | ||
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CA7 | 47 | 60 | 98 |
CB5 | 76 | 91 | ||
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CA9 | 39 | 40 | 99 |
CC4 | 99 | 48 |
Footnote |
† Electronic supplementary information (ESI) available: The optimized geometries of the dimeric complexes in paths I–IV, and their relative Gibbs free energies and intermolecular interaction energies; QTAIM analyses and for the complexes, transition states and intermediates; the mechanisms of paths III and IV for the enantioselective (S)-C6 catalyzed atroposelective C–H amination reaction; and Cartesian coordinates. See DOI: 10.1039/d0qo01160f |
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