Article
Copper-catalyzed Enantioselective Boron Conjugate Addition: DFT and AFIR Study on Different Selectivities of Cu(I) and Cu(II) Catalysts Miho Isegawa, W. M. Chamil Sameera, Akhilesh K. Sharma, Taku Kitanosono, Masako Kato, Shu Kobayashi, and Keiji Morokuma ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b01152 • Publication Date (Web): 30 Jun 2017 Downloaded from http://pubs.acs.org on July 1, 2017
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Copper-catalyzed Enantioselective Boron Conjugate Addition: DFT and AFIR Study on Different Selectivities of Cu(I) and Cu(II) Catalysts Miho Isegawa,† W. M. C. Sameera,†‡ Akhilesh K. Sharma,† Taku Kitanosono,§ Masako Kato,‡ Shū Kobayashi,*§ Keiji Morokuma*† †
Fukui Institute for Fundamental Chemistry, Kyoto University, Kyoto 606-8103, Japan
‡
Department of Chemistry, Faculty of Science, Hokkaido University, Kita-Ku, Sapporo, 060-0810, Japan
§
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
ABSTRACT: We present a mechanistic survey on the LCu-catalyzed (L = chiral 2,2′-bipyridine ligand) enantioselective boron conjugate addition reaction, carried out using density functional theory (DFT) and the artificial force induced reaction (AFIR) methods. The computed catalytic cycle for Cu(I)- and Cu(II)-based catalysts consists of three steps: (a) boron–boron bond cleavage of B2(pin)2, (b) boron conjugate addition on the β-carbon of chalcone, and (c) protonation. The enantioselectivity of the reaction with LCu(I) or LCu(II) catalysts is solely governed at the boron conjugate addition step. The multicomponent (MC)-AFIR search and the subsequent DFT calculations for the LCu(I) catalyst determined transition states (TSs), which lead to Cu(I)-O-enolate and Cu(I)-C-enolate, and both equally contribute to the C–B bond formation with no enantioselectivity. On the other hand, a MC-AFIR search and the subsequent DFT calculations for the analogous LCu(II) catalyst showed that only the transition state (TS) leading to Cu(II)-O-enolate contributes to the reaction. Furthermore, the TSs leading to the R- and S-forms of Cu(II)-O-enolates are energetically well separated, with the R-form being of lower energy, which is consistent with experimental observations. Our study provides important mechanistic insights for designing transition metal catalysts for Cu-catalyzed enantioselective boron conjugate addition reactions. Keywards: Enantioselectivity, Density functional theory, Copper catalyst, Oxidation state, Reaction mechanism, AFIR, Borylation
I. INTRODUCTION Synthesis of optically active organoboron compounds is important for medicinal applications and the development of electronic materials.1 Optically active boron compounds can be converted into other optically active organic compounds in a selective fashion through replacement of the carbon–boron bond by carbon–carbon, carbon–nitrogen, and carbon–oxygen bonds.2-6 Following the pioneering work of Brown et al.,7,8 many types of coupling reactions have been developed and studied.9-10 Represented by the Suzuki–Miyaura coupling,11,12 synthetic methodology using organoboron compounds has greatly contributed to the synthesis of various pharmacologically active compounds. Cu(I)-based catalysts have been studied for many types of enantioselective carbon–boron bond formation reactions. 13-25 Marder and coworkers used density functional theory (DFT) to study the mechanism of alkene insertion into a Cu(I) boryl complex,26 diboration of alkenes,27 and diboration of aldehydes.28 Characteristically, in the reaction of a Cu(I)-based catalyst with an α,β-unsaturated substrate molecule, the insertion occurs at the C=C bond of the substrate rather than at the C=O bond. The former scenario gives rise to a ‘Cu-C-enolate’, while the latter leads to a ‘Cu-O-enolate’.27,29 Cu(II)-based catalysts have been studied experimentally;29-35 however, details of the reaction mechanism and the origin of the enantioselectivity have not been established. Recently, Zhu et al.35 reported a
Cu(II)-catalyzed asymmetric β-borylation reaction (Scheme 1). In this reaction, an optically active product is generated from chalcone in a selective fashion after subsequent oxidation. The enantiomeric excess (ee) of the reaction was 94%, and the product yield was 95%. In contrast, Cu(I)-based catalysts in tetrahydrofuran (THF) solvent showed almost no enantioselectivity. The dielectric constant of THF (ε = 7.43) is not significantly different from that of diethyl ether (ε = 4.24), and both the nonpolar solvents may not coordinate to the metal.35 Therefore, it is proposed that the difference in enantiomeric excess is due to the oxidation state of Cu. Scheme 1. Copper-catalyzed enantioselective βborylation of chalcone in the formation of chiral alcohol. Ligand (6 mol%)
tBu
N OH
N OH
tBu
Cu(OAc)2 (5 mol%) MeOH (1 equiv.)
O + B 2(pin) Ph
Ph
solvent, rt, 12 h then NaBO 3 H 2O/THF, 3 h
Ph
O
OH Ph
94% ee (Cu(II)) 1% ee (Cu(I))
Figure 1 shows a comparison of the proposed catalytic cycles, where the LCu(I) and LCu(II) catalysts give
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different reaction mechanisms.35,29 The mechanisms
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consist of three steps: (a) boron–boron bond cleavage, (b)
Figure 1. Proposed catalytic cycles for (a) Cu(I)-based catalyst and (b) Cu(II)-based catalyst. The different binding modes of the Cu(I)- and Cu(II)-based systems are shown in orange.
boron conjugate addition on the β-carbon on chalcone, and (c) protonation. It is proposed that the mechanistic difference originates at the enantioselective carbon– boron bond formation step; Cu(I) has a larger metal coordination sphere (d10) that facilitates metal coordination at the C=C double bond rather than interacting with carbonyl oxygen.29 However, to date, precise mechanistic details of the reaction, and how Cu(I) and Cu(II) interact with the chalcone substrate, have not been established. In this study, the proposed mechanisms for the reactions with the Cu(I)- and Cu(II)-based catalysts shown in Figure 1 were explored using DFT in conjunction with an implicit solvation model. The mechanistic difference between LCu(I) and LCu(II) catalysis was established. To explain the enantioselectivity of the reaction and the underlying mechanisms, a systematic sampling of the transition states (TSs) is critical. For this purpose, the multicomponent artificial force induced reaction (MCAFIR) method36 was used. The MC-AFIR approach determines the approximate reaction pathways and TSs, which originate from various approach directions of the reactants and their orientations. Approximate TSs can be used as the starting guess structures to locate the corresponding true TSs using standard methods. The AFIR methodology is a general approach to obtain approximate reaction paths and TSs, and it has been successfully applied to a range of complex catalytic reactions.37-39
II. COMPUTATIONAL DETAILS All computations in this study were performed using the Gaussian 09 program.40 All structures were fully
optimized without any constraints using the M06-L functional.41 The Stuttgart/Dresden (SDD)42 basis set and the associated effective core potential were used for copper, and 6-31G(d) basis sets43 were used for the other atoms (BS1). The SMD implicit solvation model44 was used for the solvation effects in diethylether (ε = 4.24). Vibrational frequency calculations were performed at the same level of theory to confirm the minima (no imaginary frequencies) or TSs (one imaginary frequency), and to obtain zero-point vibrational energy (ZPE) corrections. The thermal corrections were computed at 298.15 K and 1 atm pressure. Connectivity of the stationary points was confirmed by the ‘pseudo’ intrinsic reaction coordinate (IRC) approach,45 where IRC calculations were performed for 20 steps from the TS (in both forward and backward directions), and subsequent structures were fully optimized to obtain the minima. Potential energies of the optimized stationary points were calculated using the M06-L46 functional and the SDD basis set for Cu and def2-TZVP47 basis sets for the other atoms (BS2), where the SMD model was used as the solvation model. The MC-AFIR calculations were performed for the B–C bond formation with the two-layer our own N-layered integrated molecular orbital and molecular mechanics 48 (ONIOM) method. Partitioning of the molecular system is shown in Figure 2a. The M06-L functional was applied 42 for the high-layer, where the SDD basis set was used for 49 Cu, and 3-21G basis sets were used for the remaining 50 atoms (BS3). PM6 was used for the low-layer. The artificial force parameter of 200 kJ/mol was used to explore the approximate reaction paths and TSs (Figure 2b). In the MC-AFIR searches, we have stopped the reaction path search after 300 steps. Then, we manually inspected them to pickup the approximate TSs, fixed the B–C bond length,
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and optimized. Then, the resulting structures were fully optimized without any constraints to find the real TS.
III. RESULTS AND DISCUSSION
(b) LCu(I)−OH (AI)
(a) LCu(II)−OH (AII)
N2
N1
N2
Cu(II)
N1 Cu(I)
1. Cu(I) and Cu(II) catalysts
O2
As shown in the proposed reaction mechanism (Figure 1), LCu(I)- or LCu(II)-catalyzed reactions start from LCu(I)−OH (AI) and LCu(II)–OH (AII) complexes, respectively (L = chiral 2,2′-bipyridine ligand, shown in Scheme 1).51-52 For the geometry optimization, the initial guess structure of LCu(II)–OH was created from the crystal structure of LCu(II)–Br2.53 Optimized geometries and total spin density distributions of AI and AII complexes are shown in Figure 3. The chiral 2,2′bipyridine ligand holds two chiral centers, both of which are in the S-form. The chiral ligand in the LCu(II) catalyst is essential for the enantioselective production of the R-alcohol.
Figure 2. (a) Partitioning of the molecule into ONIOM high (black) and low (blue) levels. (b) Artificial force was added between highlighted atoms (red) to study the B–B bond cleavage step (left) and the C–B bond formation step (right). For the C–B bond formation step, various approach directions and orientations of Fragment 1 and Fragment 2 are considered in MC-AFIR.
O2
Cu−O1 = 2.18 Cu−O2 = 3.02 Cu−O3 = 1.82 Cu−N1 = 1.98 Cu−N2 = 2.18
O3
O1
ρ (Cu) = 0.623 ρ (O1) = 0.049 ρ (O2) = 0.001 ρ (O3) = 0.203 ρ (N1) = 0.048 ρ (N2) = 0.085
O3
O1
Cu−O1 = 2.95 Cu−O2 = 2.84 Cu−O3 = 1.89 Cu−N1 = 2.12 Cu−N2 = 2.00
II
Figure 3. Optimized geometries of (a) LCu(II)–OH (A ) I and (b) LCu(I)–OH (A ). Selected bond lengths are given in Å. Total spin densities (ρ) for selected atoms are also shown for LCu(II)–OH.
In the LCu(II)–OH complex (AII), the ground state is a doublet. Calculated spin densities on Cu (ρ = 0.62) and O3 (ρ = 0.20) suggest that the unpaired electron is mainly localized on the metal, and the partial spin delocalization into O3 would increase its reactivity toward the B–B bond activation. The metal coordination sphere of AII consists of four ligands, giving rise to a distorted square planar structure. Furthermore, the 2,2′bipyridine ligand is coordinated to Cu(II) through two nitrogen atoms and one OH group. We have checked the possibility of deprotonation of the coordinated OH group with a water molecule as a proton acceptor, however, it is not favorable. The resulting complex is 58.5 kcal/mol higher in energy. In contrast, the metal coordination sphere of the Cu(I) system (AI) has three ligands in singlet spin state, where the chiral 2,2′bipyridine ligand is coordinated through only two nitrogen atoms. This difference originates from the electronic structure of Cu(I) and Cu(II) ions. The metal 3d orbitals of Cu(I) are completely filled (d10). This electron-rich nature does not allow coordination of the OH group of the 2,2′-bipyridine ligand, while the hydrogen atoms of OH groups interact with the Cu(I) ion. As a result, the metal coordination sphere of the Cu(I) system is relatively flexible. Because Cu(II) has the d9 configuration, a lone-pair of the oxygen atom of the OH group of the 2,2′-bipyridine ligand can be coordinated, leading to a relatively rigid metal coordination sphere.
2. Free energy profiles Figure 4 summarizes the computed catalytic cycle of the Cu(II) system. Calculated spin densities of the stationary points are given in Figure S1 in the Supporting Information. All energies are given relative to the sum of free energies of LCu(II)–OH (AII), B2(pin)2, chalcone, and a water molecule. As mentioned earlier, the catalytic cycle involves three main steps: (a) boron–
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boron bond cleavage, (b) boron conjugate addition on the β-carbon on chalcone, and (c) protonation (Figure 1). First, we will discuss the mechanism of the Cu(II)catalyzed reaction. (1) B–B bond cleavage for the Cu(II) catalyst: In this step, the conventional AFIR method was used to determine approximate TSs (Figure 2b, left). Starting from Cu(II)−OH (AII), the B−B bond cleaves in a single step, leading to a Cu(II)−B(pin) species (CII). The reaction involves electrophilic attack of the electronpoor B–B bond to the electron-rich Cu–OH unit. In the prereaction complex, BII (–9.7 kcal/mol), one of the two boron atoms (B2) of B2(pin)2, interacts with the OH group of the catalyst. In BII, the distance between Cu(II) and B1 is 3.12 Å and is decreased to 2.38 Å at the subsequent TS (TS-BII-CII, –0.7 kcal/mol). The molecular structure at the TS, TS-BII-CII, has a fourmembered ring (–B1–Cu–O–B2–), which is typical for the metathesis process.54 In this step, B–B and Cu–O bonds are cleaved, and Cu–B and B–O bonds are formed,
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simultaneously. This step proceeds by overcoming 9.0 kcal/mol barrier, leading to a stable intermediate, CII (– 21.6 kcal/mol). Calculated spin densities of TS-BII-CII, ρ(Cu) = 0.41, ρ(O3) = 0.15, and ρ(B1) = 0.20, suggest some amount of spin density transfer from the Cu–OH unit to B1. Cu–O and B1–B2 bond lengths are increased by 0.02 and 0.20 Å, respectively. In CII, the unpaired electron is delocalized on Cu and B1; ρ(Cu) = 0.53 and ρ(B1) = 0.33. Optimized geometries of the TS (Figure 5a) and the associated two local minima of the precursor (BII) and the intermediate (CII) are shown in Figure S2. We have introduced a water molecule to intermediate BII to check whether H2O play a role in this step. We found a minima with an explicit water molecule attached to B atom, where water molecule binds B atom of BII, and this intermediate is 16.0 kcal/mol higher than BII, which is higher energy than TS-BII-CII. Therefore we suspect that water does not play a major role on the B–B bond cleavage.
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Figure 4. Calculated free energy profile for Cu(II)-based catalyst. ∆G and ∆H (in parentheses) are given in kcal/mol.
Starting from CII, LCu(II)−B(pin) (DII, –28.8 kcal/mol) can be generated at the complete dissociation limit of the B1–B2 bond; this process is exothermic. DII is the active intermediate for the next steps in the mechanism. In DII, spin density on Cu is 0.62, with some spin delocalization on B1 (0.18). DII has a distorted square planar geometry (Figure S2c), where the oxygen atom (O4) of the B(pin) unit forms hydrogen bonds with the OH group of the 2,2′-bipyridine ligand. The boron atom
of B(pin) does not interact with the oxygen atom of the OH group of the 2,2′-bipyridine ligand, as proposed in an experimental study.6 A different conformation of DII (DII’) was also located (Figure S2d), in which B(pin) coordinates to Cu at the axial position. DII’ is 6.1 kcal/mol higher than DII, and the boron does not bind to the oxygen atom (O1 and O2) of the OH group as well as DII. It is noted that the coordination of water to Cu center of DII destabilizes the system by 6.6 kcal/mol.
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(a) Cu(II) B−B bond cleavage
Cu B1 B2
O Cu−O = 1.93 Cu−B1 = 2.38 O−B2 = 1.48 B1−B2 = 1.92
TS-BII-CII
(b) Cu(II) C−B bond formation
Cu
B
O Cα Cβ Cu−O = 2.06 Cu−Cα = 2.58 Cu−Cβ = 2.06 B−Cβ = 2.29
TS-EII-FII Figure 5. Optimized transition states for (a) the B−B bond cleavage and (b) the C−B bond formation for Cu(II) catalyst. Selected bond lengths are given in Å
(2) C− −B bond formation for the Cu(II) catalyst: In the C–B bond formation process, a number of TSs can originate from the chalcone substrate’s approach directions and orientations. We performed a MC-AFIR search to determine approximate TSs (Figure 2b, right). Among the calculated TSs, TS-EII-FII is the lowest energy TS (vide infra). The selectivity of the reaction is discussed in detail in the next section. Starting from DII, the barrier for C–B bond formation is 14.0 kcal/mol (TSEII-FII), and the resulting Cu(II)-O-enolate intermediate (FII′′) is 15.2 kcal/mol more stable than the active species, DII. Figure 5b and Figure S2 shows the optimized geometry of TS-EII-FII, the prereaction complex (EII) and subsequent minima, and the Cu(II)-O-enolate species
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(FII). The TS-EII-FII involves 1,4 addition to the chalcone substrate, where Cu addition occurs at the oxygen atom, while B(pin) adds to the β-carbon to afford FII. Calculated spin densities of Cu in TS-EII-FII and FII are 0.15 and 0.09, respectively. Therefore, the Cu ion in TSEII-FII and FII can be characterized as Cu(I). In both stationary points, the α-carbon of the substrate has a significant spin density (0.55 in TS-EII-FII and 0.69 in FII). In FII, the 2,2′-bipyridine ligand coordinates to Cu through one nitrogen atom and a single OH group. A more stable intermediate, FII’, is formed by coordination of the second nitrogen atom of the 2,2′bipyridine ligand. In FII’, the spin density on Cu and the α-carbon of the substrate is 0.37 and 0.42, respectively, which is significantly changed from the spin densities of FII. We have previously characterized the intermediate FII′′ from electrospray ionization-mass spectroscopy.6 FII’ can be rearranged to the Cu(II)-C-enolate species (GII). Here, structural difference between the two complexes FII’ and GII arises from the coordination position of Cu to the substrate. In FII’, Cu coordinates to the carbonyl oxygen, whereas in GII, Cu coordinates to the β-carbon of the chalcone substrate. Conversion from FII’ to GII has a barrier of 8.0 kcal/mol (TS-FII’-GII). (3) Protonation for the Cu(II) catalyst: The next step of the mechanism is protonation of carbonyl oxygen. A water molecule binding on GII results in intermediate HII, which is 12.3 kcal/mol above GII. Protonation then occurs, through TS-HII-III (–24.3 kcal/mol) to afford III. Once complex III is generated, the borylated chalcone (P1) can be separated from Cu, and the catalyst (AII) can be regenerated for the next catalytic cycle. Finally, keto– enol tautomerism of P1 leads to the more stable keto form of the product (P2). We also investigated the possibility of water coordination to Cu(II)-O-enolate (FII’) and the subsequent protonation process leading to LCu(II)–OH (AII) and P1. The calculated barrier of this process (not shown in Figure 4) is, however, 19 kcal/mol higher than TS-HII-III. We have also checked the role of two and three water molecules in the protonation process (Figure S3). The free energy of TSs with two (–19.4 kcal/mol) and three (–13.6 kcal/mol) explicit water molecules were higher than one water molecule (–24.3 kcal/mol). Since the corresponding enthalpy of the TSs was lower with two (–59.3 kcal/mol) and three (–64.6 kcal/mol) explicit water molecules, relatively high energy TSs of two and three water molecules originates from the entropy. According to our computed mechanism (Figure 4), the rate-determining step of the reaction is the protonation process (TS-HII-III), while the enantioselectivitydetermining step is the C–B bond formation (TS-EII-FII). (4) Mechanism of Cu(I) catalyst: After establishing the mechanism for the full catalytic cycle with the Cu(II)-based catalyst, we are now in the position to
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prereaction complex EI, Cu(I) coordinates to the βcarbon and carbonyl oxygen of the chalcone substrate. In contrast, it is important to note that Cu(II) coordinates to the carbonyl oxygen atom of the substrate in the prereaction complex EII. Unlike the case of the Cu(II) catalyst, the protonation of the Cu(I)-based catalyst occurs at the β-carbon of the chalcone from Cu(I)-O-enolate via TS-JI-KI (–16.4 kcal/mol). This is more favorable than the protonation from Cu(I)-Cenolate (TS-FI′′-GI, –11.8 kcal/mol).
discuss the mechanism for the analogous Cu(I)-based system. The free energy profile for the Cu(I)-based catalyst is shown in Figure 6, and the optimized key stationary points are shown in Figure 7 and Figure S4. The reaction mechanism of the Cu(I) catalyst is qualitatively similar to that of the Cu(II) catalyst. The B– B bond cleavage process in the case of Cu(I) catalyst has a barrier (12.1 kcal/mol, TS-BI-CI), which is larger than the Cu(II) catalyst (9.0 kcal/mol). After formation of the intermediate DI (–19.3 kcal/mol), the C–B bond is formed with a barrier of 18.3 kcal/mol (TS-EI-FI). In the
L L Cu
O
O H O
L
O
Cu O
B
H
O
Ph Ph
Cu OH O B1 B2O O O
LCu—OH
Cu
H
O H
O H B O Ph
O
O B O Ph
Ph
JI
L
Ph
TS-JI-KI
KI
O B O
L Cu
AI
TS-BI-CI + Chalcone + H2O
+ B2(pin)2 + Chalcone + H2 O
0.0 (0.0)
O Ph Ph O
4.2 (–12.2)
OH O O B1 B2 O O
BI + Chalcone + H2 O
EI + CI B(pin)OH + + –19.3 Chalcone H2O (–21.0) + H2O O
LCu B O
DI + B(pin)OH + Chalcone + H2 O
B–B bond cleavage
H L O O H Cu B O O Ph Ph
Ph
TS-FI’-GI + B(pin)OH + H2O
–1.0 –4.2 (–20.1) (–21.9)
–8.6 (–23.7)
O Cu B O Ph
+ B(pin)OH + H2O
12.1 (–6.9)
Cu
L
TS-EI-FI
L
∆G [kcal/mol]
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L
H
O B O
Ph
B–C bond formation
FI’ + B(pin)OH + H2O
L
O B O Ph
GI + B(pin)OH + H 2O
O B O OH
Ph
II
+ B(pin)OH
O Cu
Ph
+
–16.4 –17.5 –17.5 Ph (–46.8) (–47.1) (–45.4)
FI + TS-JI-KI B(pin)OH + H2O –28.6 –28.4 –28.7 (–46.6) –29.9 (–47.9) (–58.6) (–61.3) –35.7 H JI (–53.3) O
O
AI
TS-HI-II + B(pin)OH
–11.8 (–31.3)
Cu
LCu—OH
Ph
P1 + B(pin)OH
–28.2 (–40.3)
–40.8 –36.3 (–53.0) (–64.9) LCu— OH KI AI +
HI + B(pin)OH
CuL transformation
O B O O Ph Ph
Protonation
P2 + B(pin)OH
Keto–enol tautomerism
Protonation
Figure 6. Calculated free energy profile for Cu(I)-based catalyst. ∆G and ∆H (in parentheses) are given in kcal/mol. Profile given in red is the favored pathway for the protonation step. The corresponding chemical structures are given in the box.
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According to the free energy profiles, the ratedetermining step of the mechanism of Cu(I)-based catalyst is the C–B bond formation. This differs from the Cu(II)-based catalyst mechanism, where the protonation process is the rate-determining step.
(a) Cu(I) B−B bond cleavage
Cu B1 B2 O
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3. Computational enantioselectivity
prediction
of
In this section, we focus on the enantioselectivity of the reaction. According to experimental findings, the Cu(II)based catalyst is enantioselective (94% ee), whereas the Cu(I)-based system does not show enantioselectivity. As we have already discussed above, the enantioselectivity originates at the C–B bond formation step. We used MCAFIR to search approximate TSs systematically for the C–B bond formation. This approach captured many TSs from the relative position of the substrate and its orientations. Furthermore, depending on the position of the copper, TSs have found to be classified into three types: Type a, Type b, and Type c (see Figure 8). It is important to note that these ‘approximate’ TSs were automatically obtained by a MCAFIR search; they are generally difficult to guess from traditional approaches (manual guess of TSs). (1) Type a
Cu−O = 2.06 Cu−B1 = 2.39 O−B2 = 1.52 B1−B2 = 1.78
O
L Cu
B O
O
TS-BI-CI
(b) Cu(I) C−B bond formation
Ph
β
α
Ph
(2) Type b L
O
Cu O
Ph
β α
Ph
Cu
B O
B
O
(3) Type c Cα
L
Cβ
O Cu O B O
TS-EI-FI
Cu−O = 2.00 Cu−Cα = 2.65 Cu−Cβ = 2.04 B−Cβ = 2.18
Ph
β α
Ph
(5)
(4) LCu−B(pin) attack R-form
Figure 7. Optimized transition states for (a) the B−B bond cleavage and (b) the C−B bond formation for Cu(I) catalyst. Selected bond lengths are given in Å
L
O Cu
O Cα
Cβ
LCu−B(pin) attack S-form
Ph
B O H β
Ph
α
φ (Cu−B−Cβ−Cα)
Figure 8. (1)–(3) Three types of TSs corresponding to the lowest energy conformations in the Cu(II) system with the
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selected bond lengths. (4) Distinction of R- and S-attack and (5) definition of the key dihedral angle.
determines the relative orientation of LCu−B(pin) and the chalcone substrate. As shown in Figure 9, the dihedral angle φ of Type a TSs of Cu(II) or Cu(I) ranges from –30° to +40°, where copper binds to the α-carbon of the substrate and boron binds to the β-carbon. Type b of Cu(II) distributes at φ = –45° to –65° or 40° to 75°, whereas a broad distribution of TSs in the Cu(I) system, φ = –35° to –100° or 40° to 110°, is found, which implies that the Cu(I) loosely binds to the carbonyl oxygen. In Type c of Cu(II) and Cu(I), TSs distribute at φ = –80° to 160° and 70° to 180°, respectively. It is important to note that in Type c TSs Cu(I) and Cu(II) do not coordinate to the substrate.
In Type a, copper coordinates to the C=C double bond, while in Type b, copper coordinates to the carbonyl oxygen. In Type c, copper is not close to the substrate (it is >2.5 Å away). Because of the different stereochemistry of the β-carbon that arises from the approach direction of the substrate (see Figure 8(4)), Sor R- forms of the products can be formed through six types of TSs; namely, TS-R-a, TS-S-a, TS-R-b, TS-S-b, TS-R-c, and TS-S-c. Figure 9 maps the relative free energies of TSs as a function of the dihedral angle φ(Cu–B–Cβ–Cα), which
(2) Cu(II), S-form
tBu
(1) Cu(II), R-form
tBu
CuII O tBu φ Ph α
H
O φ
Ph
CuII
tBu H
α
O Ph O
O Ph O
Type c Type c
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Type c
10 8 6 4 2
Type a
0 -180
-120
Type b
-60
0
60
120
180
10 8 6 4 2
Type a
0 -180
-120
ϕ (degree)
(3) Cu(I), R-form
-60
0
60
CuI O tBu φ Ph α
(4) Cu(I), S-form
tBu
α
CuI
tBu H
O Ph O
Type b
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∆G (kcal/mol)
Type c
10 8
Type a
4 2 0 -180
180
Type c
Type b
6
O φ
Ph
O Ph O
12
120
ϕ (degree)
tBu
H
14
Type c
12
∆G (kcal/mol)
∆G (kcal/mol)
14
Type b
12
∆G (kcal/mol)
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Type c
Type c
10 8 6
Type a
4 2
-120
-60
0
60
120
180
0 -180
-120
ϕ (degree)
-60
0
60
120
180
ϕ (degree)
Figure 9. Free energy ∆∆G (kcal/mol) mapping of TSs as a function of the dihedral angle, φ(Cu–B–Cβ–Cα) (in degrees) for (1) Rform of Cu(II) complex, (2) S-form of Cu(II) complex, (3) R-form of Cu(I) complex, and (4) S-form of Cu(I) complex. ∆∆G (kcal/mol) is calculated relative to the most stable transition state. The definition of dihedral angle φ(Cu−B–Cβ–Cα) is given in the Newman projection.
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Table 1. Low-energy TSs for Cu(II)-catalyzed C–B bond formation step. The C–B bond length at the TS is in Å, the dihedral angle φ is in degrees, ∆∆E is the electronic energy (kcal/mol) including zero-point vibrational energy, and ∆G and ∆∆G are the free energy (kcal/mol) relative to the reactants and the most stable transition state, respectively. % represents the existence probability of TSs. Type
R(B–C)
φ
∆∆E
∆G
∆∆G
%
TS1-R-b(II)
2.29
–68.03
0.00
–14.76
0.00
55.07
TS2-R-b(II)
2.25
–61.77
1.00
–14.37
0.39
28.47
TS3-R-b(II)
2.27
–64.99
0.60
–13.80
0.96
10.85
TS4-R-a(II)
2.30
–26.25
3.37
–10.45
4.31
0.04
TS5-R-b(II)
2.18
–56.95
5.36
–9.92
4.84
0.02
TS6-R-b(II)
2.18
–57.50
5.66
–9.06
5.70
0.00
TS7-R-b(II)
2.19
–59.53
5.68
–8.65
6.11
0.00
TS8-R-a(II)
2.46
–25.61
5.57
–8.65
6.12
0.00
TS9-R-b(II)
2.17
–57.17
5.81
–8.30
6.46
0.00
TS10-S-b(II)
2.28
64.87
1.78
–13.37
1.39
5.30
TS11-S-b(II)
2.21
57.36
5.14
–11.25
3.51
0.15
TS12-S-b(II)
2.22
85.94
4.11
–10.42
4.34
0.04
TS13-S-a(II)
2.37
27.37
4.01
–10.17
4.59
0.02
TS14-S-b(II)
2.20
57.03
5.20
–10.14
4.62
0.02
TS15-S-b(II)
2.16
73.51
4.15
–9.78
4.98
0.01
TS16-S-b(II)
2.19
57.00
5.36
–9.08
5.69
0.00
TS17-S-b(II)
2.21
57.65
5.30
–8.84
5.92
0.00
TS18-S-a(II)
2.33
18.27
5.16
–8.46
6.30
0.00
Table 1 and Table S1 summarize the calculated TSs of Cu(II)- and Cu(I)-based catalysts, respectively. TSs within 7 kcal/mol are reported in these tables; a complete list of TSs can be found in the Supporting Information (Tables S2 and S3). It is important to note that the low-energy TSs are either Type a or Type b; no Type c TS, in which Cu does not coordinate in the substrate, was found within 3 kcal/mol for both Cu(I) and Cu(II) systems. Therefore, only Type a and Type b TSs contribute to the reaction. We have calculated the enantioselectivity of the reactions using the Boltzmann distribution of TSs at
298.15 K. The enantiomeric excess can be calculated using the following equation55
∑ P(Ri ) − ∑ P(Si ) ee = i
i
i
i
(1)
∑ P(Ri ) + ∑ P(Si )
where the P(Ri) and P(Si) are percentages of existence for the ith transition state of the R- and S-forms,
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respectively. P(Ri) and P(Si) can be calculated from the following equation
−∆∆G(Ri ) P(Ri ) = ∑ exp RT i
(2)
where ∆∆G(Ri) is the Gibbs free energy relative to the most stable transition state, R is the gas constant, and T is temperature (298.15 K). In the case of the Cu(II) system, the major product (Rform) comes from TS1-R-b(II) (55.1%). TS2-R-b(II) (28.5%) and TS3-R-b(II) (10.9%) also provide minor contributions to the R-form of the product. On the other hand, the main contributor to the minor product (S-form) is TS10-S-b(II) (5.3%). Based on all the TSs of the Cu(II) system, the calculated enantiomeric excess of 88.9% is in a good agreement with the experimental value (94%). For the Cu(I) system, TS-R-b(I) (45.1%), TS2-R-a(I) (13.7%), and TS3-R-a(I) (1.5%) contribute to the R-form of the product formation, whereas TS8-S-a(I) (21.8%), TS9-S-a(I) (11.3%), and TS10-S-a(I) (4.6%) contribute to the S-form of the product. Our calculated enantiomeric excess for the Cu(I) system (20.9%) suggests that the reaction is not enantioselective, which is in agreement with experimental observations. For CuII catalyst, the enantiomeric excess from ΔE becomes 93.4%, and is consistent with the value obtained from ΔG (88.9%). Therefore, entropy plays a minor role on the selectivity. However, in the case of CuI catalyst, ratio for the R- and S-form from ΔG and ΔE are 60:40 and 13:87, respectively, suggesting that the entropy lowers the selectivity of the reaction. Figure 10 gives the free energy profiles for the Cu(II)and Cu(I)-catalyzed borylation step involving the lowest energy TSs of Type a, Type b, and Type c. The lowest energy TS for Type a and Type b corresponds to TS4-Ra(II) and TS1-R-b(II) for Cu(II) (Table 1), and TS8-Sa(I) and TS1-R-b(I) for Cu(I) (Table S1). In the Cu(II) borylation process, only Type b contributes to the reaction due to the well energy separation with Type a (Figure 10a). Furthermore, the most stable R-form (TS1R-b(II)) is more stable than the most stable S-form (TS10-S-b(II)), by 1.39 kcal/mol. Such a stabilization of the R-form is also obtained when using the M06 (2.48 kcal/mol) and ωB97XD (3.98 kcal/mol) functionals. This energy separation leads to the enantioselectivity of the Cu(II) system. In the case of the Cu(I) system, both Type a and Type b contribute to the reaction mechanism. This is because Type a (TS8-S-a(I)) and Type b (TS1-R-b(I)) TSs are energetically close (Figure 10b). In addition, these two TSs have different chirality; therefore, the Cu(I) system does not show enantioselectivity.
Figure 10. Comparison of the most stable transition states for each type (Type a, Type b, and Type c) in the enantioselective process for (a) Cu(II) and (b) Cu(I) systems.
4. Energy decomposition analysis (EDA): After establishing the key TSs for the reaction, our next step is to explain the origin of the enantioselectivity of the Cu(II) catalyst. For this purpose, we performed EDA,56-59 for the lowest energy TSs, which contribute to the major (TS1-R-b(II)) and minor (TS10-S-b(II)) products. We applied a simple form of EDA for each Cu(II) complex (Figure 11). For the Cu(II) system, ∆∆E is 1.78 (2.38 when we do not consider ZPE) and ∆∆G is 1.39. The entropic contribution is therefore very small; the main contributor for energy separation comes from ∆∆E. We then decomposed ∆∆E (without ZPE) into interaction and deformation contributions.
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The activation energy ∆E of the TSs can be written as ∆E = ∆Edef + ∆Eint
(3)
where the terms ∆Edef and ∆Eint are the deformation and interaction energy, respectively. The deformation energy corresponds to the energy difference that originates from structural changes toward the TS formation. The interaction energy is the energy difference between the catalyst plus the substrate and the complex at the TS structure.
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To improve the enantioselectivity in the Cu(II) system, less positive deformation energy ∆∆Edef or more negative interaction energy ∆∆Eint is required in TS1-R-b(II). The latter case can be achieved by increasing the steric repulsions in the S-form, perhaps by modifying the phenyl group of the chalcone and tert-butyl group of L into more bulky chemical group.
(a) R-form
View1
View2 tBu OH
N N
Figure 11. Schematic diagram for EDA. LCu–B(pin) (A) and chalcone (B) are, respectively, the active intermediate and the substrate at the TS. A0 is the optimized structure of the LCu–B(pin), and B0 is the optimized structure of the chalcone.
Table 2 summarizes the calculated deformation energy and interaction energy (without ZPE) for the lowest energy TSs, TS1-R-b(II) and TS10-S-b(II), leading to the R- and S- forms of the products. EDA indicates that the activation energy of the TSs arises from a large cancellation between contributions of deformation energy and interaction energy. Furthermore, the calculated ∆∆Eint and ∆∆Edef are –18.2 kcal/mol and 15.5 kcal/mol, respectively. Therefore, ∆∆Eint contributes more to the ∆∆Eact. The deformation energy of chalcone, ∆Edef (chalcone), is very similar for two key TSs (20.2 kcal/mol for TS1-R-b(II) and 19.9 kcal/mol for TS10-Sb(II)). However, the deformation energy of the catalyst, ∆Edef (chalcone), is larger for TS1-R-b(II) (43.8 kcal/mol) than for TS10-S-b(II) (28.0 kcal/mol). In terms of the smaller interaction energy ∆∆Eint of Sform (TS10-S-b(II)) than R-form (TS1-R-b(II)), we can see from the different structural features (Figure 12). In the S-form, the larger distance between Cu and βcarbon, 2.96 Å, compared with the R-form, 2.06 Å, is observed. Further, the steric repulsions arise between phenyl group of chalcone and tert-butyl group of the bipyridine ligand. This is the origin of the selectivity.
Cu O B O OH
tBu
O
α
Ph
H Ph
β
Cu−O = 2.06 Cu−Cα = 2.58 Cu−Cβ = 2.06 B−Cβ = 2.29
(b) S-form
View1
View2 tBu OH
N
Cu O N B O OH tBu Ph
Ph
α β
H
Cu−O = 2.01 Cu−Cα = 3.20 Cu−Cβ = 2.96 B−Cβ = 2.28
O
Figure 12. The lowest energy transition state for each (a)Rform (favorable) (TS1-R-b(II)) and (b)S-form (unfavorable) (TS10-S-b(II)) in the Cu(II) system. Selected bond lengths are given in Å.
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Table 2. EDA for the lowest energy transition state leading to R- and S-products for the Cu(II) system. Cu(II) system ∆Edef([LCu–B(pin)]a chalcone)
∆Edef(LCu–B(pin))
∆Edef(chalcone)
∆Eint
∆Eact
∆Hact
∆Gact
Type b-R (TS1-R-b (II))
43.77
20.20
23.58
–46.45
–2.67
–2.74
14.02
Type b-S (TS10-S-b (II))
27.99
19.91
8.08
–28.29
–0.29
–0.62
15.40
∆∆Edef([LCu–B(pin)]chalcone)
∆∆Edef(LCu– B(pin))
∆∆Edef(chalcone)
∆∆Eint
∆∆Eact
∆∆Hact
∆∆Gact
15.78
0.29
15.50
–18.16
–2.38
–2.12
–1.38
a
The total deformation energy ∆Edef ([LCu–B(pin)]-chalcone) is given by the sum of ∆Edef (LCu–B(pin)) and ∆Edef (chalcone).
IV. CONCLUSIONS In summary, we have explained the reaction mechanism for the Cu-catalyzed boron conjugate addition reaction. Computed Cu(II) or Cu(I) catalytic cycles consist of three main steps: (a) boron–boron bond cleavage of B2(pin)2, (b) boron conjugate addition to the β-carbon of chalcone, and (c) protonation. Our computed free energy profiles suggest that in the Cu(II) system, the rate-determining step is the protonation of Cu(II), while the enantioselectivity-determining step is the C–B bond formation. On the other hand, in the Cu(I) system, the C–B bond formation is rate-determining. TSs for the selectivity-determining step of the reactions were systematically determined by the MC-AFIR method and the subsequent DFT calculations. Based on the computed TSs, the calculated enantioselectivity of the Cu(II)-based catalyst agrees well with the experimental value. For the Cu(I) system, calculated TSs explain the loss of enantioselectivity. The mechanistic difference between Cu(I) and Cu(II) catalysis originates from the selectivity determining C–B bond formation step; this difference is critical for the enantioselectivity. For the Cu(II) system, the TS that leads to the Cu(II)-O-enolate (Type b) only contributes to the reaction; furthermore, the R- and S- forms are energetically well separated, and therefore the reaction is enantioselective. On the other hand, both Cu(I)-Oenolate (Type b) and Cu(I)-C-enolate (Type a) contribute to the reaction mechanism in the Cu(I) system. These two TSs are energetically very close, leading to the different enantiomers, and therefore the reaction is not enantioselective.
This study provides important mechanistic insights for the copper-catalyzed enantioselective boron conjugate addition reaction and should guide the design of new catalysts to synthesize optically active organoboron compounds in a selective fashion.
SUPPORTING INFORMATION Complete lists of transition states and Cartesian coordinates of all optimized geometries are provided. This material is available free of charge via the Internet at http://pubs.acs.org.
Corresponding authors *Email:
[email protected],
[email protected] Acknowledgment MI acknowledges the Fukui Fellowship, Kyoto University. WMCS acknowledges the Japan Society for the Promotion of Science (JSPS, No. P14334) for a Foreign Postdoctoral Fellowship, and Hokkaido University. This work was in part supported by Grantsin-Aid for Scientific Research (KAKENHI 15H00938 and 15H02158) to KM at Kyoto University. TK and SK gratefully acknowledge partial support by Grant-in-Aid for Research Activity Start-up (KAKENHI 15H06134) and Grant-in-Aid for Specially Promoted Research (KAKENHI 15H05698). Computer resources at the Academic Center for Computing and Media Studies at Kyoto University, Research Center of Computer Science at the Institute for Molecular Science are also acknowledged. We thank Prof. Satoshi Maeda for allowing us to use the development version of the GRRM program.
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ACS Catalysis
56. Kitaura, K.; Morokuma, K., Int. J. Quantum Chem. 1976, 10, 325–340. 57. Szalewicz, K., WIREs Comput. Mol. Sci. 2012, 2, 254– 272. 58. Mo, Y. R.; Gao, J. L.; Peyerimhoff, S. D., J. Chem. Phys. 2000, 112, 5530–5538.
Cu(II) catalyst
Cu(I) catalyst
Enantioselective (94% ee)
L
O
Cu O Ph
α
No enantioselectivity
Cu O
Ph
Cu-O-enolate (R )
O
L
B O β
59. von Hopffgarten, M.; Frenking, G., WIREs Comput. Mol. Sci. 2012, 2, 43–62.
Ph
α
L B O
O
Cu O
β
Ph
Cu-O-enolate (R )
Ph
α
B O β
Ph
Cu-C-enolate (S )
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