Mechanism and Origin of Et2Al(OEt)-Induced Chemoselectivity of

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Mechanism and Origin of Et2Al(OEt)-Induced Chemo-Selectivity of NickelCatalyzed Three-Component Coupling of One Diketene and Two Alkynes Yuxia Liu, Yanan Tang, Yuan-Ye Jiang, Xiaomin Zhang, Xiao-Ping Li, and Siwei Bi ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03543 • Publication Date (Web): 24 Jan 2017 Downloaded from http://pubs.acs.org on January 24, 2017

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Mechanism and Origin of Et2Al(OEt)-Induced Chemo-Selectivity of Nickel-Catalyzed Three-Component Coupling of One Diketene and Two Alkynes

§

§

Yuxia Liu, Yanan Tang, Yuan-Ye Jiang, Xiaomin Zhang, Ping Li and Siwei Bi*

School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P.R. China

CORRESPONDING AUTHOR: Dr & Professor Siwei Bi E-mail:

[email protected]

Phone:

+86-537-4458308

Fax:

+86-537-4456305

* To whom correspondence should be addressed. E-mail: [email protected] §

Authors with equal contribution

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ABSTRACT Density functional theory (DFT) calculations have been performed to unravel the mechanism of Lewis-acid-induced Ni(cod)2-catalyzed selective coupling reactions of one diketene and two alkynes. Complex mixtures (unsymmetrical phenylacetic acid P1, symmetrical phenylacetic acid P2 and (3E)-4-ethyl-5-methylene-3-heptenoic acid P3) were obtained in the absence of Et2Al(OEt). P1 formation involves C(sp2)-O oxidative addition of diketene, twice alkyne insertion, intramolecular C=C insertion, acidolysis, and β-H elimination. For P2/P3 formation, the common key issue related to the C=C double bond cleavage of the substrate diketene was explored and found that it was accomplished via a four-membered-ring-closure/four-membered-ring-opening process. And then, P2 was produced via the second alkyne insertion while P3 was accessed by a stoichiometric reaction with HCl. The Et2Al(OEt)-induced chemoselectivity was also probed. It is found that the Ni-O (from Al reagent) bonding facilitates the second alkyne insertion, and the Al-O (from carboxylate) bonding weakens the four-membered ring-closure step, which consequently leads to the formation of P1 exclusively. Additionally, HCl plays a promoting role as a cocatalyst in producing P1 and P2. The theoretical results not only well rationalize the experimental observations but provide insights into the mechanism of the Ni-catalyzed multicomponent coupling reactions. Keywords: nickel, multicomponent coupling, DFT, organoaluminum, selectivity, diketene, alkynes.


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1. INTRODUCTION

Phenylacetic acid is not only an active auxin but also acts as critical structural motif in many physiologically and biologically active compounds including carbenicillin, ibuprofen, analgesics, and nonsteroidal anti-inflammatory drugs (NSAIDs) etc.1-3 To meet the demand for efficient preparations of phenylacetic acid and its analogues, metal-catalyzed carboxylation of benzyl halides with CO2,2 hydrocarboxylation of styrene derivatives,4-6 and carboxylation of dialkylzinc species7,8 have been developed in the early years. Unsatisfactorily, the handling and harsh reaction conditions among these early scenarios have limited their potential application scope. Therefore, the straightforward and selective transition-metal-catalyzed alternative methods employing readily available starting materials would be highly desirable. Nickel-catalyzed couplings of multiple functional groups have emerged as one of the most powerful strategies for the construction of complex molecular frameworks.9-14 In these multicomponent reactions, chemoselectivity become a crucial issue due to unavoidable complications such as competing oligomerization or polymerization of one of the components. Recently, Kimura and co-workers developed the Ni(cod)2-catalyzed selective three-component coupling reactions of one diketene and two alkynes in toluene which were demonstrated to be accessible at ambient temperature.15 As shown in Scheme 1, in the presence of Et2Al(OEt), the unsymmetrical phenylacetic acid (denoted as P1) is exclusively obtained in 98% isolated yield (eq 1). Intriguingly, their further study revealed that, under similar catalytic conditions without involvement of Et2Al(OEt), besides the expected product P1, the symmetrical phenylacetic acid P2 and (3E)-4-ethyl-5-methylene-3-heptenoic acid P3 are also generated (eq 2). These phenomena


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show that Et2Al(OEt) has an unique influence on the control of reaction selectivity.

Scheme 1. Ni(cod)2-catalyzed three-component coupling reactions of one diketene and two alkynes reported by Kimura and co-workers.5

With regard to the intriguing Ni(cod)2-catalyzed coupling reactions displayed in Scheme 1, Kimura et al. postulated that, as indicated in Scheme 2, the reaction starts from the oxidative cyclization of alkyne (R1) and diketene (R2) with the Ni(0) catalyst to generate the nickel-acyclopentene intermediate B, a common and necessary intermediate leading to different products. From B, two possible pathways are involved. On one hand, the reaction proceeds via the C(sp3)-O bond cleavage to give the seven-membered oxanickelacycle C, followed by the insertion of the second alkyne molecule, resulting in the vinylnickel intermediate E. Subsequent transmetalation between E and Et2Al(OEt) affords complex F, which goes through 6-endo-trig cyclization and β-H elimination to form product P1 with the release of the Ni(0) catalyst. On the other hand, intermediate B experiences various structural rearrangements via the resulting nickel


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carbene complex H16-18 to provide five-membered oxanickelacycle K. Further insertion of the second alkyne molecule on K followed by transmetallation with Et2Al(OEt) generates P2 while direct protonolysis of K with aqueous HCl produces P3.

1 Ni Et

2

O 1

Ni 3

Ni

Et

4 O

O

Et

Et

O

Et A

Ni

Et

Et

Et

O

Et

O

O

B

Ni

Et

O O

O

H

J

I

Et Et Et Ni O

Et

Ni O Et

O

O

H Et

Et

Et

Ni O

- NiII

O

O

+ H+

OH

Et

Et

Et C

D

Et K

P3 Et

Et

Et2Al(OEt) Et

Et

NiOEt OAlEt2

Et

O O

Et

Et E

Et

Et

Et Ni

Et

O

Ni+ Et

Et

Et

Et F

N

Et

CO2-

Et M

CO2NiH

Et

Ni+

Et

Et

Et

Et

CO2-

L

II

- Ni + Et2Al(OEt) - HEt Et - NiII Et - HOEt

Et

+ H+

Et Et P1

CO2H

Et

Et

Et Et

NiOEt OAlEt2

Et Et

O

G

Et

+ H+

Et

Et Et

CO2AlEt(OEt) O

Et

CO2H

P2

Scheme 2. The possible pathways proposed by Kimura and co-workers5 for the Ni(cod)2-catalyzed three-component coupling reactions of one diketene and two alkynes in the presence and absence of Et2Al(OEt).

Recent years have witnessed the rapid growth of nickel-catalyzed cross-couplings of unsaturated compounds due to their high atom economy.19-24 The related selectivity control is not only challenging to experimental chemists but also attracts extensive attention of theoretical


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chemists.25-29 To obtain deeper insights into the Ni-catalyzed selective three-component coupling reactions, systematic density functional theory (DFT) calculations were performed herein, from which we expected to unravel i) the detailed mechanisms of the Ni-catalyzed coupling reaction in the absence and presence of Et2Al(OEt), ii) the intrinsic reasons for the Et2Al(OEt)-dominated product distribution, and iii) the role of HCl in the formation of P1, P2 and P3. It is anticipated that the calculated results would be informative for efficient design of new related coupling reactions. 2. COMPUTATIONAL DETAILS Geometry optimizations were performed at the Becke3LYP level of density functional theory,30-33 which has been shown to describe Ni-catalyzed and other transition-metal catalyzed organometallic systems well.34-38 The standard 6-31G(d,p) basis set39 was chosen for all atoms except for Ni, Al, and Cl, which were described by the effective core potentials (ECPs) of Hay and Wadt combined with double-ζvalence basis set (Lanl2DZ).40 And also a polarization function was added with Ni(ζf ) = 3.130, Al(ζd) = 0.190 and Cl(ζd ) = 0.64041 to obtain more accurate energies since d and f functions are not available for the ECPs. Vibration frequency calculations at the same level of theory were performed to verify that a local minimum has no imaginary frequency and each transition state has only one single imaginary frequency. Calculations of intrinsic reaction coordinates (IRC)42,43 from transition states have also been conducted to confirm that such structures indeed connect two relevant minima. To take the solvent effects into account, the conductor-like polarizable continuum model (CPCM)44-47 was used for the single-point calculations based on the optimized geometries in the gas


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phase with the UAKS radii. All SCRF calculations were conducted at the M06 level by using a larger basis set of SDD for Ni, Al, Cl and 6-311++G(d,p) for other atoms. Here, the dielectric constant ε=2.3741 was employed to simulate toluene as the solvent, corresponding to the experimental conditions. It was well-known that the gas-phase calculations overestimate the entropic contribution to the Gibbs free energy for the reaction step with different numbers of reactant and product molecules in solution,48-49 and thus the reasonable corrections are necessary to add to the relative free energies according to the free volume theory.50 For the one-to-one or two-to-two change, it is unnecessary to add the corrections. However, for the two-to-one (or one-to-two) transformation, a correction of −4.3 (or 4.3) kcal/mol is required at the temperature of 298.15 K.51 In all of the figures that contain potential energy profiles, solvent-corrected relative free energies were presented and used to analyze the reaction mechanism. All calculations were performed with the Gaussian 09 software package.52 3. RESULTS AND DISCUSSION 3.1. Mechanisms without Involvement of Et2Al(OEt). According to the mechanism proposed in Scheme 2, the reaction is initiated by direct [2+2+1] oxidative cyclization (alkyne R1 + diketene R2 + Ni(0) catalyst) to afford the nickel-acyclopentene B, a common and requisite intermediate accessing to products P1, P2 and P3. Our calculated results (Scheme 3) indicate that the direct oxidative cyclization step requires an activation barrier of 34.0 kcal/mol, which is unachievable under ambient temperature. Thus, more favorable alternative pathways are expected to exist. In this work, we first study initial formation of the common intermediate and then investigate the mechanisms for competitive generations of P1, P2 or P3. ACS Paragon Plus Environment

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Scheme 3. Calculated activation barrier for direct [2+2+1] oxidative cyclization (alkyne + diketene + Ni(0) catalyst) based on to the proposal of the Kimura group.5

3.1.1. Mechanisms of Forming the Common and Requisite Intermediate As mentioned above, the direct [2+2+1] oxidative cyclization mechanism shown in Scheme 3 is inaccessible. Instead, the alternative C(sp2)-O oxidative addition/alkyne insertion mechanism was proposed. The energy profile calculated for these steps are shown in Figure 1. Initially, coordination of Ni(cod)2 (cod = 1,5-cyclooctadiene) to R1 gives the R1-coordinated intermediate 1, and liberation of one cod ligand affords the mono-cod-ligated complex 2.53 Ligand exchange of the alkyne 2 with the diketene generates the R2-coordinated intermediate 4. 4 is less stable than 2 by 3.0 kcal/mol, indicating R1 has a stronger coordination ability than R2. It is notable that to achieve stable 16-electron configuration on the Ni center, the cod in 2 adapts bidentate coordination mode. In contrast, in 3 the Ni center coordinates with both an alkenyl and an alkynyl ligand. As a result, the cod behaves as a monodentate ligand to coordinate to the Ni atom. Subsequently, (sp2)C2-O1 oxidative addition occurs to deliver a five-membered oxanickelacycle 5 with a barrier of 19.5 kcal/mol.54 Finally, with addition of alkyne R1, the C≡C bond insertion into the Ni-C2 bond overcomes a barrier of 12.9 kcal/mol, producing the seven-membered oxanickelacycle 7, in which


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the tethered C=C double bond is found coordinating to Ni(II) to satisfy 16e configuration. As indicated from Figure 1, intermediate 7 is kinetically available and has the highest stability. This oxanickelacycle complex is found to be a common and requisite intermediate in forming P1, P2 and P3.

Et

Ni(cod)2 0.0 R1 Et

Et

Et

Et

Et

Et

cod

cod

Ni

O Ni O TS4-5 Ni(cod)2 cod 1 12.1 6.7 3 R1 cod -4.2 -4.4 -7.4 4 2 R2 Ni(cod) Et Et O 1 O 1 2 4 Ni(cod) 3

Ni

Et

O

O O TS6-7 O -4.1

R1 -10.7

Et

5 cod Et Ni O O

2.2

6

cod

7 -24.0

Ni O Et O Et

cod Ni O O

ligand exchange/C-O oxidative addition

first alkyne insertion

Figure 1. Calculated free energy profile in toluene for forming common intermediate 7 based on the pathway established in the present work. The relative free energies are given in kcal/mol.

3.1.2. Mechanism of Forming Product P1 As shown in Figure 2, intermediate 7 undergoes the second alkyne insertion55 affording the nine-membered oxanickelacycle 10 with a barrier of 15.9 kcal/mol (7→TS8-10).56 Step 10→ →11 is a coordination isomerization with the internal C=C coordination switching to the tethered C=C coordination, which is necessary for subsequent C=C bond insertion. The C=C bond insertion step is calculated to overcome a barrier of 17.0 kcal/mol (11→TS11-12), giving the spirocyclic intermediate


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12. This insertion step (11 → 12) is substantially exergonic (-40.0 kcal/mol). The five- and six-membered rings formed via C=C insertion is responsible for high stability of 12.

Figure 2. Calculated free energy profile in toluene solvent for the second alkyne insertion/intramolecular C=C insertion mechanism from the intermediate 7 in the absence of Et2Al(OEt) according to the pathway established in the present work. The relative free energies are given in kcal/mol. For P1 formation57 from 12 with HCl involved (Figure 3), two pathways were examined, acidolysis/β–H elimination pathway and β–H elimination/acidolysis pathway. Combination of HCl with 12 affords adduct 13. In the acidolysis/β–H elimination mechanism (black line), acidolysis first occurs, breaking the Ni-O bond, forming a carboxyl group and a Ni-Cl bond. The acidolysis step (13 →TS13-14→14) is facile with a barrier of 8.9 kcal/mol and remarkably exothermic with an energy


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change of -12.4 kcal/mol. For β–H elimination, 14 has to isomerize into the intermediate 15 containing an agostic (β-C-H)-Ni interaction. Instability of 15 relative to 14 is a result of breaking the C=C bond coordination. The facile β-H elimination (15→16) arises from the efficient β-C-H bond activation via agostic interaction in 15. Finally, product P1 is obtained by liberation from 16 and intermediate 4 is regenerated by ligand exchange and HCl reductive elimination (17→18→4).

Figure 3. Calculated free energy profile in toluene for forming product P1 from intermediate 12 based on the pathways established in the present work. The relative free energies are given in kcal/mol.

In the β–H elimination/acidolysis mechanism (red line in Figure 3), the β–H elimination step was proposed to take place first. However, intermediate 14’ generated from 13 with the C=C coordination switching to the (β-C-H)-Ni agostic interaction is calculated to be less stable than 15 by


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5.4 kcal/mol. Noted that 15 is the stationary point with highest energy in the black pathway. Therefore, this pathway is energetically disfavored regardless of the subsequent stationary points (TS14’-15’, 15’ and TS15’-16) being stable or not. TS14’-15’ is the β–H elimination transition state. TS15’-16 is the acidolysis transition state and was not located considering this pathway is not favored. In summary, formation of product P1 is predicted to undergo the acidolysis/β–H elimination pathway. As HCl is not involved, the β–H elimination/acidolysis mechanism leading to P1 was also considered. However, the initial β–H elimination is calculated to be energetically unfavored over the HCl-included pathway (13→14→15→16) (see Figure S6). Thus, addition of HCl promotes the β–H elimination/acidolysis mechanism. The β-H elimination step is predicted to be rate-determining with a barrier of 22.4 kcal/mol (14→15) in formation of P1. 3.1.3. Mechanisms of Forming Products P2 and P3 The reaction pathways from 7 to products P2 and P3 and calculated free energy profiles are shown in Figures 4 and 5, respectively. In the pathway leading to product P2 (Figure 4), the tethered C=C bond insertion takes place (7→19), forming σ bonds C1-C5 and C2-Ni and simultaneously breaking the Ni-C5 σ bond and C1-C2 π bond.58-61 This insertion step leads to forming a four-membered carbocyclic moiety in 19. Then, the ring opening step is followed to break the C1-C2 σ bond and forms a butadienyl moiety, giving intermediate 20. The barrier for breaking the C1-C2 σ bond is calculated to be not very high (23.2 kcal/mol). One reason is that a four-center-four-electron conjugation system is present in transition state TS19-20, which plays a role in stabilizing the transition state. As a whole, the C1=C2 double bond is predicted to be cleaved via


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ring-forming (7→19) and ring opening (19→20). The ring-forming step breaks the C1=C2 π bond and the ring opening step breaks the C1-C2 σ bond.

Figure 4. Calculated free energy profile for forming the product P2 from 7 based on the pathway established in the present work. The relative free energies are given in kcal/mol. Based on the Kimura’s proposal (Scheme 2), substrate alkyne R1 could insert into Ni-C(sp2) (K→L) and finally access into product P2. Our calculations indicated that the alkyne insertion step from 20 is less kinetically favored (Figure S10) as compared to the acidolysis of 20 (Figure 4). The barrier to the alkyne insertion is higher than that to the acidolysis by 11.4 kcal/mol. The acidolysis of 20 with HCl enables the Ni-O bond cleavage and a carboxyl formation, giving intermediate 22. Substitution of alkyne R1 for the coordinated cod ligand (22→23) is required for the next alkyne insertion step.62 Calculations show that the insertion step (23→24) is quite facile and significantly


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exogonic. Subsequently, formation of the six-membered carbocycle occurs via the terminal C=Ｃ bond insertion into the Ni-C(sp2) bond (24→25). In 25, the carbocycle binds with Ni(II) in a η3 fashion. Generation of the six-membered carbocycle renders the insertion step significantly thermodynamically favorable. In the end, β-H elimination from 25 takes place to generate a benzene ring, giving the P2-coordinated intermediate 26. Calculations predict that the binding of Ni(II) with the benzene ring is in a η6 fashion. Thus, P2 is easily obtained by substitution of the cod ligand (26→17). As shown in Figure 3, 17 easily transforms to intermediate 4. In summary, the unique C1=C2 double bond cleavage is completed via a four-membered carbocycle formation/a four-membered carbocycle opening. The former completed by C=C insertion enables the C=C π bond broken and the latter enables the C-C σ bond broken. The C-C σ bond cleavage (19→20) is predicted to be rate-determining with a barrier of 23.2 kcal/mol in the process of forming P2 . The Kimura group proposed in Scheme 2 that product P3 can be accessed by protonolysis of intermediate K with HCl. Herein, the mechanism for accessing into P3 has been investigated. In comparison with formation of P2, P3 formation occurs from intermediate 23 (Figure 4).63 Our calculations confirmed that HCl can indeed induce the Ni-C2 cleavage (23→27) (Figure 5). In 23 Ni-C2 is 1.924 Å while in TS23-27 it is elongated to 2.063 Å. In summary, P3 is accessed by a stoichiometric reaction with HCl.


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Figure 5. Calculated free energy profile for forming the product P3 based on the pathway established in the present work. The relative free energies are given in kcal/mol.

3.1.4. Comprehensive Evaluation of the Competitive Mechanisms Above discussions disclose the mechanisms for formation of unsymmetrical phenylacetic acid P1 (Section 3.1.2), symmetrical phenylacetic acid P2 and chained carboxylic acid P3 (Section 3.1.3). For convenient comparison, the three competitive mechanisms are schematically collected in Scheme 4. Only key stationary points are given in this scheme. The reaction starts with initial C-O oxidative addition followed by the first alkyne insertion to generate the common requisite intermediate 7, a seven-membered oxanickelacycle complex. Then, three competitive pathways leading to P1 (green line), P2 (pink line) and P3 (blue line) are proposed to occur. From 7, the second alkyne insertion via TS8-10 occurs and finally accesses to P1; P2 and P3 share the path from 7 to 22. From 22, the second alkyne insertion, cyclization and β-H elimination leads to P2; direct acidolysis with HCl leads to P3.


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Et

Et

Et

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Et

Et

Ni cod

Et

O

Et COOH

Et

TS8-10 O -8.1

P1

second alkyne insertion C-O oxidative addition

Ni(cod)2

+ 2 Et

first alkyne insertion

Et

Et Et

+

3

4

1

2

O

O O

Ni

Ni

ring-closure ring-opening O1

Et Et TS19-20 -9.3

3 4O 7 -24.0

O1 1 2

cod

cod 5

acidolysis Et

Cl

Et Et

-H elimination

Ni cyclization

H

Et O

Cl

cod

O

Ni

second alkyne insertion

OH O

Et

Et Et

COOH

Et

P2

Et

Et

TS23-24 -35.8

22 -40.0 acidolysis Et Cl

Et Cl H

O

H OH

Et Et P3

Ni O

H

Et Et TS23-27 -34.6

Scheme 4. Three competitive pathways leading to P1, P2 and P3 established in the present work. The relative free energies are given in kcal/mol.

By comparing the three possible pathways, it is found that starting from 7, alkyne insertion transition state TS8-10 (the highest stationary point in the formation of P1) is energetically comparable to the four-membered ring-opening transition state TS19-20 (the common highest stationary point leading to P2 and P3) (-9.3 kcal/mol). Thus, the pathway forming P1 and that forming P2 and P3 are competitive with the former slightly more favorable kinetically. Starting ACS Paragon Plus Environment

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from the bifurcation point 22, TS23-24 (the highest stationary point leading to P2) and TS23-27 (the highest stationary point leading to P3) have similar free energy, -35.8 vs -34.6 kcal/mol, respectively. Thus, the pathway forming P2 and that forming P3 are also competitive with the former slightly more favorable kinetically. With the Arrhenius equation, 1.2 kcal/mol energy difference between TS8-10 leading to P1 and TS19-20 leading to P2+P3 gives a P2+P3/ P1 ratio of 88:12. On the other hand, 1.2 kcal/mol energy difference between TS23-27 resulting in P3 and TS23-24 resulting in P2 gives a P2/P3 ratio of 88:12. Overall, the predicted product ratios of P1: P2: P3 are 12: 77: 11.These results derived from our computations are in roughly agreement with the experimental observation regarding complex mixture shown in eq 2.

3.2. Mechanisms with Involvement of Et2Al(OEt). As mentioned in the Introduction, upon the participation of Et2Al(OEt), the unsymmetrical phenylacetic acid product P1 is exclusively obtained in excellent yield (eq 1),5 in sharp contrast to the situation in the absence of Et2Al(OEt). For comparison, we also performed calculations for forming P1, P2 and P3 with Et2Al(OEt) involved, expecting to reveal how Et2Al(OEt) dominates the chemoselectivity. Figure 6 exhibits the optimized geometries for species 4 in Figure 1, 30 and 31 in the following Figure 7. And Figures 7, 8 and 9 present the reaction mechanism for formation of P1. Binding of 3 and Et2Al(OEt) gives more stable adduct 29 with the O→Al bond formation. Release of the cod ligand followed by the Ni←O bond formation affords the 16e species 31. Subsequently, the C-O oxidative addition to Ni(0)64 is followed, giving 32 that contains a 7-membered nickelacycle. The


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other oxygen coordination to Ni leads to the conversion of 32 (14e) to more stable 33 (16e). Note that the C-O cleavage in 31→32 requires an activation barrier of 6.2 kcal/mol, remarkably lower than that in 4→5 (16.5 kcal/mol, Figure 1).65 Two main reasons are considered. One is that the electron-deficient Al atom makes the C2-O1 bond weaker in 31 as compared to the one in 4. The argument was supported with the calculations that the C2-O1 bond length in 4 (1.468 Å) is appreciably shorter than that in 31(1.508 Å). The cyclization with Al might be the other key factor of weakening the C2-O1 bond. As shown in Figure 6, the C2-O1 bond length in the precyclization intermediate 30,

1.466 Å, is much shorter than that in the cyclization complex 31, 1.508 Å. On the

other hand, The smaller C2-O1 bond order (0.77) in 31 in contrast to those (0.84 and 0.83) in 4 and 30 also further confirms the weaker C2-O1 bond in 31. From 33, the alkyne insertion into the Ni-C bond takes place, giving the insertion product 34 with the tethered C=C double bond coordinating to Ni.

Figure 6. Optimized geometries for species 4, 30, and 31. The hydrogen atoms have been omitted for clarity. Bond distances are given in Å. The bond orders are given in square brackets.


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Continually in Figures 7 and 8,66 we found that the reaction follows similar mechanisms with similar energy barriers as shown in Figures 2 and 3 (Table 1). In other words, Et2Al(OEt) is formally a spectator in the transformations from 34 to P1, and thus the relevant mechanism details are not discussed again for simplification.

Table 1. The energy barriers for forming product P1 in the absence and presence of Et2Al(OEt). The relative free energies are given in kcal/mol. second alkyne insertion

intramolecular C=C insertion

acidolysis

β-H elimination

without Et2Al(OEt)

15.9

17.0

8.9

22.4

with Et2Al(OEt)

6.3

14.0

10.8

15.7

After delivering product P1 from 42, as displayed in Figure 9, adduct 43 is simultaneously obtained. To ensure the regeneration of the active catalyst 2, 14e complex 43 is needed to coordinate with the alkyne R1, affording stable 16e intermediate 44. The Ni-attached H atom then transfers to the O(Et) atom with a barrier of 7.3 kcal/mol to give the species 45, in which the migrating H atom has almost bonded to the O(Et) atom. At the last step, the cod released from 29 in Figure 6 re-coordinates to Ni center and provides the active catalyst 2 after delivering 46 (EtOH·AlClEt2).


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Figure 7. Calculated free energy profile in toluene solvent for forming common intermediate 34 from the initial materials (2R1+R2) in the presence of Et2Al(OEt) according to the pathway established in the present work. The relative free energies are given in kcal/mol.

Figure 8. Calculated free energy profile in toluene solvent for the second alkyne

insertion/intramolecular

C=C

insertion

mechanism

from

the

intermediate 34 in the presence of Et2Al(OEt) according to the pathway established in the present work. The relative free energies are given in kcal/mol.


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Figure 9. Calculated free energy profile in toluene solvent for forming the precursor of product P1 from the C=C insertion intermediate 38 in the presence of Et2Al(OEt) according to the pathways established in the present work. The relative free energies are given in kcal/mol.

When P2 and P3 formation in the presence of Et2Al(OEt) are considered, the reaction bifurcates from 34. As exhibited in Figure 10 (green line), 34 undergoes four-membered ring-closure process via TS34-35’ with a barrier of 18.6 kcal/mol to form intermediate 35’ that finally evolves into product P2 or P3. The potential energy profile for the four-membered ring-closure step is found to be 15.5 kcal/mol higher than that for the alkyne insertion from 34 (black line). With the Arrhenius equation, the substantially high energy difference (15.5 kcal/mol) gives almost 100% yield of P1. This is in accordance with the experimental findings that only P1 was obtained in the presence of Et2Al(OEt) under the given conditions. Besides, in Kimura's paper,15 when PPh3 ligand was participated in the same reaction, P2 product can be obtained in 54% yield. It is believed that PPh3


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ligand might inhibit the second insertion of alkyne to form intermediate 35. From 34, the combination of PPh3 ligand and Et2Al(OEt) accelerates four-membered ring-closing process. And then second alkyne insertion might occur via dienyl nickel intermediate to provide P2 product.

EtO Ni

Et

AlEt2 TS34-35'

O O

Et

5 1

Et 2

34

Ni

-26.7

Et

Et O AlEt2 O1

EtO AlEt2 -42.2

4 O 3

-45.3

-48.5 R1

Et Et

35 Et

Et Et Ni Et

OEt O

Et

Ni

Et

TS35-36 Et Et O Ni AlEt2 O

O O

Et 35' -51.6

O

AlEt2

-64.4

O Et EtO Ni

36 AlEt2 O

O

Et Et

Et

Figure 10. Calculated free energy profiles in toluene solvent for four-membered ring closure step and the second alkyne insertion step from the intermediate 34, respectively, in the presence of Et2Al(OEt) according to the pathway established in the present work. The relative free energies are given in kcal/mol.

3.3. Origin of the Chemoselectivity As our calculations indicated, formation of P1 and P2/P3 bifurcates from intermediate 7 in the absence of Et2Al(OEt), and from 34 in the presence of Et2Al(OEt). Herein, we uncover how Et2Al(OEt) dominates the chemoselectivity. Figure 11 collects the crucial steps, the second alkyne ACS Paragon Plus Environment

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ACS Catalysis

insertion and the four-membered ring-closure67 in the absence and presence of Et2Al(OEt), respectively.

Et Et

Et Et

Et Ni

Et

cod

Ni

Et

O

O

O

O

1.268 1.958 (a)

cod

1.816

1.889

TS8-10

cod

1.878 2.033 2.129 1.452

2.053

TS7-19

7 13.5 kcal/mol

the second alkyne insertion

four-membered ring-closure

6.3 kcal/mol

18.6 kcal/mol

1.236 2.081 2.110

1.892 (b)

Et

1

5 1.386

8

1.279

O

3 4 O

15.9 kcal/mol

2.101

Ni O

Et

1 O1

Et

2.163 1.892 1.931

2.041 1.975

cod Ni

2

2.036

2.111

Et

Et

1.951 1.918

1.958

1.883 2.029 5 1 2.019 1.393

1.878 2.094 1.460

1.971

2.069 TS35-36 Et Et

35

Et Ni

Et O O

Et O

Et

Et

Et

Et Ni

AlEt2 Et

OEt O

AlEt2

5 1

Et 2

O

TS34-35'

34 Et O

EtO AlEt2

Ni

O1

Ni

Et

AlEt2 O O

3 4 O

Et

Figure 11. Comparison between the first alkyne insertion and four-membered ring-closure steps: (a) no-Et2Al(OEt)-involved system and (b) Et2Al(OEt)-involved system. The hydrogen atoms have been omitted for clarity. The energy barriers are given in kcal/mol.

7→TS8-10 and 34→TS35-36 are related to the second alkyne insertion, in the absence and


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presence of Et2Al(OEt), respectively. 7→TS7-19 and 34→TS34-35’ are associated with the four-membered ring-closure, in the absence and presence of Et2Al(OEt), respectively. From 7, the rate-determining transition states TS8-10 leading to P1 and TS19-20 leading to P2/P3 have similar energy (-8.1 vs -9.3 kcal/mol) and thus become competitive. From 34, the rate-determining transition states TS35-36 leading to P1 and TS34-35’ leading to P2/P3 have a large energy difference (-42.2 vs -26.7 kcal/mol) and thus P1 formation is exclusively chemo-selective. Both the second alkyne insertion and four-membered ring-closure are found to be closely related to the Ni-C5 bond cleavage. It is predicted that the Ni-C5 bond strength is a crucial factor for the different chemo-selectivity. As shown in Figure 11, the barrier related to the second alkyne insertion in the absence of Et2Al(OEt) (15.9 kcal/mol) is significantly larger than that in the presence of Et2Al(OEt) (6.3 kcal/mol). The origin for the difference can be attributed to different coordination (cod coordination in TS8-10, and oxygen coordination in TS35-36). In comparison with the cod coordination in 8, Ni-O(from Al reagent) bond formation in 35 has stronger trans influence and enables the Ni-C5 bond much weaker. This argument is supported by the calculated parameters. The Ni⋅⋅⋅C5 distance in 8 is 1.889 Å while that in 35 is 1.918 Å, clearly demonstrating the former Ni⋅⋅⋅C5 interaction is stronger than the latter one. In summary, the coordination of oxygen of the aluminum reagent makes the alkyne insertion much easier. For the four-membered ring-closure step, the Et2Al(OEt)-involved system (34→TS34-35’ with a barrier of 18.6 kcal/mol) is unfavorable over the non-Et2Al(OEt)-involved system (7→TS7-19 with a barrier of 13.5 kcal/mol). This step is accomplished by C=C insertion into the Ni-C5 bond, with C5


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ACS Catalysis

linking to the terminal olefinic carbon. As shown in the geometries of 7 and 34, Ni-C5 is weaker in the former than in the latter, supported by the calculated bond lengths (1.892 vs 1.883 Å). Therefore, C=C insertion in 7 is easier than in 34. The origin can be derived from the different trans influence of Ni-O1 imposed on the Ni-C5 bond. Ni-O1 (1.931 Å) in 7 has stronger trans influence to Ni-C5 bond than that (2.029 Å) in 34. The weaker Ni-O1 (2.029 Å) in 34 is clearly resulted from the Al-O1 bonding formation. Consequently, presence of the Al reagent increases the difficult of breaking Ni-C5 bond in the process of the C=C insertion step. Overall, the Et2Al(OEt)-induced chemoselectivity originates from the capability of breaking Ni-C5 bond. Ni-O(from Al reagent) bond formation weakens the Ni-C5 interaction and facilitates the second alkyne insertion. And the presence of the Al-O (from carboxylate) bonding enhances the Ni-C5 interaction and makes the four-membered ring-closure difficult. 4. CONCLUSIONS The detailed mechanisms of Ni(cod)2-catalyzed three-component coupling reactions of two alkynes (R1) and one diketene (R2) have been investigated by DFT calculations. For P1 formation in the absence of Et2Al(OEt), the following processes were proposed, C(sp2)-O oxidative addition of R2 (R1→ →5), twice alkyne insertion (5→ →7→ →10), intramolecular C=C insertion (10→ →12), acidolysis by HCl (12→ →14), and β-H elimination (14→ →16). For P2/P3 formation, the reaction bifurcates from intermediate 7 and the following processes were proposed, C=C double bond cleavage of diketene R2 via four-membered ring-closure )/four-membered ring-opening (7→ →19→ →20), and acidolysis (20 →22). Then, the reaction experiences either the second alkyne insertion→ cyclization → β-H elimination to furnish P2 or the direct acidolysis to form P3. The first alkyne insertion accessing to


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P1 and four-membered ring-opening process accessing to P2 or P3 are found to be energetically comparable. Meanwhile, from the common bifurcation point 22, the second alkyne insertion evolving into P2 is also energetically competitive to the direct acidolysis evolving into P3. Therefore, a mixture of three products is obtained in the absence of Et2Al(OEt). The

Et2Al(OEt)-involved

system

is

found

to

have

similar

mechanisms

to

the

non-Et2Al(OEt)-involved system. But upon the introduction of Et2Al(OEt) into the reaction, the Ni-O (from Al reagent) bonding facilitates the second alkyne insertion, and the Al-O (from carboxylate) bonding is not in favor of the four-membered ring-closure step. Therefore, the chemoselectivity exclusively generating P1 is presented.

Supporting Information Figures giving the calculated free energy profiles in toluene for the other possible pathways from the Ni(cod)2-catalyzed three-component coupling reactions of one diketene and two alkynes, and Cartesian coordinates of all the species involved. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgment This work was jointly supported by the National Natural Science Foundation of China (Nos. 21473100 and 21403123), Project of Shandong Province Higher Educational Science and Technology Program (No. J14LC17), Opening Foundation of Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers (KLDTTM2015-9), and the Doctoral Start-Up ACS Paragon Plus Environment

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Scientific Research Foundation of Qufu Normal University (Grant No. BSQD2012018).

References (1) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315 -319. (2) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 14137 -14151. (3) León, T.; Correa, A.; Martin, R. J. Am. Chem. Soc. 2013, 135, 1221-1224. (4) Hoberg, H.; Peres, Y.; Kruger, C.; Tsay, Y.-H. Angew. Chem., Int. Ed. Engl. 1987, 26, 771-773. (5) Williams, C. M.; Johnson, J. B.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 14936-14937. (6) Greenhalgh, M. D.; Thomas, S. P. J. Am. Chem. Soc. 2012, 134, 11900-11903. (7) Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P. Angew. Chem., Int. Ed. 2010, 49, 4665-4668. (8) Bernhardt, S.; Metzger, A.; Knochel, P. Synthesis 2010, 3802-3810. (9) Montgomery, J. Acc. Chem. Res. 2000, 33, 467-473. (10) Ikeda, S.-I. Acc. Chem. Res. 2000, 33, 511-519. (11) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127-2198. (12) Moslin, R. M.; Moslin, K. M.; Jamison, T. F. Chem. Commun. 2007, 4441- 4449. (13) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417-1492. (14) Han, F.- S. Chem. Soc. Rev. 2013, 42, 5270-5298. (15) Mori, T.; Akioka,Y.; Kawahara, H.; Ninokata, R.; Onodera, G.; Kimura, M. Angew. Chem., Int. Ed. 2014, 53, 10434 -10438. (16) Trost, B. M.; Hashmi, A. S. K. J. Am. Chem. Soc. 1994, 116, 2183-2184.


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(17) Trost, B. M.; Yanai, M.; Hoogsteen, K. J. Am. Chem. Soc. 1993, 115, 5294-5295. (18) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1988, 110, 1636-1638. (19) Tobisu, M.; Takahira,T.; Morioka,T.; Chatani, N. J. Am. Chem. Soc. 2016, 138, 6711-6714. (20) Quasdorf, K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Snieckus, V.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352-6363. (21) Ramgren, S. D.; Silberstein, A. L.; Yang, Y.; Garg, N. K. Angew. Chem., Int. Ed. 2011, 50, 2171-2173. (22) Mesganaw, T.; Silberstein, A. L.; Ramgren, S. D.; Nathel, N. F. F.; Hong, X.; Liu, P.; Garg, N. K. Chem. Sci. 2011, 2, 1766-1771. (23) Shimasaki, T.; Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2010, 49, 2929-2932. (24) Yu, D.-G.; Li, B.-J.; Zheng, S.-F.; Guan, B.-T.; Wang, B.-Q.; Shi, Z.-J. Angew. Chem., Int. Ed. 2010, 49, 4566-4570. (25) Wititsuwannakul, T.; Tantirungrotechai, Y.; Surawatanawong, P. ACS Catal. 2016, 6, 1477-1486. (26) Xu, L.; Chung, L. W.; Wu,Y.-D. ACS Catal. 2016, 6, 483-493. (27) Hong, X.; Holte, D.; Götz, D. C. G.; Baran, P. S.; Houk. K. N. J. Org. Chem., 2014, 79, 12177-12184. (28) Hong, X.; Liang, Y.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 2017-2025. (29) Hong, X.; Liu, P.; Houk, K. N. J. Am. Chem. Soc. 2013, 135, 1456-1462. (30) Lee, C.; Yangand, W.; Parr, R. G. Phys. Rev. B, 1988, 37, 785-789.


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(31) Michlich, B.; Savin, A.; Stolland, H.; Preuss, H. Chem. Phys. Lett., 1989, 157, 200-206. (32) Becke, A. D. J. Chem. Phys.,1993, 98, 5648-5652. (33) Stephens, P. J.; Devlinand, F. J.; Fnsch, M. J. J. Phys. Chem., 1994, 98, 11623-11627. (34) Yuan, R.; Lin, Z. Organometallics 2014, 33, 7147-7156. (35) Xie, H.; Sun, Q.; Ren, G.; Cao, Z. J. Org. Chem. 2014, 79, 11911-11921. (36) Wu, W. R.; Liu,Y. X.; Bi, S. W. Org. Biomol. Chem., 2015, 13, 8251-8260. (37) Liu, Y. X.; Yang, X.; Liu, L. J.; Wang, H. L.; Bi, S. W. Dalton Trans., 2015, 44, 5354-5363. (38) Liu, C. C.; Liu, Y. X.; Tang, Y. N.; Liang, H. S.; Bi, S. W. Org. Biomol. Chem., 2016, 14, 2522-2536. (39) Andzelm, J.; Huzinaga, S.

Gaussian

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for

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(49) Tuttle, T.; Wang, D. Q.; Thiel, W. Organometallics 2006, 25, 4504-4513. (50) Benson, S. W. The Foundations of Chemical Kinetics; Krieger Publishing Co.: Malabar, FL, 1982. (51) Martin, R. L.; Hay, P. J.; Pratt, L. R. J. Phys. Chem. A. 1998, 102, 3565-3573. (52) Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Starov-erov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc.: Wallingford, CT, 2009. (53) We also calculated the alternative Ni(cod)2 direct coordination with the C=C bond of the substrate R2. The generated Ni-alkene adduct 1’ is 0.4 kcal/mol higher in free energy than Ni-alkyne adduct 1. Please see Figure S1 in the Supporting Information for more details. (54) Other possible pathways for the C2-O1 oxidative addition from the intermediate 3 are theoretically proposed and collected in Figure S2. It is found that C2-O1 oxidative addition


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from 4 is energetically most favorable. (55) The possible acidolysis process starting from 7 is also investigated. The calculated results indicated that the acidolysis transition state is 7.3 kcal/mol less stable than the second alkyne insertion transition state TS9-10. Please see Figure S3 in the Supporting Information. (56) The alternative pathways for the second alkyne insertion are given in Figures S4-S5. (57) Figure S7 presents the possible pathways for forming the product P1 from the C=C insertion intermediate 13-Et with the alkyne as ligand. (58) Nakajima, K.; Nojima, S.; Sakata, K. ; Nishibayashi, Y. ChemCatChem 2016, 8, 1028-1032. (59) Xua, S.; Cai, T.; Yun, Z. Synlett. 2016, 27, 221-224. (60) Singh, A. K.; Chawla, R.; Yadav, L. D. S. Tetrahedron Letters 2015, 56, 653-656. (61) Wang, T.; Jiao, N. J. Am. Chem. Soc. 2013, 135, 11692-11695. (62) For the transformation 7→23, the potential energy profiles using the alkyne as ligand along possible pathways are higher than that using one cod as ligand in Figure 4. The relative results are shown in Figures S8-S9. (63) The possible pathway starting from the intermediate 22 is given in Figure S11, which is energetically unfavorable over that starting from 23. (64) The direct [2+2+1] oxidative cyclization of diketene (R1) and alkyne (R2) with the Ni(0) catalyst with the involvement of Et2Al(OEt) is significantly inferior to the C2-O1 oxidative addition, since the former transition state is 19.9 kcal/mol higher in free energy than the latter transition state. See Figure S12 in the Supporting Information for more details. (65) It is noted that even compared 31 with 3 instead of 4, the barrier of 3→TS4-5 (16.3 kcal/mol)


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still significantly higher than the one from 31 to TS31-32 (6.2 kcal/mol). (66) The alternative pathway starting from the β-H elimination of 38 in the presence of Et2Al(OEt) has performed in Figure S13. It is found the potential energy profile is significantly higher than that starting from acidolysis of 38. (67) Since the four-membered ring-closure step from 34, as the common initial step accessing to P2 or P3, has been in remarkable inferiority as compared to the alkyne insertion (Figure 10) and later transformation into P1 (Figures 8 and 9) in the potential energy profile. Therefore, for the convenience of discussion, the four-membered ring-closure step, instead of subsequent rate-controlled four-membered ring-opening process, is analyzed in details.


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Table of Contents Graphic


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Mechanism and Origin of Et2Al(OEt)-Induced Chemoselectivity of

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