A Computational Study on the Mechanism and Origin of the

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A Computational Study on the Mechanism and Origin of the Reigioselectivity and Stereospecificity in Pd/SIPr-Catalyzed RingOpening Cross-Coupling of 2-Arylaziridines with Arylboronic Acids Akhilesh K. Sharma, W. M. Chamil Sameera, Youhei Takeda, and Satoshi Minakata ACS Catal., Just Accepted Manuscript • Publication Date (Web): 26 Mar 2019 Downloaded from http://pubs.acs.org on March 26, 2019

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ACS Catalysis

A Computational Study on the Mechanism and Origin of the Reigioselectivity and Stereospecificity in Pd/SIPr-Catalyzed Ring-Opening Cross-Coupling of 2-Arylaziridines with Arylboronic Acids Akhilesh K. Sharma,† W. M. C. Sameera,*,‡ Youhei Takeda, ∆ Satoshi Minakata,∆ †Fukui

Institute for Fundamental Chemistry, Kyoto University, Takano-Nishishiraki-cho, 34-4, Sakyo-ku, Kyoto 606-8103, Japan. ‡ Institute

of Low Temperature Science, Hokkaido University, Sapporo, Hokkaido, 060-0819, Japan.

∆Department

of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan. KEYWORDS Computational catalysis, aziridine ring-opening, DFT, ONIOM(QM:MM3) , Suzuki-Miyaura coupling ABSTRACT: The mechanism, regioselectivity, and stereospecificity of Pd/NHC-catalyzed ring-opening cross-coupling of 2-arylaziridines with arylboronic acids (Takeda et al. J. Am. Chem. Soc. 2014, 136, 8544-8547) is rationalized from density functional theory calculations. Pd(0)SIPr complex, the active species, can be formed through the reduction of (η3cinnamyl)(Cl)Pd(II)SIPr complex, where arylboronic acid in solution plays a key role. Then, Pd(0)SIPr complex acts as the active species of the catalytic cycle that consists of the regioselective and stereospecific oxidative addition, proton transfer, rate-determining transmetalation, and reductive elimination. Transition states for the oxidative addition were systematically determined from a multi-component artificial force induced reaction (MC-AFIR) search, and explained the regioselectivity and stereospecificity of the reaction. An energy decomposition analysis (EDA) on the key transition states suggested that the interactions between Pd(0)SIPr and 2-arylaziridines are important to the selectivity. Computed mechanism of the full catalytic cycle is consistent with the experimental data. Our detailed mechanistic survey provides important mechanistic insights for enantiospecific and regioselective ring-opening reactions of 2-arylaziridines.

INTRODUCTION Aziridines undergo ring-opening reactions with a range of organic molecules, releasing their ring strain energy. A variety of ring-opening functionalization methods of aziridines, including nucleophilic substitution, the Friedel-Crafts-type reaction, and cycloaddition with unsaturated components for instance, have been developed to afford pharmaceutically relevant amine compounds.1 More recently, transition metalcatalyzed ring-opening cross-coupling of aziridines has been emerged as an efficient and diverse synthetic transformation of aziridines into biologically important βfunctionalized amine motifs.2–4 This non-classical crosscoupling reaction shows high regioselectivity, which may be determined at the oxidative addition of the aziridines into the transition metal complexe.5 When the crosscoupling works either in a stereospecific or stereoconvergent fashion,6 enantio-enriched βfunctionalized amines can be synthesized, which are ubiquitous motifs in the natural products and

pharmaceuticals. In this direction, Takeda and Minakata reported a Pd/NHC-catalyzed enantiospecific and regioselective ring-opening cross-coupling of 2arylaziridines with arylboronic acids to give β-aryl-βphenethylamine derivatives (Figure 1).4a Also, Sigman and Doyle developed a Ni-catalyzed stereoconvergent reductive cross-coupling of racemic 2-arylaziridines with aryl iodides to give enantioenriched β-arylated βphenethylamine derivatives.4b

FIGURE

1

ACS Paragon Plus Environment

Pd/NHC-catalyzed

regioselective

and

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stereospecific ring-opening cross-coupling arylaziridines with arylboronic acids.4a

of

2-

The classic transition metal-catalyzed SuzukiMiyaura cross-coupling reactions work under the basic conditions. The mechanism of the catalytic cycle consists of oxidative addition, transmetalation, and reductive elimination.7 The Suzuki-Miyaura cross-coupling catalyzed by Pd/phosphine systems have been extensively studied by experimental methods.8,9,10 The mechanism of the catalytic cycle was investigated by computational methods.11 Recently, Pd/NHC (N-heterocyclic carbenes) systems have been used for the Suzuki-Miyaura coupling reactions.12,13,14 The mechanism for arylation of aryl halides and amides with phenyl boronic acid, catalyzed by Pd/NHC(allyl)Cl, was studied using computational methods.13 Further, the computed mechanism follows the classic cross-coupling mechanism mentioned above, where oxidative addition is the rate-determining step. Recently, we have developed a Pd/bis(tertbutyl)methylphosphine-catalyzed regioselective and stereospecific borylative ring-opening reaction of 2arylaziridines. Most importantly, this reaction works smoothly under the neutral conditions.3 Therefore, the mechanism for the borylation is slightly different from the commonly accepted mechanism. According to our detailed mechanistic survey, the oxidative addition occurs in a regioselective fashion, where the aziridine ringopening occurs at the terminal position. Then, water acts as the H+ and HO– source in the solution to produce a Pdhydoxo intermediate, which is the active species for the transmetalation process. Finally, the reductive elimination provides the product. Aziridines are relatively new substrate for the Suzuki-Miyaura coupling reactions.2c,2f,4a Hence, quantitative details of the mechanism of the full catalytic cycle is very important for further development of the reactions. Herein, we present a detailed mechanistic study on the Pd/NHC-catalyzed enantiospecific and regioselective ring-opening Suzuki-Miyaura arylation of 2-arylaziridines (Figure 1).4a In this reaction, aziridine ring-opening occurs at the benzylic position. Therefore, regioselectivity of the Pd/NHC catalyst is different from the Pd/phosphine-catalyst.2c,2f,3 However, origin of the regioselectivity and stereospecificity of this reaction and the mechanism of the catalytic cycle are not established. Therefore, we have used density functional theory (DFT) to rationalize the mechanism. DFT has been used for detailed mechanistic studies of transition metal catalysis.15 The ring-opening of 2-arylaziridine molecule (i.e. oxidative addition) is complex due to substrate orientations and its approach directions to the catalyst. Therefore, we have used the multicomponent artificial force induced reaction (MC-AFIR) method to determine possible reaction paths.16 As the MC-AFIR determines expected and unexpected reaction paths systematically, the lowest energy TSs leading to the major and minor reaction paths and the overall enantiomer excess can be determined more accurately. We have successfully

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applied MC-AFIR approach to determine reaction paths of various transition metal catalyzed reactions.17 COMPUTATIONAL METHODS Gaussian1618 program was used for structure optimizations without any constrain. The B3LYP-D3BJ functional, including Grimme’s dispersion correction with Becke-Johnson damping, was used.19 The PCM implicit solvation model was employed,20 where toluene was used as the solvent (=2.3741). The SDD basis sets and associated effective core potentials were applied for Pd,21 6-31+G(d) basis sets were used for S, Cl, N, O and B atoms, and 6-31G(d) basis sets were employed for C, H and Na atoms (BS1).22 Vibrational frequency calculations, at 298.15 K and 1 atm, were performed to confirm the nature of the stationary points [i.e. no imaginary frequency for a local minima (LM) and one imaginary frequency for a transition state (TS)], and to calculate zero-point energies. Psudo-IRC calculations, 20 steps for both forward and backward directions, were performed to confirm the connectivity between TSs and LMs. Final potential energy of the optimized LMs and TSs were calculated as the single-point energies using the B3LYPD3BJ method and the PCM solvation model. For this purpose, the SDD basis stets was used for Pd, and the ccpVTZ23 basis sets were employed for the remaining atoms (BS2).

FIGURE 2 (a) Partition of the molecular system into highand low-layers for ONIOM(B3LYP:MM3) calculations. Red circles indicate the low-layer. (b) Adding artificial force between Pd (Frag 1) and the aziridine ring (Frag 2) for the MC-AFIR search. A MC-AFIR search was performed for the oxidative addition step that systematically determined TSs for the selectivity determining aziridine-ring opening step. For the TSs of the remaining steps of the mechanism, we manually guessed possible geometrical isomers. In order to perform an efficient MC-AFIR search,24 the ONIOM(B3LYP:MM3) method as implemented in the SICTWO26a program was used (See Table S1 for atom type definitions), where the SDD basis sets was used for Pd and 3-21G27 basis sets were applied for the remaining atoms (BS3). ONIOM(B3LYP:MM3) performs well compared to the commonly used


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ACS Catalysis

ONIOM(B3LYP:UFF) method, as the dispersion interactions are better described by the MM3.26b

Therefore, we have used the MM3 force field for the ONIOM low-level.

FIGURE 3 Free energy profile for the formation of Pd(0)SIPr catalyst. Relative free energies are in kcal/mol (ΔE values are in parentheses). See Figure 4 for molecular structures of the optimized transition states. Partitioning of the molecular system into highand low-layers is shown in Figure 2a. The artificial force parameter () of 300 kJ/mol was applied between Pd (Frag 1) and the aziridine ring (Frag 2) as shown in Figure 2b. All reaction paths from the MC-AFIR search were inspected to pickup the approximate TSs. Then, all approximate TSs were fully optimized using the B3LYPD3BJ/BS1 level of theory, and duplicate TSs were eliminated. The reaction path ratios were calculated using the Boltzmann distribution of transition states at 298.15 K and 1 atm. The energy decomposition analysis (EDA) was performed to explain the origin of the selectivity.28 Unless otherwise stated, relative free energies (ΔΔG) were used for the results and discussions. Cylview program was used to generate ball and stick geometries of the optimized structures.29 RESULTS AND DISCUSSIONS Formation of Pd(0)SIPr species. Our first step is to discuss the mechanism for Pd(0)SIPr active species formation starting from the precatalyst, (η3cinnamyl)(Cl)Pd(0)SIPr (1). The stoichiometric reaction of 1 with phenylboronic acid, in the presence of Na2CO3 and water, gives rise to SIPr-Pd(0) species, 1,3diphenylpropene (53%) and cinnamyl alcohol (8%).4a Computed free energy profile is shown in Figure 3, and molecular structures of the optimized TSs are shown in Figure 4. We have used sum of calculated free energy of (1), [PhB(OH)3]–, and 2-arylaziridines (Sub), and three

H2O molecules as the reference energy point. Under the basic conditions, PhB(OH)2 in solution reacts with the OH–, giving rise to [PhB(OH)3]–. Despite several attempts, we were unable to locate a transition states for the reaction, PhB(OH)2 + OH–  [PhB(OH)3]–. A barrierless reaction was suggested by a relaxed potential energy surface scan (See the Figure S1). Therefore, [PhB(OH)3]– species can be formed in solution under the experimental conditions.10,11 When (η3-cinnamyl)(Cl)Pd(0)SIPr and – [PhB(OH)3] meet, a prereactant complex (I1) can be formed, and is only 5.9 kcal/mol above the entry point of the free energy profile. Then, the Cl– can be dissociated from the metal coordination sphere. Calculated free energy barrier for this ligand exchange process is 16.9 kcal/mol (TS1).30 The resulting intermediate, I2, is 2.9 kcal/mol above the entry point. After rearranging I2 into I3 through TS2 (15.7 kcal/mol), the -Ph group migration from B to Pd can be occurred through TS3 (17.2 kcal/mol), giving rise to I4, which is –1.2 kcal/mol below the entry point of the free energy profile. We have located several alternative TSs for TS3, which were however higher in energy (Figure S2). Starting from, I4, the reductive elimination is occurred through TS4 (14.7 kcal/mol), leading to 1,3-diphenylpropene. If B(OH)3 ligand in I4 dissociates from the metal coordination sphere, a lowenergy path may originate. Moreover, after dissociation of B(OH)3 from Pd, the allyl group can be coordinated to the metal in the η3 manner, and the resulting intermediate,


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I5, is 10.0 kcal/mol stable than I4. Then, the reductive elimination is occurred through TS4 (9.5 kcal/mol). Once the B(OH)3 is dissociated from the metal coordination sphere, B(OH)3 + OH–  [B(OH)4]- [ΔG (ΔH) = –40.2 (– 49.2) kcal/mol] reaction may be occurred, as this is thermodynamically favorable. However, concentration of [B(OH)4]- is very low compared to the concentration of [PhB(OH)3]-, and therefore we suspect that the former species would not affect the transmetalation. In summary, free energy barrier for Pd(0)SIPr (I6) formation is 20.7 kcal/mol (I5  Ia), and this barrier can be achieved under the reaction conditions. We have calculated several alternative reaction paths that originate from 1 (Scheme 1, Figure S3-S7). However, these reaction paths cannot compete with the main reaction path shown in Figure 3.

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formed during the reduction of (η3cinnamyl)(Cl)Pd(II)SIPr into Pd(0)SIPr). However, we have found that cinnamyl-carbonate formation is not possible in our system (Scheme 1c) due to the fact that the overall free energy barrier is 28.0 kcal/mol (Figure S5). When we use an explicit base (i.e. Na2CO3) in the reaction mechanism, calculated free energy barrier for the reaction is 25.0 kcal/mol (Scheme 1d, Figure S6). Therefore, explicit Na2CO3 may not play a role on the rate of the active species formation. At the same time, it is important to note that concentration of Na2CO3 in the organic layer of the reaction mixture may be very low. Then, we have studied the reaction in absence of the base (Scheme 1e), where the computed barrier becomes 42.1 kcal/mol (Figure S6). Therefore, reaction would not work in the absence of the base, which is consistent with our experimental results. 4a SIPr Ph

SIPr SIPr

(a)

Pd

26.4

Pd

Cl

SIPr

Ph

Pd

Ph

‡

Pd

Ph

Ph

Ph ‡

SIPr Ph

Pd SIPr

(b)

SIPr

Cl

Pd

32.3

Pd

Cl

SIPr

O

‡

Pd

Na O

Cl

Cl

Ph

Ph

(c)

Ph

O

SIPr

Na

Pd

Cl 28.0

SIPr

Ph

Cl

Pd Ph

Na O

O Ph

Na

O

SIPr OH

FIGURE 4 Molecular structures of the optimized TS1, TS2, TS3, TS4, and TS4. Bond lengths are in Å. We have found that 3,3-diphenylpropene side product formation is not possible (Scheme 1a), as the overall free energy barrier is 26.4 kcal/mol (Figure S3). This is consistent with our experimental results, where 3,3-diphenylpropene was not observed in the stoichiometric reaction of the Pd(II) complex 1 with arylboronic acid.4a Free energy barrier for the side product, cinnamyl-chloride formation through the direct reductive elimination from 1 (Scheme 1b), as proposed in a recent computational study,13a is not possible in our case, because the computed free energy barrier is 32.3 kcal/mol (Figure S4). According to a recent computational study,13c cinnamyl-carbonate can be

(d)

SIPr Cl

Pd

‡

Pd

HO B Ph Na O O O Na 18.8 Cl

Ph

‡

SIPr Pd SIPr Pd

Ph

Ph

SIPr 25.0

Pd

Ph

Ph

Ph

Ph

Ph

‡

SIPr Cl Pd SIPr

(e) Cl

Pd Ph

Ph HO B OH 42.1

Ph

SIPr SIPr Ph

Pd

Pd Ph

Ph

Ph

SCHEME 1 Alternative reaction paths we investigated for the active species formation. Free energy profiles for the reaction paths can be found in Figure S3-S7. TABLE 1. Possible (L)Pd(0)SIPr complexes in solution and their relative energies (in kcal/mol).


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(L)Pd(0)SIPr complexes L ΔG (ΔΔG) ΔE (ΔΔE) 1,3-diphenylpropene (Ia) –31.3 (–19.3) –37.4 (–25.9) [PhB(OH)3]– (Ib) –24.6 (–13.2) –28.8 (–17.3) 2-phenylaziridine (I7) –24.3 (–12.9) –27.9 (–16.4) PhB(OH)2 –18.1 (–6.7) –21.3 (–9.8) H2 O –17.1 (–5.7) –15.3 (–3.8) Empty (I6) –11.4 (0.0) 11.5 (0.0) In order to start the oxidative addition step of the catalytic cycle, 2-phenylaziridine (Sub) must be coordinated to Pd(0)SIPr complex (I6). The resulting complex, (Sub)Pd(0)SIPr (I7), is 12.9 kcal/mol stable than I6. At the same time, other ligands in the organic layer of the solution, in particular 1,3-diphenylpropene, [PhB(OH)3]–, PhB(OH)2, B(OH)3, and H2O may compete with 2-phenylaziridine for coordination at Pd. Therefore, we have checked the relative free energies of the possible complexes in solution (Table 1). According to the calculated relative free energies, coordination of the ligands in Table 1 on I6 is thermodynamically favorable. Among the calculated complexes, 1,3-diphenylpropene (Ia) and [PhB(OH)3]– (Ib) are 7.0 and 0.3 kcal/mol stable than I7, respectively. Therefore, complexes Ia, Ib, and I7 may be formed in solution. Formation of I7 is important to proceed the catalytic cycle. If Ia and Ib are formed, ligand exchange processes are required to form I7, and this would be possible under the reaction conditions. In the following sections, we discuss the key steps of the mechanism. Oxidative addition. Computed free energy profile for the initial steps of the mechanism is shown in Figure 5. The first step is the aziridine ring-opening (i.e. oxidative addition). We have systematically searched TSs for the

ring-opening using a MC-AFIR search. Resulting approximate TSs were fully optimized and categorized into five groups as shown Figure 6. Group A represents the TSs cleaving the benzylic C(2)–N(1) bond, which leads to the desired cross-coupling product. Group B illustrates the TSs cleaving the terminal C(3)–N(1) bond, which leads to the regioisomeric form of the major product. TSs in Group C and Group D give the enantiomer of the major product and its regioisomeric form, respectively. In Group E, the ring-opening occurs through the cleavage of the C(2)–C(3) bond. Relative free energies of the TSs, their groups, and existence probabilities are summarized in Table 2. Among the calculated TSs, TS5a (Group A) is the lowest energy TS that contributes to 80.5% of the major product, where aziridine ring-opening occurs at the benzylic position (Figure 7). At the same time, TS5b (11.4 %), TS5c (2.4%), and TS5e (1.7 %) also provide minor contributions to the major product. TS5d is the lowest energy TS in the group E, where the ring-opening occurs through the C(2)–C(3) bond cleavage. However, the C–C bond cleavage does not play a significant role, because the calculated existent probability of TS5d is only 2.4 %. TS5i of Group D and TS5o of Group B are the lowest energy TSs for the ring-opening at the terminal position with the existence probabilities of 0.1% and 0.0%, respectively. It is important to note that our MC-AFIR search did not locate TSs for group C, where both N–Ts and –Ph units of the aziridine and bulky SIPr-ligand would prevent the substrate approach to Pd in the required orientation. For our curiosity, we have manually created a TS for group C, and the optimized TS structure was 7.0 kcal higher in energy than TS5a. Therefore, we concluded that the group C is not important for the reaction.


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FIGURE 5 Free energy profile for 2-phenylaziridine binding, oxidative addition, and protonation steps of the catalytic cycle. Relative free energies are in kcal/mol (ΔE values are in parentheses). –13.8 (–4.7) Based on the computed TSs, calculated TS5g A 3.2 (5.5) 0.4 (0.0) –13.4 (–5.9) regioselectivity for the ring-opening at the benzylic TS5h E 3.6 (4.2) 0.2 (0.1) –12.9 (–7.7) position is 97.2% (and 96.3% when we use potential TS5i D 4.0 (2.4) 0.1 (1.4) –12.8 (–7.7) energies). This is in agreement with the experimental TS5j D 4.1 (2.4) 0.1 (1.6) –12.6 (–5.6) results. We have observed qualitatively similar results TS5k E 4.3 (4.5) 0.1 (0.0) –12.0 (–6.6) with the M06L31 method (Table S3). TS5l D 5.0 (3.5) 0.0 (0.2) –8.8 (–3.0) TS5m D 8.2 (7.1) 0.0 (0.0) Ts Ts –8.2 (–2.6) Ts TS5n D 8.7 (7.5) 0.0 (0.0) Ph H N1 N –6.7 (0.7) N TS5o B 10.3 (10.8) 0.0 (0.0) Ph 2 Ph Ph Ph 3 –6.3 (0.6) Ts N N Ts TS5p B 10.6 (10.7) 0.0 (0.0) H H H H –4.9 (1.3) TS5q B 12.0 (11.4) 0.0 (0.0) Pd Pd Pd Pd Pd 3.0 (7.1) TS5r B 19.9 (17.2) 0.0 (0.0) SIPr SIPr SIPr SIPr SIPr 5.2 (7.7) TS5s B 22.2 (17.8) 0.0 (0.0) 6.0 (13.9) TS5t B 22.9 (24.0) 0.0 (0.0) (C) (B) (D) (E) (A) FIGURE 6 Transition state groups for the aziridine ringopening.

Then, we have checked whether H2O molecules in solution play a role on the aziridine ring-opening. For TABLE 2. Relative free energies (kcal/mol) and existence this purpose, explicit nH2O molecules (n=1-3) were probabilities (%) of TSs for the aziridine ring-opening. incorporated with the lowest energy TSs of each group Values in parentheses are relative potential energies (Table S2). Among the calculated TSs, TS5a.H2O (–17.8 (including zero-point energies). kcal/mol), TS5a.2H2O (–16.8 kcal/mol), and TS5a.3H2O (– 15.5 kcal/mol) are energetically closer to TS5a (–16.9 TS kcal/mol). Therefore, H2O molecules in solution stabilize TS group ∆G (∆E) ∆∆G (∆∆E) % –16.9 (–10.1) TS5=TS5a A 0.0 (0.0) 80.5 (87.6) the TS5a. However, H2O molecules in solution do not play –15.8 (–8.0) TS5b A 1.2 (2.1) 11.4 (2.5) a major role on the stability of the TSs in the other groups –14.9 (–8.3) TS5c A 2.1 (1.8) 2.4 (4.1) (see Table S2). When we take all computed TSs into –14.9 (–6.9) TS5d E 2.1 (3.3) 2.4 (0.4) account, calculated regioselectivity of 99.5 % (and 99.1 % when we use potential energies) reproduced the –14.7 (–7.7) TS5e A 2.3 (2.4) 1.7 (1.6) –14.2 (–7.0) TS5f A 2.8 (3.1) 0.8 (0.5) experimental data.


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In Group A TSs that lead to the major product, the aziridine ring-opening occurs through the SN2 backside attack. Therefore, the reaction proceeds with a stereo-inversion at the benzylic carbon of 2phenylaziridine. In addition, the reaction is highly enantiospecific, as the reaction does not proceed through group C TSs.

FIGURE 7. Molecular structures of the optimized TS5a, TS5d, TS5i and TS5o.

Proton transfer. After the regioselective aziridine ringopening, a 3--benzyl Pd complex, I8 (–17.1 kcal/mol) is formed, where calculated NBO charge of the N atom of the –N-Ts unit is –0.94. (Figure S8), and therefore water molecules in solution interact with the nitrogen atom through hydrogen bonding. We have included explicit nH2O molecules (n=1-3) to I8 (See figure S9 for calculated I8.nH2O complexes). Starting from I8.nH2O complexes (i.e. n=2,3), we have searched TSs for the proton transfer process. Based on the computed LMs and TSs, lowest energy paths involved I8 (–17.1 kcal/mol) I8.2H2O (– 25.3 kcal/mol)  I8’.2H2O (–27.7 kcal/mol)  TS6.2H2O (–27.7 kcal/mol). Despite several attempts, the TS6 with one explicit water molecule could not be located. Resulting Pd-hydroxo intermediate I9.1H2O (–34.1 kcal/mol), I9.2H2O (–33.7 kcal/mol), and I9 (–33.1 kcal/mol) are energetically similar. Therefore, we suspect that water molecules in solution may not stabilize the intermediate I9. In summary, our calculations suggested that two or three water molecules may be involved in the proton transfer process, and is almost barrierless. As the protonation step of our system is not the ratedetermining step of the mechanism, we suspect that the pitfalls of using explicit water molecules32 play a minor role in our system.

FIGURE 8 Free energy profile showing the transmetalation and reductive elimination steps of the catalytic cycle. Relative energies are in kcal/mol (ΔE values are in parenthesis). See Figure 9 for molecular structures of the optimized transition states.


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Transmetalation. Free energy profile for the remaining steps of the mechanism is shown in Figure 8, and molecular structures of the optimized TSs are shown in Figure 9. After Pd-hydroxo species (I9) is formed, PhB(OH)2 can be coordinated to Pd through a hydroxyl group, and the resulting complexes, I10, is only 0.8 kcal/mol stable than I9. Then, the boron atom of PhB(OH)2 can be reacted with the Pd-hydroxo unit, giving rise to a thermodynamically stable intermediate I11 (–51.3 kcal/mol). After the rearrangement of I11 into I12 (– 36.3 kcal/mol) through TS7 (-32.5 kcal/mol), the transmetalation is occurred through TS8 (-30.4 kcal/mol), and I13 (–51.8 kcal/mol) is formed. We have found several isomeric forms for TS8 (Figure S10), which were, however, relatively higher in energy. Then, B(OH)3 molecule may be removed from the metal-coordination sphere, and the resulting intermediate, I14, is 2.6 kcal/mol stable than I13. In our reaction, Na2CO3 (the base) is used as an additive. Then, formation of NaPhB(OH)3 in the reaction system is thermodynamically favorable, PhB(OH)2 + H2O + Na2CO3  NaPhB(OH)3 + NaHCO3, ΔG (ΔH) = –5.7 kcal/mol (–15.0 kcal/mol). In order to understand the roles of Na2CO3 and NaPhB(OH)3 on the transmetalation process, we have calculated the mechanism with explicit NaPhB(OH)3 and Na2CO3 (Figure 8, See Figure S13 and S14 for detailed energy profiles). Computed TS8-Na is 0.6 kcal/mol lower in energy than TS8, where as TS-Na2CO3 (not shown in Figure 8) is 3.3 kcal/mol higher than TS8. Therefore, tranmetalation would occur through both TS8 and TS-Na. It is important to note that a recent experimental study on the Suzuki-Miyaura coupling reaction9a,9b detected the intermediates relevant to energetically similar I11 and I11-Na.

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for the reductive elimination from both I13 and I14. In the former case, calculated barrier is 17.0 kcal/mol (TS9, not shown in Figure 8), while in the latter case, reaction barrier is 14.9 kcal/mol (TS9). Therefore, we suspect that the reaction goes through I14 and TS9, which is the lowest energy path. We have searched several isomeric forms for TS9 (Figure S11), but they were relatively higher in energy. After the reductive elimination, I15 (-73.8 kcal/mol) is formed, where the product (P) is still at the metal coordination sphere. Finally, the product can be removed from the metal-coordination sphere, and Pd(0)SIPr (I6) can be regenerated to start the next catalytic cycle. Based on the computed free energy profile for the mechanism of the full catalytic cycle, we argue that the regioselectivity and stereospecificity of the reaction is determined at the aziridine ring-opening step (i.e. oxidative addition), TS5. Then, water stabilizes the subsequent intermediate (I8), allowing the proton transfer to form the Pd-hydroxo intermediate. Then, PhB(OH)2 reacts with the Pd-hydroxo species, and the rate-determining transmetalation takes place. Finally, the reductive elimination gives the product. Beside the mechanism discussed above, we have explored alternative reaction mechanisms that originate from the intermediate I8 (Figure S12-S14). Among them, only the reaction path in Figure S13 may contribute to the reaction. Computed free energy profile for the catalytic cycle with the M06L is shown in Figure S15 and S16. Consistent with the B3LYPD3BJ results, M06L method also suggested that the transmetallation is the rate-determining step.

H

N

Ts ‡ L

Pd

Pd

L

A0 +

A1 +

B1

INT1

e

B0 DEF2

(AB)1

A2 +

B2

INT2

(AB)2

N

Ts

B

A

AB

DEF1

H

+

DEF = DEF1 - DEF2 INT = INT1 - INT2 e = DEF - INT

Figure 10. EDA for two transition states.

FIGURE 9 Molecular structures of the optimized TS6.2H2O, TS7, TS8, and TS9. Reductive elimination. The final step of the catalytic cycle is the reductive elimination. We have searched TSs

Energy decomposition analysis (EDA). In order to gain more insights about the selectivity of the reaction that determines at the oxidation addition step, we have performed an energy decomposition analysis (EDA) for the lowest energy TSs leading to the major (TS5a) and minor (TS5d, TS5i and TSo) reaction paths. For this purpose, we have used potential energy of the TSs without including the zero-point energy contribution. For EDA, the transition state (AB) is divided into the catalyst (A) and substrate (B) (Figure 10). Interaction between the catalyst and the substrate at the transition state is defined


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ACS Catalysis

as the interaction energy, INT. The deformation energy of the transition state, DEF, is defined as the energy of A and B at the TS relative to the energy of optimized structures of A and B (denoted as A0 and B0). Then, potential energy difference (∆∆e) between two transition states, (AB)1 and (AB)2, can be defined as the sum of the interaction energy difference (∆INT) and deformation energy difference (∆DEF) (Figure 10 and Table 3). Table 3. Energy decomposition analysis. TS TS5a TS5d TS5i TS5o TS5d TS5i TS5o

DEF (DEFA, DEFB) 20.8 (2.3, 18.5) 13.3 (0.8, 12.5) 18.7 (1.8, 18.6) 27.5 (1.0, 26.5) ∆DEF –7.5 (–1.5, –6.0) –0.4 (–0.5, 0.1) 6.7 (–1.3, 8.0)

INT –42.6 –31.5 –39.9 –38.0 ∆INT 11.1 2.7 4.6

The EDA suggested that the origin of the regioselectivity is determined by the interactions between the catalyst and the aziridine substrate. After the ring-opening, resulting intermediate is stabilized by H2O in solution, allowing the proton transfer process. Then, the transmetalation takes place, which is the ratedetermining step of the mechanism. Finally, the reductive elimination gives the cross-coupling product and regenerates the Pd(0)SIPr complex. Overall, our proposed mechanism can operate under the reaction conditions, and explain the regioselectivity and stereospecificity of the reaction. Our detailed mechanistic study provides important mechanistic insights for the Pd-catalyzed aziridine ring-opening reactions.

∆∆e 3.6 2.3 11.3

Ligand Exchange Cl –

SIPr Pd

Cl

HO B

Ph

Rearrangement

Pd

HO [PhB(OH)3] –

SIPr

SIPr Ph

OH

Ph

Reductive Elimination

Pd

Ph

Ph H Ph

H N P

Ph H

Ts SIPr

N

Ts

S

Pd SIPr

H

H N

Pd

Reductive Elimination

Aziridine Ring Opening

– N Ts

H

Ts Pd SIPr

2 H2O

Interact with Water

B(OH)3

H O O H H

Transmetalation

H H SIPr H HO

H N

Pd

HO B HO

CONCLUSIONS

O O S p-tol

SIPr

HO

Pd

B

OH

HO

– N

Pd

Ts

SIPr

The first step of the catalytic cycle is aziridine coordination to Pd(0)SIPr. Then, regioselectivity- and stereospecificity-determining oxidative addition proceeds at the benzylic position in an SN2 fashion. We have used a MC-AFIR search to determine TSs for the oxidative addition step. Based on the computed TSs, calculated regioselectivity nicely explains the experimental results.

B(OH)3 SIPr Pd

Ph

Proton Transfer

Rearrangement

We have used DFT to rationalize the mechanism of the full catalytic cycle for Pd/NHC-catalyzed ringopening cross-coupling of 2-arylaziridines with arylboronic acids. Starting from (η3cinnamyl)Pd(II)SIPr(Cl) precatalyst, Pd(0)SIPr must be generated to initiate the catalytic cycle (Figure 11). Further, this process begins with [PhB(OH)3]– coordination to the Pd center. Then, the -Ph group of [PhB(OH)3]– migrates to the Pd, and the reductive elimination gives rise to the active species, Pd(0)SIPr that initiates the catalytic cycle.

Ph

B

Transmetalation SIPr

In the case of TS5d, ∆DEF is –7.5 kcal/mol and ∆INT is 11.1 kcal/mol, and therefore ∆INT is the main contributor to the ∆∆e (3.6 kcal/mol). Similar fashion, ∆INT is the main contributor to the ∆∆e (2.3 kcal/mol) of TS5i. Therefore, ∆INT is the reason for the stability of TS5a over TS5d or TS5i. Interactions between the catalyst and aziridine substrate of TS5i may be favorable due to the fact that Pd interacts with the –Ph unit of the substrate (Figure 7), whereas the aziridine unit of the substrate interacts with Pd in TS5d or TS5i. The ∆DEF (6.7 kcal mol) of TS5o is the dominant component for the ∆∆e (11.3 kcal/mol), where deformation of the substrate (DEFB, 8.0 kcal/mol) is significant compared to that of the catalyst (DEFA, –1.3 kcal/mol), and this may stabilize TS5a over TS5o. Compared to TS5a, distance between Pd and the –Ph unit of the substrate is longer in TS5o (Figure 7), and therefore ∆INT of TS5o may be small.

HO

HO HO

Ph

Pd

H

H H N

H Ts

H2 O

N Ts

SIPr Pd O H PhB(OH)2

Figure.11 Mechanism of the full catalytic cycle for Pd/NHC-catalyzed ring-opening and cross-coupling of 2arylaziridines with arylboronic acids.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Atom type definitions for ONIOM(DFT:MM3) calculations, addition discussions about alternative reaction mechanisms, isomers of some LMs and TSs, NBO


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charges of the atoms in TS5a and TS5a.H2O, free energy profiles with the M06l functional, energies of the calculated structures, Cartesian coordinates of the optimized structures. (file type, PDF)

AUTHOR INFORMATION Corresponding Author

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* [email protected] Author Contributions AKS performed calculations. WMCS wrote the manuscript. YT and SM did experiments. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENTS WMCS thanks to the Japan society for the promotion of science (P14334) and to the MEXT KAKENHI grant 17H066445. YT thanks to a Scientific Research on Innovative Area “Precisely Designed Catalysts with Customized Scaffolding” (JSPS KAKENHI Grant Number 16H01023 to YT) from MEXT. Japan society for the promotion of science for Grants-in-Aid for Scientific Research (KAKENHI 15H00938 and 15H02158) is also acknowledged. Super computing resources at the Institute of Molecular Science in Japan and the Academic Center for Computing at Media Studies at Kyoto University in Japan are also acknowledged. We thank to Prof. Keiji Morokuma for useful discussions and for giving access to the MC-AFIR method. (3)

ABBREVIATIONS DFT, density funcational theory; MC-AFIR, multicomponent artificial force induced reaction method; EDA, energy decomposition analysis; ONIOM, our own Nlayered integrated molecular orbital and molecular mechanics.

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A Computational Study on the Mechanism and Origin of the

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