Mechanism and Origin of Enantioselectivity in Nickel-Catalyzed Alkyl

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Mechanism and Origin of Enantioselectivity in Nickel Catalyzed Alkyl-Alkyl Suzuki Coupling Reaction Sukriti Singh, and Raghavan B. Sunoj J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.9b04284 • Publication Date (Web): 11 Jul 2019 Downloaded from pubs.acs.org on July 17, 2019

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The Journal of Physical Chemistry

Mechanism and Origin of Enantioselectivity in Nickel Catalyzed Alkyl-Alkyl Suzuki Coupling Reaction Sukriti Singh and Raghavan B. Sunoj* Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India Abstract: Enantioselective Suzuki coupling reactions are a widely used method in asymmetric synthesis of chiral compounds. In an important extension of this protocol, 1bromo-1-fluoroalkanes were coupled with alkyl-9-BBN using chiral NiCl2L* as the catalyst (where L* = bis-pyrrolidine ligand) under Suzuki conditions to obtain a product with a stereogenic center bearing a fluorine. In view of the current interest in chiral fluorine containing compounds as well as lack of clarity on the mechanism of Ni-catalyzed asymmetric Suzuki coupling reactions, we decided to examine various mechanistic pathways of the title reaction. The (U)M06 density functional theory computations have been employed to identify the energetically preferred pathway first, and then to probe the origin of high enantioselectivity. In particular, we have compared the likely involvement of different redox couples such as Ni(0)/Ni(II) and Ni(I)/Ni(III) in the catalytic cycle. For Ni(0)/Ni(II) pathway, both singlet and triplet spin states have been considered whereas a doublet spin multiplicity have been examined in the case of Ni(I)/Ni(III) system. The most preferred catalytic pathway is found to proceed through a Ni(I)/Ni(III) redox cycle with key mechanistic steps such as (a) a transmetalation involving the transfer of the alkyl group of 9-BBN to the Ni-catalyst, (b) an oxidative addition of bromo(fluoro) alkane to give a penta-coordinate Ni(III) intermediate, and (c) an enantio-controlling reductive elimination (RE) that facilitates the C−C bond formation between the Ni-bound fluoro alkyl and alkyl moieties to yield the final product. The transmetalation is found to be the turn-over determining transition state (TS) according

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to the activation span model. The RE is found to be the enantio-controlling step, wherein the TS for the addition of the si prochiral face of the Ni-bound fluoro alkyl moiety to the alkyl group is 4.3 kcal/mol lower than the corresponding re face addition. Distortion-Interaction analysis suggested that the extent of distortion in the catalyst Ni(Br)L* fragment in the si face reductive elimination TS is much lower than in the re face addition, thus making a vital contribution to the energy difference between diastereomeric TS. Introduction The transition metal-catalyzed cross-coupling reactions, particularly between organo electrophiles and organometallic nucleophiles, have emerged as a powerful tool for the construction of C−C bonds.1,2 The developments in coupling reactions involving saturated C(sp3) centers have been relatively slower than that between C(sp2) coupling partners. The alkyl electrophiles are less stable as compared to aryl/alkenyl analogues and thus make the alkyl-alkyl coupling practically more challenging.3,4 These alkyl metal species are prone to undesired side reactions such as β-hydride elimination or hydrodehalogenation. Among the transition metal-catalyzed cross-coupling reactions, Suzuki coupling is one of the most widely used variant owing to its key advantages such as milder reaction conditions, functional group tolerance, air and moisture stability, and ease of purification of products.5,6 The alkyl-alkyl coupling witnessed impressive growth since its early discovery by the Suzuki group.7,8 Over the years, a gamut of cross-coupling reactions of primary alkyl electrophiles with organometallic reagents using a wide range of transition metal catalysts, such as Pd, Ni, Fe, Co have been reported.9,10 However, the cross-coupling reactions of secondary alkyl electrophiles remained a challenging task for long.11,12,13 The use of lighter nickel catalysts turned out to be a promising development in the Suzuki coupling of secondary alkyl halides.14,15 More successful alkyl-alkyl Suzuki coupling could be realized by using Ni catalysts.16


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More ambitious extensions of Suzuki coupling appeared in the form of construction of tertiary and quaternary stereogenic centers using secondary alkyl-alkyl coupling. A rapid increase in the number of examples on Ni-catalyzed enantioselective alkyl-alkyl coupling reaction is a testimony to the scope and acceptability of this protocol.3 Studies on mechanism of Ni-catalyzed reactions are inherently complicated due to the propensity of Ni for both oneand two- electron redox processes. Despite the success in Ni-catalyzed asymmetric crosscoupling reactions, transition state models for understanding the origin of enantioselectivity is not widely found.17,18,19 In view of the importance of fluorine containing compounds in pharmaceutical, agricultural and medicinal compounds,20,21 the Suzuki coupling of 1-halo-1-fluoroalkanes with alkyl-9-BBN forms an interesting method toward the synthesis of secondary fluoroalkanes.22 Methods for asymmetric fluorination have become a field of great contemporary interest. Despite various methods,23,24 enantioselective formation of C─F bond still remains a challenging task. In 2015, the Gandelman group reported a valuable protocol for the synthesis of secondary fluoroalkanes through enantioselective Suzuki coupling (Scheme 1).25 In keeping with our current research efforts towards understanding the mechanism and origin of enantioselectivity,26,27 we became interested in gathering molecular insights into the origin of enantioselectivity of this important class of cross-coupling reaction. We have employed density functional theory (M06) method to examine the mechanism of this reaction by identifying all the key intermediates, transition states and the corresponding energetics.



Scheme 1. Ni-catalyzed enantioselective Suzuki cross-coupling between bromo(fluoro) alkane (R1) with alkyl-9-BBN (R2) leading to a chiral fluoroalkane. Herein we wish to present (a) a detailed mechanistic description using the most preferred pathway of the Ni-catalyzed Suzuki cross-coupling reaction involving bromo(fluoro) alkane and alkyl-9-BBN, (b) a comparison of open-shell and closed-shell pathways involving Ni(I)/Ni(III) and Ni(0)/Ni(II) redox couples, and (c) the origin of the high enantioselectivity induced by the chiral 1,2-diamine ligand. Computational Details Gaussian09 program was employed for all electronic structure calculations reported in this study.28 All the stationary points such as reactants, intermediates, and transition states were optimized in the condensed phase using the (U)M06 functional29 with the 6-31G** basis set30 for all atoms except for nickel. The SDD basis set with an effective core potential (ECP) for 10 core electrons and explicit basis set for 18 valence electrons were used for nickel.31 For the radical systems, spin-unrestricted calculations were performed. Various mechanistic pathways were considered with Ni in the singlet, doublet, as well as in the triplet spin states as applicable. The issues due to spin contamination on the computed spin densities and energies are known to be less prominent in DFT calculations.32,33 Frequency calculations on all the stationary points were carried out to characterize the nature of each stationary points and also to evaluate the respective molecular entropic terms. The transition states were characterized by a unique imaginary frequency, characteristic of a first order saddle point on the potential energy surface, and found to pertain to the desired reaction coordinate. Intrinsic Reaction Coordinate (IRC) calculations were further performed on the transition state geometries to ascertain that the transition state connected to reactants and products on either side of the first order saddle point, as expected for a given elementary step.


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All computations were performed inclusive of solvent effects by using the continuum solvation model SMD developed by Truhlar and Cramer.34 The solvent used in the reaction is di-isopropyl ether and hence we have used the continuum dielectric of di-isopropyl ether (ε=3.38) in our computations. The discussions in the text employ Gibbs free energies (G298K) obtained by incorporating thermal and entropic terms to the electronic energies obtained in the condensed phase. The ionic salts involved in the reaction were microsolvated using explicit solvent molecules so as to capture the specific interaction between the ion and solvent molecules. The limitation of the continuum solvation model in capturing the shortrange interactions could be partly overcome by considering explicitly bound solvent molecules.35 The Gibbs free energies of such salt-solvent clusters in the solvent continuum were evaluated using the SMD continuum solvation model to arrive at an optimum number of di-isopropyl ether molecules that are likely to be present in the first solvation shell as described in Supporting Information.36 The energetic span was calculated using the energetic span model that expresses the turnover frequency (TOF) of a catalytic cycle in terms of the energetics of stationary points such as the turn over determining intermediate (TDI) and transition state (TDTS).37,38 Topological analysis of the electron density distribution was performed using Bader’s atoms in molecules (AIM) formalism by using AIM2000 software39,40,41 with the wave function generated at the SMD(ε=3.38)/UM06/SDD(Ni),6-31G** level of theory. This analysis was employed for identifying weak inter-atomic interactions within a given transition state geometry for the enantioselective C−C bond formation step of the reaction. In addition, we have carried out the distortion−interaction analysis on the enantio-controlling transition states to probe the origin of enatioselectivity in this reaction.42,43



Results and Discussion The different mechanistic pathways are considered in this study to identify the most preferred route for the conversion of the reactants to the product. These pathways primarily differ in two key aspects; the redox couple of nickel involved in the catalytic cycle and in terms of the sequence of various mechanistic steps within a given pathway. These can be broadly classified into following four classes; (1) Path-A: a doublet Ni(I)/Ni(III) redox cycle with transmetalation as the first step followed by oxidative addition and reductive elimination, (2) Path-B: a doublet Ni(I)/Ni(III) redox cycle with oxidative addition as the first step and transmetalation and reductive elimination as the ensuing steps, (3) Path-C: a singlet Ni(0)/Ni(II) redox cycle with oxidative addition as the first step followed by transmetalation and reductive elimination and similarly, (4) Path-D: a triplet Ni(0)/Ni(II) redox cycle with same sequence as in Path-C. Although all these possibilities were examined in detail, we present only the most favorable mechanistic pathway in the following sections. A succinct comparison with the higher energy alternatives is provided toward the later half of the manuscript and fuller details in the Supporting Information.44,45 The reaction involves the coupling of 1-bromo-1-fluoro-2-arylethane (R1) with alkyl9-BBN (R2) under the conditions broadly described in Scheme 1. The pre-catalyst [NiCl2(glyme)] is employed in the reaction along with a chiral ligand (R,R)-2,2′-bispyrrolidine (L*). A ligand exchange between the native glyme and the chiral bis-pyrrolidine ligand can give NiCl2L*. Under the reaction conditions, NiCl2L* can convert to a catalytically active Ni(I)ClL* complex (1).46 Interestingly, there are several experimental evidences for the formation of such Ni(I) complexes.47,48,49 The action of KOt-Bu/i-BuOH on substrate alkyl-9-BBN is predicted to lead to the facile formation of the tetravalent –ate complex 1Ꞌ with a Gibbs free energy of formation of -24.8 kcal/mol.


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Scheme 2. Catalytic cycle for Ni-catalyzed Suzuki cross-coupling between bromo(fluoro) alkane and alkyl-9-BBN proceeding through the Ni(I)/Ni(III) redox couple. The most favorable pathway in the doublet spin state shown here is identified on the basis of Gibbs free energies. The catalytic cycle is envisaged to begin with the Ni(I) active catalyst 1, as shown in Scheme 2.50 We have considered the role of additives, such as KOt-Bu and i-BuOH, in the activation of alkyl-9-BBN in the form of a tetravalent –ate complex.16 The action of tetravalent boronate complex 1Ꞌ on the Ni(I)ClL* complex 1 can result in the formation of intermediate 2 and expulsion of KCl. Two possibilities for the transmetalation, one involving KOt-Bu as the base and the other when KOi-Bu acts as the base (generated from KOt-Bu and i-BuOH) are examined. The Ni(I) complex 2 undergoes transmetalation via a four-membered transition state [2-3]‡ wherein the alkyl group gets transferred from the boron to the nickel



center and leads to a Ni(I)-alkyl complex 3 (Figure 1). The relative Gibbs free energy of [23]‡ is found to be 17.3 kcal/mol. The transition state for transmetalation with KOi-Bu as the base is 0.5 kcal/mol higher as compared to that with KOt-Bu. It therefore appears that both KOt-Bu and KOi-Bu are equally likely to play the role of the base in the transmetalation step. Next, the 9-BBN-tBuO gets displaced by the substrate 1-bromo-1-fluoro-2-arylethane to give intermediate 4. At this stage, both the substrates are positioned around the transition metal site. An oxidative addition to the C−Br bond of the substrate (bromofluoro alkyl) can convert Ni(I) to Ni(III) either through a concerted two-electron oxidative addition or a step-wise singleelectron oxidative addition. In the concerted oxidative addition step, the cleavage of the C−Br bond is accompanied by the formation of Ni−Br bond in a single step via a three-membered transition state [4-6]c‡ to form the penta-coordinate Ni(III) intermediate 6. The relative Gibbs free energy of [4-6]c‡ is found to be 25.4 kcal/mol. The geometries of the transition states for several of these possibilities are provided in Figure 1. In the step-wise oxidative addition, a direct transfer of bromide from the substrate to the catalyst via [4-5]s‡ gives a weakly bound system consisting of a planar Ni(II) complex and an alkyl radical intermediate 5. The Gibbs free energy of this transition state is 9.3 kcal/mol lower than the concerted pathway through [4-6]c‡. In the subsequent step, a very low barrier addition of the alkyl radical to the Ni(II) center via transition state [5-6]‡ forms the penta-coordinate Ni(III) intermediate 6. The relative free energy of the transition state as well as the corresponding elementary step barrier for the concerted oxidative addition is found to be higher than that for the step-wise oxidative addition. The final step prior to the product formation is the reductive elimination in the penta-coordinate intermediate 6. The reductive elimination via a three-membered transition state [6-7]‡ furnishes the product and a Ni(I)BrL* intermediate 7. Intermediate 7 can undergo


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a ligand exchange with the tetravalent –ate complex to regenerate intermediate 2 to re-enter the catalytic cycle as shown in Scheme 2.

[2-3]‡ (17.3)

[4-5]s‡ (9.3)

[5-6]S‡ (-7.3)

[5-6]R‡ (-7.1)

[4-5]c‡ (18.6)

Figure 1. Optimized geometries and corresponding relative Gibbs free energies (in parentheses, kcal/mol) of the important transition states. Distances are shown in Å. Only selected hydrogen atoms are shown for improved clarity.

It is of significance to note that several intermediates and transition states along the reaction pathway are open-shell species. Hence, the spin density in intermediates such as 3, 4, 5, and 6 as well as the interconnecting transition states are examined to understand the spin distribution. The spin density iso-surfaces, provided in Figure 2, reveal that spin density is primarily located on the nickel center in the transmetalation transition state [2-3]‡ as well as in nickel-alkyl intermediates such as 3 and 4. Interestingly, the spin density gets distributed between both the nickel center and the homobenzylic carbon atom during the one-electron



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stepwise oxidative addition transition state [4-5]‡, suggesting the incipient formation of a carbon-centered radical. Accumulation of the spin density at the homobenzylic position becomes more prominent when the homolytic cleavage of the C−Br bond is complete, as can be noted in intermediate 5. A similar spin density distribution is also found in the radical addition transition state [5-6]‡. In Ni(III)-bromodialkyl intermediate 6, spin density again gets localized on the nickel center. A similar localization of spin density on nickel is also found in the case of the reductive elimination transition state [6-7]‡.

[2-3]‡

3

4

[4-5]s‡

5

[5-6]‡


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6 [6-7]‡ Figure 2. Spin density iso-surface plots for various intermediates and transition states, shown in Scheme 2, generated with an iso-surface value of 0.02. Mulliken spin density distribution of Ni and/or C atom is given (wherever applicable). Next, we analyzed the full Gibbs free energy profile, as provided in Figure 3, pertaining to the most favorable pathway that proceed through a Ni(I)/Ni(III) redox cycle.51 The efficiency of the catalytic cycle is evaluated by using the energetic span model (described in computational methods section). It can be noticed that intermediate 2 is the TDI and the transmetalation transition state [2-3]‡ is the TDTS. The δE for the catalytic cycle is therefore 15.5 kcal/mol, which is generally consistent with the experimental observations and the conditions employed.38



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Figure 3. Gibbs free energy profile (kcal/mol) for the lower energy pathway involving Ni(I)/Ni(III) redox couple. Thus far, the details of catalytic pathways involving the Ni(I)/Ni(III) redox cycle in the doublet spin state has been presented. A comparison of the computed energetics of the Ni(I)/Ni(III) cycle with the alternative higher energy pathways, particularly those proceeding through the Ni(0)/Ni(II) redox cycle (in singlet or triplet spin states), as well as the likely involvement of a quartet spin multiplicity within the Ni(I)/Ni(III) cycle, are of relevance at this juncture. While full details of the Gibbs free energy profile of such higher energy pathways can be gleaned from Figures S1-S3 in the Supporting Information,44,45 we wish to focus on how the energetic span varies between different pathways. A direct comparison of the energetic span δE, for all four pathways, as presented in the last row in Table 1, clearly suggests that Ni(I)/Ni(III) redox cycle (path-A) is the most preferred pathway. The δE for paths B, C, and D are more than double than that for path-A. Table 1. Comparison of Relative Gibbs free Energies (in kcal/mol) of Important Transition States and Intermediates and the Corresponding Energetic Span for Mechanistic Paths A to D. Paths A and B Correspond to Ni(I)/Ni(III) Redox Cycle in the Doublet Spin State. Paths C and D are Ni(0)/Ni(II) Redox Cycle Respectively in the Singlet and the Triplet Spin States Path-A

Path-B

Path-C

-i-

(int)R

TS

(int)F

(int)R

TS

TM

1.8

17.3

2.8

23.2

37.1

2.8

OA-1

4.8

9.3

-8.1

2.8

22.0

OA-2

-8.1

-7.3

-26.1

9.8

RE

-26.1

-15.1

-60.5

-22.8

δE

15.5

(int)F (int)R

Path-D

TS

(int)F

(int)R

TS

(int)F

-15.8

-14.1

-23.8

-43.3

-34.7

-51.7

9.8

9.8

19.2

-31.1

5.8

9.2

-37.5

11.6

1.5

-ii-

-ii-

-ii-

-37.5

-34.6

-61.2

-31.2

-58.1

-53.1

-12.0

-26.7

-51.7

3.5

-52.3

35.6

45.6

64.6

TM = transmetalation; OA-1, OA-2 = oxidative addition; RE = reductive elimination; δE = energetic span. In each path, the TDI and TDTS are highlighted respectively in yellow and


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green and the corresponding energetic span is given in the last row for easier comprehension. A typical row should be read as follows. Path-A first row corresponds to the Gibbs free energies of the transmetalation transition state and the lower energy intermediates in the backward and forward directions of the transition state. -i- (int)B and (int)F refer to the preceding and succeeding intermediates with respect to the transition state along the IRC paths. -ii-

Path-C being a concerted mechanism, oxidative addition is a single step.

Origin of Enantioselectivity One of the most important aspects of this catalytic coupling reaction is high enantioselectivity noted in the formation of the product. As can be noticed from Scheme 1 that an enantioselectivity of 99% could be accomplished by using (R,R)-2,2′-bispyrrolidine as the chiral ligand L*. A reliable transition state model to rationalize the origin of stereoselectivity in these class of coupling reactions are highly desirable. Thus, we herein propose a stereochemical model for unraveling the origin of enantioselectivity in this Ni-catalyzed Suzuki coupling reaction. As noted in the earlier section, a square-planar Ni(II) complex and a fluoro alkyl radical (5) is formed through the step-wise oxidative addition. Thus, the origin of enantioselectivity could arise from the facial selectivity when prochiral fluoro alkyl radical adds to the Ni(II) center. The optimized geometries and the corresponding relative Gibbs free energies of the radical addition transition states through both its prochiral faces are given in Figure 1. Interestingly, the difference in the relative Gibbs free energies of the two transition states for radical addition through its si and re prochiral face is found to be only 0.2 kcal/mol. Such a negligible difference in the energies of the diastereomeric transition states suggests that the chiral ligand environment of the Ni-catalyst is unable to distinguish between the si or re prochiral faces of the incoming fluoro alkyl radical. Comparison of the geometries of the radical addition transition states provided in Figure 4 reveal certain interesting details. It can be learned from the space-filling representations (c) and (f) that the position of the fluoro



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alkyl radical with respect to the chiral catalyst is roughly similar for both si-face and re-face additions. In other words, both the prochiral faces of the radical fits equally well with the chiral cavity offered by the bis-pyrrolidine ligand around the nickel center. These features indicate that the observed high enantioselectivity is unlikely to originate in the radical addition step. (a) si-face

(b)

(c)

(d) re-face

(e)

(f)

Figure 4. Different representation of the catalyst geometry as noted in the respective lowest energy transition state for the addition of the fluoro alkyl radical to the Ni(II) center through its prochiral faces. Space-filling models for [5-6]S‡ and [5-6]R‡ are, respectively, shown as (c) and (f). Distances are shown in Å. We have therefore focused on the C−C bond formation between the Ni-bound fluoro alkyl and alkyl moieties to examine whether the enantioselectivity could be rationalized by using these reductive elimination step transition states. Both the transition states, involving the addition of the si face of the fluoro alkyl group leading to the (S) enantiomer and the re face to form the (R) enantiomer are located. The relative Gibbs free energy of the transition state [6-7]R‡ for the formation of the (R)-enantiomer is found to be 4.3 kcal/mol higher than that


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for the transition state [6-7]S‡ for the (S)-enantiomer. A number of weak noncovalent interactions are identified in the reductive elimination transition states using the atoms in molecule topological analysis as shown in Figure 5. Alphabetical notations are employed for categorizing these interactions. Although the transition state [6-7]R‡ for the (R)-enantiomer is energetically less favorable than [6-7]S‡, more number of noncovalent interactions could be identified in [6-7]R‡. Interactions such as N-H···π (a), C-H···π (b,c,d,e,f,g,h) and F···H-C (i) is found to be more effective in [6-7]R‡ than that in [6-7]S‡. These observations suggests that the origin of energy differnce between [6-7]R‡ and [6-7]S‡ should arise from factors other than the weak interactions between the catalyst and substrates. [6-7]S‡

[6-7]R‡ (A)

(-15.1)

(-11.2) (B)

Figure 5. (A) Optimized geometries and the corresponding relative Gibbs free energies (in parentheses, kcal/mol) of the enantio-controlling reductive elimination transition states.



Distances are shown in Å. Only selected hydrogen atoms are shown for improved clarity. (B) Topological map obtained by using the AIM formalism, depicting the bond paths and bond critical points (indicated using letters a – j that corresponds to the noncovalent interactions described (for more details see Table S3 in the Supporting Information) in the enantioselective transition states. The key interactions are only shown for improved clarity. In order to gain additional insights into the origin of the energy difference between [67]R‡ and [6-7]S‡ that controls the enantioselectivity, we analyzed the reductive elimination transition states by using the Activation-Strain Distortion-Interaction Model.42 In the distortion−interaction model, the activation energy ΔE‡ is considered as the sum of ΔEd‡ and ΔEi‡. The destabilizing distortion energy (ΔEd‡) stems from the distortions in the geometries of the reactants in the transition state as compared to the respective undistorted ground state geometries whereas interaction energy (ΔEi‡) between the distorted fragments in the transition state geometries leads to some stabilization. The activation barrier is therefore written as ΔE‡ = ΔEd‡ + ΔEi‡. We have partitioned the overall transition state geometry into three minor fragments, NiBr(L*) (f1), -CH(F)CH2Ph (f2) and –(CH2)3Ph (f3), as shown in Figure 6, to evaluate the total interaction as well as to calculate the distortions in the individual fragments.43 The distortion energy of a given fragment, say f1, is calculated as the energy difference between the distorted f1 at the same geometry as seen in the transition state [Ef1(TS)] and a relaxed geometry of f1 when subjected to an independent optimization (Ef1). The total distortion in a given transition state is calculated using the equation given in the figure below. Similarly, the total stabilization energy in a transition state (ΔEi‡) arising due to favorable interactions between the distorted fragments are calculated as the difference in energy between the transition state and the sum of energies of the distorted fragments (Ef1, Ef2 and Ef3) as seen in the transition state.


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Figure 6. Illustration of interaction and distortion energies in the Activation Strain Analysis for the stereoselective reductive elimination transition state leading to the formation of C−C bond between the Ni-bound fluoro alkyl and alkyl moieties. It is noted that the total distortion in the reductive elimination transition state [6-7]S‡ leading to the S enantiomer is 5.6 kcal/mol lower than that in [6-7]R‡ for the formation of the the R enantiomer. However, the interaction energy between the distorted fragments is found to be 1.2 kcal/mol more in the higher energy [6-7]R‡ as compared to that in [6-7]S‡. This is consistent with the more number of noncovalent interactions in [6-7]R‡ found in our AIM analysis (Figure 5). In the reductive elimination transition state, the re or si prochiral face of the fluoro alkyl radical (f2) can participate in the C−C bond formation with the alkyl moiety (f3). Hence, the distortions in these fragments might be different in [6-7]S‡ and [6-7]R‡. Surprisingly, no noticeable difference in distortions in both f2 and f3 fragments of [6-7]S‡ and [6-7]R‡ could be found.52 The main source of difference in the energies of the two reductive elimination TSs should therefore originate from the difference in distortion in the chiral



catalyst, i.e., fragment f1. If we calculate the total destabilizing energy of [6-7]R‡ with respect to [6-7]S‡ on the basis of distortion−interaction analysis, it comes out to be 4.4 kcal/mol (5.61.2 kcal/mol), which is comparable to the difference in the Gibbs free energies between the two transition states (4.3 kcal/mol). In other words, the distortion of the chiral ligand in the two enantio-controlling TSs is the prime contributor to the higher energy of [6-7]R‡ than [67]S‡. This prediction that the formation of (S)-enantiomer is energetically more favored offers a firmer basis for the exclusive enantioselective preference noted under the experimental conditions (% ee=99).

Conclusions A comprehensive mechanistic investigation on a Ni-catalyzed enantioselective Suzuki crosscoupling reaction between bromo(fluoro) alkane and alkyl-9-BBN as the alkylating agent has revealed important molecular insights. Identification of key intermediates and transition states involved in the catalytic cycle by using unrestricted M06 density functional theory helped us find the most preferred pathway. The most likely mechanistic route has been determined by comparing the activation span (δE) of mechanistically different catalytic pathways. The energetic span for the catalytic cycle involving the Ni(I)/Ni(III) redox couple proceeding through the doublet spin state has been found to be 15.5 kcal/mol, which is much lower than the other alternatives such as the Ni(0)/Ni(II) pathway in their singlet or triplet spin states. In the most preferred pathway, the catalytic cycle begins with the turn-over determining transmetalation step wherein the boron-bound alkyl moiety gets transferred to the nickel center to form a Ni(I)-alkyl intermediate. Uptake of bromo(fluoro) alkane and subsequent oxidative addition yields a penta-coordinate Ni(III)-bromo dialkyl intermediate. The enantiocontrolling reductive elimination leads to a C−C bond formation between the Nibound alkyl and fluoro alkyl moieties and forms a new stereogenic carbon bearing the C−F


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bond. It has been found that the transition state for the addition of the si prochiral face of the fluoro alkyl moiety to the alkyl group is more preferred than the re face addition by 4.3 kcal/mol. This prediction is consistent with the experimentally noted high enantioselectivity in favor of the S enantiomer of the product. The origin of such high energy difference between the enantiocontrolling transition states, as analyzed using the distortion-interaction model, helped us trace it to a critical difference in the extent of distortion experienced by the chiral catalyst Ni(Br)L*. The distortion in the transition state responsible for the S enantiomer is 5.6 kcal/mol lower than that in the R transition state. These molecular insights on the origin of enantioselectivity suggest that the difference in distortion centered on the chiral ligand in the enantiocontrolling transition states could be exploited for further developments in this family of asymmetric Suzuki alkyl-alkyl coupling reactions. ASSOCIATED CONTENT Supporting Information. Cartesian coordinates of all the stationary points (reactants, products, intermediates, and transition states) and alternative higher energy pathways and other relevant information are available free of charge via the Internet at https://pubs.acs.org. AUTHOR INFORMATION Corresponding Author [email protected]

Notes The authors declare no competing financial interest. Funding Sources ACKNOWLEDGEMENT: The SpaceTime supercomputing facility at IIT Bombay is gratefully acknowledged for providing generous computing time.



References and Notes

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(36) See Figure S5 and Table S1 in the Supporting Information for details on the effect of explicit solvation in the energy of the stationary points. (37) Kozuch, S. A Refinement of Everyday Thinking: the Energetic Span Model for Kinetic Assessment of Catalytic Cycles. WIREs Comput Mol Sci 2012, 2, 795-815. (38) See Table S2 in the Supporting Information for a compilation of various possible ways to determine the maximum δE for the catalytic cycle presented here. (39) Bader, R. F. W. A Quantum Theory of Molecular Structure and its Applications. Chem. Rev. 1991, 91, 893-928. (40) Biegler-Konig, F.; Schonbohm, J.; Bayles, D. AIM2000 A Program to Analyze and Visualize Atoms in Molecules. J. Comput. Chem. 2001, 22, 545-559. (41) Topological analysis of electron density using atoms in molecule analysis is provided in Table S3 in the Supporting Information. (42)

Bickelhaupt,

F.

M.;

Houk,

K.

N. Analyzing

Reaction

Rates

with

the

Distortion/Interaction-Activation Strain Model. Angew. Chem. Int. Ed. 2017, 56, 1007010086. (43) See Table S4 in the Supporting Information for more details on how the transition state is partitioned into fragments in Activation Strain analysis. (44) See Schemes S1-S3 and Figures S1-S3 in the Supporting Information for more details on the other higher alternative pathways. (45) See Section 10 and Figure S6 in the Supporting Information for more details on the quartet spin state of Ni(I)/Ni(III). (46) See Scheme S4-S5 in the Supporting Information for more details on the formation of Ni(I) species.


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(47) Guard, L. M.; Beromi, M. M.; Brudvig, G. W.; Hazari, N.; Vinyard, D. J. Comparison of dppf Supported Nickel Precatalysts for the Suzuki–Miyaura Reaction: the Observation and Activity of Nickel(I). Angew. Chem. Int. Ed. 2015, 54, 13352–13356. (48) Lin, C. Y.; Power, P. P. Complexes of Ni(I): a ‘‘Rare’’ Oxidation State of Growing Importance. Chem. Soc. Rev., 2017, 46, 5347-5399. (49) Beromi, M. M.; Nova, A.; Balcells, D.; Brasacchio, A. M.; Brudvig, G. W.; Guard, L. M.; Hazari, N.; Vinyard, D. J. Mechanistic Study of an Improved Ni Precatalyst for Suzuki– Miyaura Reactions of Aryl Sulfamates: Understanding the Role of Ni(I) Species. J. Am. Chem. Soc. 2017, 139, 922-936. (50) A direct transmetalation of 1 with alkyl-9-BBN is found to be 20.6 kcal/mol higher. See Figure S4 in the Supporting Information. (51) See Table S6 in the Supporting Information for standard state corrected energies. (52) Distortion in f2(R) is 6.73 and f2(S) is 6.67 kcal/mol where as it is respectively 15.38 and 15.44 kcal/mol for f3(R) and f3(S). TOC


Mechanism and Origin of Enantioselectivity in Nickel-Catalyzed Alkyl

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