Flexible Reaction Pocket on Bulky Diphosphine–Ir Complex Controls

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Flexible Reaction Pocket on Bulky Diphosphine−Ir Complex Controls Regioselectivity in para-Selective C−H Borylation of Arenes Brandon E. Haines,† Yutaro Saito,‡ Yasutomo Segawa,‡,∥ Kenichiro Itami,*,‡,∥,§ and Djamaladdin G. Musaev*,† †

Cherry L. Emerson Center for Scientific Computation, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan ∥ JST-ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan § Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya 464-8602, Japan ‡

S Supporting Information *

ABSTRACT: We used DFT calculations to elucidate the mechanism and source of regioselectivity for Ir-catalyzed paraselective C−H borylation with the bulky Xyl-MeO-BIPHEP diphosphine ligand (L1). We found that the bulky diphosphine−Ir complex forms a flexible reaction pocket that roughly mimics the role of an enzyme active site by modulating access of the substrate to the Ir center. It is shown that the regioselectivity of the reaction arises from a complicated balance of the attractive and repulsive interactions between the substrate and ligand and their corresponding entropic penalties across the high-energy C−H activation and C−B bond formation transition states in the reaction pocket. We predict a trend of increasing para-selectivity with an increase in the size of the substrate substituent in the order SiH3 (and Me) < SiMe3 < Si(t-Bu)3, which is consistent with the experimentally observed trend. It is shown that an increase in the steric bulk of the ligand by introducing bulkier 3,5-substituents to the phenyl rings of the diarylphosphino groups of L1 decreases the para-selectivity. This computational prediction was validated by experiments on C−H borylation of trimethyl(phenyl)silane by using the 3,5-di-tert-butylphenyl analogue of MeO-BIPHEP (L3) as a diphosphine ligand that showed a decrease in para/meta ratio from 88:12 (L1) to 50:50 (L3). Combination of the presented computational and experimental results illustrates that the regioselectivity of the reaction is not fully governed by repulsive steric interactions but instead by a complex balance of steric and electronic interactions between the substrate and flexible reaction pocket. We expect that the provided detailed mechanistic study will greatly enhance our ability to design the next generation of ligands with increased para-selectivity and generality. KEYWORDS: C−H borylation, bulky diphosphine ligand, flexible reaction pocket, para-selectivity, ligand design, mechanism, DFT calculations

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substituent.9 For several substrates (for example, 1,2substituted benzenes and heterocycles), the observed regioselectivities have been rationalized by empirically determined rules10 and directing effects,11 as well as correlations with substrate pKa8b,12 and the strength of the forming Ir−C bond.13 However, the typical iridium catalysts still cannot distinguish between the meta- and para-C−H bonds of monosubstituted benzenes. To this end, we have recently succeeded in developing an Ircatalyzed para-selective C−H borylation reaction by utilizing a bulky diphosphine ligand (Figure 1).14 We have shown that catalyst system containing [Ir(cod)OH]2 and Xyl-MeOBIPHEP (L1) can borylate the para-C−H bond of

INTRODUCTION Recently, para-selective C−H functionalization of monosubstituted benzenes has attracted considerable attention due to its importance in late-stage diversification of a variety of organic materials and pharmaceutical compounds.1 However, despite the bourgeoning research in this field, there has been only limited success in the development of general methods to functionalize the para-C−H bond selectively.2−4 In general, it is shown that the site-selectivity of Ir-catalyzed C−H borylation reactions using the standard 2,2′-bipyridine-type5 or small phosphine ligands6 depends mainly on the steric effect of the substituents. For example, 1,3-disubstituted benzenes are borylated at the 5-position with excellent selectivity independent of the electronic effect of the substituents.5b,7 In the case of monosubstituted benzenes, however, a mixture of meta- and para-products are formed in an ca. 2:1 ratio except in the presence of a strong electronic effect8 or a very large © 2016 American Chemical Society

Received: August 12, 2016 Revised: September 29, 2016 Published: September 30, 2016 7536

DOI: 10.1021/acscatal.6b02317 ACS Catal. 2016, 6, 7536−7546

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the C−H activation transition state as having significant proton character.12 Herein we report the first mechanistic study of para-selective aromatic C−H borylation catalyzed by a bulky diphosphine−Ir complex using DFT calculations. We uncover the key mechanistic details of the catalytic cycle including characterization of important reaction intermediates and also provide valuable insight into the role of the bulky diphosphine ligand L1 in determining the observed para-selectivity of the reaction. We found that the combination of L1 with the Ir catalyst forms a flexible reaction pocket that roughly functions like the active site of an enzyme. When the substrate binds to this pocket, the resulting attractive and repulsive interactions between the substrate and ligand determine the para-selectivity in this catalytic system. The provided new experiments with the [Ir(cod)OH]2 and 3,5-di-tert-butylphenyl analogue of MeOBIPHEP (L3) catalytic system validate these computational findings.

Figure 1. para-Selective C−H borylation of monosubstituted benzenes catalyzed by a bulky diphosphine−Ir complex.

monosubstituted benzenes with up to 91% selectivity. Because the para-selectivity in this reaction was correlated to the bulkiness of the substituents on the benzene ring of substrates (e.g., t-Bu > i-Pr > Et), we proposed that the steric hindrance of the catalyst is the dominant factor for para-selectivity.14 However, to better understand how specific factors determine the para-selectivity, a comprehensive mechanistic study of this reaction becomes absolutely necessary. As such, we expect that a detailed mechanistic study will greatly enhance our ability to design the next generation of ligands with increased paraselectivity and generality. Previous mechanistic studies led to conflicting conclusions. Indeed, numerous studies with 2,2′-bipyridine-type ligands have provided evidence that the Ir-catalyzed C−H borylation proceeds through an Ir(III)/Ir(V) catalytic cycle initiated by rate-determining C−H oxidative addition to a tris-boryl Ir(III) active catalyst (Figure 2).7,15,16 Catalyst turnover is then

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COMPUTATIONAL METHODS Geometry optimizations and frequency calculations for all reported structures were performed with the Gaussian 09 suite of programs19 at the B3LYP-D3/[6-31G(d,p) + Lanl2dz (Ir)] level of theory (B3LYP-D3/BS1) with the corresponding Hay− Wadt effective core potential for Ir and Grimme’s empirical dispersion-correction for B3LYP.20 Frequency analysis is used to characterize each minimum with zero imaginary frequencies and each transition-state (TS) structure with only one imaginary frequency. Intrinsic reaction coordinate (IRC) calculations were performed for selected TSs to ensure their true nature and the reactants and products to which they are connected. The calculated Gibbs free energies are corrected to a solution standard state of 1 M at 298.15 K (G298) and 358.15K (G358),21 which is the temperature used in the experiments. In the text, the G298 values will be primarily considered, while the G358 values will be discussed where appropriate. The free-energy barriers of several association and dissociation steps over the course of the reaction were estimated as previously described22 (for more details, see SI). Bulk solvent effects are incorporated for all calculations using the self-consistent reaction field polarizable continuum model (IEF-PCM)23 with n-hexane as the solvent.24 We used single point energy calculations to determine the effect of the DFT functional on the calculated barriers and regioselectivity: in these calculations, we used an extended basis set BS2 = 6-311+G(d,p) + Lanl08(f) (Ir). We tested B3LYP, mPW1K, B3LYP-D3, M06, and wB97xD and found that B3LYP-D3 gives the barriers and regioselectivities that are most consistent with the experimental results. (See SI for more details.) Therefore, the final reported energies include (a) electronic energies of each structure computed at the B3LYPD3/BS2 level of theory and B3LYP-D3/BS1 calculated geometries and (b) thermal corrections for the free energy and enthalpy calculated at the B3LYP-D3/BS1 level of theory.

Figure 2. Catalytic cycle for C−H borylation starting from the trisboryl Ir(III) active catalyst and proceeding through rate-limiting C−H activation.

initiated by oxidative addition of H−Bpin (or B2pin2) to the resulting bis-boryl Ir(III) hydride intermediate and subsequent formation of H2 (or H−Bpin).7,15,16 The formation and competency of tris-boryl Ir(III) complexes in catalysis are well-established,7a,12,17 and Ir(V) complexes have been experimentally isolated.18 On the other hand, the C−H activation intermediate with 1,2-bis(dimethylphosphino)ethane (dmpe) has also been described as a σ-borane Ir(III) complex.12 The nature of these intermediates suggests a σbond metathesis-type mechanism, where the Ir is formally redox neutral, rather than an oxidative addition mechanism for C−H activation. Singleton, Smith, and Maleczka have described

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RESULTS AND DISCUSSION Borylation Mechanism. To understand the impact of the chiral, bulky diphosphine ligand L1 (Xyl-MeO-BIPHEP) on the reactivity and selectivity of the Ir-catalyzed C−H borylation, we first study the formation of a tris-boryl Ir(III) complex by reaction of 1 with diboron species B2pin2. Tris-boryl Ir(III) complexes have been extensively shown to be active species for 7537

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ACS Catalysis Ir-catalyzed C−H borylation.5,10,14,15 As shown in Figure 3, coordination of an oxygen lone pair of B2pin2 to the initial

Figure 4. Structural analysis of the active tris-boryl Ir(III) complex, 3, showing several features including (a) the “left-up, right-down” structural motif, (b) specific interactions (e.g., CH−π interactions) between the B1 and B3 boryl ligands with the a and e rings of diphosphine ligand, respectively, and (c) the π−π interaction between rings c and f. For simplicity we omitted ligands on B2 and B3 centers. Distances are given in Å.

Figure 3. Calculated free-energy surfaces of the competing B−B (black) and C−H (green) activation reactions by the initial Ir(I) complex 1.

The axial boryl ligand of B2 is rotated toward B1 (O1−B2−Ir− B1 = 5.7° and O1−B1 = 3.14 Å) and is positioned between rings b and d of the ligand. The position trans to B2 is an open site, where presumably the substrate interacts with the Ir-center. An existing π−π interaction between rings c and f is expected to play a key role in determining of the size and shape of the area accessible to the substrate. The calculated shortest distance between rings c and f is 3.14 Å, and the distance between the bottom edges of these rings is 4.51 Å, as illustrated in Figure 4. From the intermediate 3, we next examined the full reaction pathway for C−H borylation of trimethyl(phenyl)silane (Figure 5). At first, we discuss the C−H borylation at the para position, which later will be used as a reference for comparison to activation at the meta positions. Calculations show that para-C−H activation occurs through 28.4 and 37.6 kcal/mol free-energy barriers on the B1, TSCH(B1), and B3, TSCH(B3), sides of the catalyst, respectively (see also Figure 6).26 In both transition structures, the boryl ligands rotate so that the transferring H1 interacts with the B−Ir σ-orbital (B1− H1 = 1.74 Å and B3−H1 = 1.61 Å). However, on the B3 side, the TS is significantly distorted to avoid repulsive interactions between the substrate and ring f. These findings clearly show that with the bulky and chiral diphosphine ligand, the B1 and B3 sides of the catalyst are not equivalent. From this point forward, we will refer the energetically most favorable TSCH(B1) as TSCH. The C−H activation, occurring via the kinetically more favorable B1 side (TSCH) to form 5, is highly endergonic (ΔG = 25.6 kcal/mol relative to 3 + substrate), but it is exergonic by ΔG = 18.7 kcal/mol relative to initial reactants 1 + B2pin2 + substrate. The resulting aryl-Ir intermediate (5) contains a short B1−H1 bond (1.39 Å) and an elongated B1−Ir bond (2.20 Å) (Figure 6). Thus, 5 should be described as a σ-boraneIr(III) complex with a weak B1−H1 bond (as that is illustrated in Figure 2). These complexes are experimentally known and

monoboryl Ir(I) complex 1 leads to the formation of intermediate 2. This process is found to be exergonic by 15.2 kcal/mol. Then dissociation and rotation of the B2pin2 allows for activation of the B−B through TSBB, which requires only 6.6 kcal/mol free-energy barrier (calculated relative to the prereaction complex, 2). The formed oxidative addition product, tris-boryl Ir(III) complex 3, is highly exergonic (−44.3 kcal/mol) relative to the reactants (B2pin2 and 1). Thus, the overall reaction 1 + B2pin2 → 3 is highly favorable even in the presence of a bulky diphosphine ligand (Figure 3). We also examined a free-energy surface of the reaction of the initial Ir(I) complex 1 with C−H bond of trimethyl(phenyl)silane (as the substrate), as a potentially competing pathway. This pathway was previously ruled out in studies using bipyridine ligands,16 but in the current case it is imperative to find out if the bulky diphosphine ligand impacts the relative energies of C−H and B−B activation. Even though the calculations show that C−H activation of the arene (TSCH′) proceeds through a lower free-energy barrier than B−B oxidative addition (TSBB), it is unlikely that this pathway is operative for two reasons25 (Figure 3). First, the diboron reagent will out-compete the arene for coordination sites on the initial Ir(I) complex 1 (ΔG[2′−2] = 9.0 kcal/mol). Second, the resulting aryl-hydride-Ir(III) intermediate 3′ is much less exergonic than the formation of 3 (ΔG[3′− 3] = 24.0 kcal/ mol). Therefore, the conversion of the initial monoboryl Ir(I) catalyst to a tris-boryl Ir(III) complex (1 + B2pin2 → 3) through B−B oxidative addition is still more likely to occur than C−H activation. As shown in Figure 4, the structure of 3 is a five-coordinated Ir(III)-complex, where the ligand forms a “left-up, right-down” structural motif, and the B1 and B3 of boryl ligands interact through CH−π interactions with rings a and e, respectively. 7538

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Figure 5. Calculated complete free-energy surface for C−H borylation of trimethyl(phenyl)silane at the para position starting from tris-boryl Ir(III) complex, 3. Energies are given relative to the reactants 1 + B2pin2.

process as the “metal-assisted σ-bond metathesis” reaction.28 This conclusion is consistent with “proton transfer” character of the C−H activation transition state as described by Singleton, Smith, and Maleczka.12 Subsequent 180° rotation of the σ-borane group in 5, positions B1 in proximity to the aryl ligand for product formation (Bpin−Ar) in intermediate 6.29 However, the TS (TSCB′) leading to Bpin−Ar from 6 is 8.8 kcal/mol uphill, which increases the overall free-energy barrier to 36.2 kcal/mol calculated relative to 3 + substrate. An alternate pathway from 6 is found to be H1 transfer to B2 through a very low energy TS (TSB2) that results in the formation of the B2 σ-borane complex 7.30 The resulting complex 7 has a slightly weaker (relative to 5) σ-borane−Ir interaction (H1−B2 = 1.34 Å) located trans to the aryl group (C1−Ir = 2.12 Å) and a reconstituted B1−Ir bond (2.09 Å). (See SI for the structures of the intermediates not shown here.) Although 7 is overall the most stable σ-borane complex on the free-energy surface, it can transfer H1 to B3 through a modest, 11.1 kcal/mol, free-energy barrier (at the transition state TSB3) to form the B3 σ-borane complex 8, which has a stronger σ-borane−Ir interaction (H1−B3 = 1.48) and a reconstituted B2−Ir bond (2.16 Å) (Figure 7.) Subsequent Figure 6. Important geometrical features of the C−H activation transition-state structure of trimethyl(phenyl)silane at the para position on either side of the catalyst [TSCH(B1) and TSCH(B3)] and the most likely C−H activation product complex (5). Distances are given in Å.

are stabilized by B−H σ-bond donation to the metal and concomitant back-donation from the metal to the p-orbital of B.27 Closer examination of structure 5 suggests that it is a σ-bond metathesis-type product, with the broken C1−H1 and B1−Ir bonds and formed C1−Ir and B1−H1 bonds. Thus, during the C−H activation by complex 3, the formal oxidation state of Ir does not change. However, extensive analysis of the transition state TSCH, associated with this process, reveals the existence of an Ir−H1 (with 1.61 Å) bond. Therefore, we describe this

Figure 7. Important geometrical features of the C−B bond-forming reactant complex (8) and transition-state structure (TSCB) for trimethyl(phenyl)silane at the para position. Distances are given in Å. 7539

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ACS Catalysis Bpin−Ar product formation through a C−B bond-forming TS (TSCB) occurs through a 1.6 kcal/mol free-energy barrier calculated from 8 (corresponding with an overall free-energy barrier of 26.9 kcal/mol relative to the reactants 3 + substrate). Formation of Bpin−Ar from 8 is found to be highly exergonic (−26.4 kcal/mol) indicating that C−B bond formation is effectively irreversible. As shown in Figure 5, the borylation reaction 3 + Ar−H → 10 + Bpin−Ar is slightly endergonic by 1.6 kcal/mol. However, regeneration of 3 (i.e., catalyst turnover) through oxidative addition of B2pin2 and subsequent reductive elimination of Bpin−H, as described previously with modest barriers,16 is exergonic by 11.4 kcal/mol relative to 10 + Bpin−Ar. Therefore, the complete catalytic cycle, that is, 3 + Ar−H + B2pin2 → 3 + Ar−Bpin + Bpin−H, is found to be exergonic by 9.8 kcal/mol. In summary, the above-presented data show that (a) the para C−H activation of trimethyl(phenyl)silane by a catalytic active complex 3 with chiral and bulky diphosphine ligand L1 occurs on the B1 side of the catalyst and then H1 is shuttled to the B3 side of the catalyst where fast C−B bond formation occurs, and (b) the C−H activation step is the rate-limiting step and is irreversible because TSCH is higher in energy than the C−B reductive elimination transition state TSCB by 1.5 kcal/mol. Interestingly, because TSCH and TSCB take place on opposite sides of the catalyst (B1 and B3, respectively), they occur in different ligand environments and are therefore expected to have different controlling factors. Due to the similarity in energy of TSCH and TSCB, this could bring complexity to the determination of regioselectivity. Regioselectivity. At the next step, we analyzed the structures along this reaction coordinate to identify vital steric and electronic interactions that control the reported regioselectivity of the reaction. We find that coordination of the substrate to the Ir-center of 3 disrupts the aforementioned π−π interaction between rings c and f of the bulky diphosphine ligand, and produces an “open” conformation of the ligand. In this “open” conformation, the shortest distance between rings c and f is increased to 3.26 Å, and the distance between the bottom edges of the rings is increased to 5.26 Å (Figure 8). Rings c and f combine with ring a to form a triangular reaction

pocket on the catalyst, where the methyl groups on rings a and f are the outermost points of the pocket. This reaction pocket forms the basis for interactions between the substrate and the ligand. In examining the para-isomers of the reaction pathway (see Figures 6 and 7), we find a π−π interaction between the arene ring of substrate and ring f of the ligand in all of the arylIr intermediates following C−H activation in Figure 5 (with the closest distances of 2.93−3.02 Å). However, the SiMe3 substituent of the substrate does not make significant contacts with the ligand (all distances between the heavy atoms are found to be >3.8 Å). To understand how these interactions impact the regioselectivity of the reaction, we next investigated the pathway presented in Figure 5 with activation at the meta-position of the arene substrate. We found two isomers for activation at the meta position as illustrated in Figure 9. The “meta-in” isomer

Figure 9. Pathways leading to para and meta products examined in this study.

points the substrate substituent (R) directly into the reaction pocket formed by the catalyst, while the “meta-out” isomer places the substrate substituent away from the reaction pocket and toward ring a. For the examined pathways leading to the meta-substituted products, C−H activation through TSCH requires free-energy barriers of 29.4 and 26.7 kcal/mol for the meta-out (blue) and meta-in (red) isomers, respectively (Figure 10). However, the next high-energy demanding step of the reaction, which is the C−B bond-forming step through TSCB, requires the same freeenergy barrier of 28.5 kcal/mol for both meta isomers. Comparison of these findings for the meta pathways with those for the para pathway shows that the meta-out pathway follows the same scenario as the para pathway: The C−H activation step is the rate-limiting step and is irreversible because TSCH is higher in free energy than TSCB by 0.9 kcal/ mol. However, in the meta-in pathway, the relative free-energy barriers switch: TSCB is higher in free energy than TSCH by 1.8 kcal/mol. This indicates that C−H activation is reversible and C−B bond formation is the rate-limiting step for the metain product formation. It is indeed the case that the rate-limiting step is dependent on the regioisomer and all the transition states are close in energy. This increases the complexity of the description of the regioselectivity, as it must encompass two energetically similar but structurally different transition states (TSCH and TSCB).

Figure 8. Structural analysis of “open” conformation of the ligand in TSCH. In this structure, the π−π interaction between rings c and f has been disrupted. The substrate has been removed from the vdW representation to clearly illustrate the reaction pocket. Distances are given in Å. 7540

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(Figure 6), but both of the meta isomers make closer contacts with the ligand (Figure 11). The SiMe3 group of the meta-out isomer interacts with the methyl group of ring a (3.68 Å) and the B3 boryl ligand (3.72 Å). These interactions contribute to increase the energy of TSCH for the meta-out isomer relative to the para isomer. For the meta-in isomer of TSCH, the closest calculated interactions are formed between a substrate methyl group and rings f (3.54 Å) and c (3.63 Å). The fact that the meta-in isomer of TSCH is lower in energy than the para isomer indicates that these interactions are attractive and stabilize the transition state. Once again, this effect arises from the formation of a reaction pocket that is flexible enough to adjust to the shape of the substrate. To gain further insight into the origin of the relative energies of TSCH, we performed a distortion/interaction (or activation/strain) analysis,13,31 as shown in Table 1. This analysis indicates that the interactions between the substrate and catalyst are more favorable in the meta-out and meta-in isomers than the para isomer: In both cases, the difference in interaction energy (ΔΔE‡int = −0.8 and −5.3 kcal/mol, respectively) is greater than the difference in distortion energy (ΔΔE‡dis total = 0.0 and 2.2 kcal/mol, respectively). By comparing the ΔG‡ and ΔE‡ values, it appears that changes in the order of these transition states comes from entropy contributions. Indeed, the calculated entropy values (ΔS‡T) for TSCH are −16.4, − 17.8 and −17.5 kcal/mol for the para, meta-out, and meta-in isomers, respectively (Table 1). These data indicate that (a) the para isomer of TSCH is less ordered than either of the meta isomers, and (b) the interactions between the substrate and ligand are less attractive for meta-out isomer than those in the meta-in isomer. The end result is that the meta-in isomer of TSCH is the lowest of the regioisomers in free energy. We next hypothesized that the same type of distortion/ interaction analysis could also explain the factors impacting the relative energies of the C−B bond formation transition state TSCB. Indeed, the calculated entropy values for TSCB are −15.7, −18.5, and −19.3 kcal/mol for the para, meta-out, and meta-in isomers, respectively, showing again that the para isomer is less ordered than either of the meta isomers (Table 1). However, in this case, the difference in entropy between the para isomer and the meta isomers is significantly larger, which makes the para isomer of TSCB the lowest of the regioisomers in free energy. We next compared how the above identified substrate− ligand interactions are changed upon going from in the regioisomers of TSCH to TSCB. The stabilizing π−π interaction between the substrate arene ring and ring f of the ligand discussed for TSCH is maintained in the para-TSCB (3.01 Å) but is elongated in the meta-out and meta-in isomers (3.17 and 3.10 Å, respectively). However, the interactions between the SiMe3 group and the ligand, in general, are stronger in TSCB than TSCH (Figure 12). Close comparison of the structures of TSCH and TSCB of the meta-out isomer show that the SiMe3 group makes additional contacts with the methyl group of ring a (3.53 and 3.70 Å) in TSCB. For the meta-in isomer of TSCB, the interactions mentioned previously are both stronger than in TSCH: the closest calculated distances between the substrate methyl group and rings f and c are 3.45 and 3.37 Å, respectively. This structural analysis shows that, in general, the additional contacts made in the meta-out and meta-in isomers of TSCB contribute to their increase in free energy relative to the para isomer.

Figure 10. Simplified free-energy surface for comparing the important transition states on the reaction pathways leading to para (black) and meta (red, blue) products with trimethyl(phenyl)silane substrate.

Analysis of the complex free-energy surface presented in Figure 10 for the para-, meta-out (blue), and meta-in (red) pathways shows that the rate-limiting barrier for the para pathway is lower than that for the meta-in pathway by 0.1 kcal/ mol at room temperature (298.15 K) and 0.6 kcal/mol at the reported reaction temperature of 85 °C (358.15 K). This corresponds with a calculated selectivity of para/meta = 54:46 at 85 °C. Thus, these computational data qualitatively reproduce the observed para-selectivity of the [Ir(cod)OH]2and Xyl-MeO-BIPHEP (L1)-catalyzed C−H bond borylation of trimethyl(phenyl)silane. Below, we further augment this major finding by additional calculations and the following experiments, and we apply the findings to understand the origin of regioselectivity of the Ir(I) and bulky diphosphine-ligandcatalyzed C−H bond borylation. In order to get deeper insights the factors controlling regioselectivity of the reaction, we closely compare important geometry parameters of all the regioisomeric structures of TSCH. These analyses show that in all the regioisomeric structures of TSCH (i.e., para, meta-out, and meta-in), the arene ring of the substrate forms the aforementioned π−π interaction with ring f of the ligand: The shortest calculated distance between the substrate and ring f is 3.02 Å for para; 2.98 Å for meta-out, and 3.05 Å for meta-in as illustrated in Figures 6 and 11. However, in TSCH, the SiMe3 group of the para isomer does not make significant contacts with the ligand

Figure 11. Important geometrical features of the C−H activation transition structures (TSCH) of trimethyl(phenyl)silane at the meta-in and meta-out positions. Distances are shown in Å. 7541

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Table 1. Thermodynamic and Distortion/Interaction Analysis for the Regioisomeric TSCH and TSCB Transition Structures with Trimethyl(phenyl)silane ΔG‡ TSCH para meta-out (meta-out) − para meta-in (meta-in) − para TSCB para meta-out (meta-out) − para meta-in (meta-in) − para

ΔS‡(T)

28.4 29.4 1.0 26.7 −1.7 ΔG‡

−16.4 −17.8 −1.4 −17.4 −1.0 ΔS‡(T)

26.9 28.5 1.6 28.5 1.6

−15.7 −18.5 −2.8 −19.3 −3.6

ΔE‡

ΔE‡dist Ir

12.6 11.8 −0.8 9.5 −3.1 ΔE‡

12.8 11.8 −1.0 13.0 0.2 ΔE‡dist Ir

5.8 4.9 −0.9 3.9 −1.9

18.0 21.3 3.3 19.3 1.3

ΔE‡dist Ar−H

ΔE‡dist total

ΔE‡int

69.9 70.9 1.0 72.0 2.1 Ar−Bpin

82.7 82.7 0.0 84.9 2.2 ΔE‡dist total

−70.1 −70.9 −0.8 −75.4 −5.3 ΔE‡int

101.8 101.2 −0.6 107.1 5.3

−96.0 −96.3 −0.3 −103.2 −7.3

ΔE‡dist

83.8 79.9 −3.9 87.8 4.0

Figure 12. Important geometrical features of the C−B bond-forming transition structures (TSCB) of trimethyl(phenyl)silane at the meta-in and meta-out positions. Distances are given in Å.

In summary, the aforementioned computational data provide valuable insight into the role of the bulky diphosphine ligand L1 in para-selectivity in C−H borylation. As shown, the regioselectivity of the reaction arises from a balancing of the attractive interactions between the substrate and ligand and their corresponding entropic penalties across the transition states for C−H activation (TSCH) and C−B bond formation (TSCB). We attribute this effect to the geometrical flexibility of the reaction pocket. Here, we wish to make an intriguing analogy between this organometallic and enzymatic catalytic systems, where complex interactions govern the binding of a substrate to the active site.32 Below, we use this mechanistic information to further probe the impact of the substrate and ligand on the regioselectivity of the reaction. Substrate Effect. As shown in the previous section, the regioselectivity of the reaction of 3 with trimethyl(phenyl)silane is not dominated by repulsive steric interactions as previously thought. However, it would be erroneous to say that repulsive steric interactions are not important or do not have the potential to impact the regioselectivity with this ligand scaffold. Therefore, to gain a better understanding of how the repulsive steric interactions might play a role in the reaction, we set out to study the calculated reaction pathway with two additional substrates including one smaller, phenylsilane, and one larger, tri(tert-butyl) (phenyl)silane, than the model substrate, trimethyl(phenyl)silane, used in the aforementioned discussion. When phenylsilane is used as the substrate, the free-energy surface shows fewer energetic differences between the regioisomeric pathways (Figure 13). The rate-limiting barrier

Figure 13. Simplified free-energy surface for comparing the important transition states on the reaction pathways leading to para (black) and meta (red, blue) products with a smaller substrate, phenylsilane.

for the meta-out pathway (C−B bond formation) is 0.7 and 0.6 kcal/mol lower than the rate-limiting barrier for the para pathway (C−H activation) at room temperature (298.15 K) and at 85 °C (358.15 K), respectively. This corresponds with a calculated selectivity of para/meta = 18:82, indicating that the smaller substituent leads to loss of the para-selectivity. Structural analysis of the transition structures (see SI) shows that the interactions between the substrate phenyl ring and the ligand are largely the same between regioisomers. The SiH3 group of phenylsilane may form some weak attractive interactions with the ligand that leads to a slight preference for the meta product, but these effects are subtle. On the basis of these results, we hypothesized that the ligand would not be able to distinguish between the meta- and paraC−H bonds of an even smaller substrate, such as toluene. Indeed, calculations with toluene show that the para and meta pathways are essentially the same, leading to a calculated selectivity of para/meta = 27:73 (See SI for full details). This result represents a statistical distribution of the products (i.e., para/meta = 1:2) and shows that the ligand cannot distinguish between the meta- and para-C−H bonds in toluene. Together these results are consistent with experiments showing no para selectivity for small substrates.14 When the much bulkier tri(tert-butyl) (phenyl)silane is used as the substrate, there is a clear shift of the selectivity to the 7542

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ACS Catalysis para pathway: The rate-limiting C−H activation barrier for the para pathway is lower than the rate-determining C−B bond formation barrier for the meta-out pathway by 3.6 kcal/mol at room temperature (298.15 K) and 4.1 kcal/mol at 85 °C (358.15 K), which corresponds with a calculated selectivity of para/meta = >99:1 (Figure 14). Based on structural analysis of

Figure 15. Proposed strategy for modification of the ligand to impact increase of para-selectivity by increasing the steric bulkiness of the ligand.

commercial availability of L3. However, we feel that both of these ligands represent a similar increase in the steric bulkiness relative to L1 and therefore should allow us to draw general conclusions about the effect of steric bulk on regiochemical outcome of the reaction. At the outset, on the basis of the aforementioned findings, we hypothesized that increasing the steric bulkiness at these positions would destabilize the meta-in and meta-out pathways through repulsive interactions within the reaction pocket and therefore would provide a general strategy for increasing para-selectivity. First, in examining the free-energy surface for the regioisomeric reaction pathways with L2 (Figure 16), to our

Figure 14. Simplified free-energy surface for comparing the important transition states on the reaction pathways leading to para (black) and meta (red, blue) products with a larger substrate, tri(tert-butyl) (phenyl)silane.

the corresponding transition-state structures (see SI for structures), when the very bulky Si(tBu)3 group is placed in the reaction pocket in the meta-in pathway, TSCH and TSCB are both highly distorted. This is evidenced by elongation of the distance between the substrate arene ring and ring f of the ligand to 3.19 and 3.33 Å, in TSCH and TSCB, respectively. In the meta-out pathway, there is space for the bulky Si(tBu)3 group in TSCH, but the bulkiness of the substrate impedes its exit from the reaction pocket in TSCB. Remarkably, the Si(tBu)3 group makes only a few interactions with the ligand in the para-TSCH and para-TSCB, indicating that para transition states are less congested than their meta-in and meta-out counterparts. In summary, the above-presented results predict a trend of increasing para-selectivity with increase in the size of the substrate substituent via SiH3 (Me) < SiMe3 < Si(t-Bu)3, which is consistent with experimentally observed trend in paraselectivity based on size of the substrate substituent via Et < iPr < t-Bu.14 This calculated trend was explained by the fact that in TSCH and TSCB the para-position of the activated substrate is the least congested position. The aforementioned findings provide a basis to understand roles of steric interactions in regioselectivity of the reaction and could be used to design new ligands to effect para-selectivity on smaller substrates such as toluene. Ligand Modification. Next, we investigated the impact of increasing the steric bulkiness of the ligand on the regioselectivity of the reaction. To do this, we extended our computational studies to the L2 ligand, which replaces the 3,5dimethyl substituents on rings a, b, e, and f of L1 with i-Pr substituents. We also experimentally investigated the L3 ligand, which is different from L1 and L2 by having t-Bu substituents instead of Me and i-Pr substituents, respectively (Figure 15). The inconsistency in the computational and experimental ligand used arises from lower computational expense of L2 and

Figure 16. Simplified free-energy surface for comparing the important transition states on the reaction pathways leading to para (black) and meta (red, blue) products with L2 and trimethyl(phenyl)silane.

surprise, we find that adding bulkier groups to rings a, b, e, and f actually decreases the calculated para-selectivity of the catalyst. The meta-out and para pathways have the same free-energy barrier at room temperature (298.15 K), and the para pathway is lower only by 0.3 kcal/mol at 85 °C (358.15 K), which corresponds with a calculated selectivity of para/meta = 47:53. Further analysis shows that the bulkier ligand L2 does not have any impact on the free-energy barrier of the meta-out pathway. The distortion/interaction analysis given in Table 2 shows that the additional bulky i-Pr groups slightly destabilize the interactions between the substrate and ligand in the meta-out TSCH, but these slight differences are offset by a slight increase 7543

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ACS Catalysis Table 2. Distortion/Interaction Analysis for the Regioisomeric TSCH Transition Structures with L2 with Trimethyl(phenyl)silane L2:TSCH para meta-out meta-out − para meta-in meta-in − para

ΔG‡

ΔS‡(T)

ΔE‡

ΔE‡dist Ir

ΔE‡dist PhSiMe3

ΔE‡dist total

ΔE‡int

29.8 29.8 0.0 31.0 1.2

−15.0 −16.5 −1.5 −18.2 −3.2

14.5 14.3 −0.3 12.2 −2.3

16.3 15.3 −1.0 17.1 0.9

70.4 70.7 0.3 71.4 1.0

86.7 86.0 −0.6 88.6 1.9

−72.1 −71.8 0.4 −76.3 −4.2

in the entropy of the TS. Because the free-energy barrier of the para pathway is also increased, the para-selectivity is canceled out altogether. Thus, the computational data indicate that increasing the size of the meta-substituents on rings a, b, e, and f will not increase the para selectivity and could actually reduce the reactivity of the catalyst. Next, we performed experimental studies on C−H borylation of 1a by using the 3,5-di-tert-butylphenyl analogue of MeOBIPHEP (L3) under the conditions reported previously.14 As shown in Scheme 1, borylation of 1a took place in low yield

III. The factors that control the regioselectivity of the reaction are very complex due to contributions from two energetically similar but structurally different transition states (TSCH and TSCB). Ultimately, the selectivity arises from balancing of the attractive and repulsive interactions between the substrate and ligand, as well as their corresponding entropic penalties within the reaction pocket. IV. The size of the substrate and geometrical flexibility of the reaction pocket strongly impact the para-selectivity. We predict a trend of increasing para-selectivity with an increase in the size of the substrate substituent in order SiH3 (Me) < SiMe3 < Si(t-Bu)3, which is consistent with experimentally observed trend in para-selectivity.14 V. The studies with L2 (i-Pr) and L3 (t-Bu) show that introducing bulkier 3,5-substituents to the phenyl rings of the diarylphosphino groups of L1 decrease the paraselectivity of the reaction. This outcome indicates that simply increasing steric bulk of the ligand is not a viable strategy for optimizing para-selectivity and that further ligand design studies will need to carefully consider the substrate−ligand interactions within the reaction pocket formed by the ligand. Thus, the combination of presented computational and experimental results illustrates that the regioselectivity of the reaction is not fully governed by repulsive steric interactions. Therefore, when designing new ligands, one must consider the impact of the bulky groups of the diphosphine ligand beyond that of pure steric interactions because coordination of the substrate to the flexible reaction pocket on the catalyst is governed by many attractive and repulsive interactions. As such, we expect that the above-presented detailed mechanistic study will greatly enhance our ability to design novel ligands with increased para-selectivity and generality, and we suggest that the role of a flexible reaction pockets be considered for other reactions that employ bulky diphosphine (or similar) ligands.

Scheme 1. Experimental Study on the C−H Borylation of 1a with a Bulkier Ligand L3

(14%) with decreased para-selectivity (para/meta = 50:50) relative to L1. Although, not directly comparable, this result is in good agreement with the above-presented computational prediction that increasing the size of the 3,5-substituents of ligand decreases the para-selectivity of the substrate. These computational and experimental data together allow us to conclude that the regioselectivity of the reaction is not fully governed by repulsive steric interactions. Therefore, increasing the steric bulk of the ligands is not in itself a viable strategy for maximizing para-selectivity. We are currently working to better understand the interactions between the substrate and reaction pocket in order to design novel ligands with increased paraselectivity and generality.

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CONCLUSIONS Here, we elucidate the mechanism and source of regioselectivity for Ir-catalyzed para-selective C−H borylation with the bulky Xyl-MeO-BIPHEP diphosphine ligand. Briefly, we found that I. The reaction of Ir(I) precatalyst 1 with B2pin2 forms catalytic active tris-boryl Ir(III) intermediate 3, where the bulky diphosphine ligand L1 forms a geometrically flexible reaction pocket organized by a π−π interaction between rings c and f of the ligand. This reaction pocket roughly mimics the role of an enzyme active site and modulates access of the substrate to the Ir center. II. The para C−H activation of trimethyl(phenyl)silane by 3 occurs via rate-limiting C−H activation through a “metal-assisted σ-bond metathesis” transition state (TSCH) and is irreversible.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b02317. Experimental details, computational methodology, additional computational details for B−B and C−H activation by Ir(I), additional computational details for the paraborylation pathway, substrate effect, increasing ligand sterics, energies for calculated structures (PDF) Cartesian coordinates for all calculated structures (XYZ)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. 7544

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ACS Catalysis *E-mail: [email protected].

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation under the CCI Center for Selective C−H Functionalization (CHE-1205646 for D.G.M.), the ERATO program from JST (K.I.) and the Funding Program for KAKENHI from MEXT (16K05771 to Y.Se.). Y.Sa is a recipient of the JSPS research fellowship for young scientists. The authors gratefully acknowledge NSF MRI-R2 grant (CHE-0958205 for D.G.M.) and the use of the resources of the Cherry Emerson Center for Scientific Computation. ITbM is supported by the World Premier International Research Center (WPI) Initiative, Japan.

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