Unravelling the Origins of Hydroboration Chemoselectivity Inversion

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Unravelling the Origins of Hydroboration Chemoselectivity Inversion Using an N,O-Chelated Ir(I) Complex: A Computational Study Huining Bai, Huimin Zhang, Xinchao Zhang, Lidong Wang, Shi-Jun Li, Donghui Wei, Yanyan Zhu, and Wenjing Zhang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00329 • Publication Date (Web): 06 May 2019 Downloaded from http://pubs.acs.org on May 7, 2019

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The Journal of Organic Chemistry

Unravelling the Origins of Hydroboration Chemoselectivity Inversion Using an N,O-Chelated Ir(I) Complex: A Computational Study Huining Bai,§ Huimin Zhang,§ Xinchao Zhang, Lidong Wang, Shijun Li, Donghui Wei, Yanyan Zhu and Wenjing Zhang* College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan Province 450001, P. R. China

Abstract It has been widely reported that the transition metal catalysts can invert the chemoselectivity of hydroboration of multifunctional substrates, but the fundamental reasons for this inversion have rarely been studied. In this work, mechanistic details and chemoselectivity of the hydroboration of various E–C (E = CH, CH2, O, N, etc.) multiple bonds has been explored through density functional theory calculations, including reactions using free HBCy2 or captured HBCy2 by an N,O-chelated Ir(I) complex which includes a phosphoamidate group. The computational results demonstrate the formation of a 3-center π complex before the 4-center transition state when using free HBCy2. When the Ir(I) complex is added, the HBCy2 would be captured to form a metallaheterocyclic Shimoi-type intermediate in which a δ-[M]…H–B agostic interaction appears. Afterwards, the E–C functional group goes to intersect this hemilabile interaction rather than the P=O…B coordination bond, and the following hydride transfer is figured out to be rate-determining. The frontier molecular orbital analysis discloses that the olefins who has typical delocalized π electrons tends to give more effective overlap with the LUMO of free HBCy2, but the aromatic substituents could significantly reduce its reactivity due to the enhanced electron delocalization. The polarized carbonyl group facilitates the σ coordination with the metal center, but the vinyl group favors to interact through π coordination. The superiority of σ coordination results in the priority of hydroboration of aldehyde over the olefins when using the captured HBCy2. So it is the conversion of the more favored bonding groups by the transition metal that should be fundamentally responsible for the chemoselectivity inversion. Keywords: Hydroboration; Chemoselectivity Inversion; DFT; N,O-chelated Ir(I) Complex; HBCy2

§ *

H.B. and H.Z. contributed equally. Corresponding author: [email protected]

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1. Introduction Organoboranes are important intermediates in many organic transformations.1-5 They can serve as synthons for construction of various functional groups6-7 and are often subject to a consecutive carbon-carbon or carbon-heteroatom bond-forming reactions.7-17 Since first reported by Brown in 1956,18 hydroboration of element-carbon (E–C, E = CH, CH2, O, N, etc.) multiple bonds has become a most often applied protocol for preparation of various organoboranes. Particularly, the introduction of transition metal catalyst, which was first observed by Kono and Ito,19 has highly broadened its application scope in organic chemistry and natural product/drug synthesis.20-22 One most important reason is that the transition metal catalysts are usually able to invert the chemoselectivity of reactions of multifunctional substrates, and concurrently offer alternatives for manipulating the chemo-, regio- and stereoselectivity of hydroborations.23-27 As a result, the transition metal-catalyzed hydroboration has been developed to be a valuable technique in organic and drug chemistry. Despite of intense experimental and theoretical studies to the reaction mechanism of direct28-33 or transition metal-catalyzed4,

23, 34-36

hydroborations, the detailed

mechanistic steps or transition states are still of considerable dispute, although there has been some common consensus. For example, the uncatalyzed reaction should proceed through a 4-center transition state, with or without32-33 a loose 3-center π complex formed in the early stage. Most catalyzed hydroborations are initiated by oxidative addition of the B-H bond to the transition metal center and ended by reductive elimination of the hydroborated product to simultaneously regenerate the transition metal catalyst. Nonetheless, Schafer and Love37 recently reported a completely new strategy. As it is shown in Scheme 1, they treated the hemilabile κ2-N,O-chelated

rhodium(I)

and

iridium

(I)

complexes

to

capture

the

dicyclohexylborane (HBCy2) to cooperatively and reversibly form the base-stabilized δ-B-H agostic complexes, which are then subjected to hydroboration of various unsaturated

functional

groups,

including

alkyl/aromatic

alkyl/aromatic olefins, aromatic alkyne, nitrile, and so on. 2 ACS Paragon Plus Environment

aldehyde/ketone,

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Scheme 1. The experimental results.

To enclose a borane into the transition metal complexes to get access to species incorporating the [M]…H-B interaction (σ or agostic) is an effective way to reach the B-H bond activation. In this context, the synthesis and characterization of metal complexes with a [M]…H-B motif has been a subject of intense research for decades.38-42 However, a number of these complexes42-47 cannot be applied in hydroboration of unsaturated bonds because the B-H bond is covalently tethered into the ligand framework and thus difficult to be transferred. This challenge can be overcome by Schafer and Love’s catalytic system. The B-H bond is incorporated into the δ-B-H agostic complex by coordinately inserting between the O→M bond, resulting in the trapped but labile B-H bond, meaning the hemilabile metallaheterocycle. Similarly with many other transition metal catalysts, this N,O-chelated Ir(I)/Rh(I) system can completely invert the chemoselectivity of hydroborations of aldehyde and olefins. In particular, the reaction can be changed from chemoselective alkene hydroboration by free HBCy2 to aldehyde hydroboration by captured HBCy2 by the Ir(I) complex.37 Given proof to the six-membered chelating structures generated from addition of HBCy2 to the hemilabile ring-opening of the M–O bond through combination of experimental techniques and theoretical computations, Love and co-workers proposed two possible catalytic cycles for the reaction. As shown in Scheme 2, the reaction is initiated by formation of the δ-B–H complex A, followed by insertion of the E–C multiple bond to the O→B hemilabile bond to break the base stabilization or coordination to the transition metal center to intersect the [M]…H–B agostic bond. 3 ACS Paragon Plus Environment


Either pathway promises the hydroboration product and regeneration of the N,O-chelated metal complexes Cat1 or Cat2, but which one is more favorable has not been answered. Beyond of this, there are still a number of issues ambiguous in regarding with the catalytic mechanism, for example, how exactly is the Shimoi intermediate A generated? Why is it so stable (confirmed by X-ray diffraction crystallography37)? Why is it unable to be isolated if the P=O bond has been substituted by P=S bond? How does the hydroboration occur in detail? Which step is the rate-determining step? Finally but most importantly, what are the fundamental factors rendering the chemoselectivities being completely inverted compared with reactions with free HBCy2? Answers to all these mechanistic issues are the fundaments to unravel the origin of the chemoselectivity inversion. It should also be of valuable guidance to experimentalists to design more efficient transition metal catalysts to get more desired organoboranes.

Scheme 2. The proposed catalytic cycles in experiment.

In this work, we used the density functional theory (DFT)48-49 method to gain more insight into the mechanistic details of both catalyzed and uncatalyzed hydroborations, 4 ACS Paragon Plus Environment

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since the DFT method has been widely applied and demonstrated to be most effective in mechanistic and selectivity studies.50-57 Based on these details, we then carried out analysis to the frontier molecular orbitals (FMOs) of the key species to figure out the factors that determine the chemoselectivity and finally rendered our understanding to the essential reasons for the selectivity change.

2. Computational Details 2.1 Model Selection After comprehensive assessment towards all the experimental results, the Ir(I)-catalyzed competitive hydroboration of benzaldehyde with oct-1-ene was chosen as the representative models for reaction mechanism studies. Specifically speaking, the experimental results show that the anti-Markovnikov adduct of HBCy2 to benzaldehyde would be the main product when the Ir(I) complex Cat1 was used (>99%:0%), while when reacts with free HBCy2, the oct-1-ene would be hydroborated in great priority (2%:98%). For the sake of convenience, compounds HBCy2, benzaldehyde, and oct-1-ene will be respectively denoted as R1, R2a, and R2b in the rest of this paper. 2.2 Computational Methods All theoretical calculations were performed by using the Gaussian 09 suit of program58. The geometrical structures of all stationary points were optimized using the Minnesota M06-L59 functional, which has been widely adopted in mechanism studies of transition-metal-catalyzed reactions, and the mixed basis set of LanL2DZ60-62 for Ir/Rh, 6-31g(2df, 2pd)63 for P, and 6-31g(d, p)64-65 for the rest (Level A). The harmonic vibration frequencies were calculated based on the optimized geometries at the same level with pressure set as 1 atmosphere and temperature as corresponding experimental settings. The results of these frequency calculations not only help to confirm the characteristics of the optimized structures (all reactants, products, and intermediates have no imaginary frequency, and each transition state has only one imaginary frequency), but also provide the zero-point vibrational energies (ZPE) and the thermal corrections to Gibbs free energies. The same level of 5 ACS Paragon Plus Environment


intrinsic reaction coordinate (IRC)66-67 calculations were performed to make sure each transition state leads to the expected reactant and product. Based on the optimized structures, all energies were further refined by single-point energy calculations using the M06-L functional, LanL2DZ basis set for Ir/Rh, 6-311++G(2df, 2pd) for P, and 6-311++G(d, p) for the rest (Level B). The solvent effects were simulated by the SMD model,68 with C6D6 replaced by C6H6. The suitability of energy refinement by adding the single-point energies obtained at a higher level with solvent effect included to the thermal corrections at a lower level in gas phase have been definitely confirmed69-70 in previous reports. In order to give further confirmation to the computational predictions, energies of some critical steps were recalculated by using the B3LYP-D371-73 or ωB97X-D74 functionals based on the optimized structures at Level A, with the same basis set and solvation model as Level B.

3. Results and Discussion 3.1 Reaction mechanism In this section, we will present all corresponding computational results and discussions about mechanisms of the hydroborations by free or captured R1. 3.1.1 Reactions with free R1 As what has been mentioned above, the basic consensus has been reached about the mechanism of the hydroboration of unsaturated functional groups using the free boron hydride source. There are two steps included, in particular formation of a loose 3-center π complex in the early stage and the hydroboration via a 4-center transition state. On basis of this common view, we have firstly carried out calculations to the reactions of free R1 with R2a and R2b, respectively. More details about the reaction mechanism and the theoretically predicted energy profiles are shown in Figure 1. As we can see, formation of the pre-complex Int0a/Int0b is obviously endothermic in view of the Gibbs free energies (7.2/5.0 kcal/mol, respectively) but exothermic in respect of the enthalpy energies (–4.4/–7.4 kcal/mol, respectively). This is basically consistent with previous reports28-33 since it 6 ACS Paragon Plus Environment

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was actually the relative enthalpy energies that were adopted to determine whether the 3-center pre-complex forms or not. Actually, combination of the two reactants is an entropic penalty process, which will certainly result in higher Gibbs barrier than enthalpy barrier, let alone the entropic penalty based on the ideal gas-phase model is often overestimated because the suppressing effects of the solvent and pressure on the translational and rotational degrees of freedom of the reactants cannot be properly accounted for by the gas-phase model.70, 75-76

Figure 1. The possible hydroboration mechanism using free R1, the predicted Gibbs free energy profiles and all the optimized structures involved in. Orange numbers in parentheses are relative enthalpies. Energies of R1+R2a/R2b were set as 0.0 kcal/mol for the red/royal lines, respectively. Bond lengths are in angstrom.

In the second step, the hydroboration of the unsaturated bond E3–C4 of R2 via the 4-center transition state TS0 undergoes through the cleavage of the B1–H2 bond of 7 ACS Paragon Plus Environment


R1 and formation of the H2–C4 and E3–B1 bonds. The gradual changes of corresponding bond lengths (Figure 1) clearly indicate this chemical reaction process. The distance between the E3 and C4 atoms are elongated from 1.22/1.34 Å in Int0a/Int0b to 1.27/1.35 Å in TS0a/TS0b and finally to 1.42/1.54 Å in Pa/Pb, respectively, while the lengths of H2–C4 and E3–B1 bonds are shortened from 1.96/2.27 Å and 1.73/2.10 Å in TS0a/TS0b to 1.10/1.10 Å and 1.37/1.58 Å in Pa/Pb, respectively. The total free energy barriers via TS0a and TS0b are 14.8 and 10.4 kcal/mol, respectively, indicating that the reactions with free HBCy2 are easy to occur under mild conditions. This is in good agreement with the fact that the control experiments between substrates R2a/R2b and free HBCy2 resulted in rapid anti-Markovnikov hydroborated products (r.t., < 5 min). Besides, the lower barrier via TS0b than that via TS0a (4.4 kcal/mol) illustrates from the molecular level that why the alkene hydroboration is more preferred in present of aldehyde.

3.1.2 Reactions with Ir(I)-captured R1 Given proof using both experimental techniques and theoretical calculations to the generation of the Shimoi-type metallaheterocycle intermediate, it is reasonable to presume the whole catalytic reaction initiated by capture of R1 by the N,O-chelated Ir(I)-complex (as shown in Scheme 2). Afterwards, two possible interaction strategies of the unsaturated functional group with the six-membered intermediate have been proposed. One suggests the E–C group to insert between the P=O…B interaction (denoted as BOINS pathway), and the other states the possibility of the multiple bonds inserting between the Ir…H–B interaction (denoted as MHINS pathway). In the following section, we will present our computational results and discussions about these two possible reaction routes in details.

BOINS pathway More details about the catalytic cycle going through the BOINS pathway are illustrated in Scheme 3. There are generally four steps included, namely the borane capture to give the Shimoi-type intermediate Int1, the E–C multiple bonds insertion 8 ACS Paragon Plus Environment

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between the O5→B1 bond, the hydride transfer from the B1 atom to the C4 atom, and finally the dissociation of the catalyst companied with yield of the hydroborated product P.

Scheme 3. Proposed mechanism of the Ir(I)-catalyzed hydroboration going through BOINS pathway.

The first step occurs through the boat-like 6-center transition state TS1 (see Figure 2 for the optimized geometries), and the Gibbs free energy barrier is 10.5 kcal/mol (see Figure 3 for energy profiles of the Ir(I)-catalyzed reaction), indicating the borane capture is very easy to occur under experimental conditions. The yielded intermediate Int1 is 8.2 kcal/mol more stable than the initial reactants, which is well consistent with the experimental fact that the X-ray crystal structure of the δ-Ir…H–B agostic complex Int1 can be isolated.



Figure 2. The optimized geometries of some key species involved in the BOINS pathway. All hydrogen atoms not involved in the reactive center are omitted. Bond lengths are in angstrom.

Figure 3. The Gibbs free energy profiles of the Ir(I)-catalyzed reaction. The subscript &

indicates adding energies of R2a or R2b, while subscript a/b represents

corresponding stationary points involved in hydroboration of R2a or R2b, respectively. Numbers in light blue are the energies predicted by the B3LYP-D3/ωB97X-D calculations, respectively.

The following step is to involve the hydroboration substrate R2 through bonding of the E3 atom with the electron-deficient B1 atom via transition state TS2, yielding the intermediate Int2. We have succeeded in optimizing the structure of Int2a, but 10 ACS Paragon Plus Environment

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unfortunately failed to locate TS2a, TS2b, or Int2b. Nonetheless, the only one we have has been enough to help us to reasonably exclude the possibility of this BOINS pathway. From the energy profiles shown in Figure 3 we can see that, the intermediate Int2a locates 3.4 kcal/mol (2.4/3.8 kcal/mol predicted by the B3LYP-D3/ωB97X-D calculations, respectively) higher than the highest stationary point, i.e. TS3a, via the MHINS pathway, so it is reasonable to infer that the energy barrier via transition state TS2a should be higher than that via TS3a. Namely, involving of R2a by inserting the O3–C4 bond to the P=O…B coordination is less likely to occur. Since the hydroboration of R2a has been experimentally revealed to be much more preferred over that of R2b (Pa:Pb = >99%:0%), and the possibility to give Int2a through the BOINS pathway has been excluded, it is rational to conclude that the C3 atom is unlikely to bond with the B1 atom to yield Int2b as well. Therefore, we abandoned to conduct further studies towards the remaining steps.

MHINS pathway The whole catalytic cycle going through the MHINS pathway has been illustrated in Scheme 4. Given the intermediate Int1, there are four steps remained for the whole catalytic cycle undergoing through the MHINS pathway, in particular the E–C insertion, hydride transfer, borylation and finally dissociation of the product from the catalyst Cat1.



Scheme 4. Proposed mechanism of the Ir(I)-catalyzed hydroboration going through MHINS pathway.

Considering the steric hindrance of the two cyclohexane groups, the E–C multiple bond is proposed to approach to the transition metal center via coordination perpendicularly to the square planar ligand field in Int1, followed by deformation from the five-coordinated square pyramid conformation in Int3 back to the square planar field as in Int4, with the B–H σ coordination replaced by the E3–C4 σ coordination. In particular, for the substrate R2a, the computational results predict equal energies of Int3a and Int4a by the M06-L calculations, which we think should be not so justified due to the different metal-aldehyde oxygen bond. In order to further confirm the energetic difference of this deformation process, the B3LYP-D3 and ωB97X-D calculations were conducted. Please see the light blue numbers shown in Figure 3 for their predictions to the relative energies of some key structures. It is 12 ACS Paragon Plus Environment

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shown that Int4a is predicted to lie 2.3/3.3 kcal/mol higher than Int3a, respectively, while TS3a lies 2.0/0.8 kcal/mol above Int4a, respectively. Therefore, the deformation from Int3a to Int4a should be an endothermic process. We failed to locate the transition state for this deformation, but the flexible scan to the dihedral angle of ∠ O3Ir6O5B1 beginning from the optimized structure of Int3a indicates the low barrier for the interconversion of Int3a and Int4a (see Figure S1 in supporting information). For the vinyl group however, the four-coordinated planar conformation in Int4b is found to locate 13.2 kcal/mol higher than the five-coordinated pyramid conformation in Int3b, which may be mainly attributed to the excessively weak coordination in Int4b. As we can see from Figure 4, the lengths of the C3–Ir6 and C4–Ir6 bonds in Int3b are 2.17 and 2.18 Å, respectively, indicating typical π coordination of the C3=C4 double bond to the Ir6 atom. However, in the deformed complex Int4b, the lengths of the C3–Ir6 and C4–Ir6 bonds are significantly elongated (2.99 and 4.00 Å, respectively), implying only very weak σ interaction kept between the terminal methylene group and the metal center.

Figure 4. The optimized geometries of some key species involved in the MHINS pathway. All hydrogen atoms not involved in the reactive center are omitted. Bond lengths are in angstrom.



The following step is to transfer the hydride H2 from the B1 atom to the C4 atom via TS3, yielding the zwitterion intermediate Int5. The gradual elongation of the B1– H2 bond length along with the shortening of the H2–C4 bond length clearly indicates this transfer process. The energy barriers are predicted to be 3.1 and 12.1 kcal/mol via TS3a and TS3b, respectively. Accordingly, the total barriers for transformation from Int1 to Int5a or Int5b are 18.0 or 42.1 kcal/mol, respectively, implying that the reaction with benzaldehyde R2a is absolutely favorable over that with oct-1-ene R2b. This corresponds excellently with the experimental result about the chemoselectivity (Pa:Pb >99%:0%). The fourth step is the terminal group borylation which proceeds through nucleophilic attack of the E3 atom to the B1 atom via transition state TS4. In the resulted intermediate Int6, the six-membered ring is restored with the δ-B–H agostic interaction in Int1 replaced by the B–E→Ir structure. The length of the B1–E3 bond is shortened from 3.56/4.17 Å in Int5a/ Int5b to 2.48/2.26 Å in TS4a/TS4b and finally 1.54/1.64 Å in Int6a/Int6b, respectively, indicating the full formation of the B1–E3 bond (see Figure S2 for the optimized geometries). The energy barriers of this step are 2.7/17.3 kcal/mol via TS4a/TS4b, respectively, implying the borylation of the olefin bond (E = CH2) of substrate R2b is more difficult than conversion of the carbonyl group (E = O) of substrate R2a. In the last step, the two coordination bonds, namely the O5–B1 and the E3–Ir6 bonds are broken, which results in the release of the final product P and regeneration of the catalyst Cat1. Dissociation of the hydroboration product leads to further shortening of the B1–E3 bond from 1.54/1.64 Å in Int6a/Int6b to 1.39/1.61 Å in TS5a/TS5b and finally 1.37/1.58 Å in Pa/Pb, respectively. The energy barriers via TS5a/TS5b are 5.2 and 6.8 kcal/mol, respectively, indicating a fast dissociation process under mild conditions. All these results are well consistent with the property of coordination bonds cleavage. Taking all above discussions about the MHINS pathway into consideration, we can achieve conclusions as follows: (i) the hydride transfer process is the rate-determining step of the whole reaction and the energy barriers are separately 18.0 and 42.1 14 ACS Paragon Plus Environment

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kcal/mol for the aldehyde and olefin substrates, which corresponds well with the experimental fact that the reaction terminates within 5 minutes at room temperature with excellent chemoselectivity. (ii) the absolute predominance of hydroboration of R2a rather than R2b should be attributed to the more facile combination of the carbonyl group to the transition metal center and the irreversible feature after the hydride transfer. On account of all these reasonable results, we conclude the MHINS pathway should be a rational reaction mechanism for the title reaction. As mentioned above, to enclose a borane into the transition metal complexes to get access to species incorporating the [M]…H-B interaction (σ or agostic) usually intends to reach the B-H bond activation. So in addition of the above discussed pathways, the other two reaction pathways based on the B-H activation strategy have also been calculated but definitely excluded. Please see Figure S3 in supporting information for more details. 3.1.3 Activities of different catalysts Besides of the N,O-chelated Ir(I) complex Cat1, Schafer and Love have also explored the catalytic activities of the N,O-chelated Rh(I) complex Cat2, N,S-chelated Ir(I) complex Cat3, and N,S-chelated Rh(I) complex Cat4. In this section, we would present our theoretical prediction and discussion to these experimental facts. Noteworthy, since the hydride transfer has been demonstrated to be the rate-determining step of the whole reaction, unless otherwise specified, the energy barrier of this step was used to predict activities of the various catalysts. M = Ir or M = Rh As shown in Table 1, both experimental results and theoretical predictions indicate the inertness of this transition-metal framework, no matter Ir or Rh, to the hydroboration of alkyl/aryl olefins R2b/R2c and aryl alkyne R2d. The experiment demonstrates no conversion of these three substrates, whilst the energy barriers are predicted to be approximately 30 ~ 42 kcal/mol, indicating the quick hydroboration of these unsaturated compounds can be inhibited by adding Cat1 or Cat2 to the reaction system. For the carbonyl group however, no matter the aryl/alkyl aldehyde R2a/R2f or the aryl ketone R2g, the conversions are all excellent (> 99%), and the energy barriers 15 ACS Paragon Plus Environment


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are predicted to be around 20 kcal/mol (r.t.) or 26 kcal/mol (R2g, 70 °C). All these results are well consistent with each other, which provides further support to the rationality of our selected computational model and method for mechanism study. It is on the basis of the better activity of Cat1 in promoting hydroboration of R2a than Cat2 that the experimentalists employed only the Ir(I) complex for further studies. Table 1. Activities of Cat1/Cat2 and the theoretically predicted energy barriers (ΔG). ΔG Substrate Notation Catalyst Conditions Products1 Conversion (kcal/mol) R2a

Cat1 Cat2

r.t., < 5 min r.t., 24 h

> 99% > 99%

18.0 19.9

R2b

Cat1 Cat2

r.t., 24 h

n.r.

42.1 41.1

r.t., 24 h

n.r.

r.t., < 5 min

n.r.

R2c R2d

Cat1 Cat2 Cat1 Cat2

36.4 35.0 29.6 30.1

R2e

Cat1

r.t., 24 h

60%

28.82

R2f

Cat1

r.t., < 5 min

n.a.3

21.1

R2g

Cat1

70 C, 1 h

> 99%

26.1

1

B = BCy2.

2

The rate-determining step is the coordination of Int1 with R2e to give Int3e.

3

The experimental conversion is not available (n.a.) but results of the competitive

reaction of R2b with R2f (entry 3 in Table 2) has been reported.

phosphoramidate or phosphoramidothioate Beyond of the transition metal center, different phosphoramidate complexes have also been tested. As illustrated in Figure 5, the experimental results reveal that neither the phosphoramidothioate Ir(I) complex Cat3 nor the phosphoramidothioate Rh(I) complex Cat4 is able to capture the borane HBCy2 to form the stable δ-B–H agostic 16 ACS Paragon Plus Environment

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complexes. In order to give some explanation to this experimental observation, we conducted calculations to the reaction of Cat3 with R1. Accordingly, the energy barrier is found to be 20.4 kcal/mol, which is significantly higher than that of the reaction of Cat1 with R1 (10.5 kcal/mol), and actually is even higher than the barrier of rate-determining step of the whole Cat1-catalyzed hydroboration of R2a (18.0 kcal/mol). More importantly, the resulting intermediate Int1-S locates 4.7 kcal/mol higher than the initial reagents, indicating generation of Int1-S is unfavorable in thermodynamics as well.

Figure 5. The experimental results of reactivities of various catalysts with R1, and the theoretically predicted free energy profiles of reactions of Cat1/Cat3 with R1.

All these computational results are in excellent agreement with the experimental observations, demonstrating not only the computational methods and levels that are used in this work are proper for the reaction system, but also that the proposed mechanism going through the MHINS pathway is rational.



3.2 Origin of chemoselectivity inversion With a possible reaction mechanism which is reasonable in both reactivity and chemoselectivity prediction in hand, we have then conducted calculations to the three reported competitive reactions to get deeper insight into the origin of chemoselectivity inversion due to addition of the transition metal catalyst. These systematic researches should have essential significance not only in further verification of the proposed mechanism, but also, even more importantly, in chemoselectivity prediction and manipulation towards the hydroboration of multiple E–C bond with or without application of transition metal catalysts. 3.2.1 Chemoselectivity of three competitive reactions There are three groups of competitive reactions that have been reported by Schafer and Love.37 As listed in Table 2, the experimental results reveal that the hydroboration by free HBCy2 of alkyl-substituted olefin occurs predominantly over both phenyl- and alkyl-substituted aldehydes (entries 1 and 3, respectively), but the styrene is converted a little bit slower than benzaldehyde (entry 2). For the Cat1-catalyzed reactions, however, chemoselectivities of reactions shown in entries 1 and 3 are completely inverted, but the one shown in entry 2 is greatly improved, rather than being inverted. All the theoretically predicted energy barriers (the last column of Table 2) correspond well with these experimental observations. In particular, for the uncatalyzed hydroboration of R2b, it desires energies of 4.4 and 4.3 kcal/mol less than R2a (Pb:Pa = 98%:2%, entry 1) and decanal R2f (Pb:Pf = >99%:0%, entry 3), respectively, but for the catalyzed reactions, the energy barrier to convert R2b is 24.1 and 21.0 kcal/mol higher than that to convert R2a (Pb:Pa = 0%:>99%, entry 1) and R2f (Pb:Pf = 0%:>99%, entry 3), respectively. The energy barrier to convert R2a under catalysis of Cat1 is 18.4 kcal/mol lower than that to convert styrene R2c (Pa:Pc = >99%:0%, entry 2), but if reacts with the free HBCy2, the barriers to convert these two substrates are predicted to be equal (Pa:Pc = 66%:33%, entry 2), which we consider should be due to the so small barrier difference that has beyond the range that DFT can predict precisely. All these results provide further evidence to the rationality of the selected computational methods and 18 ACS Paragon Plus Environment

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levels in the present study, and as well the necessary data for explorations of the origin of chemoselectivity inversion. It is worthy to specify that the Cat1-catalyzed reaction energy barriers that were used above are barriers of the rate-determining step of the whole reaction, namely the energy difference between TS3 and Int1 (see Scheme 4 and Figure 3).


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Table 2. Experimental results of chemoselectivities of three competitive reactions1 and theoretically predicted energy barrier of each substrate. Entry

Substrates

1

2

3

Notations

Products2

R2a + R2b

Complex

Conversions

ΔG (kcal/mol)

HBCy2 Cat1

2%:98% > 99%:0%

14.8 vs 10.4 18.0 vs 42.1

66%:33%

> 99%:0%

14.8 vs 14.8 (19.4 vs 20.3)3 (14.5 vs 12.2)3 18.0 vs 36.4

> 99%:0% 0%:> 99%

10.4 vs 14.7 42.1 vs 21.1

HBCy2 Cat1

R2a + R2c

HBCy2 Cat1

R2b + R2f

1

Reaction conditions: r.t., < 5 min.

2

B = BCy2.

3

Predictions by using the B3LYP-D3 (red) or ωB97X-D (blue) functionals.


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3.2.2 Origin of chemoselectivity Taking all above discussions about the MHINS pathway into consideration, we can see that the total energy barrier of the Cat1-catalyzed reaction is contributed by the obstacles due to the E=C insertion and the hydride transfer. The reactions afterwards are irreversible. Accordingly, we conclude that the chemoselectivity can be determined by the different potential of the competitive unsaturated substrates to interact with the metal center along with the different resistance from the hydride transfer. In order to explore the origin that affects the E=C insertion, we have conducted analysis to the frontier molecular orbitals (FMOs) of Int1 and R2s. As it is displayed in Figure 6, the lowest unoccupied molecular orbital (LUMO) of Int1, which is predominantly contributed by the Ir(p) (0.22) and Ir(d) (0.17) atomic orbitals of the Ir6 atom, shows significant potential to accept electrons of the occupied molecular orbital perpendicular to the square planar coordination field. From the occupied molecular orbitals of the various substrates we can see that, due to the polarization of the carbonyl group, the aldehyde tends to form a typical σ coordination bond with the metal center by using its second highest occupied molecular orbital (HOMO–1) rather than interacts using its HOMO because the HOMO is symmetrically unmatched with the LUMO of Int1. The olefins would interact with the Ir6 atom through donating the π electrons of the vinyl group to the vacant d orbital of the metal center. In the context of this studied system, the π→p/d coordination should be less effective than the σ→p/d donation because edging the vinyl group into the coordination field would inevitably give rise to more severe distortion of Int1, especially disturbing to the δ-B-H agostic bond (see Figure S4 in supporting information). So it is rational to infer that the aldehyde would combine with the transition metal catalyst preferentially over the olefins. Figure 7 illustrates the specific contributions from the two reaction processes. It is easy to found that the energy barriers due to multiple bond insertion of aldehydes R2a and R2f (14.9 and 19.5 kcal/mol, respectively) are significantly lower than that of the olefin R2b and R2c (30.0 and 26.1 kcal/mol, respectively). 21 ACS Paragon Plus Environment


Figure 6. The FMO analysis to Int1 and R2s.

Figure 7. Contributions of energy barriers due to the E=C insertion and hydride transfer, along with the NBO charges populated on the C4 atom in Int4.

In regarding the hydride transfer, it is reasonable to propose that the electrophilicity of the C4 atom in Int4 should be largely responsible. In particular, the more electrophilic the C4 atom is, the easier the transfer should be. The natural bond orbital (NBO)77-79 charge calculations provide quantitative verification to this proposal. As shown in Figure 7, we can easily figure out the negative correlation between NBO charges and the energy barrier. Fundamentally, the polarization of the carbonyl group 22 ACS Paragon Plus Environment

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leads to not only the active nucleophilic center (O3) to form the σ coordination with the transition metal, but also the active electrophilic center (C4) to facilitate the hydride transfer. As for the direct hydroboration, we consider the energy gap between the effective interaction FMOs and also the interaction model should be mainly responsible for the reactivity of various substrates. As displayed in Figure 8, the LUMO of R1 appears to be a quasi π orbital which forms by the hyperconjugation between the vacant p orbital of the B1 atom and s orbital of the H2 atom. In Figure 6, the HOMOs indicate that the olefins (R2b and R2c) has typical π bonding electrons around the C3=C4 double bond, but the aldehydes (R2a and R2f) would donates electrons from the HOMO-1 because the symmetry of the HOMO is different with that of the LUMO of R1. This tends to give wider FMO gap. From Figure 8 we can see the HOMO of R2b and R2c locates higher than the HOMO-1 of R2a and R2f, which indicates smaller FMO gap for olefin than aldehyde. This provides partial illustration to the selectivity of entries 1 and 3 listed in Table 2. Furthermore, because of polarization of the carbonyl group, the electron density around the C4 atom of the aldehyde has been largely reduced, making the π delocalization deformed to be the more like lone pair electrons population. As a result, the overlap between HOMO–1 of aldehyde and the π-like LUMO of R1 would be less effective than that between HOMO of olefin and LUMO of R1. This corresponds well with the experimental preference of hydroboration of alkyl aldehyde R2b over alkyl and aryl olefins R2a and R2f.

Figure 8. The FMO energy analysis to R1 and R2s. 23 ACS Paragon Plus Environment


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In addition, the effective FMO interaction mainly contributes to facilitate bonding of the boron atom with the terminal group of the substrate, but in regarding migration of the hydride, it should be basically affected by the electrophilicity of the C4 atom. The Parr functions80 Pk+ and Pk– are effective indexes to evaluate the electrophilicity and nucleophilicity of specific atoms in a molecule, respectively, so we calculated the Pk+ at the C4 atom in the four substrates. The results are listed in Table 3. Due to the conjugation effect of electron donating by the benzyl group, the electrophilicity of the C4 atom in the benzyl aldehyde R2a or olefin R2c is less significant than that in the alkyl aldehyde R2f or olefin R2b. In addition, considering the polarization of the carbonyl group, the highly electronegative oxygen atom would lead to the more significant electrophilicity of the C4 atom in the aldehyde R2a/R2f than that in the olefin R2c/R2b, respectively. As a result, the C4 atom shows outstanding electrophilicity in all substrates except R2c, which could even lead to inversion of the chemoselectivity of olefin over aldehyde.

Table 3. The Pk+ at the C4 atom in R2s. Substrates

R2a

R2b

R2c

R2f

Pk+ (C4)

0.223

0.362

0.048

0.494

Taking all above discussions into consideration, we conclude that the energy gap between the effective interaction FMOs and interaction model should be mainly responsible for the preference of olefin over aldehyde when react with free HBCy2, but the substituent effect of the conjugated aromatic group may inverse the selectivity through reducing the electrophilicity of the C4 atom.

4. Conclusion In summary, this paper presents a DFT study to the mechanistic details of the hydroboration of various unsaturated functional groups using free HBCy2 or captured 24 ACS Paragon Plus Environment

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HBCy2 by the N,O-chelated Ir(I) complex. The calculated results support the formation of a loose 3-center π complex before the 4-center transition state when using free HBCy2 and suggest the MHINS pathway for the reaction with captured HBCy2. Insertion of the multiple bonds and the hydride transfer are verified to both contribute to the energy barrier of the whole catalyzed reaction (except the nitrile). The FMO combined with NBO and Parr function explorations suggest that it is the conversion of the more favored bonding group from the typical delocalized π electrons in olefins to the polarized lone pair electrons in aldehyde that should be fundamentally responsible for the chemoselectivity inversion when using the transition metal catalyst.

Supplementary Information The flexible scanning curve to the dihedral angle of ∠ O3Ir6O5B1 from the optimized structure of Int3a, the optimized structures involved in the MHINS pathway, the possible reaction pathways based on the B-H activation strategy, superposition of the optimized geometries of Int1 with the Int1 moiety in Int3a and Int3b, list of related energies and Cartesian coordinates of all structures involved in this work. This material is available free of charge via the internet at http://pubs.acs.org.

Notes The authors declare no competing financial interest

Acknowledgements The work described in this study was supported by the National Natural Science Foundation of China (No. 21503191) and the China Postdoctoral Science Foundation (No. 2015M572115).

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Table of Contents


Unravelling the Origins of Hydroboration Chemoselectivity Inversion

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