Impact of Ligand and Silane on the Regioselectivity in Catalytic

Apr 4, 2016 - Hengbin Wang , Gang Lu , Grant J. Sormunen , Hasnain A. Malik , Peng Liu , John Montgomery. Journal of the American Chemical Society ...
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Impact of Ligand and Silane on the Regioselectivity in Catalytic Aldehyde−Alkyne Reductive Couplings: A Theoretical Study Tao Liu† and Siwei Bi*,‡ †

Department of Chemistry and Chemical Engineering, Jining University, Qufu 273155, Shandong Province, People’s Republic of China ‡ School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong Province, People’s Republic of China S Supporting Information *

ABSTRACT: The reaction mechanisms of the (NHC)Ni(0)catalyzed aldehyde−alkyne reductive couplings with silanes as reducing agent have been theoretically investigated with the aid of DFT calculations. The impacts of N-heterocyclic carbene (NHC) ligands and silanes on the reversal of regioselectivity and the rate-limiting step alteration were rationalized. It is found that the steric effects play a dominant role. The reversal of the regioselectivity is found to be related to the switching of the steric effect, from the aldehyde phenyl hindrance with the adjacent alkyne substituent to the NHC ligand hindrance with the adjacent alkyne substituent, when the NHC ligand employed is changed from small to large. The rate-limiting step alteration caused by using bulkier silanes is due to the generated strong steric effect, which makes the σ-bond metathesis transition state relatively high in enthalpic energy, thus with the entropy penalty making the metathesis step rate-limiting instead of the oxidative cyclization step.

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INTRODUCTION

Scheme 1. Mechanism of Nickel-Catalyzed Aldehyde− Alkyne Reductive Couplings Using Silane Reducing Agents

The control of selectivity of reactions, especially for the addition reactions to nonpolar π-components (e.g., alkynes), represents a considerable challenge in the development of new synthetic transformations.1 In these reactions, substrates that lack steric or electronic biases typically undergo regiochemically unselective additions. The reactions with biased structures are sometimes selective, but the selectivity is often difficult to reverse. Regiochemical reversal is an effective regiocontrol strategy, in which more than one regiochemical product can be selectively accessed by employing substrate direction strategies or by altering the mechanism2 and rate-limiting step3 in the catalyst system. The nickel-catalyzed reductive coupling of aldehydes with alkynes, which has been widely studied, is a representative reaction class where regiochemical reversals can be achieved through changing the ligand environment on nickel.4 The general reaction mechanism for the above-mentioned nickel-catalyzed aldehyde−alkyne reductive couplings using silane reducing agents is illustrated in Scheme 1.5 Oxidative cyclization of the Ni(0)−aldehyde−alkyne complex (A) affords a five-membered metallacycle (B), and then σ-bond metathesis of the silane Si−H with the O−Ni bond follows to generate the ring-opening intermediate (C). Finally, reductive elimination occurs to produce the product and regenerate the nickel catalyst. The oxidative cyclization (A → B) or the σ-bond metathesis (B → C) is considered as the rate- and © XXXX American Chemical Society

regiochemistry-limiting step,5,6 based on different ligand, silane, and substrate structures. Recently, Montgomery and co-workers found that a rational change in the regioselective and rate-limiting step of phenyl propyne−benzaldehyde reductive couplings leads to a significantly improved regiocontrol strategy using commercially available N-heterocyclic carbene (NHC) ligands and silanes (Scheme 2).6 They disclosed that an interplay of silane structure and ligand structure in these reactions could tune the Received: February 13, 2016

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Scheme 2. Montgomery’s Nickel-Catalyzed Phenyl Propyne−Benzaldehyde Reductive Couplings Using Silane Reducing Agents

Figure 1. Gibbs free energy diagrams calculated for the NiL1-catalyzed reaction R1 + R2 + Et3SiH. The relative Gibbs free energies and relative enthalpic energies (in parentheses) are given in kcal/mol. I stands for the IMes ligand, prox and dist represent the large group proximal or distal to the forming bond, and Et stands for Et3SiH.

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regiocontrol ability via the alteration in reversibility of a key step that allows highly regioselective outcomes. A full understanding of the reaction mechanisms is still, to date, a major challenge for experimentalists as well as theoreticians.7 In Montgomery’s experimental study,6 the origins leading to different products using different ligands, silane reducing agents, and substrates and how to obtain the desired product through regiochemical reversal still remain unclear, although the reaction mechanisms were generally proposed. To address the question, a detailed investigation on the reaction mechanisms is needed. In this work, we choose theoretical studies as an available tool to explore the reaction mechanisms and interpret the experimental observations. We expect the understanding of the reactions with regiochemistry reversals could be a benefit in the design of new related reactions.

COMPUTATIONAL DETAILS

All the structures were optimized and characterized to be energy minima (zero imaginary frequencies) or transition states (one imaginary frequency) at the B3LYP8/BSI level, in which BSI denotes the LanL2DZ9 basis set for Ni and 6-31G(d,p) for nonmetal atoms. The energies calculated were then improved by M0610/BSII singlepoint calculations in tetrahydrofuran solution, which took the solvent effects into account by using the PCM11 solvent model. BSII denotes the SDD12 basis set for Ni and 6-311+G(d,p) for nonmetal atoms. The thermal corrections for enthalpies and Gibbs free energies were carried out at 298.15 K and 1 atm, by using B3LYP/BSI harmonic frequencies. When necessary, intrinsic reaction coordinate (IRC)13 calculations were conducted in order to verify the transition states actually connecting the two corresponding minima. In all of the figures that contain potential energy profiles, calculated relative Gibbs free energies (kcal/mol) are presented and relative enthalpic energies (kcal/mol, in parentheses) are also given for reference. Unless otherwise stated, the Gibbs free energies are used to discuss the energetics involved in the B

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Figure 2. Geometric structures with key structural parameters of the transition states involved in the reaction R1 + R2 + Et3SiH catalyzed by NiL1 (L1 is a relatively less bulky NHC ligand). The hydrogen atoms not participating in the reaction have been omitted for clarity. All the transition states have been given in Figure 1. Bond distance is given in Å. I stands for the IMes ligand, prox and dist represent the large group proximal or distal to the forming bond, and Et stands for Et3SiH. reaction. All the calculations were carried out with the GAUSSIAN 09 packages.14 The previous computational studies illustrated a significant entropic penalty associated with the σ-bond metathesis step in related Nicatalyzed alkyne−aldehyde couplings.5d,e It should be noted that the ideal gas-phase model intrinsically overestimates the entropic contributions,15−17 and thus the development of general schemes to correct the overestimation of entropic contributions is desired. Yu et al.15 have carried out a comparison between the entropies experimentally determined and those computed with the ideal gas model and demonstrated that the latter could overestimate entropic contributions by 50−70% as compared to the former. In view of the overestimation of entropies with the ideal gas-phase model, we applied a scaling factor of 0.5 to the gas-phase entropic contributions to correct the free energies for 2:1 and 1:2 transformations. Such a correction has been applied in other theoretical studies.16,17

Ligand. In this section, we examine the regioselectivity of the reaction shown in Scheme 2 with a small NHC ligand in the Ni(0) catalyst. The silane R3SiH employed is small with R = Et. Based on the general reaction mechanism proposed in Scheme 1, the detailed Gibbs free energy diagrams for the Ni-induced reaction of phenyl propyne (R1) with benzaldehyde (R2) were calculated (see Figure 1). The catalyst is denoted as NiL1 (L1 = IMes with methyl groups at the benzene rings). The first stage is an oxidative cyclization process (NiL1 + R1 + R2 → I-prox-3 or I-dist-3). Binding of NiL1 with alkyne R1 affords complex I1, where I stands for the IMes ligand. Further coordination of aldehyde R2 to I-1 results in two possible isomeric intermediates, I-prox-2 and I-dist-2, in which different orientations of the alkyne are positioned. prox and dist in Iprox-2 and I-dist-2 represent the large group proximal or distal to the forming bond, respectively. Both intermediates are lower in free energy than I-1, demonstrating strong interaction between complex I-1 and aldehyde R2 despite the bulkiness of the NHC ligand. I-dist-2 is less stable than I-prox-2, which can be attributed to stronger steric hindrance of the NHC ligand L1 with the Ph group of alkyne R1 in I-dist-2 as compared to the hindrance of the NHC ligand L1 with the methyl group of alkyne R1 in I-prox-2. Phenyl is confirmed to have a greater steric effect than methyl.5b Both intermediates are predicted to be in equilibrium because their interconversion is energetically feasible via I-1. For the oxidative cyclization step involving a new C−C bond formation, two transition states, I-dist-TS23 and I-prox-TS23, were located connecting I-dist-2 and I-prox2, giving the 14e T-type cyclization products I-dist-3 and Iprox-3, respectively. Geometric structures of the two transition

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RESULTS AND DISCUSSION In this work, we attempt to investigate the influence of the NHC ligand, silane, and subsituted alkynes on the reaction of (NHC)Ni(0)-catalyzed alkyne−aldehyde reductive couplings using silane as the reducing agent. On the basis of the mechanistic information, we hopefully explore the origins of the regiochemistry reversal and rate-limiting alteration phenomena involved in the coupling reactions. t-BuOK that is added experimentally is used just to remove the HCl in the ligand· HCl and is not involved in the reaction mechanisms. We thus do not consider the base in our calculations, although in some other catalytic systems such bases are often involved in reaction mechanisms.18 1. Influence of NHC Ligands on the Regioselectivity of the Coupling Reactions. 1.1. Influence of a Small NHC C

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Organometallics Scheme 3. Relative Stabilities of Oxidative Cyclization Transition Statesa

a

Among cases (1), (2), (3), and (4), the auxiliary ligands are different. Among cases (1), (5), and (6), the substituents are different. The relative Gibbs free energy difference (ΔG⧧(prox) − ΔG⧧(dist)) in each pair of transition states is given in kcal/mol.

reduced to 0.9 kcal/mol from 3.1 kcal/mol between I-prox-3 and I-dist-3. Clearly, the weaker steric hindrance of L1 with the methyl in I-prox-3 favors the binding of silane with the metal center. The σ-bond metathesis is followed to give the hydrido vinyl Ni complexes I-dist-5Et and I-prox-5Et, featuring a fourcoordinate and square planar 16e configuration. The Si···H distances calculated in I-dist-TS45Et (1.78 Å) and I-prox-TS45Et (1.79 Å) indicate that the former is a relatively earlier transition state compared to the latter, consistent with the calculated results that the former is more stable than the latter. The metathesis step is both kinetically and thermodynamically favorable because of the weakness of the Si−H bond. The last step is the C(sp2)−H reductive elimination from Ni(II), producing the prox and dist products and regenerating the Ni(0) catalyst. The two transformations leading to prox and dist products are also confirmed to be both kinetically and thermodynamically favorable. The activation barriers via transition states I-prox-TS56Et and I-dist-TS56Et are 11.8 and 8.9 kcal/mol and the reaction energies for the two steps are 18.8 and 14.4 kcal/mol, respectively. The reductive elimination product I-prox-6Et becomes more stable than I-dist-6Et, mainly due to the different coordination modes involved in the two species. An η2-CC→Ni mode is present in I-prox-6Et, while an η2-Ph→Ni mode is present in I-dist-6Et, which was proved by IRC calculations. In summary, when the small NHC ligand L1 and the small silane Et3SiH are employed, both the rate- and regioselectivity-limiting step is the oxidative cyclization of R1 and R2 induced by the Ni(0) catalyst. Other steps are found to proceed quite smoothly. Experiments also demonstrated that altering the size of the auxiliary NHC ligand and the substituent in R3SiH could lead to regiochemical reversal and rate-limiting alteration for the reaction studied in this work. Analyzing relative stabilities of the oxidative cyclization transition states with different substituted groups and different sizes of auxiliary NHC ligands is hence desirable and beneficial. Scheme 3 presents the Gibbs free energy difference (ΔΔG⧧) for each pair of oxidative cyclization transition states. We first examine the influence of auxiliary NHC ligands on the relative stabilities of oxidative cyclization transition states. Cases (1)−(4) present the Gibbs free energy difference for each pair of transition states with different auxiliary ligand sizes. It is found that the energy difference is

states together with key structural parameters are shown in Figure 2. As seen from Figure 1, the two competitive oxidative cyclization steps are identified to be rate-limiting for accessing the two isomeric prox and dist products, respectively. I-distTS23 is calculated to be more stable than I-prox-TS23 by 2.3 kcal/mol, consistent with the experimental fact that the product yield ratio is prox:dist = 2:98. The relative stability of the two transition states can be attributed to the relative steric hindrances of the aldehyde phenyl with the alkyne phenyl in I-prox-TS23 vs the aldehyde phenyl with the alkyne methyl in Idist-TS23. In other words, the steric hindrances between L1 and the alkyne methyl in I-prox-TS23 and that between L1 and the alkyne phenyl in I-dist-TS23 are just subordinate effect factors. Therefore, the greater steric effect of phenyl leads to less stability of I-prox-TS23 as compared to I-dist-TS23. One more thing to be noted is the influence of the α-substituent (relative to the metal) in the alkyne. Generally, an electron-withdrawing group at the α-position favors the stability of complexes, while an electron-donating group does not. But we found no contribution was found to the stability of I-dist-TS23 with an electron-withdrawing α-phenyl as compared to the situation in I-prox-TS23 with an electron-donating α-methyl. The evidence for the argument is that the Ni−C(sp2) (CH3) bond in I-proxTS23 is even slightly shorter than the Ni−C(sp2) (Ph) bond in I-dist-TS23 (1.81 vs 1.82 Å), which may arise from the weaker steric hindrance of L1 with methyl in the former transition state than with the phenyl in the latter. In contrast to the relative stability of I-prox-2 vs I-dist-2, the cyclization product I-prox-3 is less stable than I-dist-3, clearly arising from the stronger steric effect of the aldehyde phenyl with the alkyne phenyl in Iprox-2 as compared to that of the aldehyde phenyl with the alkyne methyl in I-dist-2. The greater energy difference between I-prox-3 and I-dist-3 (3.1 kcal/mol) as compared to that between I-prox-TS23 and I-dist-TS23 (2.3 kcal/mol) is a result of the C−C bond length decrease from transition state to cyclization product, resulting in increased steric hindrance and thus enlarging the energy gap. The second stage is the σ-bond metathesis between Si−H and O−Ni (I-prox-3 or I-dist-3 + Et3SiH → I-prox-5Et or Idist-5Et). Addition of Et3SiH to I-dist-3 and I-prox-3 affords the σ-complexes I-dist-4Et and I-prox-4Et (Et stands for Et3SiH). The energy gap between I-prox-4Et and I-dist-4Et is D

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Figure 3. Gibbs free energy diagram calculated for the NiL2-catalyzed reaction R1 + R2 + Et3SiH. The relative Gibbs free energies and relative enthalpic energies (in parentheses) are given in kcal/mol. S stands for the SIPr ligand, prox and dist represent the large group proximal or distal to the forming bond, and Et stands for Et3SiH.

Figure 4. Geometric structures with key structural parameters of the transition states involved in the reaction R1 + R2 + Et3SiH catalyzed by NiL2. The hydrogen atoms not participating in the reaction have been omitted for clarity. Bond distance is given in Å. All the transition states have been given in Figure 3. S stands for the SIPr ligand, prox and dist represent the large group proximal or distal to the forming bond, and Et stands for Et3SiH.

E

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Figure 5. Gibbs free energy diagrams calculated for the NiL2-catalyzed reaction R1 + R2 + (i-Pr)3SiH. The relative Gibbs free energies and relative enthalpic energies (in parentheses) are given in kcal/mol. S stands for the SIPr ligand, prox and dist represent the large group proximal or distal to the forming bond, and Pr stands for (i-Pr)3SiH.

systematically decreased (4.5 → 3.4 → 2.3 → 0.9 kcal/mol) with bulkier NHC ligands employed, which can be attributed to the increased steric hindrance of the bulkier NHC ligand with the phenyl group in the dist transition state. This theoretical prediction indicates that the regioselectivity can be reversed when the NHC ligand employed is bulky enough. We then examine the influence of substituents on the alkyne on the relative stabilities of oxidative cyclization transition states. In case (5), a t-Bu substituent is involved. As compared to case (3), the relative stability for dist vs prox transition states is reversed in case (5), clearly due to the stronger Ph vs t-Bu steric repulsion in the dist transition state. The calculation results are in agreement with Houk’s prediction that the relative stabilities of the oxidative cyclization transition states are mainly controlled by steric effects in their theoretical study on the Ni-catalyzed reductive couplings of alkynes and aldehydes.5b When benzaldehyde in case (3) is modeled by formaldehyde, case (6) is generated with the prox transition state being apparently more stable than the dist transition state. Clearly, the electronic factor instead of the steric effect becomes the dominant role. The Ph-substituted acetylenic carbon, which is more negatively charged than the Me-substituted acetylenic carbon, favors nucleophilic attack at the aldehyde carbon in the prox transition state. In summary, the energy differences become smaller and even lead to energy reversal when bulkier NHC ligands are employed in the (NHC)Ni−benzaldehyde− (phenylpropyne) oxidative cyclization. For a fixed (NHC)Ni catalyst, the relative stability for the pair of dist and prox transition states is dependent on the steric effect when the substituents are bulky enough and dependent on the electronic factor when the substituents are small enough. 1.2. Influence of Sterically Bulky NHC Ligand. For exploring the regioselectivity reversal of the coupling reactions, the larger SIPr ligand was employed experimentally. For a theoretical investigation, we also use the reaction experimentally studied

(R1 + R2 + Et3SiH) catalyzed by NiL2, where L2 is a sterically bulky NHC ligand when compared with L1. The detailed free energy diagrams for the reaction leading to product complexes S-prox-6Et and S-dist-6Et were calculated (Figure 3), where S stands for the SIPr ligand, prox and dist represent the large group proximal or distal to the forming bond, and Et stands for Et3SiH, respectively. The catalyst is denoted as NiL2 (L2 = SIPr). Geometric structures with key structural parameters of the transition states related to σ-bond metatheses and reductive eliminations are displayed in Figure 4. Similar to the NiL1-catalyzed reaction mechanism, the NiL2catalyzed reaction also includes three steps, oxidative cyclization of benzaldehyde with phenyl propyne, σ-bond metathesis of Si−H with O−Ni, and C(sp2)−H reductive elimination. As shown in Figure 3, the three-component NiL2−aldehyde− alkyne intermediates S-prox-2 and S-prox-2 become less stable than the NiL2−alkyne complex S-1, clearly due to significant steric bulkiness of L2, which makes the binding of the three components relaxed. Similar to the reaction catalyzed by NiL1, the rate- and regioselectivity-limiting step is still the oxidative cyclization process. But contrarily, the relative stabilities of the dist and prox oxidative cyclization transition states are reversed in the reaction catalyzed by NiL2. The dist transition state Sdist-TS23 becomes less stable than the prox one S-prox-TS23 by 0.9 kcal/mol. The small Gibbs free energy difference of the two transition states (0.9 kcal/mol) coincides with the experimental product ratio (prox/dist = 58:42). From S-dist-2 and S-dist-2 to S-dist-4Et and S-dist-4Et, all the dist species are less stable than the prox species as a result of strong steric hindrances of L2 with the α-Ph. Different from the σ-bond metathesis step catalyzed by NiL1 (Figure 1), adducts prior to metathesis cannot be afforded due to strong repulsive interaction between Et3SiH and the larger L2 ligand. It is worth noting that S-distTS45Et becomes more stable than S-prox-TS45Et, similar to the relative stability of I-dist-TS56Et vs I-prox-TS56Et. The F

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Figure 6. Gibbs free energy diagrams calculated for the NiL2-catalyzed reaction R1 + R2 + (t-Bu)2MeSiH. The relative Gibbs free energies and relative enthalpic energies (in parentheses) are given in kcal/mol. S stands for the SIPr ligand, prox and dist represent the large group proximal or distal to the forming bond, and Bu stands for (t-Bu) 2MeSiH.

still the oxidative cyclization process, which is consistent with the experimental observations. The energy difference between the two rate-limiting transition states (S-dist-TS34Pr and Sprox-TS23) is 1.7 kcal/mol, consistent with the experimental observations that the product ratio is prox:dist = 83:17. In the last steps of reductive elimination, similar to the situation shown in Figure 3, the prox transition state S-prox-TS45Pr is higher in energy than the dist one S-dist-TS45Pr. In summary, the oxidative cyclizations and the σ-bond metatheses become competitive when sterically crowded silane molecules are employed. Clearly, introduction of sterically crowded silanes generates a strong steric effect, leading to the activation barriers to the σ-bond metatheses increasing dramatically. We now move to the examination of the reaction R1 + R2 + (t-Bu)2MeSiH catalyzed by NiL2 where the significantly bulkier t-Bu substituent in silanes is used. Figure 6 presents the energy profiles for the reaction accessing the prox and dist products. Geometric structures together with key structural parameters are shown in Figure 7. In comparison with the σ-bond metatheses in the reactions with Et3SiH and (i-Pr)3SiH as the reducing agents, the activation barriers for the metatheses step with (t-Bu) 2MeSiH as reducing agent are further heightened. As shown in Figure 6, the two transition states for σ-bond metatheses, S-dist-TS34Bu and S-prox-TS34Bu, are higher in free energy than the two transition states, S-dist-TS23 and S-proxTS23, for oxidative cyclization by 3.6 and 1.0 kcal/mol, respectively. Clearly the σ-bond metatheses become the ratelimiting steps. Following the context mentioned above, a much stronger steric effect caused by introduction of the more sterically crowded silane is responsible for the barrier heightening of the σ-bond metathesis. The free energy difference between the two rate-limiting transition states Sdist-TS34Bu and S-prox-TS34Bu is 3.5 kcal/mol, in line with

calculated results imply that the Ph−Ph repulsion is the major factor leading to instability of the prox transition states, whereas the L2−Ph repulsion in dist transition states is significantly reduced as a result of the L2−Ni−C(sp2) unit being almost linear. In summary, when the bulkier catalyst NiL2 is employed, the rate- and regioselectivity-limiting steps are still the oxidative cyclization process, but the regioselectivity is reversed. Strong steric repulsions between the NHC ligand L2 and the Ph from alkyne are responsible for instability of the dist oxidative cyclization transition state S-dist-TS23. 2. Influence of Silanes with Different Substituents. In this section, we examine the influence of silanes on the ratelimiting issues of the two reactions catalyzed by NiL2, R1 + R2 + (i-Pr)3SiH and R1 + R2 + (t-Bu)2MeSiH. The free energy diagrams calculated for the two catalytic reactions are shown in Figures 5 and 6, respectively. The structures of transition states together with key geometric parameters are displayed in Figure 7. The difference of the two reactions with the one (R1 + R2 + Et3SiH) catalyzed by NiL2 is the silanes employed. So the oxidative cyclization step experienced in these reactions is the same. The free energy barriers for the σ-bond metathesis step in Figure 5 leading to prox- and dist-products are 18.3 and 19.9 kcal/mol, respectively. It is noteworthy that the barriers for the σ-bond metatheses between Si−H and Ni−O are significantly increased as compared with those when Et3SiH is employed. As seen from Figure 5, the metathesis transition state S-dist-TS34Pr becomes even higher than the oxidative cyclization transition state S-dist-TS23, and S-prox-TS34Pr becomes close to S-proxTS23 in free energy. On the basis of the computational results, it is predicted that the rate-limiting step for the reaction accessing the dist product is switched from oxidative cyclization to σbond metathesis, while the one for accessing the prox product is G

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Figure 7. Geometric structures with key structural parameters of the transition states involved in the reaction R1 + R2 + (i-Pr)3SiH and R1 + R2 + (t-Bu)2MeSiH catalyzed by NiL2. The hydrogen atoms not participating in the reactions have been omitted for clarity. Bond distance is given in Å. The transition states have been given in Figures 5 and 6. S stands for the SIPr ligand, prox and dist represent the large group proximal or distal to the forming bond, Pr stands for (i-Pr)3SiH, and Bu stands for (t-Bu)2MeSiH.

experimental observations that the product ratio of prox:dist > 98:2. 3. Influence of Substituents on the Alkyne Substrate. The influences of auxiliary HNC ligand and substituents on the silane R3SiH on the rate-limiting and regiocontrol issues of the reaction R1 + R2 + R3SiH catalyzed by Ni(NHC) have been rationalized. In this section, we examine the influence of the substituents on the alkyne substrate on the reductive coupling reaction. The reaction R1′ + R2 + (i-Pr)3SiH catalyzed by NiL2 is employed, corresponding to the experiment’s work. The difference of the reaction from the one shown in Figure 5 is that the methyl and phenyl on the alkyne substrate are replaced with ethyl and n-propyl. Free energy diagrams for the reaction leading to formation of the prox and dist products are presented in Figure 8. Geometric structures of the transition states involved in the reaction together with key structural parameters

are in Figure 9. The activation barrier difference for the two oxidative cyclization transition states Pr-S-dist-TS23 and Pr-Sprox-TS23 is only 1.1 kcal/mol, slightly greater than that between S-dist-TS23 and S-prox-TS23 involved in the reaction R1 + R2 + (i-Pr)3SiH catalyzed by NiL2 (0.9 kcal/mol) (Figure 5). As analyzed in Figure 5, the relative stability of S-dist-TS23 and S-prox-TS23 mainly arises from the steric effects of L2 with phenyl in the former vs L2 with methyl in the latter. The decreased enthalpy difference for each pair of oxidative cyclization steps shown in Figures 5 and 8 (from 0.8 to 0.6 kcal/mol) may be attributed to the more similar steric effects of propyl vs ethyl in R1′ as compared to phenyl vs methyl in R1. The increased free energy difference (0.9 to 1.1 kcal/mol) can be thus deduced to be a result of increased entropy penalty. For the σ-bond metatheses, Pr-S-dist-TS34Pr becomes more stable than Pr-S-prox-TS34Pr by 0.9 kcal/mol, probably controlled by H

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Figure 8. Gibbs free energy diagrams calculated for the NiL2-catalyzed reaction R1′ + R2 + (i-Pr)3SiH. The relative Gibbs free energies and relative enthalpic energies (in parentheses) are given in kcal/mol. S stands for the SIPr ligand, prox and dist represent the large group proximal or distal to the forming bond, Pr stands for one of the reactants n-propyl, and Pr stands for (i-Pr)3SiH.

reducing agent (blue line, Figure 3), the transformation S-proxTS23 + Et3SiH → S-prox-TS34Et is calculated as follows, ΔG (−18.4) = ΔH (−27.6) + (−TΔS) (9.2) (given in kcal/mol). The above results show that the entropy penalties caused by introduction of (t-Bu)2MeSiH and Et3SiH are similar (9.3 vs 9.2 kcal/mol), but the σ-bond metathesis transition state Sprox-TS34Et is far from being rate-limiting. Thus, we can draw from the above discussion that if the σ-bond metathesis process becomes rate-limiting, the enthalpy difference of the transition states between oxidative cyclization and σ-bond metathesis must be small enough. The effective method to meet the requirement is to employ significantly sterically crowded silanes, with which a strong steric effect is generated, thus enabling the σ-bond metathesis transition state to be high in energy. In summary, bulky silane is essential despite the inclusion of the entropy penalty if the σ-bond metathesis is made to be rate-limiting.

the two steric effects, L2 with Pr or Et, and Ph with Pr or Et. In summary, similar steric effects caused by propyl and ethyl lead to similar energies of each pair of transition states related to oxidative cyclizations and σ-bond metatheses. In Figure 5, the σ-bond metathesis is predicted to be rate-limiting for the reaction leading to the dist product. In this reaction, the oxidative cyclization for accessing the dist product is found to be rate-limiting. One key factor is that the steric hindrance of L2 with Pr in Pr-S-dist-TS34Pr is weakened in comparison with that of L2 with Ph in S-dist-TS34Pr (Figure 5). The small energy difference of Pr-S-dist-TS23 with Pr-S-prox-TS23 (1.1 kcal/ mol) gives rise to the mixture of the prox and dist products, in line with the experimentally obtained product yield ratio (prox:dist = 68:32). 4. Comments on the Influence of the Entropy Penalty on the σ-Bond Metatheses. One can see from Figure 6 that the free energies of S-dist-TS34Bu and S-prox-TS34Bu are predicted to be rate-limiting with the highest free energies, but the enthalpy energies of the two transition states are markedly lower than those of the two oxidative cyclization transition states S-dist-TS23 and S-prox-TS23, respectively. Clearly, the entropy penalty is involved in the σ-bond metatheses process which contributes to the free energy heightening of the transition states. For example, in the reaction accessing the prox product (the blue line), the transformation S-prox-TS23 + (tBu)2MeSiH → S-prox-TS34Bu is calculated as follows, ΔG (1.0) = ΔH (−8.3) + (−TΔS) (9.3) (given in kcal/mol). The results indicate that the entropy penalty contributes to the free energy increasing of S-prox-TS34Bu to make it rate-limiting, although the enthalpy change is decreased by 8.3 kcal/mol. However, in the reaction accessing the prox product with Et3SiH as the

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CONCLUSIONS

Rate-limiting and regiocontrol reversal in organometallic catalysis is still quite challenging, and theoretical studies are rare. In this work, the (NHC)Ni(0)-catalyzed aldehyde−alkyne reductive couplings with silanes as reducing agent have been theoretically investigated with the aid of DFT calculations. Especially, the impacts of the NHC ligands and silanes on the reversal of rate- and regioselectivity-limiting steps were rationalized. It is found that the steric effects play a dominant role. (1) When a small NHC ligand is used, the aldehyde phenyl hindrance with the alkyne substituent plays a dominant role. (2) When a more sterically crowded NHC ligand is used, the NHC ligand hindrance with the alkyne substituent at the I

DOI: 10.1021/acs.organomet.6b00127 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

Figure 9. Geometric structures with key structural parameters of the transition states involved in the reaction R1′ + R2 + (i-Pr)3SiH catalyzed by NiL2. The hydrogen atoms not participating in the reaction have been omitted for clarity. Bond distance is given in Å. All the transition states have been given in Figure 8. S stands for the SIPr ligand, prox and dist represent the large group proximal or distal to the forming bond, Pr stands for one of the reactants n-propyl, and Pr stands for (i-Pr)3SiH.

other carbon atom plays a dominant role. (3) When a small silane is used, the little steric effect results in the relatively low energy of the σ-bond metathesis transition state and makes the step non-rate-limiting despite involvement of an entropy penalty. (4) When significantly bulkier silane is used, the strong steric effect results in the relatively high energy of the σbond metathesis transition state and with the inclusion of an entropy penalty makes the step rate-limiting. An in-depth understanding of the reactions with rate-limiting and regiochemistry reversals could be beneficial in designing new related reactions. (5) Previous experimental and theoretical studies4,5 illustrated specific examples where these mechanistic outcomes are possible. Our work now elucidates a more complete rationalization of when changes in ligand, silane, and alkyne will alter the mechanism and rate-determining step of these processes. With this in-depth understanding, the rational design of new strategies for regiochemical reversal will become more readily achieved.

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Optimized Cartesian coordinates (XYZ)

AUTHOR INFORMATION

Corresponding Author

*E-mail (S. Bi): [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was jointly supported by National Natural Science Foundation of China (Nos. 21473100 and 21303073). REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

Text giving the and The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.6b00127. Complete ref 14 and tables giving all computed molecular Cartesian coordinates (PDF) J

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DOI: 10.1021/acs.organomet.6b00127 Organometallics XXXX, XXX, XXX−XXX