Radical Mechanism of Ir III /Ni II -Metallaphotoredox-Catalyzed C(sp 3 )–H Functionalization Triggered by Proton-Coupled Electron Transfer: Theoretical Insight

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE1 Apr 2022Radical Mechanism of IrIII/NiII-Metallaphotoredox-Catalyzed C(sp3)–H Functionalization Triggered by Proton-Coupled Electron Transfer: Theoretical Insight Yu-Jiao Dong†, Bo Zhu†, Yun Geng, Zhi-Wen Zhao, Zhong-Min Su and Wei Guan Yu-Jiao Dong† Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024 †Y.-J. Dong and B. Zhu contributed equally to this work.Google Scholar More articles by this author , Bo Zhu† Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024 †Y.-J. Dong and B. Zhu contributed equally to this work.Google Scholar More articles by this author , Yun Geng Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024 Google Scholar More articles by this author , Zhi-Wen Zhao Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024 Google Scholar More articles by this author , Zhong-Min Su *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024 College of Chemistry, Jilin University, Changchun 130012 Google Scholar More articles by this author and Wei Guan *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202100802 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Photoredox catalysis can be induced to activate organic substrates or to modulate the oxidation state of transition-metal catalysts via unique single-electron transfer processes, so as to achieve challenging C(sp3)–H functionalization under mild conditions. However, the specific reaction mechanism and relevant electron transfer process still need to be clarified. Here, a highly regioselective IrIII/NiII-metallaphotoredox-catalyzed hydroalkylation of asymmetrical internal alkyne with an ether α-hetero C(sp3)–H bond has been investigated by density functional theory (DFT) calculations. A novel radical mechanism was predicted to merge oxidative quenching (IrIII–*IrIII–IrIV–IrIII) and nickel catalytic cycles (NiII–NiIII–NiI–NiIII–NiII) for this C(sp3)–H functionalization to construct C(sp3)–C(sp2) bonds. It consists of seven major steps: the single-electron transfer involved in the photoredox cycle for generating active Ni(I)–chloride complexes, proton-coupled electron transfer process to provide α-carbon-centered tetrahydrofuran (THF) radicals, radical capture by Ni(II), reductive elimination to obtain 2-chlorotetrahydrofuran, alkyne oxidative hydrometallation, inner-sphere electron transfer, and σ-bond metathesis to yield the desired alkyne hydroalkylation product. Importantly, both the thermodynamic performance for redox potentials and the kinetic exploration for energy barriers and electron-transfer rates have also been evaluated for the corresponding electron transfer processes. In addition, the steric effects play a major role in determining the regioselectivity of alkyne oxidative hydrometallation. Download figure Download PowerPoint Introduction The functionalization of C–H bonds to construct C–C and C–X (X = N, O, S, etc.) bonds has been recognized as an active field in current organic research.1–3 It is not only due to the readily available starting materials to satisfy the requirement of organic transformations, but also the natural features of C–H bonds broadly existing in organic molecules, such as accessibility, activity, and selectivity.4 Over the past decades, activation of C–H bonds with a wide variety of directing groups has become an economically attractive synthetic strategy, which plays an important role in determining proximal C–H reactivity.5,6 Also, transition-metal catalysts, by Pd,7–9 Rh,10,11 Ru,12,13 Ir,14,15 and Ni16–18 complexes, are crucial for the functionalization of C–H bonds as a versatile and efficient strategy to construct the C–C and C–X bonds in organic synthesis.19–21 These reactions have been realized using the directing groups strategy,22,23 radical addition,24 the concerted metalation–deprotonation,25 and single-electron transfer (SET),26 respectively. It is still a significant challenge to realize regioselective remote C–H functionalization in the absence of directing groups.4 Therefore, it is highly desirable that a novel strategy can remove basic additives and then broaden the scope of substrates under mild conditions. The visible-light photocatalysis,27–29 because of the natural advantages of the visible light, is attractive for developing important and accessible chemical conversions. Specifically, photoredox catalysis developed simultaneously by Nicewicz and MacMillan,30 Yoon et al.,31 and Stephenson et al.32 were applied to the direct asymmetric alkylation of aldehydes, efficient [2 + 2] enone cycloadditions, and SET instructional tin-free reductive dehalogenation reaction, respectively. In comparison with traditional C–H functionalization, the photocatalyst using its redox properties can directly produce reactive radical species from C–H bond substrates under extremely mild conditions.33 Furthermore, the synergistic catalysis of photocatalyst and transition-metal catalyst has been widely reported by Molander, Gutierrez, Doyle, et al.,34–39 and can be traced back to Pd/Ru cooperative catalytic system. It can convert some substrates to reactive radicals as nucleophilic coupling partners that are subsequently involved in the transition-metal-catalyzed cross-coupling reactions. This electron-transfer-mediated catalysis can break through the inherent limitations of the two-electron pattern and then as an innovative catalytic platform expand the scope of the building various C–C/C–X bonds. Based on the interest in theoretical mechanistic studies of iridium/nickel metallaphotoredox-catalyzed C–O, C–S, and C–N cross-couplings,40–42 we further questioned whether the previously proposed oxidation state modulation mechanism merging oxidative quenching and nickel catalytic cycles or an alternative radical mechanism is applicable to C–H functionalization to achieve C–C cross-couplings. Recently, a photoredox-mediated IrIII/NiII dual-catalyzed hydroalkylation of ether α-hetero C(sp3)–H bond has been achieved to construct C(sp3)–C(sp2) bonds, as shown in Scheme 1.43 Compared with transition-metal catalysis, this dual catalysis requires no basic additive and has wide substrate scope and an excellent regioselectivity of alkyne insertion. Based on the radical trapping experiments, a hypothetical radical mechanism consisting of reductive quenching and nickel catalytic cycles had been proposed to understand the dual IrIII/NiII-catalyzed C–H functionalization. Furthermore, a chlorine radical was speculated to be generated by the visible-light excitation of high-oxidation-state nickel(III) chloride, as shown in Scheme 2 (mechanism A). Next the chlorine radical may abstract an α-hydrogen atom of tetrahydrofuran (THF) to generate a key α-carbon-center radical. On the other hand, a unique photocatalytic strategy in which an excited photocatalyst is employed to directly activate substrates, such as R–H (R = C, Si, and S) bonds, by proton-coupled ET (PCET) process, has been proposed in previous studies.44–46 Thus, it is likely that the PCET process of photoexcited species *IrIII and THF may generate α-carbon-centered radical and the ground-state IrII species (mechanism B in Scheme 2). Subsequently, single-electron reduction of NiII catalyst by IrII generates active NiI and IrIII species. Another plausible mechanism is the oxidative quenching cycle (IrIII–*IrIII–IrIV–IrIII) where an active NiI species is generated via oxidative quenching of photoexcited *IrIII by NiII. Next, the oxidized IrIVCl with THF triggers a PCET process to afford α-carbon-centered THF radical (mechanism C in Scheme 2). Indeed, the generated chlorine radical as an electrophilic species can abstract hydrogen from the electron-rich α-C(sp3)–H bond of ethers via direct hydrogen atom transfer (HAT) using the polar effects.18,47,48 However, the chlorine photoelimination from a charge-transfer excited state of mononuclear nickel(III) complex49 may inevitably trigger a multistep prereaction process. Considering the successive HAT and other steps involved in the C–H functionalization reaction, a high energy barrier might need to be overcome to construct the desired C–C bond. Therefore, how the radical is generated in this radical mechanism of the C–H functionalization by such a dual catalysis still remains ambiguous but a quite crucial issue. In this regard, theoretical calculations complemented with experimental observations can predict enough short-lived reactive intermediates and transition states, and thus disclose the rational reaction mechanism in a more advantageous approach.5,28,50–68 Here, we want to investigate the existing photoredox catalysis, clarify reasonable mechanism and propose the meaningful C–H activation modes for constructing C–C bond. More importantly, we will solve some problems as follows: (1) How do we understand the PCET process induced by the quenching of the excited photocatalyst? (2) What is the origin of regioselectivity in this asymmetrical hydroalkylation reaction? Scheme 1 | Photoredox-mediated IrIII/NiII dual-catalyzed asymmetrical hydroalkylation of ether α-hetero C(sp3)–H bond to achieve C–C cross-coupling. Download figure Download PowerPoint Scheme 2 | Three possible mechanisms regarding α-C(sp3)–H functionalization of THF. Download figure Download PowerPoint Methods All calculations were carried out with the Gaussian 09 package69 using density functional theory (DFT) functional (U)M06.70 Geometry optimizations, together with frequency analyses, were used to verify whether the stationary points are minima without imaginary frequencies or a transition state with only one imaginary frequency conducted in the gas phase to acquire the thermodynamic properties at 333.15 K and 1 atm. Intrinsic reaction coordinate (IRC)71,72 analyses were performed to identify the transition states to connect the correct reactants and products. Here, a mixed basis set approach was employed with LanL2DZ73 for Ir and Ni, 6-31++G(d,p)74 for the α-hydrogen atom of THF, and 6-31G(d)75 for the other main-group elements, respectively. The single-point energies of all stationary points were performed at the (U)M06/[6-311++G(d,p)/SDD76(Ir and Ni)] level. The solvent effect of THF in single-point energies was considered by the SMD77 solvation model. In addition, the translational entropy was corrected with the method developed by Whitesides et al.78 (see Supporting Information for computational details). In this work, all of the DFT calculations employ the default pruned numerical integration grid. To avoid numerical errors in both SCF and frequency calculations, two kinds of pruned numerical integration grids, fine (75, 302) and ultrafine (99, 590), have been used to evaluate the energy barrier of rate-determining step. The result shows that the integral grid has little influence on the energy barriers. In the present calculations, the photoredox-mediated IrIII/NiII dual-catalyzed C–C cross-coupling of THF and unsymmetrical alkynes (3,3-dimethylbut-1-yn-1-yl) benzene ( AL) were selected as the model reactions, where IrIII[dF(CF3)ppy]2(dtbbpy)PF6 was adopted as photocatalyst and abbreviated as Ir III (Scheme 1). Considering the computational cost, the realistic transition-metal catalyst NiII(dtbbpy)Cl2 was simplified to NiII(bpy)Cl2 ( Ni II). In addition, the absorption spectra of Ir III and Ni II were simulated by the time-dependent DFT (TDDFT) calculation at the SMD(THF)/M06/[6-31G(d)/LanL2DZ(Ir and Ni)] level to validate the computational rationality ( Supporting Information Figures S1 and S2). Note that, when the realistic ligand dtbbpy was employed instead of the simplified ligand bpy, the Gibbs activation energy of the rate-determining step does not differ very much, indicating the rationality of simplification ( Supporting Information Table S2). Considering the diversity of oxidation state and spin state of nickel, such as the planar singlet (SNiII) and tetrahedral triplet (TNiII) states of Ni(II) and the doublet (DNiI/III) and quartet (QNiI/III) states of Ni(I) and Ni(III), all species were discussed at the lowest energy spin state in the nickel catalytic cycles ( Supporting Information Tables S3 and S4 and Figure S4). In addition, to evaluate the effects of gas- and solvent-phase optimizations on the ion migration involved in the SET process, we have compared the Gibbs free energies of the key SET processes at two levels ( Supporting Information Figure S5). The calculated results show that the solvent effect of THF has little influence on their gas-phase optimized geometries. Results and Discussion The photomediated α-C(sp3)–H functionalization of THF Generation of α-carbon-centered radical Radical trapping experiments indicate that α-carbon-centered THF radicals participate in the reaction process.43 However, the generation pathway of α-carbon-centered radical needs to be clarified. As described by the above strategies, three generation pathways of α-carbon-centered radical have been examined here (Figure 1). In mechanism A, although T Ni II may be oxidized by photoexcited * Ir III according to the redox potential comparisons ( Supporting Information Table S5), the reductive quenching process of * Ir III with T Ni II to afford Ir II and D Ni III species is predicated to be thermodynamically unfavorable with the Gibbs free energy change (ΔG°) of 13.5 kcal/mol. This reversal is speculated to be due to arduous PF6− migration between iridium and nickel to remain electrically neutral. Such inert photoredox-mediated excited-state SET process has been difficult enough to trigger the next step,31,79 and the photolysis of resultant oxidative product D Ni III and following HAT require ΔG° values of −4.5 and 7.9 kcal/mol, respectively, to deliver the α-carbon-centered THF radical. Thus, such high endothermic reactions induced by the above SET and HAT may not be the most favorable mechanism to produce the carbon-centered radical. Figure 1 | The Gibbs free energy change (ΔG°333.15 in kcal/mol) of selected key steps for generating α-carbon-centered radical in mechanisms A, B, and C. Spin densities for the main intermediates and transition states are given in grey italic font. Download figure Download PowerPoint In comparison with mechanism A, * Ir III could be reductively quenched by THF instead of T Ni II to provide an α-carbon-centered radical and Ir II in mechanism B. However, the whole PCET process is still highly endoergic at 32.0 kcal/mol, and mechanism B can be ruled out. It is noteworthy that the excited photocatalyst may simultaneously serve as a strong 1e-oxidant and -reductant, so the present photoredox catalysis could adopt an oxidative quenching mechanism, in addition to the above two reductive quenching mechanisms. In mechanism C, photoexcited * Ir III is oxidatively quenched by T Ni II via the SET process accompanied by the facile Cl− migration to generate the ground-state Ir IVCl and D Ni I with a ΔG° value of −5.6 kcal/mol, although the difference between E1/2red[IrIV/*IrIII] and E1/2red[NiII/NiI] is very small ( Supporting Information Table S5). Next, a stepwise PCET process between THF and Ir IVCl can release the desired α-carbon-centered THF radical (rather than β-carbon-centered THF radical, Supporting Information Figure S6) and regenerate Ir III to restart the photocatalytic cycle with ΔG° and ΔG°‡ values of −0.6 and 4.8 kcal/mol. Note that the dissociation of HCl from the THF•⋯HCl complex requires a ΔG° value of 4.1 kcal/mol and the HCl is more likely to interact with the α-C center rather than the O of THF• ( Supporting Information Figure S6c). In this stepwise PCET process, the proton transfer will occur prior to the ET through the redox potential comparisons ( Supporting Information Tables S5 and S6). Therefore, both ET steps are thermodynamically accessible for modulating the oxidation state of nickel catalyst and affording the α-carbon-centered radical. Kinetic evaluation for SET processes To further verify the rationality of the mechanism C, the kinetic exploration of ET processes involved in the above oxidative quenching cycle has been performed. The energy profiles of these processes are intuitive in Figure 2. Optimized structures for selected important stationary points in the energy profiles are shown in Supporting Information Scheme S1. First, the calculated absorption spectrum of Ir III is in good agreement with the experimental one and supports the robustness of our theoretical methods ( Supporting Information Figure S1). The strong absorption bands calculated at 292, 300, 341, and 372 nm mainly involve the charge-transfer transitions from the d orbital of iridium center to the ligands (denoted as S0 → SMLCT), localized π–π* transitions within the same phenylpyridine or bipyridine ligand, and the charge-transfer transitions from phenylpyridine ligands to bipyridine ligand ( Supporting Information Figure S3 and Table S1). Thereby, upon excitation by light, Ir III was initially excited to the Frank–Condon region mainly characterized as metal-to-ligand charge transfer (MLCT) and LCT states, as illustrated in Figure 2a. Subsequently, photoexcited * Ir III rapidly relaxes to the minimum state (S1) through internal conversion according to Kasha’s rule. Then the intersystem crossing between a singlet and a triplet electronic state occurs through the singlet–triplet crossing (STC) and the resultant TMLCT relaxes to its minimum state (T1). It is worth mentioning that there is competition between phosphorescence emission and SET from this T1 state. Comparing the rates of phosphorescent radiation (red line, kp = 2.35 × 104 s−1) and SET oxidative quenching (blue line, kSET = 2.22 × 1013 s−1) based on the value of reorganization energy 1, the SET process occurs much more quickly than the emission route; see Supporting Information for computational details of rate calculations. Based on this discovery, the ET processes are expected to play a crucial role in modulating the oxidation state of nickel and activating α-hetero C(sp3)–H bond of THF. Starting from the T1 state of Ir III, the SET oxidative quenching is instantaneously triggered by interaction with the ground state of T Ni II. Next, the excited-state charge-transfer * Ir III/ Ni II complex A (exciplex) is formed. The dimer configurations for * Ir III/ Ni II were initially screened out from the conformers with ≥3% probability in the Boltzmann distribution80 ( Supporting Information Scheme S2), and then the electron coupling values were calculated based on these conformers. To guarantee the ET from * Ir III to T Ni II, a relatively large electron coupling value of 0.058 eV was chosen to discuss the corresponding SET process, as shown in Figure 2b. A shorter π–π stacking distance between phenylpyridine and bipyridine ligands (3.47 Å) can be observed in such optimized dimer complex, which also effectively promotes the SET through stronger electronic coupling. Besides, the small reorganization energies with 0.13 and 0.20 eV could promote the rate of SET process. With structural relaxation and charge redistribution, the exciplex overcomes a very low energy barrier of 0.9 kcal/mol to afford Ir IVCl and D Ni I complexes (blue line in Figure 2a). Note that the energy transfer between T Ni II and * Ir III should not occur because of no overlap between the emission spectrum of Ir III and UV-absorption spectrum of T Ni II.41 Similarly, the PCET process between the resultant Ir IVCl and newcomer THF occurs with an energy barrier of 4.8 kcal/mol, the reorganization energies of 0.14 and 0.42 eV, and the electron-transfer rate of 2.64 × 1010 s−1, respectively. The isomers of THF/ Ir IVCl dimer complex have been also examined ( Supporting Information Scheme S2). Finally, the α-hetero C(sp3)–H bond of THF can be successfully cleaved to afford the desired α-carbon-centered THF radical, and the ground-state Ir III is regenerated. In addition, two nucleophilic substrates N,N′-dimethylacetamide (DMA) and dioxane employed in the experiments were chosen to confirm the feasibility of the mechanism C ( Supporting Information Figure S7). In brief, the ET processes involved in the oxidative quenching cycle have been supported by the kinetic exploration for energy barriers and electron-transfer rates. At present, mechanism C seems to be the only acceptable one. Figure 2 | (a) Energy profiles of ET processes in the oxidative quenching cycle. The kinetic calculating of reorganization energy λ1 and λ2 (eV), electronic free energy change ΔE (kcal/mol), Gibbs activation energy ΔG°⧧ (kcal/mol) and the charge-transfer rate k (s−1). The key characteristic transition points are schematically shown with their orbitals and key distances in Å. (b) The isomers of *Ir III/Ni II complex (exciplex) with the absolute value of their electronic coupling |V (eV)|. Download figure Download PowerPoint The most favorable catalytic cycle The whole nickel catalytic cycle In addition to the iridium photoredox cycle, the possible nickel catalytic cycles must be evaluated. In view of the previous studies about alkyne insertion reactions,81,82 three probable nickel catalytic cycles (Scheme 3) have been put forward to understand the present C–C cross-coupling reaction of THF and asymmetrical alkynes, which were evaluated through DFT calculations in Figures 3 and 4 ( Supporting Information Table S7 and Figure S10). Scheme 3 | Three proposed mechanisms regarding photoredox-mediated Ir III/Ni II dual-catalyzed hydroalkylation to achieve C–C cross-coupling. Download figure Download PowerPoint Figure 3 | Energy profiles (ΔG°333.15 in kcal/mol) of the most favorable nickel catalytic cycle. Selected bond distances and spin densities are given in Å and grey italic font, respectively. Download figure Download PowerPoint Figure 4 | Energy profiles (ΔG°333.15 in kcal/mol) of the two possible competitive paths (2 and 3). Selected bond distances and spin densities are given in Å and grey italic font, respectively. Download figure Download PowerPoint As illustrated in Figure 3, the α-carbon-centered electrophilic THF radical would be rapidly captured by the triplet Ni(II) complex 1 to generate a stable doublet NiIII species 2 with a ΔG° value of −7.5 kcal/mol ( Supporting Information Figure S9). Then, the C–Cl bond formation via reductive elimination occurs from 2 to afford the 2-chlorotetrahydrofuran (2-Cl–THF) through the three-membered-ring transition-state TS1 with a small ΔG°⧧ value of 8.2 kcal/mol. The formation of 2-Cl–THF aligns with the experimental proposal.41 Next, the oxidative hydrometallation between AL and 3 occurs via the concerned five-membered-ring transition-state TS2 to yield the alkyne hydrometallation intermediate 5. In TS2, the H–Cl distance is elongated to 1.63 Å from 1.33 Å in 4, while the Ni–Cl, Ni–C2, and C3–H bonds are shortened to 2.85, 2.04, and 1.37 Å, respectively, indicating the H–Cl bond is cleaved and the Ni–Cl, Ni–C2, and C3–H bonds are formed simultaneously. The ΔG°⧧ and ΔG° values of this oxidative hydrometallation step are 17.5 and −3.5 kcal/mol, respectively. Note that oxidative hydrometallation is more favorable than the alternative stepwise mechanism consisting of the oxidative addition of Ni(I) to HCl and the alkyne insertion to Ni–H bond ( Supporting Information Figure S8). Based on deuterium-labeling experiments,43 the hydrogen source of the targeted alkyne hydroalkylation product is expected to be originated from both the THF C(sp3)–H bonds and the following proton exchange with trace water in the reaction mixtures. In the present calculations, HCl is generated along with the formation of α-carbon-centered THF radical. It can be expected that H(Cl) in THF•⋯HCl complex or intermediates containing HCl (like 2, 3, and 4) could exchange with H(OH) to contribute the following hydrogen in the addition to alkyne. In the subsequent comproportionation reaction, a stable mixed valence complex 6 is initially produced with a ΔG° value of −4.6 kcal/mol, in which NiIII and NiI are bridged by a chloride ion. From the homobimetallic dimer 6, a chloride radical migration from Ni(III) to Ni(II) occurs via the transition-state TS3 to afford the Ni(II)-intermediate 7 and regenerate an initial Ni(II) catalyst 1. Such comproportionation reaction can be also regarded as inner-sphere ET. The ΔG°⧧ and ΔG° values of this inner-sphere ET are 4.6 and −12.2 kcal/mol relative to 5, respectively. In the final σ-bond metathesis, spin inversion between the singlet and triplet energy profiles effectively decreases the activation barrier and switches the ground-state profile from the singlet state to the triplet state via a minimum energy crossing point (MECP).83–86 In the favorable pathway, the σ-bond metathesis between Ni–C2 and Cl–C1(THF) bonds occurs via the MECP and the triplet transition-state TS4 to afford the alkyne hydroalkylation product P and regenerate the other triplet Ni(II) catalyst 1. The singlet transition state of σ-bond metathesis has also been examined to be unfavorable than the present triplet one ( Supporting Information Figure S11). In the four-membered Ni–C2–C1–Cl ring of TS4, the Ni–C2 and C1–Cl bonds are elongated to 2.05 and 3.04 Å from 1.88 Å in 7 and 1.86 Å in 2-Cl–THF, whereas the C1–C2 and Ni–Cl distances are shortened 3.12 and 2.42 Å, respectively, indicating the Cl–C1(THF) bond cleavage and the C1–C2 bond formation occur simultaneously. The ΔG°⧧ and ΔG° values of the rate-determining σ-bond metathesis process are 23.7 and −40.1 kcal/mol, respectively, which can be overcome under the experimental conditions (60 °C). In addition, inspired by the energetically favorable SET from photoexcited * Ir III to T Ni II forming D Ni I (Figure 1), an alternative oxidative quenching of * Ir III by 7 has also been evaluated to be unfavorable to provide Ir IVCl and Ni(I)-vinyl species. Because 1 ( T Ni II) produced simultaneously with 7 is much easier and faster to quench the *Ir III than 7 by comparing the energy barrier and redox potentials ( Supporting Information Figures S12 and S13), although the subsequent oxidative addition of 2-Cl–THF to Ni(I)-vinyl species and reductive elimination from nickel(III) intermediate just require moderate energy barriers. As the competitive paths of the above mechanism (path 1), the direct radical capture by D Ni I and the alkyne coordination with D Ni I could lead to possible inner-sphere path 2 and outer-sphere path 3, as shown in Figure 4 ( Supporting Information Figure S16). Note that the following results are discussed based on the Gibbs energy calculated on the triplet energy profiles, because the singlet profiles lie higher than the triplet ones ( Supporting Information Figure S15). Starting from the active D Ni I, the α-carbon-centered THF radical could be captured by D Ni I to generate a relatively stable Ni(II) species 8 (path 2) or coordinate with AL to from a four-coordinate Ni(I) intermediate 10 (path 3) with the ΔG° values of −7.6 and 1.1 kcal/mol, respectively. In path 2, AL is inserted into the Ni–C(THF) bond of 8 through a four-membered-ring (Ni–C3–C2–C1) transition-state TS5 to afford an intermediate 9. The ΔG°⧧ and ΔG° values of this alkyne insertion are 26.6 and −22.2 kcal/mol, respectively. In path 3, the outer-sphere electrophilic THF radical attack to the coordinated AL moiety of 10 could occur via the transition-state TS6 to afford 9 ( Supporting Information Figure S14). This alkyne bifunctionalization step requires the ΔG°⧧ and ΔG° values of 10.1 and −30.9 kcal/mol, respectively. At last, a σ-bond metathesis between 9 and HCl could yield the alkyne hydroalkylation product P and regenerate the nickel(II) chloride complex 1. However, the regioselectivity of alkyne bifunctionalization in path 3 was examined to be contrary to the experimental results (Scheme 4). Overall, paths 2 and 3 are less favorable than path 1 because they lie higher than path 1 based on the Gibbs energy calculated on the potential energy surface. Scheme 4 | The regioselect