Abstract
The 1,n-metal migration process is distinct from traditional bond-forming pathways and offers a unique approach for constructing complex organic architectures. However, in contrast to the well-documented Pd-, Rh-, Fe-, Co-, and Ni-catalyzed migration coupling reactions, studies on Cu-catalyzed variants are scarce. This report describes density functional theory (DFT) calculations aiming to investigate the mechanism of Cu-catalyzed formal hydro(borylmethylsilyl)ation, which is proposed to occur via 1,4-copper migration. The computational results support a metal non-migration mechanism. The stereoselectivity of the reaction is determined by the energy difference between the proton transfer transition state and the anionic releasing transition state after syn-to-anti isomerization. Additionally, DFT calculations were used to evaluate the effects of various substituents on the internal alkyne. Overall, this study offers a solid theoretical basis for experimental investigations into Cu-catalyzed migration coupling reactions.
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Introduction
Recent studies have investigated the migratory behavior of transition metals in catalytic coupling reactions, with increasing emphasis on optimizing catalytic efficiency through the precise modulation of metal migration dynamics1,2,3,4,5. The 1,n-metal migration process, whereby a transition metal relocates between carbon atoms during catalysis, offers a unique strategy for assembling complex organic architectures that does not involve classical bond-forming pathways. Indeed, Pd6,7,8,9,10- and Rh11,12,13,14-mediated 1,n-migrations have been systematically explored, and notably, recent studies have demonstrated the potential of earth-abundant 3 d transition metals (e.g., Fe15,16, Co17,18,19,20,21,22, Ni23,24,25,26,27,28,29,30) as migratory centers, thus offering cost-effective alternatives to precious metal catalysts. Nevertheless, compared with the established Fe-, Co-, and Ni-catalyzed migration coupling reactions, reports on Cu-catalyzed reactions are rare31 (Scheme 1a).
The state of the art in transition-metal-catalyzed migration coupling reactions. a Transition-metal-catalyzed coupling reactions that involve 1,n-metal migration. b Cu-catalyzed formal hydro(borylmethylsilyl)ation of an internal alkyne. c Proposed 1,4-copper migration mechanistic pathways.
Recently, Shintani et al. reported the copper-catalyzed regio- and stereoselective formal hydro(borylmethylsilyl)ation of internal alkynes, which involved 1,4-copper migration from an alkenyl carbon to an alkyl carbon31 (Scheme 1b). Under optimal conditions, the alkenylsilylmethylboronate product 3a was isolated in 65% yield, with the stereoselectivity for 3a over 4a being 94:6. Kinetic studies, NMR analyses, and deuterium-labeling experiments were consistent with a 1,4-copper migration process. However, the precise mechanism of this migration remains unclear, and there are lingering uncertainties regarding whether this migration process actually occurred.
Metal migration mechanisms can be classified into three main categories. (i) Oxidative addition of a metal (M) into a C–H bond can result in new C–M and M–H bonds, which undergo reductive elimination, thereby facilitating metal migration by cleaving the original C–M bond [3b 32,33]. (ii) Activation of C–H bonds in the presence of a base can generate C–M bonds via a cooperative metalation-deprotonation (CMD) mechanism. After subsequent protonation, this process allows for metal migration through various combinations34,35. (iii) β-H elimination can form metal-hydride species and alkenes, which can reinsert into the M–H bond via metal migration. A sequence of β-H eliminations followed by reinsertions can facilitate multiple metal migration steps36,37,38.
In the hydro(borylmethylsilyl)ation reaction shown in Scheme 1b, the alkenyl-Cu(I) intermediate I can follow one of three migration pathways to undergo 1,4-copper migration. However, the d-electron configuration of Cu(I) and the inherent instability of a Cu(III) intermediate typically lead to a high activation energy for the oxidative addition (OA) of the Cu(I) center into the C(sp3)–H bond39,40,41 (Scheme 1c). Additionally, although the CMD mechanism is commonly observed with Cu(II), this process is kinetically unfavorable for Cu(I)42,43,44,45. Finally, the structural constraints of this intermediate hinder the β-H elimination mechanism. Thus, the potential 1,4-copper migration process in this reaction requires further elucidation through detailed computational studies.
This report presents a theoretical investigation of the mechanism and origin of stereoselectivity of this Cu-catalyzed formal hydro(borylmethylsilyl)ation reaction. The results offer a plausible detailed reaction mechanism and reactivity profile. Computational findings indicate that the 1,4-copper migration pathway is kinetically unfavorable. The alkenyl-Cu(I) intermediate, which is formed via alkyne migration insertion, undergoes anion exchange, proton transfer, and nucleophilic substitution to yield the alkenylsilylmethylboronate product46,47,48,49,50,51. The results presented herein provide a theoretical framework for guiding further experimental investigations of Cu-catalyzed coupling reactions.
Computational methods
All density functional theory (DFT) calculations were conducted using the GAUSSIAN 1652 software suite. The B3-LYP-D353,54,55,56,57,58 density functional was employed for geometric optimization, utilizing a standard 6-31 G(d) basis set. The SDD basis set was specifically applied for copper. Harmonic frequency calculations were conducted for all stationary points to confirm their classification as local minima or transition state structures and to obtain thermochemical corrections for enthalpies and free energies. All local minima exhibited zero imaginary frequencies, while each transition state presented a single imaginary frequency. Solvent effects were included by performing single-point calculations on gas-phase stationary points using the SMD59 continuum solvation model. The M11-L60 functional was employed alongside the def2-TZVP61,62 basis set to calculate single-point energies in tetrahydrofuran solvent. The optimized structures were visualized using CYLview63. The independent gradient model (IGM)64 was applied utilizing the M11-L DFT method with the def2-TZVP basis set, employing the Multiwfn65 and VMD66 programs. The oxidation state calculations were also conducted using the Multiwfn program. To accurately evaluate the entropy of the dual metal catalysis pathway, the solution-translational entropy correction was recalculated using the THERMO67 program.
Results and discussion
Based on reported experimental results and control experiments, we proposed the reaction mechanisms illustrated in Scheme 2. Scheme 2a depicts potential mechanisms for 1,4-copper migration, and Scheme 2b presents the potential mechanisms for metal non-migration. The results from 1H NMR spectroscopy indicated that the anionic bis(phenyldimethylsilyl)cuprate A was generated in situ from a 1:2 mixture of CuI and silylboronate 2a in the presence of LiOtBu (4.0 equiv)31. Notably, when tert-butyl(phenyl)acetylene 1a was added to the in-situ generated Cu(SiMe2Ph), no reaction occurred. Conversely, a smooth reaction was observed at room temperature when 1a was added to the in-situ generated A, resulting in the formation of silylalkenyl(silyl)cuprate (see Supporting Information)31. Consequently, we selected the anionic bis(phenyldimethylsilyl)cuprate A as the catalytically active species in this hydro(borylmethylsilyl)ation reaction. The internal alkyne substrate 1a inserts into the Cu(I)–Si bond, thereby forming the silane-substituted alkenyl-Cu(I) anion intermediate B. In Path I, the C(sp3)–H bond undergoes oxidative addition with the Cu(I) center, generating the alkenyl- and alkyl-Cu(III) intermediate C. Intermediate C then undergoes reductive elimination, yielding the alkyl-Cu(I) intermediate D, thus completing the 1,4-copper migration. The subsequent metathesis between intermediate D and silylboronate 2a affords the alkenylsilylmethylboronate product 3a and regenerates the catalytically active species A, which completes the catalytic cycle. In Path II, the alkenyl-Cu(I) anion intermediate B can also participate in a CMD process, using a tert-butoxide ion as a base to form the alkenyl- and alkyl-Cu(I) intermediate E. Subsequent protonation of the allyl C–Cu(I) bond yields the alkyl-Cu(I) intermediate D.
Proposed mechanism. a Proposed 1,4-copper migration mechanism. b Proposed metal non-migration mechanism.
As shown in Scheme 2b, anion exchange between the silicon anion and the alkenyl-Cu(I) anion intermediate B results in the formation of the alkenyl-carbanion intermediate F and the regeneration of the catalytically active species A. In Path III, subsequent proton transfer from the methyl group to the alkenyl moiety generates the alkyl carbanion intermediate G. This intermediate then undergoes a nucleophilic substitution with silylboronate 2a, yielding the alkenylsilylmethylboronate product 3a. Alternatively, in Path IV, the syn-to-anti isomerization of the alkyl carbanion F generates the anti-alkyl carbanion intermediate H. A nucleophilic substitution reaction between intermediate H and silylboronate 2a then produces the silylalkenylboronate by-product 4a.
The free energy profiles associated with the formation of the anionic bis(phenyldimethylsilyl)cuprate active catalyst are shown in Fig. 1. The nucleophilic addition of the tert-butoxide anion into the silylboronate substrate 2a occurs via transition state TS1, which has an energy barrier of 11.3 kcal/mol and leads to the anionic boron intermediate INT1. In TS1, the O–B bond length is 2.81 Å. Release of the anionic silicon intermediate INT2 from INT1 occurs through transition state TS2. The free energy of INT2 is −24.2 kcal/mol, indicating that INT2 is predominant in the reaction mixture. An anion exchange between INT2 and the Cu(I)-I catalyst affords the silicon-Cu(I) intermediate INT3. Finally, a ligand exchange between INT3 and INT2 results in the formation of the anionic bis(phenyldimethylsilyl)cuprate active catalyst INT4, and this step is exoergic by 15.8 kcal/mol.
Free energy profile and selected structural information for the formation of the bis(phenyldimethylsilyl)cuprate active catalyst. Bond lengths are given in Å.
Figure 2 presents the calculated free energy profile for Path I. The computational results indicate that the migration and insertion of the internal alkyne substrate 1a into the Cu(I)–Si bond in INT4 follows a stepwise process, which includes coordination and migration insertion. Specifically, the coordination of alkyne substrate 1a onto the Cu(I) center generates the Cu(I) intermediate, INT5. We calculated the oxidation state of the Cu center in INT5 using Multiwfn program. The oxidation state of the Cu center in INT5 was determined to be +1. The coordination step is followed by the migration insertion, which yields the anionic silane-substituted alkenyl-Cu(I) intermediate, INT6. The overall free energy barrier for the migration insertion transition state TS4 is 27.8 kcal/mol, and the length of the forming C–Si bond is 2.58 Å. The subsequent 1,4-copper migration process involves oxidative addition and reductive elimination, which may occur via either a stepwise mechanism or a concerted pathway. During this process, the C(sp3)–H bond undergoes oxidative addition by the Cu(I) center, resulting in the formation of the alkenyl- and alkyl-Cu(III) intermediate INT7. The free energy barrier for the oxidative addition transition state TS5 is 33.2 kcal/mol. In TS5, the lengths of the forming C–Cu(I) bond and the breaking C–H bond are 2.08 and 1.73 Å, respectively. Then, INT7 undergoes reductive elimination through transition state TS6, thereby generating the alkyl-Cu(I) intermediate INT8 and completing the 1,4-copper migration process. Alternatively, the 1,4-copper migration may proceed via the concerted transition state TS7, which also results in the formation of INT8. In TS7, the lengths of the breaking C–H bond and the forming C–H bond are 1.57 and 1.33 Å, respectively. Notably, the free energy of TS7 is 4.6 kcal/mol lower than that of TS6; however, the free energy barrier for TS7 is high (33.6 kcal/mol), indicating that Path I is unfavorable. Subsequent metathesis between INT8 and silylboronate 2a occurs through a stepwise pathway. Nucleophilic addition of the carbanion into silylboronate substrate 2a generates the anionic boron intermediate INT9. The free energy barrier for the nucleophilic addition transition state TS8 is 32.2 kcal/mol, and the lengths of the forming C–B bond and the breaking C–Cu bond measure 2.00 and 2.09 Å, respectively. Finally, the intramolecular migration of the silicon anion yields the alkenylsilylmethylboronate product 3a, while regenerating the catalytically active species INT4, thus completing the catalytic cycle.
Bond lengths are given in Å.
The calculated free energy profile for Path II is presented in Fig. 3. The alkenyl-Cu(I) anion intermediate INT6 undergoes a CMD process via transition state TS10, using a tert-butoxide ion as a base, to form the alkenyl- and alkyl-Cu(I) intermediate INT10. The free energy barrier associated with TS10 is 29.7 kcal/mol, and the lengths of the breaking C–H bond and the forming C–Cu bond are 1.96 and 2.36 Å, respectively. Subsequent protonation of the allyl C–Cu(I) bond occurs via transition state TS11, thereby yielding the alkyl-Cu(I) intermediate INT8 and completing the 1,4-copper migration process. The overall activation barrier for this pathway is 31.2 kcal/mol, indicating that this 1,4-copper migration pathway is unfavorable. Additional calculations were employed to examine the use of silicon anions as a base to facilitate the 1,4-copper migration process. The free energy of the CMD transition state TS10’ is 9.4 kcal/mol higher than that of TS10, and the free energy of the protonation transition state TS11’ is 32.8 kcal/mol. These computational results suggest that Path II is also unfavorable.
Bond lengths are given in Å.
As shown in Fig. 4a, the anion exchange reaction between the silicon anion and the alkenyl-Cu(I) anion intermediate INT6 generates the alkenyl carbanion intermediate INT11 and regenerates the catalytically active species INT4. The free energy barrier for the anion exchange transition state TS12 is 19.4 kcal/mol. We used the silicon anion rather than the tert-butoxy anion because the former can be generated in situ in the presence of LiOtBu and methylsilyl boronic ester (Fig. 1). Moreover, we also consider the anion exchange between the tert-butoxide anion and the alkenyl-Cu(I) anion intermediate INT6. The free energy barrier for this anion exchange transition state TS30 is 4.5 kcal/mol higher than that of TS12 (Figure S4). Subsequent proton transfer from the methyl group to the alkenyl moiety occurs through transition state TS13, resulting in the formation of the alkyl carbanion intermediate INT12. The free energy barrier for the proton transfer transition state TS13 is 21.6 kcal/mol, and the lengths of the forming C–H bond and the breaking C–H bond are 1.35 and 1.53 Å, respectively. Next, the nucleophilic addition of INT12 to silylboronate 2a produces the anionic boron intermediate INT13. Then, INT13 releases an anionic silicon intermediate INT2 via transition state TS14, yielding the alkenylsilylmethylboronate product 3a. In TS14, the length of the breaking B–Si bond is 3.21 Å. These computational results show that the free energy of TS12 is 14.2 kcal/mol lower than that of TS7 and 11.8 kcal/mol lower than that of TS11, indicating that Path III is more favorable than Paths I and II.
a Free energy profile for Path III. b Free energy profile for Path IV. Bond lengths are given in Å.
Alternatively, in Path IV (Fig. 4b), the syn-to-anti isomerization of alkyl carbanion INT11 produces the anti-alkyl carbanion intermediate INT14, with a low free energy barrier associated with the transition state TS15 (2.2 kcal/mol). Subsequent nucleophilic addition of INT14 into silylboronate 2a affords the anionic boron intermediate INT15, and this process has a free energy barrier of 18.0 kcal/mol. In transition state TS16, the length of the forming C–B bond is 3.51 Å. Then, INT15 releases the anionic silicon intermediate INT2 via transition state TS17, yielding the by-product silylalkenylboronate 4a; the length of the breaking B–Si bond in TS17 is 3.46 Å. The free energy of TS17 is 1.8 kcal/mol higher than that of TS13, while the free energy of 4a exceeds that of 3a by 5.7 kcal/mol. These kinetic and thermodynamic findings are consistent with the experimentally observed stereoselectivity ratio of 94:6, which favors product 3a over 4a. These findings are also consistent with those from deuterium substitution experiments31. When hydrogen was replaced with deuterium, the energy barrier for proton transfer increased, which reduced the yield of 3a.
Our results indicated that the hydro(borylmethylsilyl)ation reaction pathway involved alkyne migration insertion, anion exchange, proton transfer, and nucleophilic substitution. Notably, the alkyne migration insertion step was identified as the rate-determining step in this reaction. This observation is consistent with kinetic experiments that demonstrate a first-order dependence on the concentration of the copper catalyst and a positive dependence (of approximately 0.5) on the initial concentration of the alkyne substrate31.
Experimental results indicated that 3b was preferentially formed over 4b when alkyne 1b containing an ortho-substituted aryl group was used in the reaction (Fig. 5). By contrast, 4c was preferentially formed over 3c when alkyne 1c containing a less bulky isopropyl group was used in the reaction (Fig. 6)31. Thus, the substituent effects of the internal alkyne were evaluated using DFT calculations.
a Free energy profile for Path III. b Free energy profile for Path IV. c IGM analyses of TS16 and TS21. Bond lengths are given in Å.
a Free energy profile for Path III. b Free energy profile for Path IV. c IGM analyses of INT15 and INT25. Bond lengths are given in Å.
The computational results for the ortho-substituted aryl group substrate 1b are presented in Fig. 5. As shown in Fig. 5a, proton transfer from the methyl group to the alkenyl moiety in the alkenyl carbanion intermediate INT16 occurs via transition state TS18. This process forms the alkyl carbanion intermediate INT17, with a free energy barrier of 20.7 kcal/mol. In TS18, the lengths of the forming and breaking C–H bonds are 1.35 and 1.53 Å, respectively. Next, nucleophilic addition of INT17 into silylboronate 2a produces the anionic boron intermediate INT18. Subsequently, INT18 releases the anionic silicon intermediate INT2 via transition state TS19, yielding the alkenylsilylmethylboronate product 3b; the length of the breaking B–Si bond in TS19 is 3.27 Å.
As shown in Fig. 5b, In Path IV, the syn-to-anti isomerization of alkyl carbanion INT16 yields the anti-alkyl carbanion INT19, with a low free energy barrier for transition state TS20 (2.1 kcal/mol). The subsequent nucleophilic addition of INT19 into silylboronate 2a forms the anionic boron intermediate INT20. This step has a free energy barrier of 23.7 kcal/mol, and the forming C–B bond in transition state TS21 is 2.89 Å. Then, INT20 releases the anionic silicon intermediate INT2 via transition state TS22, producing the by-product silylalkenylboronate 4b; the length of the breaking B–Si bond length in TS22 is 3.86 Å. Notably, the free energy of TS21 is 2.5 kcal/mol higher than that of TS18, whereas the free energy of 4b is 7.8 kcal/mol greater than that of 3b. These kinetic and thermodynamic results are consistent with the experimentally observed stereoselectivity, with a ratio of 99:1 in favor of product 3b over 4b.
Independent gradient model (IGM) calculations were performed for TS16 and TS21 to explore the origin of the high stereoselectivity for 3b over 4b when alkyne 1 has an ortho-substituted aryl group (Fig. 5c). In TS16, the closest H···H distance between the phenyl group and silylboronate 2a is 2.50 Å (Fig. 4b), while in TS21 the closest H···H distance between the ortho-substituted phenyl group and silylboronate 2a is 2.08 Å (Fig. 5b). The results indicated that the electrostatic repulsion between the ortho-substituted aryl group and silylboronate 2a in TS21 is stronger than that between the phenyl group and silylboronate 2a in TS16, which leads to the high stereoselectivity.
The computational results for the less bulky isopropyl group substrate 1c are presented in Fig. 6. Proton transfer from the methyl group to the alkenyl moiety in the alkenyl carbanion intermediate INT21 occurs through transition state TS23 (Fig. 6a). This transfer gives the alkyl carbanion intermediate INT22, which has a free energy barrier of 20.9 kcal/mol. In transition state TS23, the lengths of the C–H bonds that formed and broke were 1.37 Å and 1.51 Å, respectively. Next, nucleophilic addition of INT22 to silylboronate 2a generates the anionic boron intermediate INT23. Subsequently, INT23 transforms into the anionic silicon intermediate INT2 via transition state TS24, which results in the formation of the alkenylsilylmethylboronate product 3c. The length of the B–Si bond that breaks in TS24 is 3.37 Å.
The syn-to-anti isomerization of alkyl carbanion INT21 results in formation of the anti-alkyl carbanion INT24, with a low free energy barrier of 3.6 kcal/mol for transition state TS25 (Fig. 6b). Subsequent nucleophilic addition of INT24 to silylboronate 2a generates the anionic boron intermediate INT25, with a free energy barrier of 17.8 kcal/mol. In transition state TS26, the length of the C–B bond that forms is 3.32 Å. Next, INT25 transitions to the anionic silicon intermediate INT2 via transition state TS27, which produces the silylalkenylboronate 4c. The length of the B–Si bond that breaks in TS27 is 3.58 Å. Notably, the free energy of TS27 is 4.1 kcal/mol lower than that of TS23, but the free energy of 4c is 4.1 kcal/mol higher than that of 3c. These kinetic and thermodynamic findings are consistent with the experimentally observed stereoselectivity of products 4c and 3c.
A comparison of the results from Figs. 4b, 6b revealed that the lower energy of TS26 could be attributed to the fact that the energy of intermediate INT25 was lower than that of INT15. IGM calculations were conducted for INT15 and INT25 to investigate the origin of stereoselectivity inversion when the alkyne 1c, which contained a less bulky isopropyl group, was used as the substrate (Fig. 6c). In addition, the closest H···H distance between the tert-butyl group and dimethylphenylsilyl moiety in silylboronate 2a is 2.18 Å in INT15, while in INT25 the closest H···H distance between the isopropyl group and dimethylphenylsilyl group in silylboronate 2a is 2.51 Å. The calculated results indicated that electrostatic repulsion between the tert-butyl group and the dimethylphenylsilyl moiety in silylboronate 2 in INT15 was stronger than that between the isopropyl group and the dimethylphenylsilyl group in silylboronate 2 in INT25. This heightened repulsion contributed to the higher energy of INT15 compared with INT25.
Conclusion
In this study, DFT calculations were performed to explore the mechanism governing a Cu-catalyzed formal hydro(borylmethylsilyl)ation reaction. Specifically, the feasibility of 1,4-copper migration was evaluated within an established theoretical framework. The results indicated that the 1,4-copper migration pathway is kinetically unfavorable, regardless of whether it proceeds through an oxidative addition and reductive elimination pathway or via a cooperative metalation-deprotonation and protonation mechanism. Theoretical calculations revealed that the hydro(borylmethylsilyl)ation reaction involves alkyne migration insertion, anion exchange, proton transfer, and nucleophilic substitution. The alkyne migration insertion step was identified as the rate-determining step in this reaction. The stereoselectivity of products was dictated by the energy difference between the proton transfer transition state and the anionic releasing transition state following syn-to-anti isomerization. Additionally, the effect of substituents on the internal alkyne was assessed using DFT calculations. The results demonstrated that steric hindrance between the ortho-methyl group and the silylboronate substrate enhanced the stereoselectivity. By contrast, lower steric hindrance between the isopropyl group and the dimethylphenylsilyl moiety resulted in stereoselectivity inversion. Overall, the findings presented in this report advance the understanding of Cu-catalyzed migration coupling reactions and provide a theoretical framework for guiding future experimental investigations.
Data availability
The data supporting the findings of this study are included in the paper or the Supplementary Information and are also available upon request from the corresponding author. The geometries of all optimized compounds and transition states have been deposited in the Supplementary Data.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 22303010 and 22271034). We are thankful to the Science and Technology Research Program of Chongqing Municipal Education Commission for financial support (No. KJQN202301354). This project was also funded by the Project of Financial support of Chongqing University of Arts and Sciences (No. P2021HH04).
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S. Liu conceived and designed the project and designed the computational studies. W. Chen, X. Long, D. Zhang, and J. Chen performed the DFT calculations. S. Liu and W. Chen prepared the manuscript. Z. Zhu and H. Wei prepared the ESI.
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Liu, S., Chen, W., Long, X. et al. A theoretical study on the feasibility of 1,4-Copper migration in the Cu-catalyzed formal hydro(borylmethylsilyl)ation of internal alkynes. Commun Chem 9, 2 (2026). https://doi.org/10.1038/s42004-025-01829-z
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DOI: https://doi.org/10.1038/s42004-025-01829-z
