Nickel-catalyzed ring-opening difunctionalization of methylenecyclobutanes via strain-release-enabled C-C activation

Domain: chemistry
Published: 2026-04-06
Editorial outcome: major_revision

Abstract
The efficient construction of molecular complexity from simple building blocks is a significant goal in catalysis, and the controlled ring-opening functionalization of strained carbocycles provides a powerful strategy to achieve it. However, selective catalytic strategies for ring-opening difunctionalization of methylenecyclobutanes (MCBs) remain elusive. Here, we report a nickel-catalyzed method that enables the 1,4-dicarbofunctionalization and 1,4-hydrocarbofunctionalization of MCBs via selective C–C bond cleavage. This protocol exploits the strain energy and dual reactivity of MCBs to deliver nonadjacent C(sp³)/C(sp²) frameworks in good to excellent yields under mild conditions. A broad substrate scope, scalability to the gram scale, and versatile downstream transformations demonstrate the synthetic utility of this approach. Mechanistic studies, including control, isotope-labeling experiments, and DFT calculations, reveal a distinct cooperative pathway involving strain-driven β-carbon elimination, offering new opportunities for catalyst-controlled activation of MCBs.

Introduction
The efficient assembly of molecular complexity from simple building blocks is a significant goal in catalysis,1-3 with profound implications for synthetic chemistry, drug discovery, and materials science. In this context, catalytic multicomponent reactions that form multiple carbon–carbon bonds in a single step under mild conditions are desirable for generating molecular complexity because they enhance atom economy, reduce waste, and streamline synthetic design.4,5 Among these, the difunctionalization of unsaturated hydrocarbons has become a key strategy,6-8 enabling the selective addition of two different functional groups to access a variety of C(sp³)- and C(sp²)-hybridized frameworks commonly found in bioactive molecules and functional materials,9-11 thus making the synthesis of functional molecules easier.

A breakthrough in this field has been the 1,2-difunctionalization of terminal alkenes and alkynes (Fig. 1A),12-15 which is made possible by their readily available nature, and has advanced significantly through transition-metal catalysis (Fe, Co, Ni, Cu, Pd, etc.),16-22 photocatalysis,23-25 electrocatalysis,26 and synergistic techniques27. However, these approaches typically produce either two C(sp³)– or two C(sp²)– hybridized carbon centers, thereby limiting access to molecules with differently hybridized carbon groups. The ability to simultaneously build both C(sp³) and C(sp²) centers in one step remains a key challenge with broad implications for molecular design and increasing complexity. In this regard, terminal allenes stand out as especially useful substrates, offering a solution to this challenge due to their orthogonal π-systems and distinct electronic properties (Fig. 1B).28,29 Their regio- and chemoselective difunctionalization enables the concurrent formation of C(sp³)/C(sp²) centers, providing a more straightforward route to densely functionalized, three-dimensional structures that are difficult to access using traditional alkene or alkyne methods. This reactivity has greatly expanded the synthetic toolkit for creating complex, sophisticated molecules. Inspired by recent advances, efforts have shifted toward strain-activated olefin surrogates such as methylenecyclopropanes (MCPs) (Fig. 1C),30-32 which replace the π-bond of alkenes with a highly strained three-membered ring. These MCPs exhibit allene-like reactivity in transition-metal-catalyzed 1,3-difunctionalization, allowing the simultaneous formation of two nonadjacent C(sp³)/C(sp²) frameworks via strain-release pathways,33-36 which have made significant progress over the past years.

Similar to MCPs, methylenecyclobutanes (MCBs) are versatile organic reagents in chemical synthesis, offering a built-in reservoir of strain energy (strain energy of cyclobutane: 26.5 kcal/mol, cyclopropane: 27.5 kcal/mol) and dual reactivity through their C=C π-system and cyclobutane σ-system37-39. This duality enables transformations via C=C bond difunctionalization or strain-driven C–C bond cleavage, thus significantly enriching the chemical space of MCBs. To date, extensive studies on the applications of methylenecyclobutanes (MCBs) have been reported, with approximately 379 publications and 333 patents documented in SciFinder®. Nevertheless, progress has predominantly focused on 1,2-difunctionalization across the C=C bond40-43 and ring-expansion transformations44-47, whereas ring-opening strategies that enable 1,4-difunctionalization of cyclobutanes through selective C–C bond cleavage remain largely underexplored48, thereby limiting their utility in multicomponent reactions for molecular complexity. Given the high ring strain and electronically unbiased nature of the C=C bonds in methylenecyclobutanes (MCBs), achieving regioselective migratory insertion across these alkenes is both a fundamental challenge and a critical prerequisite for efficient ring-opening functionalization. Recently, Koh and Shi developed a state-of-the-art method for the directing-group-free difunctionalization of unactivated alkenes, and mechanistic insights have shown that bulky Ni–NHC complexes enable the selective difunctionalization of unactivated alkenes by promoting branch-selective migratory insertion of arylmetal species across terminal C=C bonds.49-51 Inspired by this advance, we hypothesized that Ni–NHC catalysis could overcome inherent steric and electronic biases in MCBs, and the branch-selective insertion into the exocyclic methylene group of MCBs would induce strain-driven β-carbon elimination, allowing for direct C–C bond cleavage and subsequent 1,4-difunctionalization (Fig. 1D). This process would produce nonadjacent sp2 and one sp3 carbon centers, which are important building blocks for furnishing many value-added molecules.52,53 Herein, we report a Ni–NHC–catalyzed multicomponent strategy that enables efficient 1,4-dicarbofunctionalization and 1,4-hydrocarbofunctionalization of MCBs in this paper.

Results
Identification of the catalytic conditions. Initially, we systematically optimized the reaction conditions of the 1,4-dicarbofunctionalization of MCBs via strain-release-enabled ring-opening, selecting 1a, 2a, and 3a as the model substrates. As shown in Table 1, the desired ring-opening product 4a was obtained in 76% yield when the reaction was conducted in cyclohexane using Ni(cod)₂ as the catalyst and nitrogen-heterocyclic carbene (NHC) L6 as the ligand. Replacing L6 with other phosphine or nitrogen-based ligands failed to promote the transformation, highlighting the unique property of L6 in this multicomponent cross-coupling reaction. Further modification of the NHC ligand through steric tuning of the aryl substituents did not enhance the reaction efficiency (L5, 36% yield; L7, 34% yield). Likewise, variations of the imidazole backbone aimed at adjusting both electronic and steric properties failed to improve the yield of 4a (L8, 34% yield; L9, 27% yield; L10, 47% yield), indicating that an appropriate balance of steric and electronic effects is crucial for this transformation and reinforcing L6 as the optimal choice. Solvent screening revealed that low-polarity solvents were more suitable for the reaction, with toluene and PhCF₃ yielding comparable yields of 66% and 73%, respectively. Variations in reaction temperature and substrate concentration were also explored, but no further improvements in yield were observed (see Supplementary Information for details). Notably, reducing the catalyst loading to 1 mol% Ni(cod) still afforded the desired product 4a in 56% yield (see Supplementary Information for details).

Substrate scope. With the optimized conditions established, we next evaluated the substrate scope to assess the generality of the approach for the 1,4-dicarbofunctionalization of MCBs (Fig. 2). We began by examining the electrophilic coupling partners (ArOTf) bearing various substituents to explore electronic and steric effects. Para-substituted aryl triflates with alkyl, trifluoromethoxy, fluoro, or methoxy groups produced the desired products in good yields (45–83%, 4a–4i). Similarly, meta-substituted analogues with comparable functionalities were well tolerated, giving products in 64–81% yield (4j–4o). Next, we explored the substrate scope of nucleophiles with a range of alkylmagnesium chlorides, all of which reacted smoothly under standard conditions to give the ring-opening products in 75–84% yield (4p–4w). In contrast, arylmagnesium halides did not produce the desired products; instead, only Kumada-type cross-coupling products54 between the aryl nucleophiles and ArOTf were detected by GC-MS analysis, highlighting the difficulty of achieving selective ring-opening in the presence of aryl nucleophiles. We also investigated the structural diversity of MCB substrates. Substrates bearing quaternary carbon centers were generally well tolerated, giving moderate to good yields (4x–4ah, 40–81%), indicating minimal steric interference. However, those containing tertiary carbon centers gave the corresponding products 4ai and 4aj in lower yields (34% and 37%) despite their high conversions, which can be attributed to the competitive β-hydride elimination to furnish the 1,4-dienes.55 Additionally, the structure of 4ah was confirmed unambiguously by single-crystal X-ray analysis.

To further extend the utility of the method, we investigated the 1,4-hydrocarbofunctionalization of MCBs (Fig. 3). Following systematic optimization (see Supplementary Information), the optimal conditions employed ligand L5 and sodium tert-pentoxide in THF, with aryl bromides as the electrophiles and sodium isopropoxide as the hydrogen source. In contrast, the use of aryl triflates, chlorides, or aryl iodides as electrophilic coupling partners resulted in diminished yields compared to the aryl bromides (see Supplementary Information, Table S6). Moreover, GC-MS analysis revealed the formation of 1,2-hydrocarbofunctionalization byproducts under these conditions, indicating that the nature of the anion plays a crucial role in governing the β-C elimination process. Under the optimal conditions, the target product 7a was obtained in 88% yield. A variety of aryl bromides bearing alkyl, ether, amino, trifluoromethyl, halogen, and fused-ring substituents were well tolerated, affording products 7b–7r in 40–85% yield. Notably, heteroaryl bromides could also undergo 1,4-hydrocarbofunctionalization, delivering 7s–7u in 30–63% yield. Furthermore, a highly conjugated substrate, 1,1,2,2-tetrakis(4-bromophenyl)ethene, could be employed to furnish tetraphenylethylene derivative 7v in 37% yield, potentially enabling access to new fluorescent scaffolds.56,57 Finally, a broad range of MCBs was subjected to 1,4-hydrocarbonation under the optimized conditions. As shown in Fig. 3 (7w–7ag), MCBs with quaternary carbon centers furnished products in up to 95% yield. Remarkably, tertiary-substituted MCBs were also well tolerated, affording 7ah–7am in 64–86% yield.

Applications of the method. To underscore the versatility and practical value of this method, gram-scale reactions and diverse downstream transformations were carried out. As shown in Fig. 4A, both 1,4-hydrocarbofunctionalization and 1,4-dicarbofunctionalization of MCBs proceeded efficiently on a gram-scale under standard conditions, delivering the desired products in high yields (7a, 86%; 4a, 59%). The operational simplicity of the protocol was further demonstrated by employing the air-stable Ni(0) precatalyst Ni(4-tBustb) ,58,59 which enabled the 1,4-dicarbofunctionalization of 1a to furnish 4a in a reduced yield of 52% (Fig. 4B), likely due to the steric bulk of Ni(4-tBustb) . Collectively, these results underscore the scalability and robustness of the method. Importantly, selective hydrogenation and oxidation of the sterically hindered C=C bond were achieved under mild conditions (Fig. 4C), showcasing excellent functional group tolerance and enabling access to structurally diverse alkanes 8 (79% yield) and 9 (51% yield). Moreover, the cobalt/photoredox-catalyzed difunctionalization of 7a delivered ketone 11 in 73% yield (Fig. 4D),60 further demonstrating the synthetic utility of the products. Notably, the bisphenol derivative as an important monomer for polycarbonate resins was synthesized in 42% yield over two steps via difunctionalization of 12 followed by demethylation (Fig. 4E), underscoring the method’s potential for constructing functional materials.

Mechanistic evaluation. Mechanistic insights were elucidated through control experiments, isotope-labeling studies (Fig. 5), and DFT calculations (Fig. 6). Complete reaction blockage without benzylmagnesium chloride (3a) and the absence of Heck-type byproducts when 2a was omitted confirm the crucial roles of both reagents in enabling C–C single-bond cleavage of MCBs (Fig. 5A). 1,4-hydrocarbofunctionation of 1a with sodium deuterated isopropoxide produced the fully deuterated product (>99% D, confirmed by 1H-NMR analysis), clearly indicating the alkoxide as the hydride source.61 Substituting sodium isopropoxide with sodium 1-phenylethan-1-olate produced 7a (38% yield) along with acetophenone (detected by GC–MS analysis), providing further evidence for this hydride transfer pathway (Fig. 5B). Additionally, a significant kinetic isotope effect (KIE = 3) suggests that hydride transfer is likely the rate-determining step. Furthermore, the radical-trapping experiments for the 1,4-dicarbofunctionalization using one equivalent of TEMPO or BHT afforded 4a in 62% yield and 66% yield, respectively, thereby excluding the involvement of a radical pathway (Fig. 5C). In addition, Ni(IPr) was evaluated as a catalyst for the dicarbofunctionalization of 1a, delivering 4a in a 43% yield (Fig. 5D), which supports the participation of an active Ni–NHC catalytic species.

To gain deeper insight into the reaction mechanism, density functional theory (DFT) calculations were performed (see Supplementary Information for computational details). Substrates 1a', 2b and 3a were selected as model systems. The computed free-energy profiles for the formation of products P1 and P2 are summarized in Fig.6, while an alternative pathway leading to P1 is depicted in Fig. S14. Initial coordination of PhOTf to the active Ni0(NHC) species is exergonic, affording intermediate int1 (ΔG = −21.0 kcal/mol), which undergoes irreversible oxidative addition via TS1 to generate the Ni(II) species int2. Subsequent coordination of alkene 1a' to int2 leads to the formation of four-coordinate Ni–MCB complexes int3 and int3', corresponding to the precursors of TS2 and TS2', respectively. Notably, formation of both int3 and int3' is endergonic, indicating that alkene coordination is thermodynamically uphill. Consequently, the free-energy barriers for olefin insertion are referenced to int2. From int2, 1,2-insertion via TS2 is favored over the competing 2,1-insertion pathway (TS2'), and the 1,2-insertion step exhibits the highest activation free energy of the catalytic cycle, identifying it as the rate-determining step.

Following olefin insertion, the resulting alkyl-Ni(II) intermediate int4 represents a key branching point of the reaction manifold. As shown in Fig. 6, int4 preferentially undergoes transmetalation with Grignard reagent 3a to generate alkyl-Ni(II)-benzyl species int5. Subsequent isomerization affords int6, in which the alkyl and benzyl groups adopt a trans relationship. From int6, β-carbon elimination proceeds via TS3, involving C–C σ-bond cleavage accompanied by π-bond formation, to give intermediate int7. Further isomerization leads to int8, which undergoes C–C reductive elimination via TS4 to furnish product P1. Alternatively, int5 can directly undergo reductive elimination through TS3' to form product P2. This direct reductive elimination pathway is kinetically less favorable, with an activation barrier of 17.8 kcal/mol relative to int5, and also thermodynamically disfavored compared to P1 formation, consistent with the experimental observations.

In addition to the pathway shown in Fig.6, Fig. S14 illustrates an alternative pathway, in which β-carbon elimination precedes transmetalation. In this scenario, int4 first undergoes β-C elimination, followed by transmetalation, isomerization, and reductive elimination to ultimately afford product P1. Importantly, the activation barriers associated with the elementary steps following int4 along both pathways are substantially lower than that of the olefin insertion step. Therefore, while the pathway in Fig. 6 is kinetically preferred, the competing pathway shown in Fig. S14 cannot be excluded and may operate in parallel after the rate-determining olefin insertion step.

In summary, we have developed a broad nickel–NHC-catalyzed strategy for the selective ring-opening 1,4-difunctionalization of methylenecyclobutanes, including hydrocarbonation and dicarbonation. This catalyst-controlled approach allows efficient access to molecules with nonadjacent C(sp³) and C(sp²) centers through strain-release pathways under mild conditions. The method’s broad functional group tolerance, scalability, and diverse post-functionalization options demonstrate its practicality for building structurally complex molecules. Detailed mechanistic studies and DFT calculations reveal the potential pathway, expanding the synthetic toolkit for challenging C–C bond cleavage and opening new avenues for designing complex molecular architectures in synthetic chemistry and drug discovery. Moreover, ongoing work in our lab on diverse 1,4-difunctionalization of MCBs will be reported in due course.

Methods
General procedure for the 1,4-dicarbofunctionalization of MCBs. In a N -filled glove box, an oven-dried 4 mL vial equipped with a stir bar was charged with Ni(cod) (10 mol%), L6 (10 mol%), and cyclohexane (1.0 mL). Grignard reagent 3 (0.3 mmol, 3.0 equiv.) was slowly added to the system subsequently. The reaction mixture was allowed to stir at room temperature for 0.5 h. Methylenecyclobutene 1 (0.1 mmol 1.0 equiv.) and aryl triflate 2 (0.2 mmol 2.0 equiv.) were then added to the system. The vial was sealed and the reaction mixture was allowed to stir at 40 oC for 24 h. After cooling to ambient temperature, the crude mixture was quenched with aqueous NH Cl. The mixture was diluted with ethyl acetate (5 mL), washed with brine, dried over Na₂SO₄, and purified by flash column chromatography to afford the desired products 4.

General procedure for the 1,4-hydrocarbofunctionalization of MCBs. In a N -filled glove box, an oven-dried 4 mL vial equipped with a stir bar was charged with Ni(cod) (10 mol%), L5 (10 mol%), t-AmONa (25 mol%) and THF (1.0 mL). The reaction mixture was allowed to stir at room temperature for 10 minutes. Aryl bromide 5 (0.2 mmol, 2.0 equiv.), cyclobutene 1 (0.1 mmol, 1.0 equiv.), and sodium isopropoxide (0.3 mmol, 3.0 equiv.) were then added to the system. The vial was sealed and the reaction mixture was allowed to stir at 40 0C for 12 h. After cooling to ambient temperature, the crude mixture was quenched with aqueous NH Cl. The mixture was diluted with ethyl acetate (5 mL), washed with brine, dried over Na₂SO₄, and purified by flash column chromatography to afford the desired products 7.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "In this manuscript, Wang and co-workers report a novel NHC-Ni-catalyzed, ring-opening multicomponent reaction of\nmethylenecyclobutanes (MCBs), leveraging ring-strain release to drive either 1,4-dicarbofunctionalization or 1,4-\nhydrocarbofunctionalization. The strategy effectively harnesses the strain energy and dual reactivity of MCBs, providing\naccess to valuable nonadjacent C(sp³)/C(sp²) frameworks with high efficiency and broad substrate scope. The synthetic\nutility of this method is demonstrated through a series of downstream transformations. The proposed mechanism, supported\nby control experiments and detailed DFT calculations, involves a key strain-driven β-carbon elimination. Based on the\nreviewer’s research experience in the chemistry of alkylidenecyclopropanes and alkylidenecyclobutanes, this study\nrepresents a significant contribution to small-ring chemistry and is recommended for publication in Nature Communications\nafter the following minor issues are addressed:\n1. While this paper examines diverse methylenecyclobutanes via NHC-Ni catalysis, extending the study to include\nmethylenecyclopropanes under the standard conditions would enhance broad readership appeal. Additionally, control\nexperiments using methylenecyclopentane and methylenecyclohexane are necessary to clarify the critical role of ring strain.\n2. Given that benzocyclobutenones serve as valuable building blocks for synthesizing valuable molecules through C–C\nactivation, it would be worthwhile to examine whether this method is applicable to benzocyclobutenone-derived alkenes\n(e.g., 7-methylenebicyclo[4.2.0]octa-1,3,5-triene). Such an exploration could open new chemical space.\n3. For the 1,4-hydrocarbofunctionalization process, although sodium isopropoxide demonstrated high reactivity as a\nhydrogen source, evaluating other hydride sources (e.g., silanes and isopropanol) would provide a more comprehensive\nunderstanding of the reaction scope.\n4. From an electronic perspective, benzylmagnesium chloride represents a somewhat unique class of Grignard reagents.\nThe reviewer suggests that the authors explore the reactions of other alkyl Grignard reagents, such as n-butylmagnesium\nchloride and cyclohexylmagnesium chloride.\n5. Formatting and labeling corrections:\nLine 52: According to the literature data (Chem. Rev. 2021, 121, 264−299), “cyclobutene” should be revised to “cyclobutane”\n(26.5 kcal/mol).\nFig. 1: “underdevelopment” should be revised to “underdeveloped”.\nLine 101: Compound 4i is not a meta-substituted product.\nLine 103: “4o-4v” should be revised to “4o-4w”.\nLine 108: “4w-4ah” should be revised to “4x-4ah”.\nLine 185: “intramolecular” should be removed.\nLine 212 and 220: “cyclobutene” should be revised to “methylenecyclobutane”.\n6. The crystal structure identifier requires correction in the manuscript.", "reviewer_2": "The present manuscript reports a nickel-catalyzed selective ring-opening and subsequent functionalization of\nmethylenecyclobutanes (MCBs) through controlled C–C bond cleavage. This approach enables both 1,4-\ndicarbofunctionalization and 1,4-hydrocarbofunctionalization, by effectively transforming the intrinsic ring strain and dual\nreactivity of MCBs into a powerful tool for building nonadjacent C(sp³)–C(sp²) frameworks. The reactions proceed under mild\nconditions, delivering the intended products in high yields. The present work is supported by experimental optimization, a\nbroad substrate scope, scalability studies, and detailed mechanistic insights corroborated by DFT calculations. Overall, the\nmanuscript may be considered for publication in Nat. Commun. after the authors address the following major concerns.\n1. In general, oxidative addition is preferable when a metal centre is electron rich. Between the ligand L6/L7, the L7\ncontaining LNi0 containing species is supposed to be more electron rich however, the optimisation conditions suggest that\nL6 provides better yield. The authors should provide suitable justification/theoretical explanation to support their observation.\n2. Authors should perform reaction by combining the present NHC-Ni system with other chelating ligands like dppe, dppf,\ndcype etc., which together may yield better catalytic system.\n3. In the substrate scope table Fig. 2 from 4p to 4aj and in Fig. 3 from 7w to 7am there is a specific choice of p-\nmethoxyphenyl triflate as coupling partner when there is variation in MCBs. Authors need to justify why there is such\nspecificity.\n4. “The operational simplicity of the protocol was further demonstrated by employing the air-stable Ni(0) precatalyst Ni(4-\ntBustb)3, which enabled the 1,4-dicarbofunctionalization of 1a to furnish 4a in 52% yield (Fig. 4B).” In this context there is a\nlack of clarity that why does Ni(4-tBustb)3 provides lesser yield. Is it governed by both steric and electronic factors?\n5. The control experiment section looks weak as there is no such clarity about how the Ni-NHC complex is significantly\ninvolved in the catalytic cycle. The authors should provide evidence for the active Ni-NHC catalyst.\n6. In the control experiment, no radical quenching experiment has been performed. However, there is a possibility that\npresent reaction may proceed through radical pathway. Hence, the authors should perform quenching experiments to\nexclude a radical pathway.\n7. The optimization table shows that NHC ligand (L6) works well for 1,4-dicarbofunctionalization of MCBs. The manuscript\nwould benefit from a more detailed discussion of the steric and electronic properties that make L6 is most effective compared\nto other ligands.\n8. The proposed β-carbon elimination pathway is plausible and well-supported by DFT. However, direct experimental\nevidence (such as detection of intermediates or kinetic studies) is limited. The authors should provide additional mechanistic\ninsights - such as stoichiometric reactions or trapping of Ni-alkyl intermediates to reinforce the proposed sequence.\n9. The authors note the suppression of 1,2-difunctionalization and Kumada-type cross-coupling side reactions. However, no\nrationale is provided for how the catalyst system selectively promotes 1,4-difunctionalization over other possible coupling\nmodes. Clarifying the factors (steric, electronic, or strain-release effects) controlling this selectivity would enhance\nmechanistic understanding.\n10. The author should provide a clear rationale explaining why the L5 ligand is particularly effective for the 1,4-\nhydrocarbofunctionalization of MCBs, whereas the L6 ligand performs better in the 1,4-dicarbofunctionalization of MCBs.", "reviewer_3": "The authors present a nice study of Ni-catalyzed difunctionalization of methylenecyclobutanes, exploiting the strain energy\nand dual reactivity of MCBs to obtain nonadjacent C(sp3)/C(sp2) frameworks. The mechanism is further disclosed by both\nexperiment and DFT study, preliminarily revealed the reaction mechanism. However, the reaction mechanism needs to be\nimproved and the computational results were not clearly expressed in pictures, and the discussion was not sufficient. In\naddition, the computed energy barrier of 27.3 kcal/mol for the 1,2-insertion step is too high for the reaction at 40 °C.\nTherefore, I suggest the authors resubmit it for review after major revision noted below.\n1) Despite the fact that for square planar Ni(II) complexes, the singlet state is typically the ground state, the energy\ndifferences of the spin-polarized singlet and triplet states for tri-coordinate Ni complexes are still worth considering.\n2) The rate-determine-step (RDS) of calculated mechanism seems to be the insertion step with 27.3 kcal/mol energy barrier\nas shown in Fig. 5c in page 10 of the manuscript. Although kinetic isotope effect indicates a RDS participated with the\nfunctionalization of the sp3-C, for different reactants, ArMgCl and iPrONa, the reaction mechanism may differ, leading to\ninconsistent RDS. Therefore, the lower activation energy of int8 to TS4 (21.0 kcal/mol) comparing with that of int5' to TS4\n(26.3 kcal/mol) in the competing reaction pathway introduced in SI, cannot determine the advantage or disadvantage of the\nreaction pathway, since both two energy barriers are available under experimental temperature (313 K) and lower than the\nactivation energy of int2 to TS2. I suggest that the author reconsider the two reaction pathways, RDS, and possibly\nsupplement the experiment of the kinetic isotope effect corresponding to ArMgCl.\n3) The pre-intermediate of TS2 and TS2', a four-coordinate Ni-MCB complex, should be under discussion instead of\nskipping. Although from the experimental results I can easily infer that TS2' does not take advantages, as mentioned in 2), I\nbelieve it is necessary to consider the pre-intermediate to further clarify the details of this step. Similar issues arise during the\ntransition from int3 to int4, due to the presence of the competing transition state TS2'' and the energetic irreversibility of the\n3a coordination process (from int3 to int4 and from int3' to int4'), the transition state of this process needs to be clarified.\n4) In my opinion, the pre-intermediate of TS3' should not be int6 but int5. The relative position of two groups in TS3' is more\nsimilar to int5 instead of int6.\n5) The distinction between the int5' and int8 cannot be discerned from Figure S13, I suggest adding a 3D structural diagram\nfor support. Furthermore, the possibility of int5' and int7 undergoing reductive elimination is worth exploring. I am confused\nby the necessity of passing through int8 before reductive elimination can occur.\n6) I hope to obtain some conjectures or arguments for the following questions related to reactivity: the possible reason of the\ninfluence of substituents on the reactants and ligands; the reason for using L5 with lower yield instead of L6 in the\ncomputation.\n7) Regarding the plotting of potential energy profiles, I suggest the following: strive to maintain a higher energy level for the\nfront part of int2 relative to the rear part to avoid unnecessary misunderstandings; set the endpoint of the reaction pathway to\nNi(0)L and detach the product to construct a complete catalytic cycle.\n8) The reaction time should be added to Figs. 2 and 3. The yield of 4a should be indicated in Fig. 2 to facilitate direct\ncomparison. The structure of 1a should be presented in a consistent manner in Supplementary Sections 5.11 and 5.12.\n9)In Fig. 5, the reaction-energy profile presented by the authors contains obvious errors; for example, TS2 is placed at –42.5\nkcal mol⁻¹ yet is drawn higher than TS1 at –11.1 kcal mol⁻¹."}, "author_response": "Point-by-point response to the editor and reviewers’ comments\n(ID: NCOMMS-25-74600-T)\nReviewer #1 (Remarks to the Author):\nIn this manuscript, Wang and co-workers report a novel NHC-Ni-catalyzed, ring-opening\nmulticomponent reaction of methylenecyclobutanes (MCBs), leveraging ring-strain release\nto drive either 1,4-dicarbofunctionalization or 1,4-hydrocarbofunctionalization. The strategy\neffectively harnesses the strain energy and dual reactivity of MCBs, providing access to\nvaluable nonadjacent C(sp³)/C(sp²) frameworks with high efficiency and broad substrate\nscope. The synthetic utility of this method is demonstrated through a series of downstream\ntransformations. The proposed mechanism, supported by control experiments and detailed\nDFT calculations, involves a key strain-driven β-carbon elimination. Based on the\nreviewer’s research experience in the chemistry of alkylidenecyclopropanes and\nalkylidenecyclobutanes, this study represents a significant contribution to small-ring\nchemistry and is recommended for publication in Nature Communications after the\nfollowing minor issues are addressed:\nResponse: We sincerely thank this reviewer for the positive comments on our work, we\nreally appreciate it.\n1. While this paper examines diverse methylenecyclobutanes via NHC-Ni catalysis,\nextending the study to include methylenecyclopropanes under the standard conditions\nwould enhance broad readership appeal. Additionally, control experiments using\nmethylenecyclopentane and methylenecyclohexane are necessary to clarify the critical\nrole of ring strain.\nResponse: We thank the reviewer for this insightful suggestion. Following the\nrecommendation, we evaluated methylenecyclopropanes, methylenecyclopentane, and\nmethylenecyclohexane under the standard 1,4-difunctionalization conditions. In all cases,\nno ring-opening products were detected by GC–MS analysis. These results further\nunderscore that both the pronounced ring-strain energy and the steric environment present\nin methylenecyclobutanes are essential for productive catalytic activation.\n2. Given that benzocyclobutenones serve as valuable building blocks for synthesizing\nvaluable molecules through C–C activation, it would be worthwhile to examine whether this\nmethod is applicable to benzocyclobutenone-derived alkenes (e.g., 7-\nmethylenebicyclo[4.2.0]octa-1,3,5-triene). Such an exploration could open new chemical\nspace.\nResponse: We thank the reviewer for this insightful suggestion. Following the\nrecommendation, we have evaluated 7-methylenebicyclo[4.2.0]octa-1,3,5-triene under the\nstandard 1,4-hydrocarbofunctionalization and 1,4-dicarbofunctionalization conditions. To\nour delight, the desired products were successfully obtained despite a low yield, we have\nadded the results to the Supplementary Information. Further investigations on these\nsubstrates will be carried out in the future course.\n3. For the 1,4-hydrocarbofunctionalization process, although sodium isopropoxide\ndemonstrated high reactivity as a hydrogen source, evaluating other hydride sources (e.g.,\nsilanes and isopropanol) would provide a more comprehensive understanding of the\nreaction scope.\nResponse: We thank the reviewer for this insightful suggestion. Following the\nrecommendation, we have evaluated isopropanol and triethylsilane under the standard\nconditions. However, no product was observed by GC-MS analysis, which further\nconfirmed the crucial role of sodium isopropoxide for the hydrogen transfer in the 1,4-\nhydrocarbofunctionalization of methylenecyclobutanes.\n4. From an electronic perspective, benzylmagnesium chloride represents a somewhat\nunique class of Grignard reagents. The reviewer suggests that the authors explore the\nreactions of other alkyl Grignard reagents, such as n-butylmagnesium chloride and\ncyclohexylmagnesium chloride.\nResponse: We thank the reviewer for this insightful suggestion. Following the\nrecommendation, we have examined additional alkyl Grignard reagents as shown below,\nincluding n-butylmagnesium bromide and cyclohexylmagnesium bromide. Unfortunately,\nthese reagents were incompatible with our catalytic system, and no desired product was\ndetected by GC–MS analysis. Further investigations aimed at optimizing the catalytic\nsystem and expanding its generality are currently underway, which we expect will open\nnew avenues for the divergent transformation of methylenecyclobutanes.\n5. Formatting and labeling corrections:\nLine 52: According to the literature data (Chem. Rev. 2021, 121, 264−299), “cyclobutene”\nshould be revised to “cyclobutane” (26.5 kcal/mol).\nFig. 1: “underdevelopment” should be revised to “underdeveloped”.\nLine 101: Compound 4i is not a meta-substituted product.\nLine 103: “4o-4v” should be revised to “4o-4w”.\nLine 108: “4w-4ah” should be revised to “4x-4ah”.\nLine 185: “intramolecular” should be removed.\nLine 212 and 220: “cyclobutene” should be revised to “methylenecyclobutane”.\nResponse: We thank the reviewer for these suggestions. We have corrected these\nmistakes in the manuscript.\n6. The crystal structure identifier requires correction in the manuscript.\nResponse: We thank the reviewer for the suggestion. We have corrected this mistake in\nthe manuscript.\nReviewer #2 (Remarks to the Author):\nThe present manuscript reports a nickel-catalyzed selective ring-opening and subsequent\nfunctionalization of methylenecyclobutanes (MCBs) through controlled C–C bond cleavage.\nThis approach enables both 1,4-dicarbofunctionalization and 1,4-\nhydrocarbofunctionalization, by effectively transforming the intrinsic ring strain and dual\nreactivity of MCBs into a powerful tool for building nonadjacent C(sp³)–C(sp²) frameworks.\nThe reactions proceed under mild conditions, delivering the intended products in high\nyields. The present work is supported by experimental optimization, a broad substrate\nscope, scalability studies, and detailed mechanistic insights corroborated by DFT\ncalculations. Overall, the manuscript may be considered for publication in Nat. Commun.\nafter the authors address the following major concerns.\nResponse: We sincerely thank this reviewer for the positive comments on our work, we\nreally appreciate it.\n1. In general, oxidative addition is preferable when a metal centre is electron rich. Between\nthe ligand L6/L7, the L7 containing LNi0 containing species is supposed to be more\nelectron rich however, the optimisation conditions suggest that L6 provides better yield.\nThe authors should provide suitable justification/theoretical explanation to support their\nobservation.\nResponse: We thank the reviewer for this insightful suggestion. To further elucidate the\nrole of steric and electronic effects of NHC ligands in this transformation, we evaluated a\nbroader set of NHC ligands. As shown below, additional modification of the NHC ligand via\nsteric tuning of the aryl substituents did not enhance the reaction efficiency (L5, 36% yield;\nL7, 34% yield). Similarly, variations of the imidazole backbone designed to modulate both\nelectronic and steric properties failed to improve the yield of 4a (L8, 34%; L9, 27%; L10,\n47%), indicating that an appropriate balance of steric and electronic effects is critical for\nthis transformation.\n2. Authors should perform reaction by combining the present NHC-Ni system with other\nchelating ligands like dppe, dppf, dcype etc., which together may yield better catalytic\nsystem.\nResponse: We appreciate the reviewer's insightful suggestion. In response, we evaluated\na range of ligand combinations for this reaction. As shown below, the addition of 10 mol%\ndppe under the standard dicarbofunctionalization conditions did not affect the product yield,\nwhereas reducing the NHC loading to 5 mol% resulted in a decreased yield of 45%.\nMoreover, the introduction of additional phosphine ligands failed to enhance the reaction\nefficiency, indicating that the incorporation of other chelating ligands is not beneficial for\nthis catalytic system. Consistent results were also observed in the\nhydrocarbofunctionalization reaction, as shown below.\n3. In the substrate scope table Fig. 2 from 4p to 4aj and in Fig. 3 from 7w to 7am there is\na specific choice of p-methoxyphenyl triflate as coupling partner when there is variation in\nMCBs. Authors need to justify why there is such specificity.\nResponse: We thank the reviewer for this insightful suggestion. To systematically evaluate\nthe structural tolerance of the reaction conditions toward MCBs, it is necessary to employ\na single, well-defined electrophile in accordance with the principle of controlling variables.\nGiven their ready availability and good functional-group tolerance, p-methoxyphenyl triflate\nand p-methoxyphenyl bromide were therefore selected as the coupling partners for this\ninvestigation.\n4. “The operational simplicity of the protocol was further demonstrated by employing the\nair-stable Ni(0) precatalyst Ni(4-tBustb)3, which enabled the 1,4-dicarbofunctionalization\nof 1a to furnish 4a in 52% yield (Fig. 4B).” In this context there is a lack of clarity that why\ndoes Ni(4-tBustb)3 provides lesser yield. Is it governed by both steric and electronic factors?\nResponse: We thank the reviewer for this insightful suggestion. As noted by the reviewer,\nthe reduced yield can be attributed to a combination of steric and electronic factors, which\nis further supported by our ligand-screening studies for this transformation. We have\nclarified in the revised manuscript that the pronounced steric bulk of Ni(4-tBustb) may\n3\nimpede the reaction efficiency, thereby leading to the diminished yield.\n5. The control experiment section looks weak as there is no such clarity about how the Ni-\nNHC complex is significantly involved in the catalytic cycle. The authors should provide\nevidence for the active Ni-NHC catalyst.\nResponse: We thank the reviewer for this insightful suggestion. Following the\nrecommendation, we synthesized the Ni(IPr) catalyst according to the reported procedure\n2\n(J. Org. Chem. 82, 6895 – 6903 (2017)). As shown below, the dicarbofunctionalization\nreaction proceeded smoothly to afford the desired product in 43% yield, further confirming\nthe involvement of an active Ni–NHC catalyst. We have added the result to the manuscript.\n6. In the control experiment, no radical quenching experiment has been performed.\nHowever, there is a possibility that present reaction may proceed through radical pathway.\nHence, the authors should perform quenching experiments to exclude a radical pathway.\nResponse: We thank the reviewer for this insightful suggestion. The radical-trapping\nexperiments for the 1,4-dicarbofunctionalization using one equivalent of TEMPO or BHT\nafforded 7a in 62% yield and 66% yield, respectively, thereby excluding the involvement of\na radical pathway. We have added the results to manuscript.\n7. The optimization table shows that NHC ligand (L6) works well for 1,4-\ndicarbofunctionalization of MCBs. The manuscript would benefit from a more detailed\ndiscussion of the steric and electronic properties that make L6 is most effective compared\nto other ligands.\nResponse: We thank the reviewer for this insightful suggestion. To further elucidate the\nrole of steric and electronic effects of NHC ligands in this transformation, we evaluated a\nbroader set of NHC ligands. As shown below, additional modification of the NHC ligand via\nsteric tuning of the aryl substituents did not enhance the reaction efficiency (L5, 36% yield;\nL7, 34% yield). Similarly, variations of the imidazole backbone designed to modulate both\nelectronic and steric properties failed to improve the yield of 4a (L8, 34%; L9, 27%; L10,\n47%), indicating that an appropriate balance of steric and electronic effects is critical for\nthis transformation. We have added the results to the manuscript.\n8. The proposed β-carbon elimination pathway is plausible and well-supported by DFT.\nHowever, direct experimental evidence (such as detection of intermediates or kinetic\nstudies) is limited. The authors should provide additional mechanistic insights - such as\nstoichiometric reactions or trapping of Ni-alkyl intermediates to reinforce the proposed\nsequence.\nResponse: We thank the reviewer for this insightful suggestion. To further probe the\nmechanism, we conducted a stoichiometric experiment using one equivalent of Ni(cod)₂\nand the ligand, as shown below. After stirring for 12 h, 1 mL of H O was added to the\n2\nreaction mixture, which was then directly analyzed by GC-MS. The formation of the 1,4-\nhydrocarbofunctionalization product was observed, thereby supporting the involvement of\na Ni–alkyl intermediate in the catalytic cycle. These results have been included in the\nSupplementary Information.\n9. The authors note the suppression of 1,2-difunctionalization and Kumada-type cross-\ncoupling side reactions. However, no rationale is provided for how the catalyst system\nselectively promotes 1,4-difunctionalization over other possible coupling modes.\nClarifying the factors (steric, electronic, or strain-release effects) controlling this selectivity\nwould enhance mechanistic understanding.\nResponse: We thank the reviewer for this insightful suggestion. In prior studies (J. Am.\nChem. Soc. 143, 9498−9506 (2021); Nat. Catal. 6, 1087−1097 (2023)), NHC–Ni-catalyzed\nregioselective 1,2-difunctionalization of terminal alkenes was largely governed by steric\neffects imposed by the catalyst, and the Kumada-type cross-coupling between aryl triflates\nand benzylmagnesium chlorides is not fully suppressed and remains a primary competing\npathway. Notably, in contrast to these precedents, the present reaction predominantly\nfurnishes the 1,4-difunctionalization product, while 1,2-difunctionalization is significantly\ndisfavored. We attribute this switch in selectivity to the strain-release associated with β-\ncarbon elimination of the cyclobutene framework, which drives the reaction along the 1,4-\ndifunctionalization pathway and is confirmed by the DFT calculations.\n10. The author should provide a clear rationale explaining why the L5 ligand is particularly\neffective for the 1,4-hydrocarbofunctionalization of MCBs, whereas the L6 ligand performs\nbetter in the 1,4-dicarbofunctionalization of MCBs.\nResponse: We thank the reviewer for this insightful suggestion. The 1,4-difunctionalization\nof MCBs proceeds in the presence of multiple competing pathways, including 1,2-\ndifunctionalization across the C=C bond, direct cross-coupling between the electrophile\nand nucleophile, and challenges associated with regioselective migratory insertion.\nTherefore, precise control over both the steric environment and the electronic properties\nof the Ni center is critical.\nFrom our ligand-screening studies, L5 and L6 display distinct reactivity profiles that we\nattribute to their different steric and electronic features. L6 possesses a slightly larger\nburied volume and stronger σ-donating character, which we propose facilitates the second\nC–C bond-forming step while simultaneously reducing side cross-coupling events, leading\nto improved yields of the 1,4-dicarbofunctionalization product. In contrast, L5 provides a\ncomparatively less encumbered coordination environment and a weaker σ-donation profile.\nWe believe this promotes a more facile β-H elimination step and enables subsequent\nprotonation, which is beneficial under the hydrofunctionalization conditions. As shown\nbelow, for the 1,4-dicarbofunctionalization of 1a, ligand L6 outperforms L5, as it\nsignificantly suppresses the formation of side products under these conditions. Conversely,\nin the 1,4-hydrofunctionalization of 1a, ligand L5 delivers superior results, owing to its\ngreater ability to minimize competitive by-product formation.\nTaken together, these observations support a ligand-controlled mechanistic divergence,\nwhere subtle differences in steric demand and electron donation modulate the balance\nbetween β-carbon elimination, cross-coupling, and protonation steps. Further\ninvestigations on the detailed catalytic mechanism is our ongoing work, which will be\nreported in due course.\nReviewer #3 (Remarks to the Author):\nThe authors present a nice study of Ni-catalyzed difunctionalization of\nmethylenecyclobutanes, exploiting the strain energy and dual reactivity of MCBs to obtain\nnonadjacent C(sp3)/C(sp2) frameworks. The mechanism is further disclosed by both\nexperiment and DFT study, preliminarily revealed the reaction mechanism. However, the\nreaction mechanism needs to be improved and the computational results were not clearly\nexpressed in pictures, and the discussion was not sufficient. In addition, the computed\nenergy barrier of 27.3 kcal/mol for the 1,2-insertion step is too high for the reaction at 40 °C.\nTherefore, I suggest the authors resubmit it for review after major revision noted below.\nResponse: We sincerely thank the reviewer for the positive evaluation of our work and for\nthe constructive and insightful comments. In the revised manuscript, we have updated the\nDFT calculations for ligand L6 and revised the manuscript according to your comments.\nRegarding the comment that “the computed energy barrier of 27.3 kcal/mol for the 1,2-\ninsertion step is too high for the reaction at 40 °C”, we agree that the absolute value of a\ncalculated activation barrier should be interpreted with caution when directly compared to\nexperimental reaction temperatures. It is important to note that the primary goal of the DFT\nstudy in this work is not to reproduce the experimental kinetics quantitatively, but rather to\nprovide a qualitative and comparative mechanistic framework that rationalizes the\nobserved regioselectivity.\nWe again thank the reviewer for this valuable comment, which has helped us to improve\nthe clarity of the computational results in the revised manuscript.\n1. Despite the fact that for square planar Ni(II) complexes, the singlet state is typically the\nground state, the energy differences of the spin-polarized singlet and triplet states for tri-\ncoordinate Ni complexes are still worth considering.\nResponse: We thank the reviewer for this insightful comment. In line with this suggestion,\nwe further evaluated the spin-state energetics of the key tri-coordinate Ni intermediates.\nAs summarized in Table S18 in the Supplementary Information, the calculated Gibbs free\nenergy differences between the triplet and singlet states (ΔG ) for intermediates int2,\nT–S\nand int5′ are 15.3, 15.4, and 16.9 kcal/mol, respectively. These calculation results clearly\nindicate that the singlet state is strongly favored over the triplet state for these tri-coordinate\nNi species, supporting the validity of describing the reaction pathway on the singlet\npotential energy surface.\nTable S18. Computed Gibbs free energy differences between the triplet and singlet states\n(ΔG ) for key reaction intermediates.\nT–S\nint2 int5 int5'\nΔG (kcal/mol) 15.3 15.4 16.9\nT–S\n2. The rate-determine-step (RDS) of calculated mechanism seems to be the insertion step\nwith 27.3 kcal/mol energy barrier as shown in Fig. 5c in page 10 of the manuscript. Although\nkinetic isotope effect indicates a RDS participated with the functionalization of the sp3-C,\nfor different reactants, ArMgCl and iPrONa, the reaction mechanism may differ, leading to\ninconsistent RDS. Therefore, the lower activation energy of int8 to TS4 (21.0 kcal/mol)\ncomparing with that of int5' to TS4 (26.3 kcal/mol) in the competing reaction pathway\nintroduced in SI, cannot determine the advantage or disadvantage of the reaction pathway,\nsince both two energy barriers are available under experimental temperature (313 K) and\nlower than the activation energy of int2 to TS2. I suggest that the author reconsider the two\nreaction pathways, RDS, and possibly supplement the experiment of the kinetic isotope\neffect corresponding to ArMgCl.\nResponse: We thank the reviewer for this insightful and careful analysis of the calculated\nreaction pathways and the interpretation of the rate-determining step (RDS). We agree that\nwhen multiple reaction pathways are kinetically accessible, caution must be exercised in\ncorrelating individual activation barriers with pathway preference.\nIn the revised manuscript, we have updated the DFT calculations for ligand L6 and\ncorresponding discussion (now shown in Figure 6 and Figure S14) to more accurately\nreflect the mechanistic features of the system. In the updated energy profiles, the olefin\ninsertion step from int2 to TS2, with an activation free energy of 27.0 kcal/mol, is identified\nas the highest barrier shared by all pathways leading to P1 and P2. This step therefore\nconstitutes the rate-determining step of the catalytic cycle, independent of the subsequent\nsequence of elementary steps.\nAfter formation of int4, the reaction bifurcates into two competing pathways that differ in\nthe order of transmetalation and β-C elimination. Importantly, all subsequent steps along\nboth pathways exhibit significantly lower activation barriers than that of the olefin insertion\nstep. As correctly pointed out by the reviewer, under the experimental conditions, these\npost-insertion steps are all kinetically accessible and therefore do not determine the overall\nreaction rate or uniquely dictate pathway preference. Accordingly, in the revised manuscript,\nwe no longer rely on comparisons between individual downstream barriers (e.g., reductive\nelimination steps) to claim the dominance of one pathway over the other.\n3. The pre-intermediate of TS2 and TS2', a four-coordinate Ni-MCB complex, should be\nunder discussion instead of skipping. Although from the experimental results I can easily\ninfer that TS2' does not take advantages, as mentioned in 2), I believe it is necessary to\nconsider the pre-intermediate to further clarify the details of this step. Similar issues arise\nduring the transition from int3 to int4, due to the presence of the competing transition state\nTS2'' and the energetic irreversibility of the 3a coordination process (from int3 to int4 and\nfrom int3' to int4'), the transition state of this process needs to be clarified.\nResponse: We thank the reviewer for this insightful comment.\nTo further clarify the details of the olefin insertion step, we explicitly examined the pre-\nintermediates preceding the 1,2- and 2,1-insertion transition states. As shown in Figure 6,\ncoordination of substrate 1a′ to the Ni(II) center in int2 leads to the formation of four-\ncoordinate Ni–MCB complexes int3 and int3′, which serve as the immediate precursors to\nTS2 and TS2′, respectively. Notably, the formation of both int3 and int3′ from int2 is\ncalculated to be endergonic, indicating that coordination of the strained\nmethylenecyclobutane to the Ni center is thermodynamically uphill. As a result, the\neffective activation barriers for both the 1,2- and 2,1-insertion pathways are appropriately\nreferenced to int2, rather than to the higher-energy pre-intermediates. Consequently,\nexplicit inclusion of these pre-intermediates does not alter the identification of the olefin\ninsertion step as the rate-determining step of the catalytic cycle.\nRegarding the transmetalation step, we fully agree that the full reaction sequence\nincluding the reactant complex, transition state, and product complex should be\ncharacterized. However, despite extensive efforts, we were unable to locate a well-defined\ntransition state or a stable reactant complex for the transmetalation between intermediate\nint4 and the Grignard reagent 3a at the employed level of theory. For the product side, a\nstable product complex could only be optimized in the gas phase. Starting from this gas-\nphase optimized structure, we subsequently performed a relaxed potential energy surface\n(PES) scan, using the C···Mg distance as the reaction coordinate. In this scan, the C···Mg\ndistance was gradually shortened (from right to left in Figure S13). The resulting energy\nprofile is shown in Figure S13, which reveals a smooth and barrierless energy descent\nwithout a discernible maximum. Notably, the optimized structures indicate a significant\ncoordination rearrangement upon association of 3a with int4. Specifically, coordination of\nthe Grignard reagent to the Ni center induces dissociation of the triflate ligand from Ni,\nfollowed by preferential coordination of OTf⁻ to the Mg center.\nFigure S13\n4. In my opinion, the pre-intermediate of TS3' should not be int6 but int5. The relative\nposition of two groups in TS3' is more similar to int5 instead of int6.\nResponse: We appreciate the reviewer’s insightful comment. In the revised calculations,\nwe carefully reanalyzed the structural relationship between TS3′ and the preceding\nintermediates by IRC calculations. By comparing key geometric parameters and the\nrelative orientations of the alkyl and benzyl fragments, the analysis clearly indicates that\nTS3′ evolves directly from int5, rather than int6, as its geometry more closely resembles\nthat of int5. On this basis, we have reassigned the pre-intermediate of TS3′ to int5, and\nthe corresponding labeling and mechanistic discussion have been consistently corrected\nin Figure 6 and in the revised manuscript.\n5. The distinction between the int5' and int8 cannot be discerned from Figure S13, I suggest\nadding a 3D structural diagram for support. Furthermore, the possibility of int5' and int7\nundergoing reductive elimination is worth exploring. I am confused by the necessity of\npassing through int8 before reductive elimination can occur.\nResponse: We thank the reviewer for this insightful comment. In the revised\nSupplementary Information, we have provided the optimized structures of intermediates\nint5' and int8 (please refer to Figure S15). Intermediate int5' and int8 differ primarily in\nthe conformation of the alkyl fragment bound to Ni, arising from single-bond rotation along\nthe Ni–alkyl chain. Importantly, the calculated results indicate that productive C–C\nreductive elimination occurs exclusively from int8, with TS4 unambiguously connected to\nthis intermediate. Attempts to locate a direct reductive elimination transition state from int7\nwere unsuccessful, indicating that int7 must first undergo isomerization to int8 to achieve\nthe proper geometry for C–C bond formation. For int5′, this intermediate can undergo\ndirect C–C reductive elimination via TS4′ (Figure S14), this pathway is kinetically less\nfavorable due to its higher activation barrier compared to that of TS4.\n6. I hope to obtain some conjectures or arguments for the following questions related to\nreactivity: the possible reason of the influence of substituents on the reactants and ligands;\nthe reason for using L5 with lower yield instead of L6 in the computation.\nResponse: We thank the reviewer for this insightful comment. To ensure consistency with\nthe experimentally optimal conditions and to avoid ambiguity arising from ligand effects,\nwe have recalculated the entire reaction mechanism using ligand L6. All computational\ndata, energy profiles, and mechanistic discussions in the revised manuscript are now\nexclusively based on the L6-ligated Ni catalyst. The corresponding figures, tables, and\nmechanistic analyses have been revised accordingly in the manuscript and Supplementary\nInformation.\n7. Regarding the plotting of potential energy profiles, I suggest the following: strive to\nmaintain a higher energy level for the front part of int2 relative to the rear part to avoid\nunnecessary misunderstandings; set the endpoint of the reaction pathway to Ni(0)L and\ndetach the product to construct a complete catalytic cycle.\nResponse: We appreciate the reviewer’s constructive suggestions on the presentation of\nthe potential energy profiles. In the revised manuscript, Figure 6 has been modified\nfollowing the reviewer’s suggestions. Specifically, the relative energy level of the front\nsegment of int2 has been adjusted to avoid potential confusion in reading the energy\nprofile. In addition, the reaction pathway is now extended to terminate at the regenerated\nNi(0)L species with explicit dissociation of the organic product, thus depicting a complete\nand closed catalytic cycle. These revisions improve the clarity and consistency of the\nenergy diagram and more accurately reflect the catalytic nature of the process.\n8. The reaction time should be added to Figs. 2 and 3. The yield of 4a should be indicated\nin Fig. 2 to facilitate direct comparison. The structure of 1a should be presented in a\nconsistent manner in Supplementary Sections 5.11 and 5.12.\nResponse: We thank the reviewer for this suggestion. We have corrected these mistakes\nin the manuscript and supplementary information.\n9. In Fig. 5, the reaction-energy profile presented by the authors contains obvious errors;\nfor example, TS2 is placed at –42.5 kcal mol⁻¹ yet is drawn higher than TS1 at –11.1 kcal\nmol⁻¹.\nResponse: In the revised manuscript, Figure 6 has been modified in accordance with the\nreviewer’s suggestions to provide a clearer depiction of the energy profile."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have thoroughly addressed the concerns raised by three reviewers. In addition, they renewed the calculation of\nthe reaction mechanism and provided the corresponding mechanistic discussions in the revised manuscript. Overall, this\nwork represents a significant contribution to small-ring chemistry. In my opinion, the current version can be accepted for\npublication in Nature Communications.", "reviewer_2": "In the revised manuscript all the concerns raised by the reviewers have been addressed properly and now it is suitable for\npublication in Nat. Commun.", "reviewer_3": "The author has carefully revised and explained the issues that I am concerned about, and the revised article is very good. I\nsuggest publishing this work in Nature Communications."}, "author_response": ""}]

Decision letter