Tunable enantioselective electrocatalytic functionalization of unactivated alkenes

Domain: chemistry
Published: 2026-01-02
Editorial outcome: major_revision

Abstract
The tunable enantioselective functionalization of alkene feedstocks represents a highly desirable yet predominantly unresolved tactic for generating high-value scaffolds. Herein, we report a tunable enantioselective electrolytic system for dehydrogenative allylation, dehydrogenative alkenylation, and hydroalkylation reactions with identical substrates to afford structurally diverse products. This success hinges on the rational design of the stereoselective coupling of an electrogenerated nickel-bound α-carbonyl radical species that can trap unactivated alkenes and engage in various subsequent radical termination processes to enable the intermolecular functionalization of unactivated alkenes. The mild reaction conditions and sustainable electrocatalytic radical platform guarantee excellent functional group tolerance and substrate compatibility with unactivated alkenes (63 examples, up to 98% e.e.), and the process evolves H₂ without the need for external chemical oxidants. The utility of this enantioselective electrolytic strategy is demonstrated by its application in the stereoselective formal synthesis of (S)-SYK inhibitor, signifying substantial progress in synthetic methods.

Introduction
The catalytic intermolecular functionalization of alkenes is a fundamental and essential transformation to construct basic organic frameworks in organic synthesis, which have important applications in pharmaceuticals, agrochemicals, catalysts, and materials1. A typical carbon−carbon bond-forming reaction, renowned as the Michael reaction2, is the addition of carbanions or their catalytic equivalents to activated alkenes bearing electron-withdrawing groups, such as α,β-unsaturated carbonyl compounds. The catalytic functionalization of unactivated alkenes is an appealing strategy for creating structurally diverse motifs and performing late-stage derivatization of medicinally relevant molecules3–5. However, the low electrophilicity of unactivated alkenes makes it challenging to achieve rapid, straightforward, and stereoselective intermolecular additions with HOMO-raised nucleophiles, particularly in a tunable manner6. This requires alternative synthetic strategies to achieve divergent synthesis and excellent enantioselectivity7,8. We rationalized that radical functionalization of alkene feedstocks, such as abundant and inexpensive hexene to undergo the initial radical addition event, followed by tunable radical termination steps to achieve multiple transformations, represents a viable strategy for enantioselective divergent alkene transformation (Fig. 1a)9–17. Organic electrosynthesis stands out as a sustainable synthetic avenue that enables the controlled occurrence of single electron transfer (SET) and facilitates the generation of radical intermediates from bench-stable substrates under mild conditions, eliminating the need for exogenous chemical oxidants18–29. However, the stereocontrolled functionalization of unactivated alkenes remains a formidable challenge. Although electrochemical oxidative allylation has been demonstrated—as exemplified by the work of the Xu group10,12—achieving analogous dehydrogenative alkenylation and hydroalkylation under electrolytic conditions continues to pose significant hurdles. More broadly, the development of electrochemical radical addition platforms capable of divergently accessing dehydrogenative allylation, alkenylation, and hydroalkylation from identical precursors with high chemoselectivity and stereocontrol represents a major unmet goal in synthetic chemistry. The integration of electrosynthesis and asymmetric catalysis has emerged as a highly potent and versatile synthetic approach for developing unconventional reaction pathways to generate reactive stereocontrollable radical intermediates for streamlined access to valuable chemical building blocks30–36, offering rational and predictable means for C−C bond formation from a common precursor in synthetic chemistry37–49.

From the outset, the endeavor to achieve tunable enantioselective functionalization of unactivated alkenes has been met with the challenge of controlling selectivity in radical addition50–54 and termination owing to the anticipated multiple side reactions. To address this issue, we devised a catalytic cycle with a chiral Lewis acid-coupled electron transfer (LCET) process and introduced a powerful electrocatalytic platform for the enantioselective α-functionalization of carbonyl compounds (Fig. 1b)34,35. A vital design criterion is the nickel-bound enolate species, which are more prone to anodic oxidation, selectively generate chirals, thus effectively controlling the stereochemistry of subsequent radical addition reactions and circumventing noncatalytic racemic background reactions arising from direct oxidation of the carbonyl substrate. Upon radical addition, we propose that the chiral electrocatalyst-mediated alkene functionalization proceeds through three competing radical termination pathways, each generating distinct products. The introduction of a secondary cobalt catalyst facilitates hydrogen atom transfer (HAT) to form dehydrogenative allylation products14–16. Alternatively, further oxidation of the alkyl radical enables a radical-polar crossover process to form oxidative alkenylation products13, whereas direct hydrogen atom transfer leads to hydroalkylation products36. In this work, we report a general and enantioselective electrocatalytic system for the divergent functionalization of unactivated alkenes. This strategy enables dehydrogenative allylation, alkenylation, and hydroalkylation from a chiral nickel-bound radical intermediate with high stereoselectivity, broad functional group tolerance, and compatibility with diverse carbon nucleophiles (Fig. 1c). The asymmetric catalytic system provides a unified platform to systematically investigate competitive radical termination pathways under mild electrochemical conditions.

Results
Reaction development
To validate our hypothesis, we initiated the reactions of racemic benzoxazolyl acetate (1a) and hexene (2a) in an undivided cell equipped with a carbon felt (CF) anode and a platinum (Pt) cathode under a constant current of 2.0 mA at 25°C (Table 1a). Encouragingly, with ferrocenemethylamine A1 functioning as the mediator and Pybox L1 acting as the chiral ligand, the alkenylated product 4a could be obtained in 11% yield and 60% enantiomeric excess (e.e.). A subsequent ligand screening (L2-L5) revealed that the use of a Box ligand with a cyclopentyl group (L5), resulted in 4a in 72% yield and 92% e.e. A subsequent evaluation of additives indicated that the chemoselectivity of the reaction is strongly dependent on additive selection, even when identical substrates are employed. Using the salen-Co additive A2, the alkenylated and allylated products were obtained with a chemoselectivity of 1:1. The similar stereoselectivities observed for both products (see Supplementary Table S2) further support that they share a common stereocontrol mode in terms of quaternary carbon center formation, whereas divergent radical termination pathways account for their structural differences. The effects of different substituted salen-Co additives on the reaction chemoselectivity were examined (A2-A5), and trifluoromethyl-substituted salen-Co A5 selectively gave rise to allylated product 3a (74% yield, 92% e.e.). The differential chemoselectivity among Co catalysts (A2–A5) correlates with their Co–H bond dissociation energies (BDE), where the higher BDE of A5 enhances HAT efficiency and favors allylation product formation (see Supplementary Table S3). Notably, employing (TMS)₃Si-H (BDE=79 kcal/mol) as a radical-terminating HAT reagent enabled the synthesis of hydroalkylated product 5a in 60% yield and 93% e.e. Remarkably, all three reaction variants delivered exceptional enantioselectivity (3a-5a), underscoring the generality of this Ni-electrocatalytic approach.

Additional control experiments were carried out to elucidate the process of electricity-driven Ni/Co dual-catalyzed dehydrogenative allylation reactions (Table 1b). The absence of a chiral Lewis acid catalyst (entry 2), additive A5 (entry 3), or electric current (entry 4) completely inhibited the generation of 3a, thus ruling out competing racemic scenarios and highlighting the criticality of these conditions for the process. Chemical oxidation with Ag₂O resulted in a loss of stereocontrol, delivering racemic 3a in 22% yield (entry 5). Additional studies revealed that product 3a forms even without the chiral Ni catalyst (entry 6), indicating that Ag₂O serves a dual function as both an oxidant and a Lewis acid, thereby promoting a competing racemic pathway. The controlled electrochemical delivery of electrons ensures a clean transformation under mild redox conditions while suppressing the racemic background reactions observed with chemical oxidants (entry 1 vs 5). These results highlight the unique advantages of electrochemistry for the catalytic asymmetric transformations reported herein in terms of the cleanness of conversion and enantioselectivity.

Substrate scope
With the optimal reaction conditions established, we investigated the versatility of this electricity-enabled enantioselective dehydrogenative allylation reaction (Fig. 2). Initially, the functional group tolerance of various unactivated alkenes was tested (3a-3w). Simple alkenes bearing potentially reactive functionalities such as chloride (3b), bromide (3c), hydroxyl (3d), protected hydroxyl groups (3e-3j), phthalimide (3k), and amide (3l) were well accommodated in this protocol, delivering the expected products effectively. Alkene substrates bearing carbon chains of different lengths were transformed to the corresponding products in good yields, with excellent chemo- and enantioselectivities (3m-3t). The absolute configuration of 3t was confirmed via X-ray diffraction, and the others were assigned analogously. Encouraged by the broad functional group tolerance under mild electrolytic reaction conditions, we explored the generality of the present protocol for complex molecules. Alkenes derived from (R)-carvone (3u) and pregnenolone (3v) were suitable substrates. The reaction with cyclic alkene also proceeded smoothly to afford product 3w in 70% yield. These results demonstrate that the Ni/Co dual electrocatalytic system has a wide substrate scope for unactivated alkenes with high functional group tolerance.

Further investigation with substituted racemic benzoxazolyl acetate 1 revealed that variations in the benzoxazole moiety had little effect on the reaction outcomes (3x-3ab). Variation of the ester group of racemic benzoxazolyl acetates had no noticeable effect on the reaction outcomes (3ac-3af). Racemic 1 bearing various substituents at the α-position of the carbonyl group also performed efficiently in enantioselective electrocatalytic reactions (3ag-3aj). Remarkably, the reaction also proved adaptable to 1,2-benzisoxazol-3-yl acetate, consistently delivering 3ak in high yield and enantioselectivity (69% yield, 88% e.e.).

Upon research on electrochemically promoted asymmetric anodic allylation reactions, we demonstrate that the reaction chemoselectivity can be precisely controlled by medium engineering, where ferrocene-based A1 selectively promotes dehydrogenative alkenylation over competing allylation pathways. Under the optimized reaction conditions, a broad range of unactivated alkenes were investigated (Fig. 3). Heteroatom-substituted alkenes proceeded smoothly under standard conditions, delivering alkenylation products with comparable yields and excellent chemoselectivities (4a-4l). Notably, the electrocatalytic dehydrogenative alkenylation approach demonstrated its practical utility for large-scale applications by effectively scaling the reaction to 6 mmol, consistently producing product 4a in high yield and excellent enantioselectivity. Alkenes with aryl (4m and 4n) or long-chain (4o) alkane substituents can effectively participate in this reaction to afford excellent enantioselectivity. X-ray diffraction analysis confirmed the R configuration of 4l. Furthermore, 1,2-benzisoxazol-3-yl acetate was also compatible with the desired product in 64% yield and 92% e.e. (4p).

Hydroalkylation via tandem radical reactions efficiently results in the formation of quaternary carbon centers in complex molecular frameworks from simple precursors. This prompted us to investigate alternative hydrogen transfer reagents as third coupling partners to effectively trap the key alkyl radical intermediate. Having optimized the reaction conditions with (TMS)₃Si-H as a hydrogen transfer reagent, we investigated the generality of this asymmetric multicomponent electrochemical difunctionalization of alkenes (Fig. 4). Notably, both unactivated alkenes and diversely substituted benzoxazolyl acetates were well tolerated, consistently affording the desired products (5a-5h) in high yields with excellent enantioselectivities.

Synthetic applications
The Ni/Co electrocatalyzed asymmetric dehydrogenative allylation reaction is also applicable to propylene gas (Fig. 5a). The alkene moiety in enantioenriched product 3a provides a versatile synthetic handle for further transformations to afford alkane 6 and alcohol 7 (Fig. 5b). The reduction of the ester group of 3a followed by hydrogenation of the alkene afforded corresponding alcohol 8 in 66% yield and 92% e.e. Moreover, the benzoxazole moiety in enantioenriched product 3x was readily converted to an aldehyde group in 9 and ketone groups in 10 and 11, enabling access to diverse chiral architectures while preserving enantiopurity.

Our enantioselective methodology was further verified via the asymmetric formal synthesis of (S)-SYK inhibitor (Fig. 5c)55. Following the reduction of enantioenriched hydroalkylation product 5d, subsequent O-mesylation cleanly afforded corresponding dimesylate 12 while maintaining the original stereochemistry. Treatment of dimesylate 12 with benzylamine provided cyclic amine 13, which underwent smooth N-deprotection followed by Boc protection to deliver N-Boc product 14 in 92% yield with complete retention of enantiopurity. Subsequent removal of the benzoxazole group generated an aldehyde that was reduced to afford enantioenriched alcohol 15, a versatile intermediate for (S)-SYK inhibitor synthesis55.

Mechanistic investigations
A range of experiments was conducted to explore the mechanism of asymmetric electrolytic transformation (Fig. 6). Initially, cyclic voltammetry (CV) experiments were run on the reaction components. Upon addition of the chiral nickel catalyst, the oxidative peak of benzoxazolyl propanoate 1b shifted negatively (Fig. 6a, left) and exhibited a concurrent increase in current with higher concentrations of 1b (Fig. 6a, middle), supporting the facile oxidation of a nickel-bound enolate intermediate. Critically, while the substrate alone with ferrocenemethylamine A1 showed no significant current response, the addition of the chiral nickel catalyst led to a substantial increase in the oxidative current with attenuation of the reduction peak. This clear contrast provides evidence for efficient electron transfer between A1 and the Ni-bound enolate intermediate (Fig. 6a, right).

To unequivocally verify the hydrogen atom transfer (HAT) mechanism in the hydroalkylation reaction, we conducted a deuterium-labeling experiment by replacing (TMS)₃Si–H with (TMS)₃Si-D (Fig. 6b). The reaction exclusively afforded deuterated product 16 with 98% D-incorporation, providing direct evidence for HAT-mediated C–H bond formation and the radical nature of the key intermediate. Radical clock experiments provide further support for the formation of the α-keto radical intermediate in the enantioselective electrochemically tunable protocol (Fig. 6c). The β-pinene 17 was treated under our electrochemical conditions, and ring-opening product 18 was obtained in 90% yield, 9:1 d.r., and 88% e.e. Furthermore, we investigated the electrochemical reaction of 1a with cyclopropane-containing alkene 19. Notably, both additives (A1 and A5) efficiently promoted the cyclopropyl ring-opening process, delivering product 20 with excellent enantioselectivity. As supported by the data in Fig. 6, these results strongly corroborate our proposed mechanism involving nickel-bound radical intermediates in the asymmetric electrochemical functionalization of alkenes.

To unravel the origin of enantioselectivity in the Ni/Co dual electrocatalytic synthesis of allylated product 3, we performed comprehensive DFT calculations (Fig. 7a). The computational studies systematically examined the reaction’s dual selectivity that controls enantioselectivity in the radical addition step and product chemoselectivity during radical termination. Initially, the chiral nickel-bound α-carbonyl radical (INT3q) undergoes Giese addition (via TS2-Siq) to generate the alkyl radical INT4q. The transition-state structures controlling the stereochemistry are shown in Fig. 7b. TS2-Siq leads to the experimentally preferred stereoisomer (R)−3a, whereas TS2-Req produces the minor enantiomer (S)−3a. The difference in the free energy of activation (ΔΔG‡) was 1.8 kcal/mol, which is consistent with the experimentally observed selectivity of 92% e.e. (Table 1). The enantioselectivity primarily stems from distinct coordination modes of the benzoxazolyl ester substrate. These different coordination modes lead to opposing facial selectivities, as illustrated in Supplementary Fig. S9. Further energy decomposition analysis (Supplementary Fig. S8) indicates that the variation in coordination geometry arises mainly from steric repulsion between the phenyl ring of the substrate and the BOX ligand. We subsequently investigated the radical termination process promoted by cobalt as an HAT catalyst in the synergistic catalytic system. Radical intermediate INT5d undergoes facile β-hydrogen atom transfer (β-HAT) when activated by CoII species. TS3-3as(BS) leads to the formation of dehydrogenative allylation product 3a, whereas TS3-4as(BS) generates dehydrogenative alkenylation product 4a. DFT calculations reveal a 2.2 kcal/mol lower free energy barrier for HAT at the favored position (TS3-3as(BS)) compared to the alternative site (TS3-4as(BS)) (Fig. 7c), rationalizing the observed chemoselectivity in dehydrogenative allylation.

Taking into account the combined results of the mechanistic studies and DFT calculations, a plausible catalytic mechanism based on electric-triggered asymmetric catalysis is outlined in Fig. 7d. The asymmetric electrochemical catalysis is initiated by the condensation of 1 with the nickel catalyst, resulting in the formation of a nickel-bound enolate intermediate (I). Anodic oxidation of I through an anodic SET pathway was proposed to form a nickel-coordinated radical intermediate (II). This radical species undergoes stereoselective interception by unactivated alkenes to establish a stereogenic center, forming alkyl radical III, a key step that governs asymmetric induction in these tunable catalytic cycles. Critically, the divergence between the dehydrogenative allylation, dehydrogenative alkenylation, and hydroalkylation pathways is governed by distinct radical termination processes. Under Ni/Co dual electrocatalytic conditions, in situ-generated alkyl radical III undergoes a sterically controlled HAT process via the cobalt catalyst, preferentially forming dehydrogenative allylation products 3 at the less hindered site. Alternatively, the introduction of (TMS)₃Si-H as the group-transfer reagent selectively traps radical III to deliver hydroalkylation products 5. Conversely, the use of additive A1 in the absence of additional termination reagents promotes single-electron oxidation of alkyl radical intermediate III to form carbocationic species V. This intermediate is stabilized by 2,6-lutidine and undergoes base-promoted β-hydride elimination preferentially from the more acidic proximal carbon, ultimately furnishing enantioenriched dehydrogenative alkenylation products 4.

We have developed a versatile nickel-electrocatalytic system that enables tunable enantioselective transformations of identical substrates to access three distinct product classes—dehydrogenative allylation, dehydrogenative alkenylation, and hydroalkylation—all with excellent enantioselectivity (up to 98% e.e.). The key to this success is the stereocontrolled coupling of electrogenerated nickel-bound α-carbonyl radicals with unactivated alkenes, where selective radical termination pathways dictate chemoselectivity. This sustainable electrocatalytic platform operates under mild conditions without external oxidants, demonstrating exceptional functional group tolerance and a broad substrate scope (63 examples). The synthetic utility of this approach is highlighted through a streamlined formal synthesis of the (S)-SYK inhibitor, indicating a significant advance in electrochemical asymmetric synthesis.

Methods
General procedure for the enantioselective Ni/Co dual-electrocatalytic functionalization of unactivated alkenes
A 10 mL flask equipped with a magnetic stir bar was charged with 1 (0.1 mmol), 2 (0.5 mmol), Ni(OAc)₂·4H₂O (0.01 mmol), L5 (0.011 mmol), A5 (0.02 mmol), morpholine (0.1 mmol), nBu₄NBF₄ (0.3 mmol), THF (0.5 mL) and TFE (2.5 mL) under an argon atmosphere. The flask was equipped with a carbon felt (1.5 cm × 1.5 cm × 3 mm) as the anode and a platinum plate (1.0 cm × 1.0 cm × 0.2 mm) as the cathode. Constant current (1.5 mA) electrolysis was carried out at 25°C until complete consumption of the starting material (monitored by TLC). The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to afford the desired product 3.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "Guo et al. report a divergent nickel-catalyzed enantioconvergent functionalization of unactivated alkenes, enabling switchable access to dehydrogenative allylation, dehydrogenative alkenylation, and hydroalkylation. The success of this strategy hinges on the rational design of an electro-oxidatively generated nickel-bound α-carbonyl radical species, which adds to unactivated alkenes and undergoes diverse radical termination pathways. The developed protocols exhibit broad substrate scope, excellent chemoselectivity, regioselectivity, and enantioselectivity, as well as scalability. The method is successfully applied to the stereoselective formal synthesis of an (S)-SYK inhibitor. Mechanistic and computational studies provide support for the proposed reaction pathway. This work represents a significant advance in asymmetric electrocatalysis and is a substantial contribution worthy of publication.\n1. The authors propose an indirect electro-oxidative generation of the nickel-bound α-carbonyl radical species mediated by a CoIII complex in allylation. What evidence rules out a direct anodic oxidation pathway since the alkenylation and hydroalkylation process do not need the CoIII complex?\n2. Besides quaternary carbon stereocenters, could these protocols construct related tertiary stereocenters? If not, what is the reason?\n3. For hydroalkylation process, the involvement of NiH from Ni precatalyst and (TMS)3SiH is well documented. Did the authors have any experimental evidence to rule out this possibility?", "reviewer_2": "Guo and co-workers report an enantioselective functionalization of unactivated alkene with benzoxazolyl acetate via electrochemically generated carbon-centered radicals. These radicals are stabilized by a chiral Ni catalyst, and subsequent enantioselective radical addition to alkenes—followed by hydrogen atom transfer (HAT), further oxidation, or reduction with hydrosilane—yields products of dehydrogenative allylation, alkenylation, and hydroalkylation, respectively. This methodology enables the formation of highly enantioriched products, including those bearing all-carbon quaternary stereocenters. The authors also provide detailed mechanistic insight into the chemo- and enantioselectivity based on cyclic voltammetry and DFT calculations.\nHowever, similar transformation by the same group have already been reported (Refs. 34 & 35), and radical addition to alkene moieties are well-established in prior literature (Refs. 10–12). Therefore, the key novelty of this work appears to lie in the switchable radical termination strategy. This reviewer recommends that the authors clarify the individual novelty and significance of each transformation pathway—namely, dehydrogenative allylation, alkenylation, and hydroalkylation. A more explicit discussion will help readers better appreciate the scope and innovation of the work. This report may be perceived as merely a combination of a known radical reaction in the first half and a known termination reaction in the latter half. The reviewer believes it is essential to provide a clear and thorough discussion on what advantages this methodology offers.\nFurthermore, the origin of the selectivity, particularly between the allylation and alkenylation pathways, requires further clarification. According to the authors, the use of a Co catalysts leads to allylation, possibly due to steric hindrance influencing HAT. In contrast, oxidation followed by deprotonation results in alkylation. However, this reviewer finds the explanation for the selective deprotonation step insufficient. What governs the divergence between these two pathways? A more detailed mechanistic rationale, possibly supported by additional data or calculations, would greatly enhance the manuscript.\nAdditional points:\n> In all electrochemical reactions, the total passed (in F/mol) should by explicitly stated. Since external oxidants rare replaced by anodic electron transfer, the charge of corresponding directly to the equivalent of oxidant used. This value can be calculated from the current and reaction time and should be respond for each transformation.\n> Page 1, line 25: “Main text” appeared to be typographical error and should be corrected to “Introduction”\n> Page 8 line 199, The phrase “alcohol 7 with all-carbon quaternary stereocenters” is incorrect, as compound 7 does not possesses an all-carbon quaternary stereocenter.\n> In the CV analysis, the authors note a significant decrease in oxidation potential upon addition of the Ni catalyst. However, the oxidation of morpholine also occurs at a similarly low potential (Figure 6a, top-left). To clearly distinguish the contribution of the Ni catalyst from that of morpholine, the cyclic voltammogram of a mixture of 1b and Ni catalyst should be measured and presented.", "reviewer_3": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts.", "reviewer_4": "The manuscript entitled “Enantioselective Switchable Selectivity in Electrocatalyzed Functionalization of Unactivated Alkenes” by Guo et al. describes the development of the asymmetric electrochemical α-functionalization of benzoxazolyl acetate derivatives with alkenes, via the use of a chiral Ni(II) complex. This method permits the transient formation of a chiral carbon-centered radical intermediate, able to diastereoselectively couple with alkenes to generate alkyl radicals which, depending on the reaction conditions, lead to the formation of alkenyl-, allyl-, or alkyl-functionalized products.\nThe reaction outcome depends of the nature of the catalyst or the reagent introduced in the reaction mixture. Employing the ferrocene derivative A1 as redox mediator alone preferentially leads to the formation of the alkenylated products, where the cobalt complex A5 permits the selective preparation of the corresponding allylated derivatives. Alternatively, when A1 is employed in the presence of (Me₃Si)₃Si–H as terminal HAT reagent, the corresponding alkylated products are formed.\nThe manuscript is very well written and the supporting information is of excellent quality.\nThe development of enantioselective electrosynthetic transformation is of high interest in organic chemistry and is still a difficult goal to achieve. In this area, the use of chiral Lewis acids or chiral organocatalysts has recently emerged as the most promising catalytic strategies. In line with previous work from Guo et al. concerning the enantioselective electrochemical amination, α‑ and γ‑Nitroalkylation, difunctionalization of terminal alkynes, and functionalization of alkenes, the strategy which is employed is based on the single electron oxidation of catalytically generated chiral nickel(II)enolate species, and the subsequent capture of the electrophilic radical which is formed by an alkene. Somehow, it can be regarded as a natural extension of previous work with one another type of radical quencher.\nIn the introduction of the manuscript, the authors emphasize the term “switchable,” seemingly as a way to highlight the versatility of their methodology in delivering different products. However, the use of this term may be somewhat misleading. In the context of catalysis, “switchable catalysis” typically refers to processes in which the reaction outcome can be altered by applying an external stimulus (e.g., light, heat, pH, or changes in electronic state). In the present case, the different transformations—α-alkenylation, α-allylation, and α-alkylation—require distinct reaction conditions rather than a single system being modulated by an external factor. Therefore, the use of the term “switchable” may not be entirely appropriate in this context.\nThe optimizations of the reaction’s conditions are rather succinct, it would be more informative to discuss the exact role of the DCE/TFE solvent mixture, why sometimes 2,6-lutidine is used and, sometimes, morpholine is preferred. How can we rationalize the fact that A5 is better than A2-A4, what is the reactivity difference of A5 vs A1 (see below)?\nWith regard to the mechanistic studies performed, several important questions remain unanswered.\nFirst, why were all cyclic voltammetry (CV) experiments conducted in the presence of morpholine rather than lutidine? Lutidine is less prone to oxidation than morpholine, and this difference could significantly impact the CV results. It is worth noting that while lutidine is employed in both the alkenylation and alkylation reactions, morpholine is used exclusively in the Co-catalyzed allylation process.\nAdditionally, the experimental details for the CV measurements are insufficient. Key parameters such as the concentrations of analytes (as a result, the stoichiometry of the various analytes in the cell cannot be determined, which is critical considering the significant current measured), the solvent system, and the scan rate are not reported. Furthermore, the rationale for selecting compound 1b as the model substrate instead of 1a is not explained.\nMore critically, the conclusions drawn by the authors are questionable. The oxidation wave attributed to the nickel(II) enolate appears very close to that of morpholine (Figure 6a, top left). Given that the reaction conditions involve a tenfold excess of morpholine relative to the chiral nickel catalyst (which is likely not the case for the CV measurements), competitive oxidation of morpholine cannot be ruled out. The earlier onset of the oxidation wave upon increasing the concentration of nickel catalyst (Figure 6a, top right) is not sufficient evidence to confirm the oxidation of the nickel enolate. The measured currents are very weak, and once again, it appears that only one equivalent of morpholine was used.\nEven more problematic is the interpretation of the role of the Co(II)-salen catalyst. The authors suggest that the disappearance of the reverse peak indicates oxidation of the nickel enolate by the Co(III) complex via a single-electron transfer (SET) process, thereby generating a carbon-centered radical. However, the CV data do not support this conclusion. Specifically, increasing the concentration of the nickel catalyst does not result in a catalytic wave (Figure 6a, bottom right). If Co(III)+ generated electrochemically were indeed oxidizing the enolate via SET, a catalytic current—similar to that observed with compound A1—should be present. Since it is not, this suggests that a two-electron oxidation is taking place, or that a chemical transformation other than a simple electron transfer is occurring between the nickel enolate and Co(III)+.\nThis finding contradicts the authors’ proposed mechanism and raises serious doubts about the validity of the allylation pathway as described. Consequently, the DFT calculations based on a SET mechanism are also questionable.\nIn addition, the proposed regeneration of the Co(II) catalyst is presented inconsistently. In Figure 7a, it is suggested via DFT calculations to occur via comproportionation between Co(I) and Co(III), whereas Figure 7d instead depicts anodic oxidation as the operative step. This discrepancy should be clarified.\nIn conclusion, the manuscript by Guo et al. presents interesting findings but lacks sufficient novelty to be considered highly innovative. The work appears to be a natural extension of previous studies, employing alkenes to trap a transient chiral, carbon-centered radical intermediate. While the authors claim that the reaction conditions allow access to three types of products—alkenylated, allylated, or alkylated—the description of the process as \"switchable\" is misleading. Rather than a single switchable process, the study describes three distinct reactions proceeding via closely related radical pathways, with alkenes serving as radical traps (reminiscent of their previous work: Sci. Adv. 2022, 8, eadd7134).\nThe fate of the transient alkyl radical follows well-established transformations, including oxidation/elimination, oxidative hydrogen atom transfer (HAT) with a cobaloxime-type catalyst, and reductive HAT using (Me₃Si)₃Si–H. However, the proposed mechanism is questionable, particularly regarding the role and mode of action of the Co(II)-salen catalyst. Cyclic voltammetry (CV) experiments suggest that the proposed single-electron transfer (SET) oxidation of the nickel enolate by electro-generated Co(III)+ is unlikely.\nFor these reasons, I do not recommend publication of this manuscript in Nature Communications. Instead, I suggest the authors revise the mechanistic rationale and consider submitting the work to a more specialized journal after addressing these concerns.", "reviewer_5": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts.", "reviewer_6": "In this manuscript, Guo et al. reported an enantioselective switchable electrolytic system for the functionalization of unactivated alkenes, which enables dehydrogenative allylation, dehydrogenative alkenylation, and hydroalkylation reactions with identical substrates to produce structurally diverse products. The success of this system relies on the stereocontrolled coupling of an electrogenerated Ni-bound α-carbonyl radical with alkenes, followed by divergent radical termination pathways. The method operates under mild, oxidant-free conditions, exhibits broad substrate scope (63 examples), and delivers high enantioselectivity (up to 98% ee). Applications include late-stage functionalization of complex molecules and a formal synthesis of (S)-SYK inhibitor, highlighting its synthetic utility. Mechanistic studies and DFT calculations support the proposed catalytic cycle. The following issues should be considered:\n1. In the optimization of switchable reaction conditions, the authors mentioned the chemoselectivity of the reaction is strongly dependent on additive selection. It could be seen that the additive A1 with any ligand could form the alkenylated product 4a, while the presence of salen-Co additives could achieve the allylated product 3a. This is really interesting. DFT calculations partly explain the role of the Co additives, the additive A1 should also be calculated to clarify the chemoselectivity of this reaction. It would be better if the different effects of salen-Co additives for the diversity in ratio of different chemoselective products could be explained.\n2. The ratios of E/Z product was mentioned in this manuscript, it would be great if the authors could also consider the possibility of E/Z product formation in the reaction.\n3. Did the authors consider the spin states of Co and Ni in the DFT calculation? The authors only mentioned “For transition states TS-3a and TS-4a, the ‘broken symmetry’ formalism was used” in Supporting Information, have the authors tried and compared different spin states for the key stationary points? It is weird that different spin states were used for stationary points along reaction pathways in the calculation without additional explanation. This should be described in the manuscript including Figure 7(a).\n4. The origin of stereoselectivity could be explained by NCI or EDA analysis. It is hard to understand TS2-Si is more favorable form the structures. Considering that TS2 is the key transition state structure that determines stereoselectivity, the discussion on its conformation in Figure S8 should be briefly mentioned in the manuscript.\n5. The structure of 2a should be given in Figure 7."}, "author_response": "Responses to Comments\nfor\nTunable Enantioselective Electrocatalytic Functionalization of Unactivated Alkenes\nTian Xie, Minghao Liu, Jiayin Zhang, Lingzi Peng, Chang Guo✉\nManuscript ID: NCOMMS-25-46490-T\nReply to comments by Reviewer 1\nWe appreciate Reviewer 1 for favorable comments!\n(1) Guo et al. report a divergent nickel-catalyzed enantioconvergent functionalization of\nunactivated alkenes, enabling switchable access to dehydrogenative allylation,\ndehydrogenative alkenylation, and hydroalkylation. The success of this strategy hinges on\nthe rational design of an electro-oxidatively generated nickel-bound α-carbonyl radical\nspecies, which adds to unactivated alkenes and undergoes diverse radical termination\npathways. The developed protocols exhibit broad substrate scope, excellent\nchemoselectivity, regioselectivity, and enantioselectivity, as well as scalability. The\nmethod is successfully applied to the stereoselective formal synthesis of an (S)-SYK\ninhibitor. Mechanistic and computational studies provide support for the proposed reaction\npathway. This work represents a significant advance in asymmetric electrocatalysis and is\na substantial contribution worthy of publication.\nAnswer: We appreciate Reviewer 1 for the favorable comments and helpful suggestions! These\ncomments are greatly valuable and helpful for revising and improving our manuscript. We have\nmade all the necessary amendments as suggested in our revised manuscript and Supplementary\nInformation.\n(2) The authors propose an indirect electro-oxidative generation of the nickel-bound α-\ncarbonyl radical species mediated by a CoIII complex in allylation. What evidence rules\nout a direct anodic oxidation pathway since the alkenylation and hydroalkylation process\ndo not need the CoIII complex?\nAnswer: Upon careful examination, we confirm that the allylation pathway does not\nnecessarily require mediation by the CoIII complex. Control experiments show that in the\nabsence of the cobalt mediator, the alkenylation product 4a can be obtained in 26% yield via\ndirect anodic oxidation (Table 1b, entry 3), which clearly demonstrates that the nickel-bound\nα-carbonyl radical species can be generated at the anode.\nWe have revised our mechanistic proposal and computational analysis. The updated\nmechanism now features direct anodic oxidation of the nickel enolate as the reaction pathway\nfor radical generation. The role of the cobalt catalyst has been redefined to specifically facilitate\nthe hydrogen atom transfer step in the allylation pathway, rather than participating in the initial\noxidation event. Accordingly, we have revised the theoretical calculations (Fig. 7a) and\nproposed catalytic cycles (Fig. 7d) in the revised manuscript.\n(3) Besides quaternary carbon stereocenters, could these protocols construct relate tertiary\nstereocenters? If not, what is the reason?\nAnswer: We evaluated substrate S1 under our standard conditions for allylation, alkenylation,\nand hydroalkylation reactions. Unfortunately, none of the desired products were detected.\nWe attribute the lack of reactivity to two primary factors. First, the radical intermediate\ngenerated from substrate S1 is less sterically hindered and consequently more reactive. This\nhigh reactivity leads to unproductive side pathways, such as dimerization and over-oxidation,\nwhich was corroborated by reaction monitoring and product analysis revealing multiple\nbyproducts. Second, and more critically, the stereocontrol in our method hinges on the dynamic\nkinetic resolution (DKR) of a trisubstituted benzoate species. The tertiary carbon-centered\nradical generated from S1 would not undergo facile racemization required for an efficient DKR\nprocess. Consequently, even if the radical could be generated, achieving enantiocontrol within\nour current catalytic framework would be unfeasible. Therefore, our protocol is not suitable for\nconstructing enantioselective tertiary stereocenters. We have included these results in the\nrevised Supplementary Information (Page S13, Table S5).\n(4) For hydroalkylation process, the involvement of NiH from Ni precatalyst and (TMS)3SiH\nis well documented. Did the authors have any experimental evidence to rule out this\npossibility?\nAnswer: Thank you for raising this point regarding the potential involvement of a Ni-H species.\nWe agree that a Ni-H pathway is a well-established mechanism in nickel-catalyzed\nhydroalkylation.\nTo evaluate the potential involvement of a Ni–H species in our system, we conducted a\ncontrol experiment under the standard hydroalkylation conditions, replacing (TMS)₃SiH with\n(MeO)₃SiH—a hydrogen atom donor widely used in and characteristic of Ni–H-mediated\nprocesses (Angew. Chem. Int. Ed. 2022, 61, e202208018; J. Am. Chem. Soc. 2023, 145, 10411;\nNat. Synth. 2024, 3, 1360; J. Am. Chem. Soc. 2025, 147, 18944; Sci. Adv. 2025, 11, eadv6571).\nDFT calculations confirm that the Si–H bond dissociation energy of (MeO)₃SiH is significantly\nhigher than that of (TMS)₃SiH. Furthermore, the observed inactivity of (MeO)₃SiH under our\nreaction conditions corroborates our earlier finding that a low BDE is essential for the reaction\nto proceed (J. Am. Chem. Soc. 2025, 147, 8917). These computational and experimental results\ncollectively support a hydrogen atom transfer (HAT) mechanism, rather than one involving a\nNi–H intermediate. We have included these results in the revised Supplementary Information\n(Page S12, Table S3).\nentry HAT reagent Results of 5a\n1 (MeO) SiH (BDE(calc.) = 96.3 kcal/mol) nd\n3\n2 2\n3\n4 (TMS) SiH (BDE = 79 kcal/mol) 56% yield, 92% e.e.\nWe appreciate Reviewer 2 for favorable comments!\n(1) Guo and co-workers report an enantioselective functionalization of unactivated alkene\nwith benzoxazolyl acetate via electrochemically generated carbon-centered radicals. These\nradicals are stabilized by a chiral Ni catalyst, and subsequent enantioselective radical\naddition to alkenes—followed by hydrogen atom transfer (HAT), further oxidation, or\nreduction with hydrosilane—yields products of dehydrogenative allylation, alkenylation,\nand hydroalkylation, respectively. This methodology enables the formation of highly\nenantioriched products, including those bearing all-carbon quaternary stereocenters. The\nauthors also provide detailed mechanistic insight into the chemo- and enantioselectivity\nbased on cyclic voltammetry and DFT calculations.\nAnswer: We appreciate Reviewer 2 for the favorable comments and helpful suggestions! These\ncomments are greatly valuable and helpful for revising and improving our manuscript. We have\nmade all the necessary amendments as suggested in our revised manuscript and Supplementary\nInformation.\n(2) However, similar transformation by the same group have already been reported (Refs. 34\n& 35), and radical addition to alkene moieties are well-established in prior literature (Refs.\n10–12). Therefore, the key novelty of this work appears to lie in the switchable radical\ntermination strategy. This reviewer recommends that the authors clarify the individual\nnovelty and significance of each transformation pathway—namely, dehydrogenative\nallylation, alkenylation, and hydroalkylation. A more explicit discussion will help readers\nbetter appreciate the scope and innovation of the work. This report may be perceived as\nmerely a combination of a known radical reaction in the first half and a known termination\nreaction in the latter half. The reviewer believes it is essential to provide a clear and\nthorough discussion on what advantages this methodology offers.\nAnswer: We thank the Reviewer 2 for their thoughtful feedback on the novelty and significance\nof our work. The asymmetric radical addition to unactivated alkenes represents a long-standing\nchallenge in synthetic chemistry. While pioneering studies (Refs. 10–12) have demonstrated\nradical additions to such alkenes, stereocontrol has remained elusive. Moreover, these\nelectrochemical methods are predominantly confined to oxidative allylation. To date, achieving\nstereocontrolled electrochemical functionalization of unactivated alkenes—particularly for\noxidative alkenylation and hydroalkylation—has been an unsolved problem. Crucially, the\nselective and stereodivergent synthesis of dehydrogenative allylation, alkenylation, and\nhydroalkylation products from identical starting materials has not been achieved. Building upon\nour previous work in dehydrogenative amination and denitrative alkylation (Refs. 34, 35), we\nhave now developed a versatile electrochemical system for chiral radical control. Distinct from\nour earlier studies, this work directly tackles the functionalization of unactivated\nalkenes. We\nherein report the first asymmetric addition of chiral catalyst bound radicals to unactivated\nalkenes, which systematically enables enantioselective dehydrogenative allylation,\ndehydrogenative alkenylation, and hydroalkylation from identical starting materials. This\ndemonstrates the remarkable versatility of our catalytic system in exerting stereochemical\ncommand over diverse reaction pathways.\nAs suggested by Reviewer 2, we have incorporated the following discussion in the revised\nmanuscript: “However, the stereocontrolled functionalization of unactivated alkenes remains a\nformidable challenge. Although electrochemical oxidative allylation has been demonstrated—\nas exemplified by the work of the Xu group10,12(Refs. 10,12)—achieving analogous\ndehydrogenative alkenylation and hydroalkylation under electrolytic conditions continues to\npose significant hurdles. More broadly, the development of electrochemical radical addition\nplatforms capable of divergently accessing dehydrogenative allylation, alkenylation, and\nhydroalkylation from identical precursors with high chemoselectivity and stereocontrol\nrepresents a major unmet goal in synthetic chemistry. In this work, we report a general and\nenantioselective electrocatalytic system for the divergent functionalization of unactivated\nalkenes. This strategy enables dehydrogenative allylation, alkenylation, and hydroalkylation\nfrom a chiral nickel-bound radical intermediate with high stereoselectivity, broad functional\ngroup tolerance, and compatibility with diverse carbon nucleophiles (Fig. 1c). The asymmetric\ncatalytic system provides a unified platform to systematically investigate competitive radical\ntermination pathways under mild electrochemical conditions.”\n(3) Furthermore, the origin of the selectivity, particularly between the allylation and\nalkenylation pathways, requires further clarification. According to the authors, the use of\na Co catalysts leads to allylation, possibly due to steric hindrance influencing HAT. In\ncontrast, oxidation followed by deprotonation results in alkylation. However, this reviewer\nfinds the explanation for the selective deprotonation step insufficient. What governs the\ndivergence between these two pathways? A more detailed mechanistic rationale, possibly\nsupported by additional data or calculations, would greatly enhance the manuscript.\nAnswer: We thank the reviewer for this valuable suggestion. In response, we have performed\nadditional computational studies to gain deeper mechanistic insights. These studies now\nprovide a clearer rationale that explains the precise origin of the observed chemoselectivity\nbetween the competing allylation and alkenylation pathways.\nOur mechanistic investigation establishes that the mediator A1-promoted alkenylation\nproceeds via an oxidation–radical addition–elimination sequence. Specifically, following the\ninitial radical addition, the resultant alkyl radical undergoes oxidation to a carbocationic\nintermediate. This key intermediate is stabilized by 2,6-lutidine (Nat. Catal. 2025, 8, 448), and\na subsequent base-promoted elimination furnishes the observed alkenylation product.\nTo elucidate the origin of chemoselectivity, we computed the key transition states for the\ncompeting alkenylation and allylation pathways. A comparative DFT analysis reveals that the\nalkenylation pathway (via TS5-4as) is energetically favored. The selectivity arises from the\nheightened acidity of the β-hydrogen atom, which is activated by three adjacent electron-\nwithdrawing groups—the benzoxazole, ester, and fluorine substituents. This synergistic\nactivation collectively enhances the acidity of the β-hydrogen, facilitates its elimination and\ndirects the outcome toward alkenylation product 4a.\nAs described in our response to Reviewer 2, the cobalt catalyst system selectively produces\nthe allylation product 4a. This selectivity is governed by steric effects in the hydrogen atom\ntransfer (HAT) step, in which the bulky cobalt catalyst preferentially abstracts the less hindered\ndistal hydrogen atom, thereby leading to the observed allylation outcome (Fig. 7c).\nThese computational insights now provide a quantitative basis for the divergence between\nthe two pathways: the alkenylation route is governed by the relative acidity of specific C–H\nbonds and their propensity for elimination, while the allylation pathway is controlled by\nsterically modulated hydrogen atom transfer. We have incorporated these findings and the\naccompanying discussion into the revised manuscript “Conversely, the use of additive A1 in\nthe absence of additional termination reagents promotes single-electron oxidation of alkyl\nradical intermediate III to form carbocationic species V. This intermediate is stabilized by 2,6-\nlutidine and undergoes base-promoted β-hydride elimination preferentially from the more\nacidic proximal carbon, ultimately furnishing enantioenriched dehydrogenative alkenylation\nproducts 4.” and Supplementary Information (Page S61) to offer a more thorough and\nconvincing mechanistic explanation.\n(4) In all electrochemical reactions, the total passed (in F/mol) should by explicitly stated.\nSince external oxidants rare replaced by anodic electron transfer, the charge of\ncorresponding directly to the equivalent of oxidant used. This value can be calculated from\nthe current and reaction time and should be respond for each transformation.\nAnswer: We have now calculated and explicitly stated the total charge passed (in F/mol) for\neach transformation in the revised manuscript. The total passed was determined to be 4.5 F/mol\nfor both the allylation and alkenylation reactions, a value that aligns well with the electron\nequivalence provided by 2 equivalents of Ag₂O used in our control experiments. For the\nhydroalkylation reaction, the total passed was measured to be 6.0 F/mol. These values have\nnow been clearly indicated in the corresponding sections of the main text.\n(5) Page 1, line 25: “Main text” appeared to be typographical error and should be corrected to\n“Introduction”\nAnswer: The term \"Main text\" on Page 1, line 25 has been corrected to \"Introduction\" in the\nrevised manuscript.\n(6) Page 8 line 199, The phrase “alcohol 7 with all-carbon quaternary stereocenters” is\nincorrect, as compound 7 does not possesses an all-carbon quaternary stereocenter.\nAnswer: We have removed the phrase \"with all-carbon quaternary stereocenters\" from Page 8,\nline 199 in the revised manuscript.\n(7) In the CV analysis, the authors note a significant decrease in oxidation potential upon\naddition of the Ni catalyst. However, the oxidation of morpholine also occurs at a similarly\nlow potential (Figure 6a, top-left). To clearly distinguish the contribution of the Ni catalyst\nfrom that of morpholine, the cyclic voltammogram of a mixture of 1b and Ni catalyst\nshould be measured and presented.\nAnswer: To definitively assign their contributions, we acquired additional CV data for a\nmixture of 1b and the nickel catalyst. Analysis of the complete CV dataset reveals a critical\ninsight: a substantial decrease in the onset oxidation potential is observed specifically in the\nternary system containing 1b, morpholine, and the nickel catalyst. In contrast, binary\ncombinations show no such effect. This evidence allows us to conclude that morpholine\nfunctions mainly as a Brønsted base to generate the enolate, while the nickel catalyst is central\nto forming the catalytically active species that is readily oxidized.\nFurthermore, we employed computational methods to evaluate the oxidation potentials of\nmorpholine and the key nickel-bound enolate intermediate separately. The calculated oxidation\npotential for morpholine is approximately +1.26 V (vs. SCE), whereas that of the catalytic\nintermediate is about +0.46 V (vs. SCE). This significant difference clearly excludes any\nsubstantial interference from morpholine oxidation in the observed low-potential signal,\nconfirming that the prominent anodic wave in the full system originates from the oxidation of\nthe nickel-associated enolate species. We have included the cyclic voltammetry (Fig. 6a, left)\nin the revised manuscript.\nReply to comments by Reviewer 3\nI co-reviewed this manuscript with one of the reviewers who provided the listed reports. This\nis part of the Nature Communications initiative to facilitate training in peer review and to\nprovide appropriate recognition for Early Career Researchers who co-review manuscripts.\nAnswer: We thank the co-reviewer for their careful evaluation of our manuscript and their\nvaluable contributions to the peer review process. We appreciate the time and expertise invested\nin assessing our work, and we have addressed all comments in our revised manuscript.\n4\n3\n2\n1\n0\n0 .0 0 .5 1 .0 1 .5 2 .0 2 .5 3 .0\nA\n4\n-0\n1\nt n\ne\nr\nr\nu\nC\n1\n1\n1\n1\n2\nm\nbbbbao\n+\n+\n+\nr\nm\nN\nm\np h\no r p\ni / L\no r p\no l in\nh5h\ne\nP\no\no\no\nl in\nl in\nt e n\ne\ne\nt\n+\nia\nN\nl / V\ni / L\n( v\n5\ne r s u s S C E )\nReply to comments by Reviewer 4\nWe appreciate Reviewer 4 for favorable comments!\n(1) The manuscript entitled “Enantioselective Switchable Selectivity in Electrocatalyzed\nFunctionalization of Unactivated Alkenes” by Guo et al. describes the development of the\nasymmetric electrochemical α-functionalization of benzoxazolyl acetate derivatives with\nalkenes, via the use of a chiral Ni(II) complex. This method permits the transient formation\nof a chiral carbon-centered radical intermediate, able to diastereoselectively couple with\nalkenes to generate alkyl radicals which, depending on the reaction conditions, lead to the\nformation of alkenyl-, allyl-, or alkyl-functionalized products. The reaction outcome\ndepends of the nature of the catalyst or the reagent introduced in the reaction mixture.\nEmploying the ferrocene derivative A1 as redox mediator alone preferentially leads to the\nformation of the alkenylated products, where the cobalt complex A5 permits the selective\npreparation of the corresponding allylated derivatives. Alternatively, when A1 is employed\nin the presence of (Me₃Si)₃Si–H as terminal HAT reagent, the corresponding alkylated\nproducts are formed. The manuscript is very well written and the supporting information\nis of excellent quality. The development of enantioselective electrosynthetic\ntransformation is of high interest in organic chemistry and is still a difficult goal to achieve.\nIn this area, the use of chiral Lewis acids or chiral organocatalysts has recently emerged\nas the most promising catalytic strategies. In line with previous work from Guo et al.\nconcerning the enantioselective electrochemical amination, α‑ and γ‑Nitroalkylation,\ndifunctionalization of terminal alkynes, and functionalization of alkenes, the strategy\nwhich is employed is based on the single electron oxidation of catalytically generated\nchiral nickel(II)enolate species, and the subsequent capture of the electrophilic radical\nwhich is formed by an alkene. Somehow, it can be regarded as a natural extension of\nprevious work with one another type of radical quencher.\nAnswer: We appreciate Reviewer 4 for the favorable comments and helpful suggestions! These\ncomments are greatly valuable and helpful for revising and improving our manuscript. We have\nmade all the necessary amendments as suggested in our revised manuscript and Supplementary\nInformation.\n(2) In the introduction of the manuscript, the authors emphasize the term “switchable,”\nseemingly as a way to highlight the versatility of their methodology in delivering different\nproducts. However, the use of this term may be somewhat misleading. In the context of\ncatalysis, “switchable catalysis” typically refers to processes in which the reaction\noutcome can be altered by applying an external stimulus (e.g., light, heat, pH, or changes\nin electronic state). In the present case, the different transformations—α-alkenylation, α-\nallylation, and α-alkylation—require distinct reaction conditions rather than a single\nsystem being modulated by an external factor. Therefore, the use of the term “switchable”\nmay not be entirely appropriate in this context.\nAnswer: We thank the reviewer for this helpful suggestion. We have revised the manuscript\naccordingly, replacing the term \"switchable\" with \"tunable\" throughout the text. We agree that\n\"tunable\" is a more precise and appropriate descriptor for the process, as it accurately reflects\nhow the product selectivity is modulated by varying specific reaction parameters.\n(3) The optimizations of the reaction’s conditions are rather succinct; it would be more\ninformative to discuss the exact role of the DCE/TFE solvent mixture.\nAnswer: We thank the reviewer for this insightful comment. The DCE/TFE solvent mixture\nwas optimized to fulfill both electrochemical and chemical requirements. Neat DCE lacks\nsufficient conductivity for efficient electrolysis, while TFE not only provides the necessary\nconductivity but also serves as a proton source for the cathodic reaction. However, using TFE\nas the sole solvent led to a significantly lower yield (44%) compared to that achieved with the\nmixed solvent system (72% yield, 92% e.e.), which we attribute to its inherent acidity\nsuppressing the crucial deprotonation step for enolate formation. Therefore, the DCE/TFE\nmixture achieves an optimal balance, ensuring adequate conductivity while maintaining a\nproper chemical environment for the key deprotonation event. These optimization results have\nbeen included in the Supplementary Information (Page S13, Table S6).\nentry Solvent (3 mL) Results of 4a\n(4) why sometimes 2,6-lutidine is used and, sometimes, morpholine is preferred.\nAnswer: Our screening revealed that both 2,6-lutidine and morpholine can promote the\nalkenylation and allylation reactions while maintaining excellent enantioselectivity. However,\nwe observed significant differences in reaction yields: for the allylation pathway, morpholine\nprovided substantially higher yields compared to 2,6-lutidine, while the opposite preference\nwas found for the alkenylation reaction. We therefore optimized the base selection specifically\nfor each transformation pathway to maximize the reaction efficiency. We have included these\nresults in our revised Supplementary Information (Page S14, Table S7 and S8).\nentry Base Results of 3a\n1 morpholine 74% yield, 92% e.e.\n2 2,6-Lutidine 42% yield, 92% e.e.\nentry Base Results of 4a\n1 2,6-Lutidine 72% yield, 92% e.e.\n2 morpholine 20% yield, 92% e.e.\n(5) How can we rationalize the fact that A5 is better than A2-A4,\nAnswer: Our DFT calculations provide an electronic structure basis for the observed catalyst\nperformance, which reveal that the Co–H species generated from catalyst A5 possesses a higher\nbond dissociation energy (BDE) than those from A2–A4. This higher BDE indicates a stronger\nhydrogen affinity, which enhances the efficiency of the hydrogen atom transfer (HAT) step.\nThis computational insight correlates well with our experimental data, rationalizing the superior\nperformance of A5 in promoting the allylation pathway. We have included the following\nsentence to the revised manuscript: \"The differential chemoselectivity among Co catalysts A2–\nA5 correlates with their Co–H bond dissociation energies (BDE), where the higher BDE of A5\nenhances HAT efficiency and favors allylation product formation (See Supplementary\nInformation).\" The complete computational data have been included in the Supplementary\nInformation (Page S60, Table S11).\nentry Co reagent BDE(Co–H)/kcal·mol-1\n(6) what is the reactivity difference of A5 vs A1 (see below)?\nAnswer: The distinct roles of A1 and A5 stem from their fundamentally different coordination\ngeometries and associated mechanistic functions. A1, being coordinatively saturated, serves\nexclusively as an electron-transfer mediator. In the alkenylation pathway, it facilitates the\noxidation of the Ni-bound enolate to generate the key radical intermediate but does not\nparticipate in the subsequent β-hydride elimination, which is instead mediated by the basic\nadditive 2,6-lutidine. In contrast, catalyst A5 possesses an accessible coordination site, enabling\nits direct involvement in the hydrogen atom transfer step during allylation. The extended planar\ngeometry of its ligand further imposes steric control over the HAT regioselectivity. These\ncombined attributes allow A5 to selectively promote the allylation pathway, as consistently\nsupported by experimental and computational evidence.\n(7) With regard to the mechanistic studies performed, several important questions remain\nunanswered. First, why were all cyclic voltammetry (CV) experiments conducted in the\npresence of morpholine rather than lutidine? Lutidine is less prone to oxidation than\nmorpholine, and this difference could significantly impact the CV results. It is worth noting\nthat while lutidine is employed in both the alkenylation and alkylation reactions, morpholine\nis used exclusively in the Co-catalyzed allylation process.\nAnswer: We appreciate the reviewer 4's observation regarding the base selection in our CV\nstudies. It is important to clarify that both 2,6-lutidine and morpholine can promote the\nalkenylation and alkylation reactions, with the primary distinction being their influence on the\nreaction yield. Our initial use of morpholine in CV measurements was motivated by its stronger\nbasicity relative to 2,6-lutidine, which produced a more distinct catalytic current and facilitated\nclearer interpretation of the electrochemical response.\n5\n1b\n2,6-Lutidine\n4 1b + 2,6-Lutidine + Ni/L5\n1b + morpholine + Ni/L5\nA3\n4\n-0\n1\nnt\nr\ne2\nr\nu\nC\n1\n0\n0.0 0.5 1.0 1.5 2.0 2.5 3.0\nPotential/V (versus SCE)\nIn response to the reviewer 4’s comment, we have conducted additional CV experiments\nusing 2,6-lutidine. These results confirm the appearance of a catalytic current at a comparable\nonset potential, albeit with lower intensity than in the morpholine system. This finding aligns\nwith the capacity of both bases to support the alkenylation and alkylation pathways, with their\nmain differential influence lying in reaction yield. We have included these results in our revised\nSupplementary Information (Page S47, Figure S6).\n(8) Additionally, the experimental details for the CV measurements are insufficient. Key\nparameters such as the concentrations of analytes (as a result, the stoichiometry of the\nvarious analytes in the cell cannot be determined, which is critical considering the\nsignificant current measured), the solvent system, and the scan rate are not reported.\nFurthermore, the rationale for selecting compound 1b as the model substrate instead of 1a\nis not explained.\nAnswer: The full experimental parameters for the cyclic voltammetry (CV) measurements—\nincluding analyte concentrations, solvent composition, and scan rate—are provided in Section\n7 (Cyclic Voltammetry Studies) of the Supplementary Information (Pages S45–48). All CV\nexperiments were performed in an electrolyte of nBu₄NPF₆ (0.05 M) using a DCE/TFE (2:1, 3.0\nmL) solvent system with a scan rate of 100 mV/s. Regarding the choice of substrate 1b over 1a\nfor the CV studies, preliminary experiments showed that 1a gave a less distinct catalytic current\nunder the same conditions. In addition, computational analysis indicated that the oxidation\npotentials of the corresponding nickel-bound α-carbonyl radical intermediates are similar for\nboth substrates: +0.46 V vs. SCE for 1b and +0.61 V vs. SCE for 1a. Based on the\nelectrochemical response observed experimentally with 1b, it was selected as the model\nsubstrate for detailed CV characterization.\n1b\n4 1b + morpholine + Ni/L5\n1a\n1a + morpholine + Ni/L5\n4\n-0\n1\nnt 2\ne\nr\nr\nu\nC\n1\n0\n0.0 0.5 1.0 1.5 2.0 2.5 3.0\nPotential/V (versus SCE)\n(9) More critically, the conclusions drawn by the authors are questionable. The oxidation wave\nattributed to the nickel(II) enolate appears very close to that of morpholine (Figure 6a, top\nleft). Given that the reaction conditions involve a tenfold excess of morpholine relative to\nthe chiral nickel catalyst (which is likely not the case for the CV measurements), competitive\noxidation of morpholine cannot be ruled out. The earlier onset of the oxidation wave upon\nincreasing the concentration of nickel catalyst (Figure 6a, top right) is not sufficient evidence\nto confirm the oxidation of the nickel enolate. The measured currents are very weak, and once\nagain, it appears that only one equivalent of morpholine was used.\nAnswer: We have conducted additional experiments and computational studies to\nunequivocally address the possibility of interference from morpholine oxidation. To exclude\npotential interference from morpholine, we performed complementary CV experiments using\n2,6-lutidine as the base. These measurements also revealed a distinct catalytic wave at\ncomparably low potentials, confirming that the observed oxidation feature originates from a\nnewly formed catalytic intermediate rather than from the oxidation of the base. Furthermore,\ncomputational studies provide independent support for this assignment. The calculated\noxidation potential for morpholine is +1.26 V (vs. SCE), while that of the key nickel-bound\nenolate intermediate is +0.46 V (vs. SCE). This substantial difference suggests limited\ncontribution from morpholine oxidation to the catalytic wave observed at lower potentials.\nThese combined experimental and computational results imply that the oxidation wave at +0.46\nV corresponds to the nickel-bound enolate species and is not affected by competitive oxidation\nof the base. \n(10) Even more problematic is the interpretation of the role of the Co(II)-salen catalyst. The\n5\n4\n3\n2\n1\n0\n0 .0 0 .5 1 .0 1 .5 2 .0 2 .5 3 .0\nA\n4\n-0\n1\nnt\ne r\nr\nu\nC\n1\n2\n1\n1\nb,6\n- L u\nb + 2\nb + m\ntid in e\n,6 - L u tid in e + N\no r p h o lin e + N\nP o te n tia l/V\ni/L\ni/L 5\n( v e\n5\nr s u s S C E )\nauthors suggest that the disappearance of the reverse peak indicates oxidation of the nickel\nenolate by the Co(III) complex via a single-electron transfer (SET) process, thereby\ngenerating a carbon-centered radical. However, the CV data do not support this conclusion.\nSpecifically, increasing the concentration of the nickel catalyst does not result in a catalytic\nwave (Figure 6a, bottom right). If Co(III)+ generated electrochemically were indeed\noxidizing the enolate via SET, a catalytic current—similar to that observed with compound\nA1—should be present. Since it is not, this suggests that a two-electron oxidation is taking\nplace, or that a chemical transformation other than a simple electron transfer is occurring\nbetween the nickel enolate and Co(III)+.\nAnswer: We sincerely thank the reviewer for this insight, which has led us to reevaluate and\nsignificantly improve our Co-involved mechanistic understanding. The reviewer is correct that\nour original proposal of a SET process between the Co(III) complex and the nickel enolate was\nnot adequately supported. Following the reviewer 4's suggestion, we performed control CV\nexperiments in the absence of both substrate 1b and base. Interestingly, varying the\nconcentration of the Ni/L5 catalyst resulted in gradual attenuation of the reduction peak while\nthe oxidation peak remained largely unchanged. This observation indicates limitations in our\ninitial mechanistic proposal and suggests that the Co-salen species A5 may not function\nprimarily as an electron-transfer mediator for Ni-bound enolate species.\nFurthermore, control reactions conducted in the absence of both ferrocene mediators and\ncobalt catalysts still afforded alkenylation product 4a in 26% yield with 92% ee (Table 1b, entry\n3). This result demonstrates that the nickel enolate intermediate can undergo direct anodic\noxidation to generate the key Ni-bound α-keto radical species, without requiring SET oxidation\nby Co(III). We have incorporated these revisions and corresponding discussions (Fig. 6a)\nthroughout the revised manuscript and Supplementary Information.\n-\n-\n0\n0\n0\n0\n0\n0\n0\n.2\n.1\n.1\n.0\n.0\n.0\n.1\n0\n5\n0\n5\n0\n5\n0\n0 .0 0 .2 0 .4 0 .6 0 .8 1 .0 1 .2\nA\n4\n-0\n1\nnt\ne\nr\nr u\nC\nA\nA\nA\nA\n5555\n+\n+\n+\nN\nN\nN\ni/L\ni/L\ni/L\n( 2\n( 5\n( 1\no te\nm o\nm o\n0 m\nn tia\nl%l%o\nl%\nl/V\n))\n)\n( v e r s u s S C E )\n(11) This finding contradicts the authors’ proposed mechanism and raises serious doubts about\nthe validity of the allylation pathway as described. Consequently, the DFT calculations\nbased on a SET mechanism are also questionable. In addition, the proposed regeneration\nof the Co(II) catalyst is presented inconsistently. In Figure 7a, it is suggested via DFT\ncalculations to occur via comproportionation between Co(I) and Co(III), whereas Figure\n7d instead depicts anodic oxidation as the operative step. This discrepancy should be\nclarified.\nAnswer: We have revised our computational model to reflect direct anodic oxidation of the\nnickel enolate, rather than Co(III)-mediated oxidation (Fig. 7a). The oxidation potential was set\nto +0.32 V vs. SCE, corresponding to the experimentally measured onset potential for the\nnickel-bound enolate species. The revised energy profile now shows an overall barrier of 20.0\nkcal/mol at this potential, which falls within the expected range for room-temperature reactions\n(<21 kcal/mol) and aligns well with our experimental observations.\nBased on our experimental and computational investigations, we have suggested that the\nsalen-Co species does not function as an electron-transfer mediator in this system.\nConsequently, the Co(I) species is oxidized to Co(II) via direct anodic oxidation rather than\nthrough oxidation by Co(III). The relevant computational sections and proposed catalytic cycles\nhave been revised accordingly in the revised manuscript.\n(12) In conclusion, the manuscript by Guo et al. presents interesting findings but lacks sufficient\nnovelty to be considered highly innovative. The work appears to be a natural extension of\nprevious studies, employing alkenes to trap a transient chiral, carbon-centered radical\nintermediate. While the authors claim that the reaction conditions allow access to three\ntypes of products—alkenylated, allylated, or alkylated—the description of the process as\n\"switchable\" is misleading. Rather than a single switchable process, the study describes\nthree distinct reactions proceeding via closely related radical pathways, with alkenes\nserving as radical traps (reminiscent of their previous work: Sci. Adv. 2022, 8, eadd7134).\nThe fate of the transient alkyl radical follows well-established transformations, including\noxidation/elimination, oxidative hydrogen atom transfer (HAT) with a cobaloxime-type\ncatalyst, and reductive HAT using (Me₃Si)₃Si–H. However, the proposed mechanism is\nquestionable, particularly regarding the role and mode of action of the Co(II)-salen catalyst.\nCyclic voltammetry (CV) experiments suggest that the proposed single-electron transfer\n(SET) oxidation of the nickel enolate by electro-generated Co(III)+ is unlikely.\nAnswer: While radical additions to alkenes are indeed known, exerting excellent stereocontrol\nover these processes—particularly for unactivated alkenes—remains a formidable challenge in\nsynthetic chemistry. The key novelty of our work lies not merely in the use of an alkene as a\nradical trap, but in the development of a unified chiral catalytic system that enables, for the first\ntime, enantioselective radical additions to unactivated alkenes with tunable termination\npathways. The stereochemical control of open-shell intermediates at unactivated alkenes is\ninherently difficult due to the short-lived nature of radical species and the lack of pre-\ncoordination sites. Our system addresses this by leveraging a chiral nickel catalyst to generate\nand manage the transient radical within a defined chiral environment, achieving high\nenantioselectivity across multiple pathways—a capability not previously demonstrated.\nWe acknowledge the reviewer 4's valid concerns regarding the initial mechanistic proposal\nfor the Co-salen catalyst. We have thoroughly revised this aspect, removing the SET oxidation\npathway as the mediator and demonstrating through control experiments and revised\ncomputations that the nickel enolate is instead directly oxidized at the anode, while the cobalt\ncatalyst primarily functions in the HAT step for the allylation pathway.\nIn summary, the advance presented here is the integration of electrochemical generation,\nenantioselective radical trapping, and tunable termination into a single platform for unactivated\nalkene functionalization—addressing a long-standing challenge in stereoselective synthesis.\nReply to comments by Reviewer 5\nI co-reviewed this manuscript with one of the reviewers who provided the listed reports. This\nis part of the Nature Communications initiative to facilitate training in peer review and to\nprovide appropriate recognition for Early Career Researchers who co-review manuscripts.\nAnswer: We thank the co-reviewer for their careful evaluation of our manuscript and their\nvaluable contributions to the peer review process. We appreciate the time and expertise invested\nin assessing our work, and we have addressed all comments in our revised manuscript.\nReply to comments by Reviewer 6\n(1) In this manuscript, Guo et al. reported an enantioselective switchable electrolytic system\nfor the functionalization of unactivated alkenes, which enables dehydrogenative allylation,\ndehydrogenative alkenylation, and hydroalkylation reactions with identical substrates to\nproduce structurally diverse products. The success of this system relies on the\nstereocontrolled coupling of an electrogenerated Ni-bound α-carbonyl radical with alkenes,\nfollowed by divergent radical termination pathways. The method operates under mild,\noxidant-free conditions, exhibits broad substrate scope (63 examples), and delivers high\nenantioselectivity (up to 98% ee). Applications include late-stage functionalization of\ncomplex molecules and a formal synthesis of (S)-SYK inhibitor, highlighting its synthetic\nutility. Mechanistic studies and DFT calculations support the proposed catalytic cycle. The\nfollowing issues should be considered:\nAnswer: We appreciate Reviewer 6 for the favorable comments and helpful suggestions! These\ncomments are greatly valuable and helpful for revising and improving our manuscript. We have\nmade all the necessary amendments as suggested in our revised manuscript and Supplementary\nInformation.\n(2) In the optimization of switchable reaction conditions, the authors mentioned the\nchemoselectivity of the reaction is strongly dependent on additive selection. It could be\nseen that the additive A1 with any ligand could form the alkenylated product 4a, while the\npresence of salen-Co additives could achieve the allylated product 3a. This is really\ninteresting. DFT calculations partly explain the role of the Co additives, the additive A1\nshould also be calculated to clarify the chemoselectivity of this reaction.\nAnswer: Our investigation reveals that the alkenylation pathway, mediated by the A1 mediator,\nproceeds through an oxidation–radical addition–elimination mechanism. Following radical\naddition, the resulting alkyl radical is oxidized to a carbocation intermediate, which is stabilized\nby 2,6-lutidine (Nat. Catal.2025, 8, 448). Subsequent base-promoted elimination then produces\nthe alkenylation product.\nTo elucidate the chemoselectivity, we computed the key transition states leading to both\nalkenylation and allylation products. DFT results clearly indicate a pronounced energetic\npreference for the alkenylation pathway (TS5-4as). This selectivity can be attributed to the\nenhanced acidity of the hydrogen atom situated near the three electron-withdrawing groups—\nthe benzoxazole, ester, and fluorine substituents—which facilitates its elimination and directs\nthe reaction toward alkenylated product 4a.\nThe use of a Co catalysts leads to allylation, due to steric hindrance influencing HAT, where\nthe cobalt catalyst selectively abstracts the less hindered distal hydrogen atom, leading to the\nobserved allylation product 4a (Fig. 7c). These computational insights now provide a\nquantitative basis for the divergence between the two pathways: the alkenylation route is\ngoverned by the relative acidity of specific C–H bonds and their propensity for elimination,\nwhile the allylation pathway is controlled by sterically modulated hydrogen atom transfer. We\nhave incorporated these findings and the accompanying discussion into the revised manuscript\n“Conversely, the use of additive A1 in the absence of additional termination reagents promotes\nsingle-electron oxidation of alkyl radical intermediate III to form carbocationic species V. This\nintermediate is stabilized by 2,6-lutidine and undergoes base-promoted β-hydride elimination\npreferentially from the more acidic proximal carbon, ultimately furnishing enantioenriched\ndehydrogenative alkenylation products 4.” and Supplementary Information (Page S61) to offer\na more thorough and convincing mechanistic explanation.\n(3) It would be better if the different effects of salen-Co additives for the diversity in ratio of\ndifferent chemoselective products could be explained.\nAnswer: We propose that the observed product distribution arises from competition between\nthe cobalt-catalyzed allylation pathway and the background alkenylation reaction (Table 1b,\nEntry 3). The variation in catalytic efficiency among different salen-Co complexes (A2-A5)\nappears to be closely related to their hydrogen atom transfer (HAT) capabilities. DFT\ncalculations of the Co–H bond dissociation energies (BDE) in the corresponding salen-Co–H\nspecies reveal that the Co–H BDE for complex A5 is 36.3 kcal/mol, higher than those calculated\nfor A2–A4. This higher BDE indicates stronger hydrogen affinity of the A5 catalyst, which\nfacilitates more efficient HAT. Consequently, A5 exhibits superior performance in promoting\nthe formation of allylation product 3a, thereby leading to enhanced chemoselectivity toward\nthe allylation pathway. We have included these results in our revised Supplementary\nInformation (Page S60, Table S11).\nentry Co reagent BDE(Co–H)/kcal·mol-1\n(4) The ratios of E/Z product was mentioned in this manuscript, it would be great if the authors\ncould also consider the possibility of E/Z product formation in the reaction.\nAnswer: To elucidate the origin of the stereochemical outcome, we computed the key transition\nstates governing the formation of E- and Z-alkenes in both the allylation and alkenylation\npathways. For the allylation reaction, the energy difference between transition states TS3-3as(BS)\n(E-pathway) and TS3-3a-Zs(BS) (Z-pathway) is relatively small (ΔΔG‡ = 0.4 kcal/mol),\ncorresponding to an E/Z ratio of approximately 6:1, which aligns well with our experimental\nobservations. In contrast, for the alkenylation pathway, a significantly larger energy difference\n(ΔΔG‡ = 4.6 kcal/mol) is observed between TS5-4as (E-pathway) and TS5-4a-Zs (Z-pathway).\nThis substantial barrier rationalizes why the Z-isomer was not detected experimentally in the\nalkenylation products. Structurally, the bulky 2,6-lutidine base introduces considerable steric\nhindrance that disproportionately destabilizes the transition state leading to the Z-alkene,\nparticularly in the alkenylation mechanism where the geometry around the forming double bond\nis more constrained. In comparison, the more planar and open coordination environment of the\nCo(salen) catalyst in the allylation pathway results in a lower energetic penalty for Z-isomer\nformation. We have included these results in our revised Supplementary Information (Page S62).\n(5) Did the authors consider the spin states of Co and Ni in the DFT calculation? The authors\nonly mentioned “For transition states TS-3a and TS-4a, the ‘broken symmetry’ formalism\nwas used” in Supporting Information, have the authors tried and compared different spin\nstates for the key stationary points? It is weird that different spin states were used for\nstationary points along reaction pathways in the calculation without additional explanation.\nThis should be described in the manuscript including Figure 7(a).\nAnswer: We have considered the possible spin states of cobalt and nickel species present in the\nsystem. The spin-state changes occurring along the reaction pathway involve well-\ncharacterized species whose spin state are either documented in prior studies or can be reliably\nassigned via theoretical analysis (J. Am. Chem. Soc. 2024, 146, 34043; Nat. Commun. 2017, 8,\n14875；Inorg. Chem. 2012, 51, 10557; Angew. Chem. Int. Ed. 2025, e202506268). Specifically,\nsix-coordinate octahedral nickel (II) complexes adopt a high-spin configuration; cobalt centers\ncoordinated by planar quadridentate ligands (such as Salen) favor a low-spin state; and the\ncarbon radical generated during the reaction exhibits weak coupling with nickel, making the\nspin-parallel configuration slightly more stable than the spin-antiparallel (broken symmetry)\nconfiguration.\nTo further validate the chosen spin states, we computed the Gibbs free energies difference\nbetween the spin state we have chosen and another plausible spin state for the cobalt and nickel\ncomplexes. Given that accurately predicting spin-state energy differences remains challenging\nwithin DFT, we performed single-point calculations using the TPSSh-D3(BJ) and MN15L\nfunctionals—selected based on benchmark studies in the literature (J. Chem. Theory Comput.\n2020, 16, 4416; Inorg. Chem. 2018, 57, 14097)—instead of the wB97X-D functional. In all\ncases, the energy differences between the spin states employed in our study and other plausible\nspin states were positive, confirming our choice correspond to the most stable spin states.\nThe chosen spin\nΔG(TPSSh-D3(BJ) ΔG(MN15L Single-\nentry Intermediate state to another\nSingle-Point) Point)\nplausible spin state\n1 [NiII]+OAc- t → s 15.3 21.8\n6 [CoII] d → q 6.9 0.5\n8 [CoI]- s → t 7.0 2.1\nThe spin states of the transition states were logically deduced from those of the adjacent\nintermediates. For TS3, which corresponds to the hydrogen atom transfer (HAT) step, the\nreactants are two radical species, while the product is a closed-shell system. For such electron\npairing processes, employing the broken-symmetry (BS) approach in DFT calculations is both\nappropriate and necessary (Chem. Phys. Lett. 2000, 319, 223).\nAdditionally, following the reviewers 6' suggestions, we have added superscripts\nrepresenting the spin states in Figure 7(a) : “Spin states are annotated as superscripts: s (singlet),\nd (doublet), t (triplet), q (quartet), and BS (broken symmetry).”\n(6) The origin of stereoselectivity could be explained by NCI or EDA analysis. It is hard to\nunderstand TS2-Si is more favorable form the structures. Considering that TS2 is the key\ntransition state structure that determines stereoselectivity, the discussion on its\nconformation in Figure S8 should be briefly mentioned in the manuscript.\nAnswer: We performed energy decomposition analysis on the energy difference between the\nkey enantioselectivity-determining transition states TS2‑Siq and TS2‑Req. Initial distortion–\ninteraction analysis revealed that the transition state energy difference originates primarily from\nthe distortion energy of the nickel-bound radical specie (Fragment 1, 2.9 kcal/mol), whereas\nboth the distortion energy of 2a (hexene, Fragment 2, -0.9 kcal/mol) and interaction energy (-\n0.6 kcal/mol) disfavor enantioselectivity. This suggests that the origin of enantioselectivity is\nlikely governed by the conformation of the nickel-bound radical specie.\nFurther distortion–interaction analysis focusing on the nickel-bound radical specie\n(Fragment 1) indicated that the energy difference arises mainly from the distortion energy of\nthe nickel catalyst (Fragment 3, 1.4 kcal/mol), followed by contributions from the distortion\nenergy of benzoxazolyl acetate radical (Fragment 4, 0.7 kcal/mol) and interaction energy (0.9\nkcal/mol). The result implies that the energy difference of the nickel-bound radical specie stem\nfrom distinct benzoxazolyl acetate substrate coordination modes, leading to varied steric\nrepulsion and consequently significant nickel catalyst distortion coupled with benzoxazolyl\nacetate substrate distortion.\nels\norb\nDFTc\ndisp\nxrep\nSince interaction energy E (0.9 kcal/mol) contributes non‑negligibly to the energy\nint’\ndifference, we conducted additional energy decomposition analysis, which identified\nelectrostatic interactions as the dominant component (5.6 kcal/mol), with orbital interactions\nplaying a minor role (1.6 kcal/mol). Consistent with our earlier findings (J. Am. Chem. Soc.\n2024, 146, 34043), the two nickel-bound radical specie exhibit a noticeable difference in N–Ni\nbond lengths (slightly longer in the TS2‑Req complex, TS2‑Siq: 2.08Å; TS2‑Req: 2.10Å),\nwhereas the O–Ni distances remain similar (TS2‑Siq: 2.13Å; TS2‑Req: 2.13Å). The\ncoordination difference correlates well with the larger electrostatic energy difference and\nsmaller orbital interaction energy difference. We thus attribute the interaction energy difference\nof the nickel-bound radical specie to the weaker N–Ni coordination in TS2‑Req.\nStructural analysis suggests that, under the TS2‑Req coordination mode, steric repulsion\noccurs between the phenyl ring of the benzoxazolyl acetate substrate and the BOX ligand. This\nstructural distinction consistently accounts for the greater distortion energy difference of the\nnickel catalyst and the smaller distortion energy difference of the benzoxazolyl acetate substrate\nin TS2‑Req. Furthermore, it leads to impaired contact between the coordinating N atom\n(adjacent to the phenyl substituent) and the Ni center, thereby resulting in a weaker N–Ni bond,\nwhereas the O–Ni bond remains unaffected.\nIntegrating the results from distortion-interaction analysis, energy decomposition analysis,\nand structural analysis, we conclude that the enantioselectivity arises from energy differences\ninduced by distinct substrate coordination modes. In particular, the coordination in TS2‑Req\nintroduces steric repulsion between the phenyl substituent of the benzoxazolyl acetate substrate\nand the BOX ligand, resulting in a disfavored transition state.\nIn response to the reviewer's suggestion, we have incorporated a discussion on the origin of\nenantioselectivity in the revised manuscript, including a brief description of Figure S8 (Figure\nS9 in revised Supplementary Information). Our analysis reveals that the enantioselectivity\nprimarily stems from distinct coordination modes of the benzoxazolyl ester substrate. These\ndifferent coordination modes lead to opposing facial selectivities, as illustrated in Figure S8.\nFurther energy decomposition analysis (see the Supplementary Information) indicates that the\nvariation in coordination geometry arises mainly from steric repulsion between the phenyl ring\nof the substrate and the BOX ligand.\n(7) The structure of 2a should be given in Figure 7.\nAnswer: The structure of compound 2a has been added to Figure 7 in the revised manuscript."}, {"round": 2, "reviewer_comments": {"reviewer_1": "All my concerns have been addressed and I does not have further concerns.", "reviewer_2": "I have reviewed the revised version of the manuscript. Overall, the authors have addressed the points raised in the previous review, and the manuscript is much improved.\nAlthough the cyclic voltammetry experiments may require further careful consideration, as also noted by Reviewer 4, this reviewer looks forward to further studies by the authors on the radical generation mechanism.\nTherefore, this reviewer is happy to recommend the manuscript for publication as is.", "reviewer_3": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts.", "reviewer_4": "After proofreading this manuscript for the second time, I acknowledge that this new version has been significantly improved and has addressed most of my previous comments. Notably, the revised mechanistic proposal, excluding any role of Co(III) as a redox mediator in the oxidation of the Ni-enolate through a SET process, is more reasonable. The analyses and DFT calculations now better support the observed selectivity.\nHowever, in my opinion, several aspects of the electrochemical studies remain unclear. To ensure relevant electrochemical measurements, the supporting electrolyte should be present in large excess compared with the substrates. In the current work, the concentration of the supporting electrolyte (50 mM) is only about twice that of 1b and the amine (33 mM), which is insufficient. Increasing the supporting electrolyte concentration could improve, even change, the CV profiles.\nThe concentrations used for each component are too high. Considering the relatively large electrode (3 mm diameter), it would be more appropriate to present current values in microamperes (µA) rather than amperes (A). In the present case, the reported currents appear low but should be around 10 µA, which is much more realistic than the 0.3 mA values shown.\nRegarding the determination of onset potentials in the Supporting Information, this point deserves closer examination, as it is used to validate the authors’ mechanistic discussion. The onset potential for morpholine appears to be below 1.16 V. The onset should be determined at the point where the current deviates from zero — with such high currents, demonstrating oxidation should not be problematic. The cyclic voltammograms (CVs) presented are not entirely convincing due to the excessively high currents observed for the 1b + morpholine mixture. A more convincing approach would be to record CVs with increasing amounts of this mixture added to a 1–2 mM Ni/L5 solution, yielding current intensities in the µA range.\nThe authors state that “the initial oxidative potential of benzoxazolyl propanoate 1b decreased significantly from +1.92 V to +0.32 V (versus SCE) upon addition of the chiral nickel catalyst.” Such comparisons are inappropriate; instead, the oxidation potential of the enolate (1b + morpholine) should be compared to that of the Ni-enolate. In this respect, the black arrow in Figure 6a is confusing. Moreover, the CVs obtained with increasing catalyst concentrations are not relevant and, in my opinion, should be removed from the main text. Under the reaction conditions, only about 10 mol% of the nickel enolate is present alongside ten equivalents of the enolate; thus, the middle panel of Figure 6a does not provide meaningful information and should likely be omitted.\nThe combination of only two reaction partners shown in the rebuttal is very informative. However, the CV of 1b with Ni alone was not presented. It would be helpful to include this binary combination, in the Supporting Information.\nThe authors claim that both 2,6-lutidine and morpholine can promote the alkenylation and alkylation reactions, yet CV data were only provided for morpholine. They justify this by stating that morpholine affords a more distinct catalytic current and clearer interpretation of the electrochemical response. However, no catalytic current is observed with either morpholine or 2,6-lutidine in the comparison CVs shown in the rebuttal. This explanation is therefore unconvincing and should be reconsidered. The only compelling observation is that displayed in Figure 6a (right), which shows that A1 can act as a redox mediator. Nevertheless, this role is not integrated into the mechanism proposed in Figure 7. It would be useful to perform CVs under conditions closer to the catalytic system — namely with a 1:1 mixture of A1 and Ni/L5, along with ten equivalents of 1b and 2,6-lutidine — rather than the conditions used in Figure S8, which are not representative.\nIn conclusion, since the stereocontrolled electrochemical functionalization of unactivated alkenes remains a largely unexplored and challenging area, I believe this work is of significant interest to the scientific community. However, the electrochemical data supporting the proposed mechanism require further improvement. For these reasons, I recommend publication in Nature Communications once the authors have thoroughly addressed all the issues mentioned above.", "reviewer_5": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts.", "reviewer_6": "The authors have revised the manuscript according to my comments, it could be acceptable now."}, "author_response": "Responses to Comments\nfor\nTunable Enantioselective Electrocatalytic Functionalization of Unactivated Alkenes\nTian Xie, Minghao Liu, Jiayin Zhang, Lingzi Peng, Chang Guo✉\nManuscript ID: NCOMMS-25-46490A\nReply to comments by Reviewer 1\n(1) All my concerns have been addressed and I does not have further concerns.\nAnswer: We appreciate Reviewer 1 for favorable comments!\nReply to comments by Reviewer 2\nWe appreciate Reviewer 2 for favorable comments!\n(1) I have reviewed the revised version of the manuscript. Overall, the authors have addressed\nthe points raised in the previous review, and the manuscript is much improved. Although\nthe cyclic voltammetry experiments may require further careful consideration, as also\nnoted by Reviewer 4, this reviewer looks forward to further studies by the authors on the\nradical generation mechanism. Therefore, this reviewer is happy to recommend the\nmanuscript for publication as is.\nAnswer: We appreciate Reviewer 2 for the favorable comments and helpful suggestions!\nFollowing this advice, we have performed additional CV experiments and included the revised\ndata as Figure 6 in the revised manuscript.\n100 4.0 25\n90 1 2 b a 3.5 2 2 m m M M N N i i / / L L 5 5 + 2mM (1b + morpholine) 20 A A 1 1 + 1b + morpholine\nCurrent μ A 8 7 6 5\n4\n0 0 0 0\n0\n1 1 1 m N b b b i o / r L + + + p 5 h N N m o i i o l / / i r L L n p 5 5 e h o + l i m ne orpholine Current μ A 3 2 2\n1\n. . .\n.\n0 5 0\n5\n2 2 2 m m m M M M N N N i i i / / / L L L 5 5 5 + + + 4 6 1 m m 0m M M M ( ( 1 1 ( b b 1b + + + m m m o o o r r p p rp h h h o o o l l i i l n n in e e ) ) e) Current μ A 1 1 5 0 5\n30 1.0\n20 0.5 -5\n10 0.0 -10\n0\n-0.5 -15\n0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0\nPotential/V (versus SCE) Potential/V (versus SCE) Potential/V (versus SCE)\nReply to comments by Reviewer 3\nI co-reviewed this manuscript with one of the reviewers who provided the listed reports. This\nis part of the Nature Communications initiative to facilitate training in peer review and to\nprovide appropriate recognition for Early Career Researchers who co-review manuscripts.\nAnswer: We thank the co-reviewer for their careful evaluation of our manuscript and their\nvaluable contributions to the peer review process.\nReply to comments by Reviewer 4\nWe appreciate Reviewer 4 for favorable comments!\n(1) After proofreading this manuscript for the second time, I acknowledge that this new\nversion has been significantly improved and has addressed most of my previous comments.\nNotably, the revised mechanistic proposal, excluding any role of Co(III) as a redox\nmediator in the oxidation of the Ni-enolate through a SET process, is more reasonable. The\nanalyses and DFT calculations now better support the observed selectivity.\nAnswer: We appreciate Reviewer 4 for the favorable comments and helpful suggestions! These\ncomments are greatly valuable and helpful for revising and improving our manuscript. We have\nmade all the necessary amendments as suggested in our revised manuscript and Supplementary\nInformation.\n(2) However, in my opinion, several aspects of the electrochemical studies remain unclear. To\nensure relevant electrochemical measurements, the supporting electrolyte should be\npresent in large excess compared with the substrates. In the current work, the concentration\nof the supporting electrolyte (50 mM) is only about twice that of 1b and the amine (33\nmM), which is insufficient. Increasing the supporting electrolyte concentration could\nimprove, even change, the CV profiles. The concentrations used for each component are\ntoo high. Considering the relatively large electrode (3 mm diameter), it would be more\nappropriate to present current values in microamperes (µA) rather than amperes (A). In the\npresent case, the reported currents appear low but should be around 10 µA, which is much\nmore realistic than the 0.3 mA values shown.\nAnswer: As suggested by Reviewer 2, we have increased the concentration of the supporting\nelectrolyte from 50 mM to 100 mM and reduced the concentration of the substrates from 33\nmM to 10 mM. As a result, the electrolyte is now in a 10-fold excess relative to the substrates.\nUnder these conditions, we observed only minor changes in the CV measurements.\nAdditionally, the current values have been converted to microamperes (µA) for better clarity.\nThe corresponding CV profile (Fig. 6a) and the related figures in the Supplementary\ninformation (Figures S1–S7) have been updated accordingly.\n(3) Regarding the determination of onset potentials in the Supporting Information, this point\ndeserves closer examination, as it is used to validate the authors’ mechanistic discussion.\nThe onset potential for morpholine appears to be below 1.16 V. The onset should be\ndetermined at the point where the current deviates from zero — with such high currents,\ndemonstrating oxidation should not be problematic.\nAnswer: We thank reviewer 4 for this comment. In accordance with the suggestion, the onset\npotentials have been re-determined following the method described in ACS Catal. 2023, 13,\n2916, where the onset is identified as the potential at which the current deviates from the\nbaseline. All onset potentials have been revised accordingly, and corresponding updates have\nbeen made in the main text (including the DFT calculations in Fig. 7a) as well as in the\nSupplementary Information (Figures S1–S5).\n(4) The cyclic voltammograms (CVs) presented are not entirely convincing due to the\nexcessively high currents observed for the 1b + morpholine mixture. A more convincing\napproach would be to record CVs with increasing amounts of this mixture added to a 1–2\nmM Ni/L5 solution, yielding current intensities in the µA range.\nAnswer: Accordingly, we have performed CV measurements by adding increasing amounts\n(2–10 mM) of the 1b and morpholine mixture to a 2 mM Ni/L5 solution. The results clearly\nshow a significant increase in the catalytic current upon addition of the substrate and base,\nsupporting our previous conclusion that the catalytic current arises from Ni-bound substrate\noxidation and occurs at relatively low potentials. These new CV profiles have been included as\nthe middle panel in Fig. 6a of the revised manuscript.\n100\n90\n80 70 60 50\n40\n30\n20\n10\n0\n0.0 0.5 1.0 1.5 2.0 2.5\nA Current μ\n1b 2a\nm orpholine N i/L5 1b + N i/L5 + m orpholine 1b + N i/L5 1b + m orpholine\nPotential/V (versus SCE)\n4.0\n3.5\n3.0 2.5 2.0\n1.5\n1.0\n0.5\n0.0\n-0.50.0\n0.1 0.2 0.3 0.4 0.5 0.6 0.7\nA Current μ\n2m 2m\n2m 2m 2m\nMMMMM N N\nN N N\ni/L5 i/L5 + 2m M (1b + m orpholine)\ni/L5 + 4m M (1b + m orpholine) i/L5 + 6m M (1b + m orpholine) i/L5 + 10m M (1b + m orpholine)\nPotential/V (versus SCE)\n25\n20\n15 10 5\n0\n-5\n-10\n-15-0.4\n-0.2 0.0 0.2 0.4 0.6 0.8 1.0\nA Current μ\nA A\nA\n11 + 1b + m orpholine\n1 + N i/L5 + 1b + m orpholine\nPotential/V (versus SCE)\n4.0\n2mM Ni/L5\n3.5 2mM Ni/L5 + 2mM (1b + morpholine)\n2mM Ni/L5 + 4mM (1b + morpholine)\n3.0\n2mM Ni/L5 + 6mM (1b + morpholine)\n2.5 2mM Ni/L5 + 10mM (1b + morpholine)\nA\nμ 2.0\nnt\ne\nurr 1.5\nC\n1.0\n0.5\n0.0\n-0.5\n0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7\nPotential/V (versus SCE)\n(5) The authors state that “the initial oxidative potential of benzoxazolyl propanoate 1b\ndecreased significantly from +1.92 V to +0.32 V (versus SCE) upon addition of the chiral\nnickel catalyst.” Such comparisons are inappropriate; instead, the oxidation potential of\nthe enolate (1b + morpholine) should be compared to that of the Ni-enolate. In this respect,\nthe black arrow in Figure 6a is confusing.\nAnswer: We agree with the reviewer 4 that a direct comparison of potentials between the free\nsubstrate and the Ni-enolate is not appropriate. To address this, we have removed the black\narrow. The revised text now focuses on the key observation—the negative shift of the oxidative\npeak upon catalyst addition. We have revised “Upon addition of the chiral nickel catalyst, the\noxidative peak of benzoxazolyl propanoate 1b shifted negatively (Fig. 6a, left) and exhibited a\nconcurrent increase in current with higher concentrations of 1b (Fig. 6a, middle), supporting\nthe facile oxidation of a nickel-bound enolate intermediate.” in our revised manuscript.\n(6) Moreover, the CVs obtained with increasing catalyst concentrations are not relevant and,\nin my opinion, should be removed from the main text. Under the reaction conditions, only\nabout 10 mol% of the nickel enolate is present alongside ten equivalents of the enolate;\nthus, the middle panel of Figure 6a does not provide meaningful information and should\nlikely be omitted.\nAnswer: In accordance with the suggestion, we have removed the CV profiles obtained with\nincreasing catalyst concentrations from Fig. 6a (right). Furthermore, the middle panel of Fig.\n6a has been replaced with new CV measurements performed by adding increasing amounts (2–\n10 mM) of the substrate 1b and morpholine to a 2 mM Ni/L5 solution, which directly reflects\nthe catalytic reaction conditions and shows the role of the nickel catalyst in facilitating the\noxidation.\n(7) The combination of only two reaction partners shown in the rebuttal is very informative.\nHowever, the CV of 1b with Ni alone was not presented. It would be helpful to include\nthis binary combination, in the Supporting Information.\nAnswer: We thank the reviewer 4 for the constructive suggestion. Accordingly, we have\nincluded the CV profile of the binary combination (1b + Ni/L5) in the updated Fig. 6a (left) to\nprovide additional mechanistic insight. The relevant figure in the manuscript has been revised\naccordingly.\n(8) The authors claim that both 2,6-lutidine and morpholine can promote the alkenylation and\nalkylation reactions, yet CV data were only provided for morpholine. They justify this by\nstating that morpholine affords a more distinct catalytic current and clearer interpretation\nof the electrochemical response. However, no catalytic current is observed with either\nmorpholine or 2,6-lutidine in the comparison CVs shown in the rebuttal. This explanation\nis therefore unconvincing and should be reconsidered.\nAnswer: We appreciate the reviewer 4's comment. It is indeed challenging to observe a strong\noxidative peak for the Ni-enolate intermediate due to its high reactivity and low concentration.\nThis is supported by DFT calculations, which indicate that the formation of the Ni-enolate\nintermediate (INT2) is energetically uphill (ΔG = +1.8 kcal/mol), underscoring its inherent\ninstability. We have further investigated the influence of different bases on the CV behavior of\n100\n90\n80 70 60 50\n40\n30\n20\n10\n0\n0.0 0.5 1.0 1.5 2.0 2.5\nA Current μ\n1b 2a\nm orpholine N i/L5 1b + N i/L5 + m orpholine 1b + N i/L5 1b + m orpholine\nPotential/V (versus SCE)\n4.0\n3.5\n3.0 2.5 2.0\n1.5\n1.0\n0.5\n0.0\n-0.50.0\n0.1 0.2 0.3 0.4 0.5 0.6 0.7\nA Current μ\n2m 2m\n2m 2m 2m\nMMMMM N N\nN N N\ni/L5 i/L5 + 2m M (1b + m orpholine)\ni/L5 + 4m M (1b + m orpholine) i/L5 + 6m M (1b + m orpholine) i/L5 + 10m M (1b + m orpholine)\nPotential/V (versus SCE)\n100\n1b\n90 2a\nmorpholine\n70 1b + Ni/L5 + morpholine\n60 1b + Ni/L5\nμ A 1b + morpholine\nnt 50\ne\nurr\n30\n20\n10\n0\n0.0 0.5 1.0 1.5 2.0 2.5\nPotential/V (versus SCE)\nthe system. The onset oxidation potential of the Ni-enolate intermediate remains nearly\nidentical regardless of whether morpholine or 2,6-lutidine is used as the base. Upon\nmagnification of the CV curves, a clear catalytic current can be observed, corresponding to the\noxidation of the Ni-enolate species. Moreover, in control experiments performed in the absence\nof the nickel catalyst, no such catalytic current is observed with either base. All relevant CV\nprofiles have been included in the Supporting Information (Figures S4–S5), and these\nconsistent findings support the proposed mechanistic pathway involving the nickel-enolate\nspecies.\n(9) The only compelling observation is that displayed in Figure 6a (right), which shows that\nA1 can act as a redox mediator. Nevertheless, this role is not integrated into the mechanism\nproposed in Figure 7.\nAnswer: We thank the reviewer 4 for this valuable observation. Figure 6a (right) demonstrates\nthat ferrocenemethylamine A1 functions as an effective redox mediator in the alkenylation\nreaction. Under the revised experimental conditions, we have reconfirmed that A1 undergoes\nefficient electron transfer specifically with the nickel-enolate catalytic intermediate. It is\nimportant to clarify that the mechanism outlined in Figure 7d describes the Ni/Co-catalyzed\noxidative allylation system, which operates in the absence of a ferrocene mediator. Therefore,\nthe role of A1 as a redox mediator has been explicitly addressed in the context of Fig. 6a. The\ncorresponding description in the main text has been updated as follows: “Critically, while the\nsubstrate alone with ferrocenemethylamine A1 showed no significant catalytic current, the\naddition of the chiral nickel catalyst led to a substantial increase in the oxidative current with\nattenuation of the reduction peak. This clear contrast provides evidence for efficient electron\ntransfer between A1 and the Ni-bound enolate intermediate (Fig. 6a, right).”\n(10) It would be useful to perform CVs under conditions closer to the catalytic system —\nnamely with a 1:1 mixture of A1 and Ni/L5, along with ten equivalents of 1b and 2,6-\nlutidine — rather than the conditions used in Figure S8, which are not representative.\nAnswer: We thank the reviewer for this constructive suggestion Using a 1:1 mixture of A1 and\nNi/L5 along with ten equivalents of 1b and 2,6-lutidine—we have repeated the CV\nmeasurements (presented in the revised Figure S8). The results clearly demonstrate that\nintroduction of the chiral nickel catalyst leads to a catalytic current, which confirms electron\ntransfer between A1 and the catalytic intermediate. By contrast, no such current is detected in\nthe absence of the nickel catalyst, underscoring the essential role of the nickel catalyst in\nfacilitating the oxidative process.\n(11) In conclusion, since the stereocontrolled electrochemical functionalization of unactivated\nalkenes remains a largely unexplored and challenging area, I believe this work is of\nsignificant interest to the scientific community. However, the electrochemical data\nsupporting the proposed mechanism require further improvement. For these reasons, I\nrecommend publication in Nature Communications once the authors have thoroughly\naddressed all the issues mentioned above.\nAμ\ntnerruC\n3\n2\n1\n-1\n-2\n0\n0\n0\n0\n0\n0-0\n.4\nA 1\nA 1\nA 1\n-0\n+\n+\n.2\nb +\ni/L\n2 ,6 -L u tid in e\n5 + 1 b + 2 ,6 -L u tid in e\n0 .0 0 .2 0 .4\nP o te n tia l/V (v e rsu s S C E )\n0 .6 0 .8 1 .0\nAnswer: We sincerely thank Reviewer 4 for their encouraging conclusion and insightful\nsuggestions, which have been invaluable in strengthening the electrochemical support for our\nproposed mechanism. All raised issues have been fully addressed in the revised manuscript and\nsupplementary information, leading to a significant improvement in the quality and clarity of\nour data and discussion.\nReply to comments by Reviewer 5\nI co-reviewed this manuscript with one of the reviewers who provided the listed reports. This\nis part of the Nature Communications initiative to facilitate training in peer review and to\nprovide appropriate recognition for Early Career Researchers who co-review manuscripts.\nAnswer: We thank the co-reviewer for their careful evaluation of our manuscript and their\nvaluable contributions to the peer review process.\nReply to comments by Reviewer 6\n(1) The authors have revised the manuscript according to my comments, it could be acceptable\nnow.\nAnswer: We appreciate Reviewer 6 for the favorable comments and helpful suggestions!"}, {"round": 3, "reviewer_comments": {"reviewer_4": "I have examined the revised version of the manuscript, which now includes additional cyclic voltammetry (CV) experiments.\nThe authors have satisfactorily addressed most of the concerns raised in the previous review, and the overall quality of the manuscript has improved considerably. Nonetheless, in their rebuttal letter, the authors continue to use the term “catalytic current,” which is not appropriate in the present context. Demonstration of a genuine catalytic process would require a much more pronounced effect, rather than the modest increase in oxidation peak intensity accompanied by an almost negligible decrease in the reduction peak. In any case, since the revised manuscript no longer refers to a catalytic current, this issue can be considered resolved.", "reviewer_5": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts."}, "author_response": "Responses to Comments\nfor\nTunable Enantioselective Electrocatalytic Functionalization of Unactivated Alkenes\nTian Xie, Minghao Liu, Jiayin Zhang, Lingzi Peng, Chang Guo✉\nManuscript ID: NCOMMS-25-46490B\nReply to comments by Reviewer 4\nWe appreciate Reviewer 4 for favorable comments!\n(1) I have examined the revised version of the manuscript, which now includes additional\ncyclic voltammetry (CV) experiments. The authors have satisfactorily addressed most of\nthe concerns raised in the previous review, and the overall quality of the manuscript has\nimproved considerably. Nonetheless, in their rebuttal letter, the authors continue to use the\nterm “ catalytic current,” which is not appropriate in the present context. Demonstration\nof a genuine catalytic process would require a much more pronounced effect, rather than\nthe modest increase in oxidation peak intensity accompanied by an almost negligible\ndecrease in the reduction peak. In any case, since the revised manuscript no longer refers\nto a catalytic current, this issue can be considered resolved.\nAnswer: We thank the reviewer 4 for thoughtful feedback and for acknowledging the\nimprovements made to the manuscript. We agree that the term “catalytic current” was imprecise\nin this context, and we have changed “catalytic current” into “current response” in the revised\nmanuscript. We appreciate the reviewer 4’s attention to this detail.\nReply to comments by Reviewer 5\n(1) I co-reviewed this manuscript with one of the reviewers who provided the listed reports.\nThis is part of the Nature Communications initiative to facilitate training in peer review\nand to provide appropriate recognition for Early Career Researchers who co-review\nmanuscripts.\nAnswer: We thank the co-reviewer for their careful evaluation of our manuscript and their\nvaluable contributions to the peer review process."}]

Decision letter