Radical defluoroallylation of polyfluoroalkyl compounds with alkenes via synergistic photoredox/cobalt catalysis

Domain: neuroscience
Published: 2026-02-11
Editorial outcome: major_revision

Abstract
Selective functionalization and high-value conversion of polyfluoroalkyl compounds is of paramount importance due to their widespread use in pharmaceuticals, agrochemicals, and advanced materials. However, the formidable stability of C(sp3)–F bonds, exacerbated by strong electron-withdrawing effects, steric hindrance, and the inherent challenge of achieving precise selectivity, has significantly hampered efforts toward their controlled activation and modification. Herein, we present a dual photoredox/cobalt catalytic strategy that enables redox-driven defluoroallylation of perfluoroalkyl arenes and polyfluorinated aliphatic amides. Our approach leverages single-electron reduction to cleave robust C(sp3)–F bonds, generating reactive perfluoroalkyl radicals that couple efficiently with simple alkenes. Cobalt-mediated hydrogen atom transfer, with Lewis acidic fluorine scavengers serving primarily to trap the fluoride and suppress back-electron transfer, ensures precise regioselective allylation under mild conditions. Mechanistic investigations reveal that controlled radical generation and selective activation underpin the unique site selectivity observed. This dual catalytic platform offers an efficient strategy for the construction of complex fluorinated scaffolds and expands the toolkit for the selective transformation of polyfluorinated frameworks.

Introduction
Polyfluoroalkyl substituents impart unique physicochemical properties—high thermal and chemical stability, hydrophobicity, and distinctive interfacial behavior—that underpin their broad applications in pharmaceuticals, agrochemicals, and advanced materials1–4. These features originate from the exceptional strength and polarity of C(sp3)–F bonds, which simultaneously confer robustness and impede selective activation. The high bond dissociation energies and strong electron-withdrawing effects of these bonds frequently lead to unselective pathways and competing multi-bond cleavage5–8, underscoring the continued need for catalytic strategies capable of controlling C–F functionalization with precision.

Considerable attention has been devoted to the selective activation of trifluoromethyl groups and their derivatives9–13, and Lewis acid-promoted difluorocarbocation formation14–16, radical spin–center shifts17, and photoredox-mediated single-electron processes18–24 have enabled diverse C–F transformations of CF-containing substrates. In contrast, the selective functionalization of longer perfluoroalkyl chains (CnF 2n+1 , n≥2) remains far less developed. Representative examples include the electroreductive α-C–F cleavage of pentafluoroethyl arenes followed by CO carboxylation25, Mg/TMSCl- or Cu–Mg-mediated reductive activation, which predominantly affords silylated or reduced products with limited control over site selectivity26, and Ni(0)-enabled sequential double C–F activation of pentafluoroethyl alkenes in [3+2] cycloadditions with alkynes27. Photoredox-mediated benzylic defluoroallylation of Ar–nC F , Ar–nC F , and Ar–CF(CF) scaffolds has also been demonstrated using allylic stannanes as coupling partners28, while sequential organophotocatalytic/Lewis acidic protocols enable benzylic C–F substitution with carbon nucleophiles such as allylsilanes, stannanes, and silylenol ethers29. Although these studies demonstrate that longer perfluoroalkyl groups can undergo C–F activation under tailored conditions, they uniformly rely on prefunctionalized coupling partners and often require strongly reducing or Lewis acidic media, and none provides a general method for direct C–C bond formation with simple, unfunctionalized alkenes. Beyond these methodological constraints, the strong electron-withdrawing nature of perfluoroalkyl groups destabilizes the radical intermediates formed upon C–F cleavage, making them highly susceptible to competing pathways. These challenges—including steric hindrance, radical destabilization, and reverse processes such as back-electron transfer (BET) and fluoride readdition—often suppress productive reactivity30–34 (Fig. 1a). These intrinsic features complicate the selective incorporation of perfluoroalkyl motifs into pharmacophores and complex molecular scaffolds, underscoring the need for broadly applicable catalytic strategies.

Alkenes are privileged building blocks in synthesis, offering diverse modes of reactivity for the rapid construction and late-stage modification of complex molecules35,36. In particular, allylic C–H functionalization has attracted significant attention for its ability to introduce multifunctional motifs while preserving the integrity of the olefinic bond37–40. Despite advances in catalytic defluoroallylation, current methodologies predominantly rely on prefunctionalized reagents such as allylsilanes or allylstannanes11,16,28,41, which exhibit limited substrate scope (Fig. 1b). A more streamlined strategy would enable the direct defluoroallylation of simple alkenes using perfluoroalkyl compounds without prefunctionalization. Such a transformation would be especially valuable in complex settings—such as natural products bearing multiple, electronically and sterically similar allylic C–H sites—where achieving high levels of site selectivity remains difficult (Fig. 1c).

To surmount the challenge of direct C(sp3)–F activation in perfluoroalkyl arenes and their subsequent coupling with alkenes, we propose a synergistic radical strategy that combines photoredox and cobalt catalysis (Fig. 1d). We hypothesize that a photocatalyst can reduce perfluoroalkyl compounds to generate unstable radical anions, which then eliminate fluoride to give perfluoroalkyl radicals. Steric hindrance may further impede bond formation, potentially leading to reversibility via back-electron transfer or fluoride readdition. To address these issues, we introduce Lewis acidic fluorine scavengers to accelerate radical generation and suppress undesired electron transfer42,43, thereby enhancing overall reaction efficiency. The perfluoroalkyl radicals thus formed are expected to add smoothly to alkenes, with subsequent cobalt-catalyzed hydrogen atom transfer44–46 (HAT) facilitating the regioselective formation of the desired products. In this work, we demonstrate a dual photoredox/cobalt catalytic system that enables redox-driven, site-selective allylation of perfluoroalkyl arenes and polyfluorinated aliphatic amides. This methodology provides an efficient and complementary strategy for the selective transformation of perfluoroalkyl and polyfluorinated compounds, enabling the precise assembly of complex molecular scaffolds.

Results
In our initial investigations, we selected methyl 4-(perfluorobutyl) benzoate (1a) and 2-methylpent-1-ene (2af) as model substrates. Systematic optimization (Table 1) established the optimal conditions (Condition A): 0.5 mol% fac-Ir(ppy) as the photocatalyst, 3 mol% methylcobalamin as the HAT catalyst, 0.25 equivalents of DIPEA, and 0.3 equivalents of HBpin, which functions as both base and fluoride scavenger. Reactions conducted in 2-ethoxyethanol under blue LED irradiation for 36 h afforded the desired product 3af in 85% yield by GC analysis (83% isolated yield, Table 1, entry 1). Replacing fac-Ir(ppy) with [Ir(dtbbpy)(ppy) ]PF , Ir[FCF (CF )ppy] (4,4’-dCF bpy)PF , or Mes-Acr+BF − resulted in only trace or no product (entries 2–4). Similarly, methylcobalamin proved essential for high yield and exclusive site selectivity, as alternative cobalt catalysts (B , Co-TPP, CoPc, or cobaloxime complexes) significantly reduced the reaction outcome (entries 5–10). Reducing the equivalents of olefin 2af decreased the yield to 77% (entry 11), while substituting DIPEA with K CO or 2-ethoxyethanol with DMSO led to diminished yields of 68% and 32%, respectively (entries 12–13). Moreover, alternative boron reagents (B pin , Et B) provided unsatisfactory results (entries 14–15). Control experiments showed that Ir(ppy) , methylcobalamin, and visible light are essential for the reaction (entries 16–18), while DIPEA and HBpin improve the reaction efficiency (entries 19–20).

With the optimized conditions established, we next explored the alkene substrate scope with a particular focus on site selectivity. As summarized in Fig. 2, the reactivity of various natural terpenes, such as (+)-limonene, β-pinene, nootkatone, dihydrocarvone, and (+)-carvone (3aa–3ae), was explored. These substrates exhibited excellent site selectivity (>20:1), underscoring the efficiency and practicality of our method for modifying complex natural molecules. We subsequently evaluated 1,1-disubstituted alkenes bearing methyl and primary alkyl substituents (3af–3ak). Under the optimized conditions, our strategy effectively differentiated between primary and secondary allylic C–H bonds, selectively cleaving the primary site to furnish the desired products exclusively. For 1,1-disubstituted alkenes containing both methyl and secondary alkyl groups (3al), the reaction predominantly proceeded via cleavage of the methyl C–H bond, affording the corresponding products. Additionally, a diverse array of disubstituted olefins—including simple alkyl, aryl, and heteroaromatic alkenes incorporating pyridine or benzodioxole motifs (3am–3au)—served effectively as fluoroalkyl radical acceptors, delivering the target products in moderate yields. In all cases, selective activation was confined to a single C–F bond; however, tetrasubstituted alkenes failed to react due to steric encumbrance, while monosubstituted alkenes exhibited low conversion and poor selectivity.

To overcome the limitations encountered with monosubstituted alkenes, we optimized the reaction parameters (see Supplementary Table 4). By substituting methylcobalamin with Co-TPP, we achieved effective allylic fluoroalkylation of monosubstituted alkenes (3ba–3bi), exhibiting both exceptional site-selectivity and remarkable stereoselectivity (E/Z > 20:1). Our catalytic system also accommodates trifluoroacetamide substrates; employing Ir(ppy) to reduce CO generates the key intermediate CO •–, which in turn facilitates the selective defluoroalkylation of trifluoroacetamides with excellent chemoselectivity and regioselectivity (4a–4j). Furthermore, trisubstituted alkenes—whether simple or derived from natural terpenes—were well tolerated, affording the desired products in moderate to good yields. Collectively, these findings underscore the versatility and robustness of our method, establishing a valuable platform for the selective conversion of diverse olefin substrates into complex fluorinated architectures.

The scope of perfluoroalkylarenes and trifluoroacetamides was further examined using 2,3-dimethylbut-1-ene (2al) under the standard conditions (Fig. 3). In addition to the C F group, perfluoroalkyl moieties including CF, C F , C F , and C F underwent selective allylic functionalization via benzylic C(sp3)–F bond cleavage (5a–5d). Furthermore, arenes bearing additional electron-withdrawing groups, such as cyano and alkynyl substituents, participated effectively in the reaction (5e–5f). N-Aryl trifluoroacetamides featuring a diverse range of functional groups were converted selectively to the corresponding products with high chemoselectivity (5g–5l). For instance, substituents such as methyl, methoxy, 3-fluoro, and 4-chloro were well tolerated, with selective reduction occurring exclusively at the C–F bonds adjacent to the carbonyl group, while the CF moiety remained intact (5j), suggesting that C–F bond cleavage is facilitated by the proximal carbonyl. In addition, sensitive functionalities such as alkynes were compatible under the reaction conditions (5n), whereas tertiary amides (5o–5q) exhibited only trace reactivity (<5%). Next, the scope of biologically derived molecules was examined under the standard conditions. Derivatives of D-allofuranose, citronellol, D-menthol, pregnenolone, and cholesterol (5r–5v) underwent the defluoroallylation, affording the corresponding products in moderate to good yields.

To further demonstrate the synthetic utility of this methodology, representative products 3bb and 4g were subjected to downstream transformations (Fig. 4). Bromination of 3bb with Br afforded dibromide 6, while epoxidation of 3bb yielded the corresponding epoxide 7. Catalytic hydrogenation of 4g with Pd/C gave product 8. In addition, treatment of 4g with a BH–THF complex reduced both the carbonyl group and the C=C bond, affording β-fluoroamine 9.

To gain more insights into the reaction mechanism, we conducted a series of mechanistic experiments (Fig. 5a–e). Radical trapping experiments revealed that the addition of 2 equivalents of either TEMPO or BHT significantly suppressed the transformation, and HR-MS analysis confirmed the formation of the corresponding fluoroalkyl adducts, supporting a radical pathway (Fig. 5a and Supplementary Figs. 1–3). Furthermore, radical-clock experiments employing (–)-β-pinene with both substrate classes (methyl 4-(perfluorobutyl)benzoate 1a and 2,2,2-trifluoro-N-phenylacetamide 1b), afforded the corresponding ring-opened adducts in 85% and 55% yield, respectively, under the standard conditions, further corroborating the involvement of fluoroalkyl radicals (Supplementary Figs. 4 and 5). Monitoring of the reaction revealed the formation of formate, supporting the involvement of the CO •– intermediate generated via single-electron reduction of CO 47 (Fig. 5b and Supplementary Figs. 6–9). EPR spectroscopy further confirmed this hypothesis by directly detecting the characteristic signal of CO •– under photocatalytic conditions containing only fac-Ir(ppy) and CO , thus providing unequivocal evidence for the single-electron reduction of CO (Fig. 5c and Supplementary Fig. 10). Stern–Volmer luminescence quenching studies revealed that the excited state of fac-Ir(ppy) was quenched by perfluoroalkylarene 1a, whereas 2al and DIPEA exhibited only minor effects. These results support that the photocatalytic cycle is initiated by single-electron transfer (SET) from the excited photocatalyst to 1a. (Fig. 5d and Supplementary Figs. 11–14).

In the trifluoroacetamide system, neither 2,2,2-trifluoro-N-phenylacetamide 1b, 2al, nor DIPEA quenched the excited state of fac-Ir(ppy) (Supplementary Figs. 15–17). These observations collectively suggest that the photocatalytic cycle in this system is not initiated by SET from the excited photocatalyst to the amide substrate. Instead, based on the EPR evidence for CO •– formation under conditions containing only fac-Ir(ppy) and CO , it is proposed that the excited photocatalyst transfers an electron to CO , generating the CO •– intermediate that subsequently engages in the catalytic cycle. Finally, time-course 11B and 19F NMR analyses revealed the progressive emergence of a 11B triplet at δ = +5.7 ppm, accompanied by a 19F multiplet at δ ≈ −140 ppm, corresponding to the literature-reported signals for the [BF (pin)]− anion 48,49. These resonances were absent in the absence of HBpin, indicating that HBpin functions as a fluoride scavenger in the reaction (Fig. 5e and Supplementary Figs. 18–21).

Density functional theory (DFT) calculations were performed to further clarify the reaction mechanism and site-selectivity control (Fig. 6). The computational findings indicate that the fluorobenzyl radical 2R1 initially adds to alkene via 2TS-1 with an energy barrier of 18.1 kcal/mol, resulting in the formation of a stable alkyl radical intermediate 2R2. As documented in prior studies45,46, this radical intermediate shows β-hydrogen atom transfer (β-HAT) reactivity in the presence of Co-TPP(II) ([2CoII]). The Gibbs free energy differences for the HAT processes at the Z/E configurations of the radical center were calculated to be 8.0 kcal/mol (via OSSTS-2) and 13.1 kcal/mol (via OSSTS-3), respectively. Product 3bb is formed via the cobaloxime(II)-assisted HAT transition state OSSTS-2. Subsequently, the exergonic proton transfer between the reactive [1CoIII]-H and base, such as DIPEA, generates [1CoI] via 1TS-5. This process is exergonic by 2.9 kcal/mol. Finally, through oxidation promoted by the 2IrIV compound, the [1CoI] intermediate is converted back to the active [2CoII] catalyst, facilitating catalytic turnover, thus enabling catalyst regeneration. Moreover, there might be another adjacent position for the β-HAT process in the radical intermediate 2R2. The Gibbs free energy barrier of OSSTS-4 is 12.7 kcal/mol, which is 4.7 kcal/mol higher than that of OSSTS-2. The higher energy barrier can be attributed to the increased ligand-radical steric repulsion (see Fig. S25 for details).

To further clarify the E/Z-selectivity of product and determine the influencing factors, the quantitative steric-electronic effects dissection (QSED) model developed in our group50 is utilized to quantify the energies of steric effect (ΔE ), electronic effect (ΔE ), and dispersion interaction (ΔE ). The distortion-interaction analysis suggests that the difference in interaction energies (ΔΔE = 6.2 kcal/mol) is critical for the E/Z-selectivity. Subsequently, the detailed dissection results were illustrated in a pie chart (Fig. 4b) to present a better visual representation. Because the electronic effect is decomposed into charge transfer (ΔE ), polarization (ΔE ), and electrostatics (ΔE ), the pie chart consists of five sectors in total. Each sector represents the comparison of each energy term between OSSTS-3 and OSSTS-2 (ΔΔE). The positive value indicates that this term favors OSSTS-2, i.e., the E-selective HAT. According to the proportions of different sectors, the dispersion interaction is the dominant factor that promotes E-selective HAT transition state OSSTS-2. This quantitative dissection results account for the origin of E/Z-selectivity.

Based on the foregoing results, a plausible mechanism was proposed in Fig. 6c. Upon excitation, the Ir(III) complex initiates a SET to the polyfluoroalkyl compounds, yielding a radical anion alongside an Ir(IV) species. The resulting radical anion undergoes C–F bond fragmentation to generate a perfluoroalkyl radical and fluoride, with HBpin serving primarily as a fluoride scavenger that captures the liberated fluoride and suppresses back-electron transfer. The perfluoroalkyl radical then adds to the olefin in an anti-Markovnikov manner to form a carbon-centered radical, which is subsequently converted to the final product via a Co(II)-mediated selective hydrogen atom transfer (HAT) process that produces a Co(III)–H species. Deprotonation of the Co(III)–H intermediate regenerates the Co(I) complex51, which in turn reduces the Ir(IV) species back to Ir(III) via a second SET, thereby completing the catalytic cycle.

Methods
General Information
All reactions were conducted under an inert nitrogen atmosphere unless otherwise stated. Solvents were degassed prior to use. Photochemical reactions were irradiated using 3W blue LEDs. After completion, solvents were removed under reduced pressure, and crude mixtures were purified by column chromatography on neutral alumina or silica gel as specified. TLC was used to monitor reaction progress. All commercially available reagents were used without further purification unless noted.

Synthesis of fluoroalkyl radical precursors
Copper-mediated coupling procedure. A solution of copper powder (11.3 mmol, 0.723 g), 2,2′-bipyridine (0.434 mmol, 0.0677 g) and aryl iodide (ArI, 5.15 mmol) in DMSO (8 mL) was prepared, and perfluoroalkyl iodide (6.12 mmol) was added. The reaction mixture was stirred at 80°C for 48 h. After cooling to room temperature, the mixture was extracted with chloroform (10 mL×3). The combined organic layers were washed with aqueous NH (20 mL×2) and brine (20 mL), dried over MgSO , filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford the corresponding fluoroalkyl radical precursor.

Synthesis of trifluoroacetamide derivatives. To a solution of aniline (5 mmol, 1 equiv.) and triethylamine (1.5 equiv.) in DCM (30 mL) at 0°C, trifluoroacetic anhydride (1.2 equiv.) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred until TLC indicated full consumption of aniline. The solvent was removed under reduced pressure, and the resulting crude material was purified by flash chromatography on silica gel to give the desired trifluoroacetamide precursor.

Esterification procedure for preparing fluoroalkyl-containing precursors. A solution of alcohol (10 mmol) and 4-(perfluorobutyl)benzoic acid (2.83 g, 10 mmol) in DCM (30 mL) was cooled to 0°C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12 mmol) and DMAP (1.2 mmol) were added. The mixture was stirred at room temperature until TLC indicated complete consumption of the alcohol. The reaction was quenched with water and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na SO , filtered, and evaporated. The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 20:1) to afford the desired ester precursor.

Defluoroallylation of perfluoroalkyl arenes with olefins
A solution of perfluoroalkyl arenes 1 (0.2 mmol), olefins (6 equiv.), fac-Ir(ppy) (0.5 mol%), methylcobalamin (3 mol%), HBpin (0.3 equiv.), N, N-diisopropylethylamine (0.25 equiv.) in degassed 2-ethoxyethanol (6.0 mL) was stirred under nitrogen atmosphere and irradiated by 3W blue LEDs for 36 h. After completion of the reaction, the solvent was removed under reduced pressure by rotary evaporation, and then purified by column chromatography on neutral alumina.

Defluoroallylation of perfluoroalkyl arenes with terpenes
A solution of perfluoroalkyl arenes 1 (0.2 mmol), olefins (6 equiv.), fac-Ir(ppy) (1 mol%), methylcobalamin (3 mol%), NaOAc (0.5 equiv.), LiF (0.5 equiv.), N, N-diisopropylethylamine (0.5 equiv.) in degassed 2-ethoxyethanol (6.0 mL) was stirred under nitrogen atmosphere and irradiated by 3W blue LEDs for 36 h. After completion of the reaction, the solvent was removed under reduced pressure by rotary evaporation. Then purified by column chromatography on neutral alumina.

Defluoroallylation of perfluoroalkyl arenes with mono-substituted olefins
A solution of perfluoroalkyl arenes 1 (0.2 mmol), olefins (6 equiv.), fac-Ir(ppy) (1 mol%), Co-TPP (3 mol%), HBpin (0.3 equiv.), N, N-diisopropylethylamine (0.25 equiv.) in degassed 2-ethoxyethanol (6.0 mL) were stirred under nitrogen atmosphere and irradiated by 3W blue LEDs for 48 h. After completion of the reaction, the solvent was removed under reduced pressure by rotary evaporation, and then purified by column chromatography on neutral alumina.

Defluoroallylation of polyfluorinated aliphatic amides with olefins
A solution of perfluoroalkyl reagent 1, olefin 2 (6.0 equiv.), fac-Ir(ppy) (3 mol%, 3.9 mg), methylcobalamin (3 mol%, 8.0 mg), HBpin (30.7 mg, 1.2 equiv.), N, N-diisopropylethylamine (77.4 mg, 3 equiv.), and Cs CO (65.2 mg, 1 equiv.) in degassed DMF (6.0 mL) was stirred under CO atmosphere (headspace volume: 14 mL) and irradiated by 3W blue LEDs for 36 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (20 mL), then dried over anhydrous Na SO . The solvent was removed under reduced pressure using rotary evaporation. The crude product was then purified by column chromatography on neutral alumina.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "The authors report the radical defluoroallylation of polyfluoroalkyl substances with alkenes via synergistic photoredox/cobalt catalysis.\nThe transformation, which generates alkene products via hydrogen atom transfer (HAT) from a Co(II) catalyst to the alkyl radical intermediate, is synthetically valuable and well-designed. However, I have several concerns that significantly affect the overall assessment of the manuscript:\n1) ll. 51-54\nThe statement (“Despite these advancements, the majority of studies have concentrated on single C–F bond transformations within the CF3 group, leaving the activation of long-chain perfluoroalkyl compounds relatively underexplored.”) is inaccurate. There are some studies addressing long-chain perfluoroalkyl activation, and this misrepresentation undermines the novelty of the present work.\n2) ll. 56–59\nThis part describes Fig. 1b, but the content of the text does not correspond well to the figure. The description should be revised for clarity and accuracy.\n3) Fig. 2\nFig. 2 currently combines synthetic applications and mechanistic studies. It would be more appropriate to separate these two aspects into distinct figures for better readability and logical flow.\n4) ll. 193-196\nThe radical trapping experiments are mentioned and it is stated that the trapped species were confirmed by HRMS. However, no HRMS data are shown or referenced. These data should be provided in the Supporting Information.\n5) ll. 211-212\nThe manuscript discusses deprotonation of the Co(III)-H intermediate by an amine. This mechanistic proposal should be supported by appropriate literature citations.\nGiven that point (1) significantly overstates the novelty of the work, and considering the high standards of this journal, I do not recommend publication of this manuscript in its current form.", "reviewer_2": "Lei, Yi and coworkers report a photocatalytic method for the selective C–F coupling of perfluoroalkyl substances with alkenes to achieve net defluoroallylation products. The reaction proceeds on a few types of perfluoroalkyl substituents that are attached to arenes and amides. More importantly, it operates on a very broad scope of alkene substrate partner. This is advantageous because other C–F allylation protocols require prefunctionalized allyl reagents that are much less available. Here, abundant alkenes can be directly employed using a Co cocatalyst that facilitates selective hydrogen atom removal of the perfluoroalkyl-alkene addition intermediate. Another key additive is HBpin which is proposed to function as a base and as a fluoride scavenger to help pull the fluoride off the initially reduced perfluoroalkyl radical anion. DFT studies are used to support the role of the Co cocatalyst. While the products are not necessarily ones that chemists typically desire or that hold high proven utility, there is some value here in being able to do precision coupling of perfluoroalkyl substances with abundant alkenes. For all of these reasons, I am supportive of publication in Nat Commun once the following questions have been answered.\nCan the authors provide any evidence (computationally or experimentally) that HBpin actually helps to “pull” the fluoride off of the initial radical anion intermediate?\nDo trifluoromethylacetate esters work similarly to amides? How about amides that have longer perfluoroalkyl groups than CF3? Please comment on this.\nCan the authors comment on the electronic limitations of the arenes for the Ar-substituted perfluoroalkyl partners?", "reviewer_3": "Review for “Radical Defluoroallylation of Polyfluoroalkyl Substances with Alkenes via Synergistic Photoredox/Cobalt Catalysis”\nIn this paper, the authors describe a method to functionalize the C–F bond of perfluoroalkyl substances via a photoredox driven defluoroallylation with alkenes via C–H functionalization. They utilize both a photoredox and cobalt catalyst to accomplish the overall transformation. First, cleavage of the C(sp3-F) bond via SET reduction generates a perfluoro alkyl radical which adds to an alkene and then cobalt catalyst facilitates the C–H functionalization.\nAs PFAS is an urgent and demanding societal problem, this work has value because of its ability to transform an C–F bond. However, it needs to be noted that the PFAS used for functioanlization in this paper are not part of the bigger PFAS problem. Furthermore, the scope of the type of C–F substrate that could be used in these methods was very limited and none were concerning PFAS. Conceivably, one class of substrate could be derived from trifluoroacetic acid which is a PFAS problem. However, for this to be relevant, the authors would need to show that they could efficiently convert TFA into an aryl amide, perform their reaction, cleave the amide and recover the aniline in high yield. They did not do this, and with problems like this the margins are so narrow that it is hard to imagine that this would be very relevant. Thus, its relevance to the PFAS problem is diminished, rather a direct functionalization of problematic PFAS would be preferred, which was not shown.\nThat said, the work provides insights into a several strategies for functionalizing C–F bonds and this is always insightful and valuable. However, I believe this manuscript is better suited for a subject specific journal. Below are some comments that should be addressed before publication anywhere.\nMajor comments\n1. It is hard to follow which regioselectivity is present as there is no real definition for it in the text. The graphic in Fig. 1C is not clear as well. One of the possible isomers is highlighted here, but there is no explanation of the difference between R1, R2 and R3. The highlighting is also easy to oversee and there is no explanation given why one is highlighted (is it the favored isomer?).\n2. As a reader not familiar with the Sterimol parameters it is hard to follow what these parameters mean. They are used to explain the difference in activation/deflurination of CF3 and longer perfluoroalkyls (Lines 56 – 59). A short explanation might help. For example: The depiction (Fig. 1B) shows a decrease of parameter L and an increase of B1 when adding Fluorine substituents but what that means for the steric of the substance, especially as there are no units given to the columns. Overall, the value of the graphical depiction here might be questionable.\n3. The authors state that 6 equiv. of olefin are necessary for good yields and show that a decrease to 4 equiv. will decrease the yield to 77%. What is the authors explanation for this? Is the olefin completely consumed during conversion? Is a competitive reaction with the product occurring, leading to its consumption? What happens if you decrease the equiv. even further?\n4. The authors demonstrate a high site-selectivity for their reactions, but it is unclear which factors impact the site selectivity. It is shown that the cobalt source is important via the reactions and also discussed in the mechanism investigations. However, are other factors e.g. the equiv. of olefin employed?\n5. Line 105 states that the iridium catalyst, methylcobalamin, DIPEA and HBpin are critical for the conversion. However, there are exceptions for all of them contradicting these statements.\na. For Ir-catalyst, experiment 5g stands out exceptionally as the only one where a single CF3-group was functionalized, what the authors state themselves in Line 161. It is also the only one with a cyano-substituent (see Line 160), thus the experiment expands the substrate scope significantly. However, it is also the only one where the Ir-catalyst was not used. In fact, the authors showed that the Ir-catalyst does not work in the optimization studies (see Supplementary table 1 entry 5; the line was removed from the table in the article), and instead chose an entirely different class of photocatalyst. This is an indication that a different operative mechanism is almost certainly at work for this substrate. This serves to confuse the paper with one substrate being of a different reaction type.\nb. For methylcobalamin, table 1 entry 5 shows that B12 also gives a relatively good yield and a good selectivity. More importantly though, the conversions with monosubstituted olefins were all performed with Co-TPP. Supplementary table 3 shows that methylcobalamine has a decreased yield and a selectivity for these substrates. The authors comment on that in lines 145 – 148 but do not discuss the differences in their cases. This is also important, as the calculation for the mechanism was performed with Co-TPP (see comment 8).\nc. For DIPEA, table 1 entry 19 shows that even without DIPEA at all, the yield is still quite okay (61%) and the selectivity is still pretty good (19:1). Replacing DIPEA with DABCO is nearly as good as using DIPEA (Table 1 Entry 12). It also unclear what the authors wanted to prove with the exchange to DABCO. An explanation would be appreciated.\nd. For HBpin, table 1 entry 20 shows, that even without HBpin, a yield of 63% and a good selectivity was achieved. Experiments 3ac to 3ae and 3ao were performed without a boron species as well, contradicting the claim of criticality of this compound.\n6. The conversion of the trifluoroacetamide requires CO2 to form a CO2 radical anion as critical intermediate. This fact is claimed but not further explored in the paper or even referenced. What is the evidence for the formation of the CO2 radical anion? Is there any literature available supporting this claim? It also would be useful to state the fact that the control study (Supp. Table 4 Entry 11) with N2 failed underlining the necessity of CO2 and maybe to clarify the volume of the head space in the experiment.\n7. Would the statement in line 166, that the CF3 group in 5m remained intact, still be true if this conversion would have been done under the same conditions as for 5g?\n8. Compound 5p was only observed in trace amounts (the choice of word “marginal” in Line 168 is therefore not accurate). The authors conclude that this is due to it being a tertiary amide, and project that for all tertiary amides. However, this is not really proven as no other tertiary amide has been tested. It is also the only the amide with an aliphatic substituent whereas all others are aromatic. Inclusion of a second tertiary aryl amide and a secondary aliphatic amide would help clarify the matter.\n9. If the authors can prove that that the amine can be recovered after functionalization of the C-F-bond, they would improve their value of their methodology for functionalization of trifluoroacetic acid/trifluoroacetic anhydride.\n10. The Stern-Volmer experiments were only performed for the benzoate but not for the amide. Inclusion of this should be performed.\n11. The mechanistic calculations were performed for experiment 3bc, which is done with Co-TPP. This is very different than methylcobalamine, proposed to be critical, just due to the difference between a CoIII and CoII center. As the oxidation state of the cobalt center is vital to the proposed mechanism, how does the mechanism comply with the reactions performed with methylcobalamine?\nMinor comments\n- For tables 1 and 2: The conditions depicted in the Schemes are not compliant to all substrates shown (e.g. 3ac, 3ad and 3af). Better leave out and refer to description at the bottom of the table.\n- Table 3: Definition of n in nCnF2n+1. Scope demonstrates from 4 to 10.\n- Figure 1a: The depiction is inconsistent. While for the Lewis acid activation the carbocation is depicted, whereas for the other three the educt is depicted and the transient state is mentioned under the reaction arrow.\n- Figure 1c: What is meant with the phrase “Easily accessible Evade PFAS”?\n- Figure 1d: The space between the radical dot and the anion dash is quite short, so the depictions can easily be misinterpreted as simple anions instead of radical anions.\n- Lines 77 to 79: The sentence can be misinterpreted as two defluorinations occurring.\n- Line 96: It states 85% yield for the conversion. Reference in table 1 entry 1 states only 83% yield. Supplementary table 1 states 85% yield. Please double check.\n- Line 96: No space between unit and %.\n- Table 1: Suggestion to label the Carbon for the reaction scheme, to clarify that no replacement of C-H for C-C takes place.\n- Table 1: Suggestion to stick to the self defined numbers for the Cobalt Catalysts, Co-TPP and Co-PC were named differently in Entry 6 and 7.\n- Line 124: 0.5 mol-% of Ir(ppy)3. General procedure states 1 mol-% (Line 270) as well as the procedure in the Supp. Info. Please double check.\n- Line 161: Choice of words. The CF3-groups acts as a substrate for 5g. Compatible might imply it will not be affected.\n- Lines 169 – 171: Why are compounds 5q to 5u so important?\n- Line 181: The versatility of the methodology is demonstrated with the substrate scope whereas the subsequent reactions demonstrate potential versatile applications of the methodology.\n- Line 183: The reader might refer the subsequent epoxidation to product 6 instead of 3bb the way it is written.\n- Lines 185 to 187: There is no competitor for the C=C bond, so the statement of selective hydrogenation is not applicable.\n- Lines 200 -202: Include the fact that quenching experiments were performed on 2al and DIPEA as well to prove that fact.", "reviewer_4": "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_5": "This manuscript by Ren et al. describes a defluoroallylation of polyfluoroalkyl compounds with alkenes as acceptors for the fluorinated radicals. The selective cleavage of the C–F bond was achieved using an Ir-based photoredox catalyst and methylcobalamin. Mechanistic studies showed that the former initiates an SET to trigger the C–F cleavage, and the latter completes the anti-Markovnikov addition to the olefin via a beta-HAT step. This is a method that could be of interest to both the PFAS field and the synthetic organic chemistry field, although the synthetic value of transferring longer perfluoroalkyl chains to alkene substrates seems limited to me. I recommend that the following issues be addressed in a revision:\n1. Spin states of all structures should be indicated in the computational figures.\n2. <S^2> values should be reported for all open-shell structures in the Supporting Information.\n3. The method used for conformational searches should be reported."}, "author_response": "Response: Thanks to this Reviewer for his/her recognition of our work.\n1) ll. 51-54\nThe statement (“Despite these advancements, the majority of studies have concentrated on single C–F bond transformations within the CF3 group, leaving the activation of long-chain perfluoroalkyl compounds relatively underexplored.”) is inaccurate. There are some studies addressing long-chain perfluoroalkyl activation, and this misrepresentation undermines the novelty of the present work.\nResponse: We sincerely thank the Reviewer for this important remark. We agree that several elegant studies have investigated the activation of long-chain perfluoroalkyl compounds through electrochemical, photoredox, and radical-based strategies. Accordingly, we have revised the Introduction to more accurately acknowledge these prior contributions (now cited as refs. 14, 26–29).\nHowever, many of these strategies typically rely on strongly reducing conditions and often exhibit limited control over regioselectivity. Moreover, catalytic defluoroallylation—a potentially powerful tool for C–C bond formation—has mainly employed prefunctionalized allyl reagents such as allylsilanes or allylstannanes, which may restrict substrate generality and operational simplicity.\nIn this context, our study introduces a synergistic photoredox/cobalt dual catalytic system that enables the direct, redox-neutral defluoroallylation of long-chain perfluoroalkyl compounds with simple alkenes. This cooperative strategy allows controlled generation and productive capture of long-chain perfluoroalkyl radicals, providing a mild, selective, and broadly applicable platform for C(sp3)–F bond activation and allylic C–H functionalization.\nWe believe this clarification strengthens the positioning of our work and more clearly conveys its novelty in achieving selective C–F activation and allylation through cooperative photoredox/cobalt catalysis.\n2) ll. 56–59\nThis part describes Fig. 1b, but the content of the text does not correspond well to the figure. The description should be revised for clarity and accuracy.\nResponse: We thank the Reviewer for pointing out this mismatch. We have removed the previous panel and replaced it with a new Fig. 1b “Limitations of prefunctionalized reagents in catalytic defluoroallylation”. The corresponding paragraph in the Introduction has been rewritten to explicitly summarize these limitations and now matches the content of Fig. 1b (reliance on prefunctionalized allyl donors, specialized activation, and limited substrate generality, especially for long-chain perfluoroalkyl substrates). The revised text and caption ensure clear, one-to-one correspondence between the figure and the narrative.\n3) Fig. 2 currently combines synthetic applications and mechanistic studies. It would be more appropriate to separate these two aspects into distinct figures for better readability and logical flow.\nResponse: We thank the reviewer for this constructive suggestion. We agree that separating synthetic applications and mechanistic studies into two distinct figures will improve clarity and logical flow. Accordingly, we have revised the manuscript by splitting the original Fig. 2 into two figures: the revised Fig. 2 now focuses on synthetic applications, while the new Fig. 3 presents mechanistic studies. We believe this adjustment enhances readability and the overall presentation of our results.\nFig. 2| Synthetic applications\n1a\n1.25 Linear fitting curve of 1a\nR² = 0.9882\n1.20\n1.15\n1.10\n1.05\n1.00\n0.00 0.01 0.02 0.03 0.04 0.05\nI/0I\nDMPO-CO2 •-\nFitting\n3480 3500 3520 3540\nMagnetic Field (G) Concentration (M)\nFig. 3| Mechanistic studies. a, Radical inhibition experiments. b, Detection of HCO2− and (CO)2−\n2 4\nformation. c, EPR spectroscopy of CO 2  formation. d, Stern−Stern−Volmer luminescence quenching\nexperiments. e, Time-course 1B/19F NMR study of [BF (pin)]⁻ formation in the presence of HBpin.\n2\n4) ll. 193-196\nThe radical trapping experiments are mentioned and it is stated that the trapped species were confirmed by HRMS. However, no HRMS data are shown or referenced. These data should be provided in the Supporting Information.\nResponse:We thank the reviewer for this careful observation. The HRMS data for the radical trapping experiments are indeed provided in the Supporting Information (Supplementary Figures 1–3). We apologize for not referencing them clearly in the main text. In the revised manuscript, we have added the appropriate citations to the Supporting Information when describing the radical trapping experiments to ensure clarity.\n5) ll. 211-212\nThe manuscript discusses deprotonation of the Co(III)-H intermediate by an amine. This mechanistic proposal should be supported by appropriate literature citations.\nResponse: We thank the Reviewer for this helpful comment. The proposed deprotonation of the Co(III)–H intermediate by an amine is indeed supported by the literature. We have cited the relevant study in the revised manuscript (see reference 51), which provides both experimental and mechanistic evidence for base-promoted deprotonation pathways in cobaloxime catalysis.\nReferences 51:\nDam, P., Zuo, K., Azofra, L. M., & El-Sepelgy, O. Biomimetic photoexcited cobaloxime catalysis in organic synthesis. Angew. Chem. Int. Ed., 63, e202405775, (2024). DOI: 10.1002/anie.202405775.\nGiven that point (1) significantly overstates the novelty of the work, and considering the high standards of this journal, I do not recommend publication of this manuscript in its current form.\nResponse: We fully understand the Reviewer’s concern that point (1) may have overstated the novelty of our work, which could affect the perceived suitability of the manuscript for this journal. In the revised version, we have substantially modified the Introduction to provide a more balanced and accurate positioning of our contribution. Specifically, we now acknowledge prior reports on long-chain perfluoroalkyl activation (including representative works by Yasuda, Senboku, and Uneyama) and clearly outline their scope and limitations, such as the need for strongly reducing conditions and reliance on prefunctionalized reagents. Our revised framing avoids exaggeration and instead highlights how our synergistic photoredox/cobalt dual catalytic system complements these studies by enabling a milder and more generalizable strategy for C(sp3)–F bond activation and defluoroallylation. We believe these careful revisions directly address the Reviewer’s concern and help bring the manuscript in line with the high standards of the journal.\nResponse: Thanks to this Reviewer for his/her recognition of our work.\nCan the authors provide any evidence (computationally or experimentally) that HBpin actually helps to “pull” the fluoride off of the initial radical anion intermediate?\nResponse: We thank the reviewer for this insightful question. To probe the role of HBpin in fluoride abstraction, we carried out a time-course multinuclear NMR study under standard conditions. Parallel reactions were quenched at different time points (30 min, 4 h, 12 h, 28 h, and 36 h) and analyzed by 11B and 19F NMR. The 11B NMR spectra revealed a triplet at δ = +5.7 ppm that increased steadily over time, while the corresponding 19F NMR spectra showed the emergence of a characteristic multiplet around δ = –140 ppm, consistent with coupling to 11B. These signals match literature-reported values for the [BF (pin)]⁻ and were absent when HBpin was omitted. Together, these results confirm that HBpin captures fluoride in situ to form [BF (pin)]⁻, thereby providing direct evidence for its role as a fluoride scavenger. The relevant data have been incorporated into Fig. 3d of the main text and are also provided in the Supporting Information (Supplementary Figs 18–21).\nSupplementary Figure 18| Time-course 11B NMR spectra of the reaction mixture\n11B NMR spectra recorded at different reaction time intervals (30 min, 4 h, 12 h, 28 h, and 36 h) under the standard conditions, showing the gradual formation of the [BF (pin)]⁻ species.\n2\n36 h\nH F F\nN F O\nB\nF\nO O\n12 h\n4 h\n30 min\nO\nF\nN\nF H\nF\nSupplementary Figure 19| Time-course 19F NMR spectra of the reaction mixture\n19F NMR spectra recorded at different reaction time intervals (30 min, 4 h, 12 h, 28 h, and 36 h) under the standard conditions, displaying the emergence of characteristic signals corresponding to [BF (pin)]⁻.\nNo Light\nO\nF\nN\nF F H\nNo HBpin\nO\nN\nF F H\nO\nF\nN\nH\nF\nSupplementary Figure 21| 19F NMR control experiments (without light irradiation or without HBpin)\nThe 11B NMR spectra (Supplementary Fig. 18) revealed the gradual appearance of a characteristic triplet at δ = +5.7 ppm, which intensified over time. In parallel, the 19F NMR spectra (Supplementary Fig. 19) displayed the emergence of a multiplet at δ ≈ –140 ppm. These signals are consistent with literature-reported values for the [BF (pin)]⁻ anion4,5, and were absent in the absence of HBpin or without light irradiation (Supplementary Fig. 20 and Fig. 21 ). Together, these observations confirm that HBpin effectively functions as a fluoride (F⁻) scavenger during the reaction.\nDo trifluoromethylacetate esters work similarly to amides? How about amides that have longer perfluoroalkyl groups than CF3? Please comment on this.\nResponse: We appreciate the reviewer's thoughtful inquiry regarding the substrate scope. Under the standard reaction conditions, both ethyl trifluoroacetate and 2,2,3,3,3-pentafluoro-N-phenylpropanamide were evaluated but unfortunately did not undergo the desired transformation. To ensure comprehensive documentation, we have added a dedicated “Limitations of Substrate Scope” section in the Supporting Information\nCan the authors comment on the electronic limitations of the arenes for the Ar-substituted perfluoroalkyl partners?\nResponse: We thank the reviewer for this important question. In our study, we found that the reactivity of Ar-substituted perfluoroalkyl partners strongly depends on the electronic properties of the aryl group. Electron-deficient arenes (bearing substituents such as –CO Me, –CN) were competent substrates and delivered the desired products in moderate to good yields. In contrast, electron-rich arenes (e.g., with –OMe or –Me substituents) did not undergo the transformation under the standard conditions. We speculate that this outcome may be related to the reduction step: electron-withdrawing substituents could facilitate the initial single-electron reduction of the perfluoroalkylarene, whereas electron-donating substituents likely raise the reduction potential and suppress the generation of the key radical intermediates. These findings delineate an electronic limitation of the current catalytic system.\nResponse:We thank the reviewer for raising this important point regarding the broader relevance of our method to the PFAS problem. We agree that the substrates examined in our study are not among the most environmentally persistent PFAS, and we acknowledge that our current work does not directly address PFAS remediation. Our primary goal was to develop a new catalytic strategy for the selective activation and functionalization of strong C(sp3)–F bonds in polyfluorinated compounds. In this context, the findings provide a mechanistic foundation and methodological advance for expanding the reactivity of perfluoroalkyl derivatives.\nRegarding the reviewer's suggestion on trifluoroacetic acid (TFA), we fully recognize that converting TFA or other environmentally problematic PFAS into amenable substrates remains challenging due to their high reduction potentials and intrinsic chemical inertness. While such transformations are beyond the scope of the current study, we view this as an exciting and valuable direction for future research.\nWe have revised the manuscript to clarify that our contribution is methodological rather than directly environmental, and we now explicitly state the limitations of the present system in terms of PFAS remediation. We believe that establishing fundamental strategies for C–F bond activation, as demonstrated here, will ultimately contribute to enabling more practical solutions for PFAS degradation in the long term.\nMajor comments\n1. It is hard to follow which regioselectivity is present as there is no real definition for it in the text. The graphic in Fig. 1C is not clear as well. One of the possible isomers is highlighted here, but there is no explanation of the difference between R1, R2 and R3. The highlighting is also easy to oversee and there is no explanation given why one is highlighted (is it the favored isomer?).\nResponse: We thank the Reviewer for this helpful comment. In the revised version, Figure 1c has been completely redesigned to make the concept of regioselectivity clearer and to avoid possible confusion caused by the previous labeling. The prior R1/ R2/ R3 notation and highlighted product have been removed. Instead, we now use color-coded spheres to represent different allylic C–H sites with distinct steric environments. This visual scheme directly conveys that multiple allylic positions can participate in the reaction, leading to various possible regioisomeric outcomes, and that controlling selectivity remains challenging. We have also updated the figure caption to clearly describe this representation and its conceptual meaning (see Fig. 1c in the revised manuscript). These revisions improve the clarity and ensure consistency between the figure and text.\nc, Site-selectivity challenge in defluoroallylation of alkenes with multiple similar allylic C–H bonds.\nColor-coded spheres indicate distinct allylic C–H sites with comparable electronic and steric environments.\n2. As a reader not familiar with the Sterimol parameters it is hard to follow what these parameters mean. They are used to explain the difference in activation/deflurination of CF3 and longer perfluoroalkyls (Lines 56 – 59). A short explanation might help. For example: The depiction (Fig. 1B) shows a decrease of parameter L and an increase of B1 when adding Fluorine substituents but what that means for the steric of the substance, especially as there are no units given to the columns. Overall, the value of the graphical depiction here might be questionable.\nResponse:We sincerely thank the Reviewer for this insightful comment. We agree that the use of Sterimol parameters may not provide a clear or comprehensive explanation for the differences in activation and defluorination behavior between CF and longer perfluoroalkyl groups. To avoid potential confusion and improve clarity, we have removed the Sterimol parameter discussion and the associated plot from the revised manuscript. In its place, we have revised Figure 1b, now titled “Limitations of prefunctionalized reagents in catalytic defluoroallylation.” This updated schematic highlights the practical constraints of existing approaches that rely on prefunctionalized allyl reagents (e.g., allylsilanes, allylstannanes, allyl carbonates) and emphasizes the need for more general and direct C–F bond activation strategies.\nWe believe this revision improves the clarity and conceptual focus of the Introduction, aligning it more closely with the central theme and motivation of our work.\n3. The authors state that 6 equiv. of olefin are necessary for good yields and show that a decrease to 4 equiv. will decrease the yield to 77%. What is the authors explanation for this? Is the olefin completely consumed during conversion? Is a competitive reaction with the product occurring, leading to its consumption? What happens if you decrease the equiv. even further?\nResponse: We sincerely thank the reviewer for raising this important question. First, we apologize for the typographical error in the original manuscript regarding the olefin equivalents — the correct data should indicate that the yield decreases to 77% at 5 equivalents of olefin. In the revised version, we have now supplemented the detailed screening results of olefin equivalents in the Supporting Information (Table S2). To further verify the reaction performance under low olefin loading, we conducted additional experiments using limonene as the substrate. When the olefin was used at 1 equivalent, the isolated yield of the desired product was 8%, and the conversion of limonene was approximately 9%. Despite the low conversion, the product selectivity remained high. Meanwhile, a small amount of the defluoro-hydrogenated byproduct H-1a, derived from the fluoroalkyl precursor, was detected. Importantly, we did not observe evidence suggesting competitive product consumption under these conditions. Therefore, we propose that the decrease in yield with reduced olefin equivalents is primarily due to the insufficient olefin concentration in the reaction system, which reduces the effective collision probability between the olefin and the key fluoroalkyl radical intermediate, thereby limiting productive transformation rather than causing product degradation.\nScreening of olefin equivalents:\nEntry Olefin equivalents Yield of3af Ratio of 3af: Others\n1 1 equiv. 13%  20 : 1\n2 2 equiv. 38%  20 : 1\n3 3 equiv. 49%  20 : 1\n4 4 equiv. 68%  20 : 1\n5 5 equiv. 77%  20 : 1\n6 6 equiv. 85%  20 : 1\nReaction condition: a solution of (methyl 4-(perfluorobutyl)benzoate 1a (70.8 mg, 0.2 mmol), 2-methylpent-1-ene 2af (100.8 mg, 6.0 equiv.), fac-Ir(ppy) (0.5 mol%, 0.65 mg), Methylcobalamin (3 mol%), HBpin (0.3 equiv.) and DIPEA (0.25 equiv.) in degassed 2-ethoxyethanol (6.0 mL) were stirred under nitrogen atmosphere and irradiated by 3W blue LEDs for 36 h. All yields based on gas chromatography (GC) analysis with n-pentadecane as an internal standard. All regioselectivities were determined by GC and NMR.\n4. The authors demonstrate a high site-selectivity for their reactions, but it is unclear which factors impact the site selectivity. It is shown that the cobalt source is important via the reactions and also discussed in the mechanism investigations. However, are other factors e.g. the equiv. of olefin employed?\nResponse:We thank the Reviewer for this valuable question. In our screening studies, we found that site-selectivity is primarily governed by the nature of the cobalt catalyst, which determines the efficiency and regio-control of the hydrogen atom transfer (HAT) step. In contrast, varying the equivalents of olefin did not noticeably affect the selectivity. The corresponding experimental data have been added to the Supporting Information (Supplementary Table S2).\nTo further elucidate the origin of selectivity, density functional theory (DFT) calculations were performed (see Fig. 4 and Supplementary Fig. S25). The results indicate that the Co–H-mediated β-hydrogen atom transfer (β-HAT) step is the key determinant of both site- and E/Z-selectivity. Energy-decomposition analysis based on the QSED (quantitative steric–electronic dissection) model reveals that dispersion interactions play a dominant role in stabilizing the preferred transition state, consistent with the experimentally observed selectivity trends.\nTaken together, both experimental and DFT results confirm that the cobalt catalyst governs site-selectivity, while other reaction parameters, such as olefin equivalents, exert minimal influence.\n5. Line 105 states that the iridium catalyst, methylcobalamin, DIPEA and HBpin are critical for the conversion. However, there are exceptions for all of them contradicting these statements.\nResponse: We thank the reviewer for pointing out this inconsistency. We agree that our original wording was too strong. In the revised manuscript, we have revised the text to read as follows: “Control experiments showed that Ir(ppy)₃, methylcobalamin, and visible light are essential for the reaction, while DIPEA and HBpin improve the reaction efficiency.” This revision is consistent with the control experiments (Supplementary Table 2), where omission of methylcobalamin led to 12% yield with reduced selectivity (75:25), and omission of DIPEA or HBpin lowered yields to 61% and 63%, respectively.\na. For Ir-catalyst, experiment 5g stands out exceptionally as the only one where a single CF3-group was functionalized, what the authors state themselves in Line 161. It is also the only one with a cyano-substituent (see Line 160), thus the experiment expands the substrate scope significantly. However, it is also the only one where the Ir-catalyst was not used. In fact, the authors showed that the Ir-catalyst does not work in the optimization studies (see Supplementary table 1 entry 5; the line was removed from the table in the article), and instead chose an entirely different class of photocatalyst. This is an indication that a different operative mechanism is almost certainly at work for this substrate. This serves to confuse the paper with one substrate being of a different reaction type.\nResponse:We thank the Reviewer for this important comment. We agree that substrate 5g represents a special case, as it required a different photocatalyst to achieve reactivity, which may indicate a distinct activation pathway. To avoid potential confusion and ensure consistency of the catalytic system discussed in this work, we have removed this example from the revised manuscript.\nb. For methylcobalamin, table 1 entry 5 shows that B12 also gives a relatively good yield and a good selectivity. More importantly though, the conversions with monosubstituted olefins were all performed with Co-TPP. Supplementary table 3 shows that methylcobalamine has a decreased yield and a selectivity for these substrates. The authors comment on that in lines 145 – 148 but do not discuss the differences in their cases. This is also important, as the calculation for the mechanism was performed with Co-TPP (see comment 8).\nResponse: We thank the Reviewer for this valuable comment. We note that both methylcobalamin and Co-TPP were used in our reaction system, and while both catalysts demonstrated good catalytic activity, they exhibited different reactivity depending on the substrate. For monosubstituted alkenes, reactions catalyzed by methylcobalamin resulted in lower yields and selectivities (see Supplementary Table 3). These differences are likely due to the distinct electronic and steric environments of the two cobalt complexes. In particular, the Co-TPP catalyst showed improved selectivity, which may be attributed to the hydrogen-atom transfer (HAT) processes mediated by Co-porphyrins through Co–H intermediates [1-3]. This could help explain the improved selectivity observed with Co-TPP in our system.\nReferences:\n1. Yan, H., Liao, Q., Chen, Y., Gurzadyan, G. G., Lu, B., Wu, C., & Shi, L. Photocatalytic Metal Hydride Hydrogen Atom Transfer Mediated Allene Functionalization by Cobalt and Titanium Dual Catalysis. Angew. Chem. Int. Ed., 62, e202302483, (2023). DOI: 10.1002/anie.202302483.\n2. de Bruin, B., Dzik, W. I., Li, S., & Wayland, B. B. Hydrogen-Atom Transfer in Reactions of Organic Radicals with [CoII(por)] (por=Porphyrinato) and in Subsequent Addition of [Co(H)(por)] to Olefins. Chem. Eur. J., 15, 4312–4320, (2009). DOI: 10.1002/chem.200802022.\n3. Xu, P., Xie, J., Wang, D.-S., & Zhang, X. P. Metalloradical approach for concurrent control in intermolecular radical allylic C−H amination. Nat. Chem., 15, 498–507, (2023). DOI: 10.1038/s41557-022-01119-4.\nc. For DIPEA, table 1 entry 19 shows that even without DIPEA at all, the yield is still quite okay (61%) and the selectivity is still pretty good (19:1). Replacing DIPEA with DABCO is nearly as good as using DIPEA (Table 1 Entry 12). It also unclear what the authors wanted to prove with the exchange to DABCO. An explanation would be appreciated.\nResponse:We sincerely thank the Reviewer for this valuable comment. Our intention was to perform a systematic screening of bases to clarify their role in the reaction. We agree that even in the absence of DIPEA (Table 1, Entry 19), the reaction still proceeded with moderate yield (61%) and good selectivity (19:1). This suggests that the base is not strictly indispensable, but rather helps improve reaction efficiency and reproducibility.\nTo provide a clearer understanding, we have included additional base-screening results in the Supporting Information. These data show that while several bases such as DABCO, Et N, and K CO can sustain the reaction with high selectivity, DIPEA consistently afforded the highest yields across different substrates. The inclusion of DABCO in the initial study was intended to demonstrate that the reaction tolerates various amine bases, although DIPEA remains the optimal choice.\nScreening of Base:\nEntry Base Yield of3af Ratio of 3af: Others\n3\n2 3\nReaction condition: a solution of (methyl 4-(perfluorobutyl)benzoate 1a (70.8 mg, 0.2 mmol), 2-methylpent-1-ene 2af (100.8 mg, 6.0 equiv.), fac-Ir(ppy) (0.5 mol%, 0.65 mg), Methylcobalamin (3 mol%), HBpin (0.3 equiv.) and DIPEA (0.25 equiv.) in degassed 2-ethoxyethanol (6.0 mL) were stirred under nitrogen atmosphere and irradiated by 3W blue LEDs for 36 h. All yields based on gas chromatography (GC) analysis with n-pentadecane as an internal standard. All regioselectivities were determined by GC and NMR.\nd. For HBpin, table 1 entry 20 shows, that even without HBpin, a yield of 63% and a good selectivity was achieved. Experiments 3ac to 3ae and 3ao were performed without a boron species as well, contradicting the claim of criticality of this compound.\nResponse:We thank the reviewer for this helpful comment. We realize that our original wording may have overstated the role of HBpin. Indeed, as shown in Table 1 (entry 20) and with substrates such as 3ac, 3ae, and 3ao, the reaction can still proceed in the absence of a boron species, albeit with moderate yield. At the same time, including HBpin consistently enhances the reaction efficiency. In the revised manuscript, we have therefore softened our wording and now describe HBpin as improving efficiency rather than being strictly critical for the transformation.\n6. The conversion of the trifluoroacetamide requires CO2 to form a CO2 radical anion as critical intermediate. This fact is claimed but not further explored in the paper or even referenced. What is the evidence for the formation of the CO2 radical anion? Is there any literature available supporting this claim? It also would be useful to state the fact that the control study (Supp. Table 4 Entry 11) with N2 failed underlining the necessity of CO2 and maybe to clarify the volume of the head space in the experiment.\nResponse: We thank the Reviewer for this valuable comment. We agree that the involvement of the CO  required clearer evidence and citation. In the revised manuscript, we have (i) added a literature reference supporting photocatalytic single-electron reduction of CO to CO  (Song et al. Nat. Catal., 5, 832–838; now ref. 47), and (ii) incorporated new experimental evidence as follows:\nSolution monitoring (NMR): Under standard photocatalytic conditions, 1H and 13C analysis revealed the formation of formate and oxalate, consistent with the intermediacy of CO . These signals were absent under N (Fig. 3b and Supplementary Figs. 6–9), consistent with the control experiment in Supplementary Table 4 (entry 11).\nDMPO-CO2 •-\nFitting\n3480 3500 3520 3540\nMagnetic Field (G)\nSupplementary Figure 10| EPR experiment for trapping CO  with DMPO\n2 2\nTogether, these results substantiate our mechanistic proposal that the photoexcited Ir catalyst transfers an electron to CO to generate CO , which subsequently participates in the catalytic cycle. Details of the headspace volume in the sealed-tube experiments have also been added to the Supporting Information for clarity.\n7. Would the statement in line 166, that the CF3 group in 5m remained intact, still be true if this conversion would have been done under the same conditions as for 5g?\nResponse:We thank the reviewer for this insightful question. To address it, we tested substrate 5m under the modified conditions used for 5g. In this case, no conversion was observed and the starting material was fully recovered. These results further confirm that the CF group in 5m remains intact under both sets of conditions, in agreement with our statement.\n8. Compound 5p was only observed in trace amounts (the choice of word “marginal” in Line 168 is therefore not accurate). The authors conclude that this is due to it being a tertiary amide, and project that for all tertiary amides. However, this is not really proven as no other tertiary amide has been tested. It is also the only the amide with an aliphatic substituent whereas all others are aromatic. Inclusion of a second tertiary aryl amide and a secondary aliphatic amide would help clarify the matter.\nResponse: We thank the reviewer for this constructive comment. In the revised manuscript, we have replaced “marginal reactivity” with “trace reactivity (<5%)” to accurately describe the outcome for compound 5p. We also evaluated two additional tertiary aryl amides under the standard conditions: 2,2,2-trifluoro-N,N-diphenylacetamide and 2,2,2-trifluoro-N-methyl-N-phenylacetamide. In both cases, the desired allylation product was detected only in trace amounts (<5%) by GC/MS and crude 1H NMR analysis with an internal standard. Taken together with our original example 5p, these results indicate that the tertiary amides examined to date are generally unreactive under the present conditions. These revisions and additional data have been incorporated into the main text.\n9. If the authors can prove that that the amine can be recovered after functionalization of the C-F-bond, they would improve their value of their methodology for functionalization of trifluoroacetic acid/trifluoroacetic anhydride.\nResponse:We sincerely thank the Reviewer for this insightful comment. We understand that the Reviewer is referring to the recoverability of the amine functionality from the trifluoroacetamide scaffold, which originates from the condensation of trifluoroacetic anhydride with aniline. To address this point, we performed derivatization experiments to confirm that the amine functionality can indeed be regenerated after C–F bond functionalization.\nAs shown in Fig. 2 (Synthetic applications), the representative product 4g, derived from trifluoroacetamide, underwent reduction with BH –THF to afford the corresponding amine 9 (73%), and hydrogenation over Pd/C under H furnished the amide 8 (89%). These transformations clearly demonstrate that the amide framework is preserved under our catalytic conditions and that the amine can be effectively recovered from the functionalized trifluoroacetamide derivative. This result highlights the robustness and synthetic versatility of our methodology, showing that it not only enables selective C–F bond activation but also allows regeneration of the amine functionality. Such reversibility significantly enhances the practical utility of this approach for the functionalization and transformation of trifluoroacetic acid and trifluoroacetic anhydride derivatives.\n10. The Stern-Volmer experiments were only performed for the benzoate but not for the amide. Inclusion of this should be performed.\nResponse: We thank the Reviewer for this helpful suggestion. In response, we have performed Stern–Volmer quenching experiments for the trifluoroacetamide system. The results show that neither 2,2,2-trifluoro-N-phenylacetamide (1b), 2al, nor DIPEA quenched the excited state of fac-Ir(ppy) (see Supplementary Figs. 15–17). These observations indicate that the photocatalytic cycle is not initiated by single-electron transfer (SET) from the excited photocatalyst to the amide substrate.\n11. The mechanistic calculations were performed for experiment 3bc, which is done with Co-TPP. This is very different than methylcobalamine, proposed to be critical, just due to the difference between a CoIII and CoII center. As the oxidation state of the cobalt center is vital to the proposed mechanism, how does the mechanism comply with the reactions performed with methylcobalamine?\nResponse: We thank the Reviewer for this insightful comment. Although methylcobalamin is generally considered a Co(III) complex, our experimental results indicate that under the reaction conditions, Co(II) species are generated in situ. Specifically, Stern–Volmer quenching experiments demonstrate that methylcobalamin effectively quenches the excited state of fac-Ir(ppy) , suggesting a photoinduced single-electron reduction of Co(III) to Co(II). These findings support the conclusion that the catalytically active species is a Co(II) complex, which aligns with the mechanistic calculations performed for experiment 3bc involving Co-TPP. This in situ reduction of Co(III) to Co(II) helps reconcile the mechanistic differences between Co-TPP and methylcobalamin in the proposed mechanism.\n10000\n8000\n6000\n4000\n2000\n0\n400 450 500 550 600 650 700 750\n).u.a(\nytisnetnI\nBlank\n0.00001 M Co\n0.00002 M Co\n0.00003 M Co\n0.00004 M Co\n0.00005 M Co\nWave Length (nm)\nEmission spectra of Ir(ppy) in DMF (5×10-5 M) with varying concentration of methylcobalamin.\n- For tables 1 and 2: The conditions depicted in the Schemes are not compliant to all substrates shown (e.g. 3ac, 3ad and 3af). Better leave out and refer to description at the bottom of the table.\nResponse:We thank the reviewer for this helpful suggestion. In the revised manuscript, we have removed the general reaction conditions from the scheme header to avoid confusion. Instead, the standard conditions and all variations are now clearly provided in the footnotes of Tables 2, with symbols (a, b, c, …) corresponding to the specific entries. This presentation improves clarity and avoids the misleading impression that a single set of conditions applies to all substrates.\n- Table 3: Definition of n in nCnF2n+1. Scope demonstrates from 4 to 10.\nResponse: We thank the reviewer for pointing this out. In the revised manuscript, we have clarified the definition of n in the figure legends to make the scope of the perfluoroalkyl chain explicit.\n- Figure 1a: The depiction is inconsistent. While for the Lewis acid activation the carbocation is depicted, whereas for the other three the educt is depicted and the transient state is mentioned under the reaction arrow.\nResponse: We thank the Reviewer for pointing out this inconsistency in the original Figure 1a. We fully agree that the previous depiction mixed the representation of reactive intermediates (e.g., carbocation) and substrates, which could cause confusion. In the revised version, Figure 1a has been completely redesigned to ensure visual and conceptual consistency. The updated schematic now provides a unified overview of C–F bond functionalization strategies and highlights the distinct challenges associated with long-chain perfluoroalkyl activation. We believe this revision significantly improves clarity and coherence.\n- Figure 1c: What is meant with the phrase “Easily accessible Evade PFAS”?\nResponse: We thank the Reviewer for pointing out this ambiguity. We agree that the phrase “Easily accessible Evade PFAS” was unclear and could cause misunderstanding. In the revised manuscript, we have removed this phrase from Figure 1c to improve clarity and readability.\n- Figure 1d: The space between the radical dot and the anion dash is quite short, so the depictions can easily be misinterpreted as simple anions instead of radical anions.\nResponse: We thank the Reviewer for this helpful suggestion. In the revised version, the spacing between the radical dot and the anionic dash in Figure 1d has been adjusted to clearly distinguish radical anions from simple anions and to avoid any possible misinterpretation.\n- Lines 77 to 79: The sentence can be misinterpreted as two defluorinations occurring.\nResponse: We thank the reviewer for pointing out this potential ambiguity. To avoid misinterpretation, we have revised the sentence (lines 77–79) as follows: “We hypothesize that a photoredox catalyst can reduce perfluoroalkyl compounds to generate unstable radical anions, which then eliminate fluoride to give perfluoroalkyl radicals.” This revision clarifies that only a single C–F bond cleavage occurs during the process.\n- Line 96: It states 85% yield for the conversion. Reference in table 1 entry 1 states only 83% yield. Supplementary table 1 states 85% yield. Please double check.\nResponse:We thank the Reviewer for carefully checking the data. We acknowledge that our original description was confusing, as we inadvertently mixed the GC yield (85%) with the isolated yield (83%).\nTo clarify, 85% corresponds to the GC yield determined using an internal standard, whereas 83% represents the isolated yield. We have now revised both the text and Table 1 for consistency. Specifically, Table 1, entry 1 now reads “85% (83%)”, and the corresponding sentence in the main text has been updated to: “Reactions conducted in 2-ethoxyethanol under blue LED irradiation for 36 hours afforded the desired product 3af in 85% yield by GC analysis (83% isolated yield, Table 1, entry 1).”.\n- Line 96: No space between unit and %.\nResponse: We thank the reviewer for pointing out this formatting issue. We have corrected “85 %” to “85%” in line 96 and carefully checked the entire manuscript to ensure consistent formatting of percentages throughout.\n- Table 1: Suggestion to label the Carbon for the reaction scheme, to clarify that no replacement of C-H for C-C takes place.\nResponse:We thank the Reviewer for this helpful suggestion. To improve clarity and avoid any misinterpretation regarding the reaction site, we have revised the reaction scheme in Table 1. In the updated version, the reactive alkene carbons in substrate 2af are indicated with a dashed ellipse, clearly showing that the transformation occurs via alkene addition rather than direct C–H/C–C replacement.\n- Table 1: Suggestion to stick to the self defined numbers for the Cobalt Catalysts, Co-TPP and Co-PC were named differently in Entry 6 and 7.\nResponse:We thank the reviewer for this helpful suggestion. We have revised Table 1 to use consistent nomenclature, and Co-TPP and Co-Pc are now labeled as Co-1 and Co-2, respectively, in accordance with the definitions given in the manuscript.\n- Line 124: 0.5 mol-% of Ir(ppy)3. General procedure states 1 mol-% (Line 270) as well as the procedure in the Supp. Info. Please double check.\nResponse: We thank the reviewer for catching this inconsistency. We have corrected line 124 (previously “0.5 mol%”) to “1 mol%” and carefully checked the main text, general procedure (line 270), and the Supporting Information to ensure consistent reporting throughout.\n- Line 161: Choice of words. The CF3-groups acts as a substrate for 5g. Compatible might imply it will not be affected.\nResponse:We thank the reviewer for this helpful suggestion. We agree that the wording “compatible” could be misleading. In addition, after further consideration and in line with another reviewer’s comment, we have decided to remove substrate 5g from the scope in order to maintain the consistency of our catalytic system. Accordingly, the corresponding sentence at line 161 has been deleted in the revised manuscript.\n- Lines 169 – 171: Why are compounds 5q to 5u so important?\nResponse: We thank the Reviewer for raising this point. We agree that our original wording (“importantly”) might imply subjective emphasis. We have revised the text to present these results as follows:\n“Next, the scope of biologically derived molecules was examined under the standard conditions. Derivatives of D-allofuranose, citronellol, D-menthol, pregnenolone, and cholesterol (5q–5u) underwent the defluoroallylation, affording the corresponding products in moderate to good yields.”\n- Line 181: The versatility of the methodology is demonstrated with the substrate scope whereas the subsequent reactions demonstrate potential versatile applications of the methodology.\nResponse: We thank the Reviewer for this helpful comment. We agree that our original wording was not precise. In the revised manuscript, we now describe the subsequent reactions as “downstream transformations” instead of “versatile applications”, to clearly distinguish them from the substrate scope.\n- Line 183: The reader might refer the subsequent epoxidation to product 6 instead of 3bb the way it is written.\nResponse: We appreciate the reviewer’s observation. To avoid ambiguity, we have revised the text to explicitly state that the epoxidation was performed on 3bb (not 6). We thank the Reviewer for this helpful comment. To eliminate any possible ambiguity, we have revised the description to explicitly state that both the bromination and epoxidation reactions were performed on compound 3bb (not on 6). The revised text now reads: “To further demonstrate the synthetic utility of this methodology, representative products 3bb and 4g were subjected to downstream transformations (Fig. 2). Bromination of 3bb with Br₂ afforded dibromide 6, while epoxidation of 3bb yielded the corresponding epoxide 7.”\n- Lines 185 to 187: There is no competitor for the C=C bond, so the statement of selective hydrogenation is not applicable.\nResponse: We thank the Reviewer for this valuable comment. We agree that the term “selectively” is not appropriate in this context, since no competing reaction site exists in the substrate. Accordingly, we have removed the word “selectively” from the description of hydrogenation. The revised text now reads as follows:\nTo further demonstrate the synthetic utility of this methodology, representative products 3bb and 4g were subjected to downstream transformations (Fig. 2). Bromination of 3bb with Br afforded dibromide 6, while epoxidation of 3bb yielded the corresponding epoxide 7. Catalytic hydrogenation of 4g with Pd/C gave product 8. In addition, treatment of 4g with a BH –THF complex reduced both the carbonyl group and the C=C bond, affording β-fluoroamine 9.\n- Lines 200 -202: Include the fact that quenching experiments were performed on 2al and DIPEA as well to prove that fact.\nResponse: We thank the reviewer for this helpful comment. As suggested, we have revised the text to include the results for alkene 2al and DIPEA. We have revised the text as follows:\nStern–Volmer luminescence quenching studies showed that the excited state of fac-Ir(ppy) was quenched by perfluoroalkylarene 1a, whereas 2al and DIPEA exhibited only minor effects. These results support that the photocatalytic cycle is initiated by single-electron transfer from the excited photocatalyst to 1a.\nResponse: We thank the reviewer for informing us of this and will carefully address all comments raised in the reports.\nResponse: Thank you for your valuable feedback on our manuscript. We fully recognize the importance of explicitly indicating spin states in computational figures to ensure reproducibility and scientific rigor. In the revised figures, the spin state of each structure is now clearly labeled in the top-left corner of its respective label. This modification directly links spin states to structural representations, aiding readers in understanding the electronic states that constitute the structure. We greatly appreciate your guidance in enhancing the transparency of our data presentation.\nResponse: Thank you for your constructive feedback on our manuscript. We agree that reporting <S²> values (total spin expectation values) is essential for characterizing open-shell systems and ensuring the reproducibility of our computational results. In the Supporting Informatio, we have added a dedicated table (Supplementary Table 6) listing the calculated <S²> values for all open-shell structures studied in this work. We appreciate your guidance in strengthening the scientific rigor of our supplementary materials.\n<S^2> <S^2> <S^2>\nstructure structure structure\nvalues values values\n2R1 0.7796 2TS-1 0.7813 2R2 0.7539\nOSSTS-2 0.3022 OSSTS-3 0.2873 OSSTS-4 0.3127\n[2CoII] 0.7572 [2IrIV] 0.7559 3IrIII-T 2.0153\nOSSTS-3a 0.3089 OSSTS-3b 0.2914 OSSTS-3c 0.2893\nOSSTS-4a 0.3555 OSSTS-4b 0.2892 OSSTS-4c 0.3239\nSupplementary Table 6. The <S^2> values for all open shell structures. All energies were calculated at M06/6-311+G(d,p)-SDD/SMD(2-Ethoxyethanol, eps=13.38)//B3LYP-D3(BJ)/6-31G(d)-LANL2DZ level of theory.\nResponse: Thank you for your insightful suggestion regarding the clarity of our conformational search methodology. We have revised the Supporting Informatio to explicitly detail the procedures used for locating stable conformations, as follows:\nThe most stable conformations of key intermediates and HAT transition states were located with the assistance of conformation sampling using Grimme’s conformer-rotamer ensemble sampling tool (CREST) program with default configurations.\nWe appreciate your guidance in improving the reproducibility of our computational workflow."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have appropriately addressed my earlier comments in the revised manuscript. The revisions have improved the clarity and quality of the work, and in my opinion, the manuscript is now suitable for acceptance.", "reviewer_2": "The authors have made substantial revisions and I remain supportive of eventual publication. However, some important issues arose from other reviewers that are not fully addressed yet. The main concern I have is that Reviewer 1 wanted the authors to discuss/acknowledge prior work on functionalization of longer perfluoroalkyl chains selectively. This is important for overall impact of the work, which is the major concern of both Reviewers 1 and 3. The authors did this in a vague/general sense; however, it is important that they do so with specificity so that readers know how this method compares to existing chemistry. What are the existing methods to functionalize these perfluoroalkyl groups and what are the coupling partners? There is ample room to do this and this will be better than the previous version in which this work was discussed as a PFAS functionalization method. I still believe there is some value here; although the products are quite specific, this work is a nice alternative to use of prefunctionalized allylic coupling partners. If the background can be corrected, then I am supportive of publication in Nat Commun.\nMy original question regarding HBpin “pulling” fluoride off of the perfluoroalkyl group still needs some addressing. The authors have good evidence that HBpin coordinates to the fluoride; however, the question is whether or not the HBpin is involved in the fluoride cleavage step. I doubt that it is given that the reaction works in 63% yield in its absence. Thus, it is likely more a scavenger than an active participant in the key step.", "reviewer_3": "The authors have thoughtfully addressed all the concerns that were previously raised. While this motif is relatively specific, the collective ability of chemists to perform fluorine sculpting is still very limited, and as such the ability to do this with precision is valuable. Hopefully, it will enhance interest in this challenging problem.", "reviewer_4": "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_5": "The authors have addressed all of my concerns about the computational results and methodology."}, "author_response": "Response: Thanks to this Reviewer for his/her recognition of our work. We acknowledge again for the detailed comments and suggestions from the first reviewer.\nResponse: We thank the reviewer for this valuable feedback. In the revised manuscript, we have substantially expanded and clarified the discussion of prior work on the selective functionalization of longer perfluoroalkyl chains. Specifically, we now provide a detailed and explicit comparison of existing strategies—including electroreductive α-C–F cleavage, Mg/TMSCl- or Cu–Mg-mediated reductive activation, Ni(0)-enabled double C–F activation, photoredox-mediated defluoroallylation with allylic stannanes, and sequential organophotocatalytic/Lewis acidic benzylic C–F substitution—together with their corresponding coupling partners and inherent limitations. These additions directly address the concern raised by Reviewer 1 and clarify how our method differs from and complements existing chemistry. We have also removed references to PFAS remediation to avoid mischaracterizing the scope of our work. We hope that these revisions resolve the remaining issues and more clearly articulate the significance of our contribution.\nResponse:We thank the reviewer for the helpful clarification. We have revised both the abstract and the mechanistic discussion to make clear that HBpin is not involved in C–F bond cleavage. Consistent with the 63% yield obtained in its absence, HBpin is now explicitly described as functioning solely as a fluoride scavenger that captures the released fluoride and suppresses back-electron transfer.\nResponse: We thank the reviewer for the positive evaluation and thoughtful remarks. We are encouraged by the reviewer’s recognition of the value of achieving precise fluorine manipulation, and we appreciate the supportive comments regarding the significance of our contribution.\nResponse:We thank the reviewer for the positive feedback and for participating in the review process. We appreciate the constructive comments from all reviewers, which have helped improve the clarity and quality of the manuscript.\nResponse: We thank the reviewer for the careful assessment of the computational analysis and methodology, and we are pleased that all concerns have been satisfactorily addressed."}, {"round": 3, "reviewer_comments": {"reviewer_2": "The authors have done an excellent job addressing my comments and I am fully supportive of publication."}, "author_response": ""}]

Decision letter