Dual-role iron species in photoelectrocatalytic radical trifluoromethylation with trifluoroacetates

Domain: chemistry
Published: 2026-02-20
Editorial outcome: major_revision

Abstract
Trifluoromethylation remains a fundamental transformation in drug discovery, underpinning many top-selling pharmaceuticals. Emerging developments in iron ligand-to-metal charge transfer (LMCT) catalysis have redefined fluoroalkylation chemistry by unlocking the repurposing of readily available trifluoroacetates as radical trifluoromethyl sources. Recent (hetero)arene trifluoromethylation methods generally require stoichiometric inorganic oxidants to turnover photoactive iron catalysts, thereby limiting their broader applicability. Herein, we present an integrated photoelectrocatalytic strategy employing in situ-generated multifunctional iron species to achieve C(sp²)–H trifluoromethylation without stoichiometric oxidants and generating only traceless byproducts. Mechanistic studies identify catalytically active iron species exhibiting a dual synergistic function: promoting the photodecarboxylation of trifluoroacetates and mediating catalytic redox turnover. This protocol offers mild, tunable, and scalable conditions powered by visible light and electric current. It features a broad substrate scope, enabling the functionalization of diverse (hetero)cyclic scaffolds, including challenging electron-rich and easily oxidizable substrates, thus demonstrating its potential for sustainable late-stage modification in pharmaceutical synthesis.

Introduction
Fluoroalkyl groups have emerged as integral structural motifs in medicinal chemistry owing to their profound impact on the physicochemical and pharmacokinetic properties of drug candidates1,2. The trifluoromethyl group (CF3) still stands out as a major player in this field as its incorporation can markedly improve metabolic stability, lipophilicity, and membrane permeability, while also modulating molecular conformation and facilitating binding affinity3. As a result, trifluoromethylation reactions continue to play a central role in the design of therapeutic agents across a wide range of disease areas, often through the direct derivatization of C(sp2)–H bonds in the parent compounds4. A compelling example of this impact is the conversion of the naturally occurring nucleoside deoxyuridine into trifluridine via C(sp2)–H to C–CF3 bond substitution, leading to a 400-fold increase in DNA uptake5 and establishing trifluridine as one of the top-selling small-molecule drugs with broad antiviral and anticancer applications (Fig. 1A)6. Beyond traditional closed-shell approaches7,8, radical C–H trifluoromethylation has become increasingly favored due to its ability to directly functionalize lead compounds without the need for prior activation. Central to this strategy is the generation of trifluoromethyl radicals (·CF3), which have driven the development of a wide array of tailored trifluoromethylating reagents displaying high enthalpic driven forces (Fig. 1B)4. Photoredox catalysis has significantly broadened the scope of these methodologies by offering an efficient platform for radical generation under mild conditions via photoinduced single-electron transfer (SET) processes9,10. However, the broader application of these methods may be constrained by the cost and accessibility of specialized reagents, as well as by scalability challenges that impact their practical utility4. To solve this, our group has recently pioneered an alternative approach by repurposing trifluoroacetates, the most available and inexpensive chemicals containing trifluoromethyl groups, as CF3 radical precursors for the trifluoromethylation of (hetero)arenes11. The use of trifluoroacetates as radical trifluoromethylating reagents has been limited by their high oxidation potential, Eox > +2.00 V (vs Fc+/Fc)12, often necessitating harsh reaction conditions for decarboxylation, which restricts their applicability in the functionalization of complex molecules (Fig. 1C)12–15. In our prior work, we reported the design of an iron-based photocatalyst that operated via an inner-sphere electron transfer mechanism11, effectively circumventing the thermodynamic redox constraints typically associated with redox-based methodologies, including canonical photoredox catalysis16,17. This process entails the coordination of trifluoroacetate to an Fe(III) active species, forming a carboxylate complex that, upon visible-light excitation to a dissociative ligand-to-metal charge transfer (LMCT) state, undergoes homolytic cleavage of the Fe–O bond18–21. This generates transient carboxyl radical species that allow the formation of trifluoromethyl radicals after rapid decarboxylation, by transforming a bimolecular process (outer sphere SET) into an intramolecular inner sphere SET (Fig. 1C). We capitalized this photodecarboxylation technology to the direct trifluoromethylation of C(sp2)–H bonds in a wide range of diversely functionalized unsaturated (hetero)cycles. Other research groups have subsequently adopted this strategy for further synthetic applications22. Complementary approaches leveraging Fe-LMCT catalysis for the fluoroalkylation of alkenes were also discovered23–27.

Although our previous protocol exhibited excellent chemoselectivity, demonstrating broad functional group tolerance and compatibility with structurally complex molecules, its practical application and scalability were limited by the requirement for stoichiometric amounts of an inorganic oxidant (K2S2O8) to regenerate the active catalytic species in the context of a net oxidative transformation11. Accordingly, we anticipate that this reactivity concept could exert a broader impact in the field of trifluoromethylation if the turnover step is achieved via a cleaner and more streamlined approach, thereby enhancing scalability and expanding its practical applicability. However, achieving this goal is far from trivial, since the Fe(II) to Fe(III) turnover event has been identified as the rate-determining step of the transformation11. Moreover, realizing this objective would provide a valuable opportunity to elucidate previously unexplored mechanistic features arising from the synergistic interplay between Fe-mediated LMCT photodecarboxylation catalysis and other enabling technologies. To this end, we initially hypothesized that the reaction could be boosted by implementing an electrochemical oxidation, altogether constituting a photoelectrocatalytic strategy28,29 through the integration of electrochemical oxidation30 and iron LMCT photodecarboxylation31,32. Recent photoelectrochemical protocols have demonstrated the feasibility of trifluoromethylating organic molecules using trifluoroacetic acid (TFA) or trifluoroacetate salts33–35. While these approaches feature elegant reaction designs, they are often limited by an narrow substrate scope, incorporating only electron-neutral or electron-deficient (hetero)arenes presumably due to undesired oxidative degradation of electron-rich substrates33,34, or require the use of specially engineered heterogeneous electrodes35,36. In view of this, a practical photoelectrocatalytic protocol for the trifluoromethylation of (hetero)aromatics involving the direct decarboxylation of trifluoroacetates and that could accommodate relatively electron-rich substrates with standardized techniques remains a significant and unmet challenge. If successful, such a synthetic protocol would hold significant potential for practical applications, particularly in medicinal chemistry, by enabling the direct trifluoromethylation of C(sp2)–H bonds in multiple (hetero)cyclic scaffolds through the repurposing of trifluoroacetate feedstocks and employing tunable and scalable photoelectrocatalytic settings while generating only traceless CO2 and H2 gaseous byproducts.

In this communication, we report the realization of this concept through a reactivity paradigm in trifluoromethylation reactions by integrating a tunable electrocatalytic strategy with photocatalytic decarboxylation of trifluoroacetates via dual-role iron catalysis (Fig. 1D). This approach enables the incorporation of CF3 groups in a wide range of substrates, including oxidation-sensitive, electron-rich (hetero)arenes, employing trifluoroacetates as trifluoromethylating reagents under standardized conditions. The protocol is characterized by the in situ formation of both electrocatalytic and photocatalytic iron species integrated in a synergistic mode of action, enabling the decarboxylation of trifluoroacetates under clean, scalable, and mild conditions using visible light and electric current as renewable energy sources. Notably, this photoelectrocatalytic method expands the substrate scope to incorporate electron-rich (hetero)arenes, which remain challenging for existing photoelectrochemical methodologies33,34.

Results
Mechanistic studies and hypothesis
At the outset of our investigations, it remained unclear whether the photocatalytically active iron species could be regenerated by implementing an electrochemical oxidation. To this end, we started investigating the speciation of iron complexes under the reaction conditions previously reported by our research group11, which involved Fe(OTf)2 (OTf, trifluoromethanesulfonate) as the precatalyst in combination with 4,4’-dimethoxy-2,2’-bipyridine (L1) in MeCN at room temperature (Fig. 2A). Cyclic voltammetry (CV) measurements were carried out to evaluate the feasibility of oxidizing Fe(II) intermediates through an electrochemical process, which underpins the catalyst turnover pathway. A mixture of Fe(OTf)2, L1 and sodium trifluoroacetate in a 1:1:60 molar ratio in MeCN exhibited two oxidation peaks, with the first redox couple becoming reversible only upon addition of trifluoroacetic acid (TFA) (Fig. 2B), accompanied by a slight shift in the corresponding half-wave potential (Ep/2). Furthermore, replacing TFA with HClO4 produced a similar CV profile, featuring two reversible redox couples, likely due to the in situ formation of TFA (Fig. S17). These results indicate that, in addition to serving as a proton source required to balance the electrochemical reaction through a hydrogen evolution, TFA also influences the stability of the species involved in the first redox pair (Fig. S19)23. To identify the nature of these species in solution, we recorded cyclic voltammograms of various combinations of the reaction components in the presence of TFA (Fig. 2C). A solution of Fe(OTf)2 and sodium trifluoroacetate displayed an irreversible CV with Ep/2 = +0.10 V (vs. Fc+/Fc) (Fig. 2C, green trace), consistent with the presence of non-ligated Fe(II) species I (Fig. 2A). Upon addition of an equimolar amount of L1 and 1.3 equivalents of TFA, the two-redox-pair system emerged (Fig. 2C, orange trace), with the first reversible wave at E1/2 –0.10 V (vs. Fc+/Fc) consistent to the formation of ligated iron trifluoroacetate species II (Fig. 2A). The effect of TFA addition may arise from the formation of TFA-bound species through hydrogen-bonding interactions, as reported in other purely photochemical Fe-mediated decarboxylations of trifluoroacetates23. The second reversible wave at E1/2 +0.36 V (vs. Fc+/Fc) is attributed to the formation of a homoleptic trisbipyridine-type Fe(II) complex (III). This assignment is supported by comparison with the CV of a mixture of Fe(OTf)2 and L1 in the absence of sodium trifluoroacetate and TFA (Fig. 2C, blue trace), as well as by literature data37. Importantly, the addition of TFA to this mixture resulted in the appearance of the two-redox-pair system, indicating that both L1 and trifluoroacetate ligands participate in the coordination sphere of iron species II. The photostability of the iron species under reaction conditions was investigated by comparing the cyclic voltammograms of Fe(II)/L1/sodium trifluoroacetate/TFA mixtures, both with and without 405 nm irradiation (Fig. 2D). While the CV of the trisbipyridine-type Fe species (III) remained unaltered upon irradiation, the redox pair corresponding to the ligated Fe trifluoroacetate species V exhibited pronounced alterations, underscoring its photochemical reactivity. We then evaluated the photoinduced decarboxylation of in situ-formed ligated (V) and non-ligated (IV) Fe(III) trifluoroacetate species via LMCT. To this end, mixtures of Fe(OTf)2, NaO2CCF3 and TFA in acetonitrile were prepared in the presence and absence of L1, and their evolution under 405 nm irradiation was monitored by UV-visible absorption spectroscopy (see Fig. S35-36). Notably, while the photodecarboxylation at ligated Fe(III) trifluoroacetatate species (V) required 20 h to reach completion, the corresponding non-ligated Fe(III) species in the absence of L1 were consumed in only 30 minutes, indicating a faster LMCT rate for IV (see Fig. S39). Complementary UV-visible spectroscopic analysis of a Fe(II)/L1/sodium trifluoroacetate/TFA mixture under reaction conditions further supported the formation of intermediate III, as evidenced by direct comparison with the spectrum of authentic [Fe(L1)3](PF6)2 (see Fig. S9). Finally, the formation of species I, II, and III was confirmed by ESI-HRMS of the reaction mixture, which revealed ions corresponding to trisbipyridine-type Fe complexes and ligated and non-ligated Fe trifluoroacetate species (see Fig. S34). Based on these experimental observations, we propose a mechanistic hypothesis in which an electrocatalytic cycle synergistically converges with an Fe LMCT photodecarboxylation reaction via two plausible pathways (Fig. 2E). Under reaction conditions, intermediate II is formed, which can undergo oxidation at the anode to form the corresponding Fe(III) species V. This intermediate plays a dual role: (1) upon visible-light excitation, V can promote LMCT photodecarboxylation, affording trifluoromethyl radicals and regenerating species II through coordination with sodium trifluoroacetate (Fig. 2E, pathway A); and (2) alternatively, V may act as a redox catalyst, promoting the single-electron oxidation of non-ligated Fe species I in solution, resulting in the formation of the corresponding Fe(III) intermediates (IV), which also promotes photodecarboxylation. It is plausible that this mediated oxidation is driven by a follow-up rapid and irreversible photodecarboxylation occurring at intermediate IV. This behavior markedly contrasts with a recent report on related photoelectrochemical fluoroalkylation reactions (excluding trifluoromethylation), in which Fe(II) carboxylate intermediates displayed reversible cyclic voltammograms even in the absence of ancillary ligands, illustrating the distinct speciation associated with trifluoroacetates38. Moreover, the necessity of TFA for stabilizing species II and V further distinguishes the CF3 radical generation mechanism from our previous work, in which the photodecarboxylation of trifluoroacetates was conducted under basic conditions11. Finally, following CF3 radical addition to the (hetero)aromatic substrate, oxidatively induced rearomatization of the resulting cyclohexadienyl-type radical could occur at the anode or be facilitated by Fe(III) trisbipyridine-type species (VI) in solution39.

Optimization studies
Guided by this mechanistic hypothesis, careful investigations to optimize the photoelectrocatalytic trifluoromethylation of C(sp2)–H bonds resulted in the conditions shown in Fig. 3. The combination of commercially available Fe(OTf)2, L1, NaO2CCF3, and TFA resulted in the in situ formation of bifunctional iron active species. At 35°C, 390 nm illumination, and applying a constant potential in an undivided electrochemical cell, the trifluoromethylation of the electron-rich substrate 1–with an oxidation potential much lower than that of trifluoroacetate–was successfully achieved, affording the corresponding product (2) in 76% yield (Fig. 3, entry 1). As discussed before, the presence of TFA served to provide the protons to close the electrochemical circuit by H2 evolution at the cathode, but also to stabilize electrochemically species II formed in situ. No product was detected in the absence of L1 (Fig. 3, entry 2) or even when using reaction conditions with solvated Fe(III) salts that proved successful for other fluoroalkylations different from trifluoromethylation38 (see Fig. S33). This illustrates the key role of the bipyridine-type ligand in forming the bifunctional catalytic species for the trifluoromethylation reaction to occur. When L1 was replaced with [Fe(L1)3](PF6)2, the catalytic activity of the system was restored (Fig. 3, entry 3), suggesting the in situ formation of species II via dynamic equilibration in solution. Remarkably, in the absence of L1, the addition of ferrocene –an established redox mediator with a CV resembling that of species II–40 led to the restoration of the reactivity of the system (Fig. 3, entry 4). This finding lends support to the viability of pathway B, in which species II facilitates the turnover of non-ligated iron species I, whose oxidation appears hindered at the anode. A comparable observation occurred with the addition of other well-recognized redox mediators, such as acetylferrocene41 and magic blue (tris(4-bromophenyl)ammoniumyl hexachloroantimonate)42 with similar electrochemical behaviors to III (Fig. 3, entries 5-6), enabling the trifluoromethylation reaction in the absence of L1. These results underscore the essential role of the electrocatalyst in enabling the turnover of Fe(II) to the photoactive Fe(III) species in pathway B, which may also contribute to facilitating the oxidative rearomatization ultimately leading to the formation of the product. Notably, we also found that the reaction proceeds effectively even at high loadings of L1 (30–50 mol%, Table S4), conditions under which the concentration of non-ligated Fe species is expected to be minimal. This supports product formation via pathway A, where the photoactive ligated species V likely drives the photodecarboxylation process. Control experiments confirmed the photoelectrocatalytic nature of the protocol, as no product formation was detected in the absence of either electrical input or light irradiation (Fig. 3, entries 7-8).

Scope of the reaction
Following optimization, the substrate scope of the photoelectrocatalytic decarboxylative trifluoromethylation protocol was investigated, resulting in the incorporation of CF3 groups into a diverse range of (hetero)cyclic scaffolds (Fig. 4). The study was conducted using standardized equipment, including a Kessil lamp and an IKA ElectraSyn® device, with H2 and CO2 formed as the sole byproducts. A range of simple, electron-rich arenes with different substitution patterns yielded the corresponding trifluoromethylated products in good yields (2–7), without observing oxidative degradation of the substrates. Other substituted 6-membered heterocycles with varying electronic properties, including also electron-deficient scaffolds, were also functionalized to give the trifluoromethylated 2-pyridinone (8), uracil (9), pyrimidine (10), pyridine (11), and α-pyrone (12) derivatives. The reaction was also applicable to industrially relevant coumarin derivatives, with regioselective trifluoromethylation at the pyrone ring (13,14). Substrates incorporating 5-membered heteroarenes such as thiophene and pyrrole were also trifluoromethylated in synthetically useful yields (15 and 16, respectively). In substrates containing multiple reactive sites, difunctionalized products were obtained, consistent with other radical trifluoromethylation reactions10,11. Strikingly, our reaction design enabled the functionalization of electron-rich pyrroles and indoles (16-18), characterized by remarkably low oxidation potentials, through the reduction of the applied cell potential. This allowed the selective functionalization of easily oxidizable heteroarenes without decomposition, demonstrating the tunability of our method in addressing substrates that are challenging under alternative protocols33,34.

To further highlight the practicality of our protocol, a variety of relatively complex molecules, including natural products and drug-like compounds, were submitted to the optimized reaction conditions. The methodology is efficient for the derivatization of caffeine (19), and doxofylline (20) featuring a dioxolane ring. It is worth remarking that we were able to prepare trifluridine (21), one of the largest-selling small-molecule pharmaceuticals6, in a single step from readily available 2-deoxyuridine in 61% yield. The method could also be applied to the direct trifluoromethylation of the muscle relaxant metaxalone (Skelaxin®) (22) and the electron-rich natural product melatonin (23), displaying an excellent functional group tolerance including unprotected alcohols (21) and carbamates (22). Trifluoromethylation preferentially occurred at the most electron-rich C(sp2)–H sites, likely due to polarity matching with the electrophilic character of the CF3 radical43–45. This offers a strategy to stabilize labile sites in bioactive molecules, potentially enhancing their activity46.

From a synthetic standpoint, the method is readily scalable through routine enlargement of the electrochemical cell. The trifluoromethylation of caffeine and 1,3,5-trimethoxybenzene was successfully performed on a larger scale without a significant decrease in reactivity. (Fig. 5).

Further mechanistic interrogation
Lastly, we decided to deepen our mechanistic understanding of the photoelectrocatalytic trifluoromethylation reaction. For this purpose, we evaluated the reactivity of the photoelectrocatalytic system using different applied anode potentials using caffeine as substrate (Fig. 6A). We determined the anode potential from the applied cell potential using a third reference electrode. Interestingly, while good levels of reactivity were determined when applying anode potentials which are in the range of the CV of the trisbipyridine-type Fe species redox pair (Fig. 6A, entries 4-7), the yield of the trifluoromethylated product dramatically dropped when the mixture was subjected to lower anode potentials (Fig. 6A, entries 1–3). Although speculative, this observation aligns with the possibility that Fe(III) trisbipyridine-type species could facilitate the oxidative aromatization, thereby promoting product formation. Finally, we studied the formation of H2 via proton reduction at the cathode, with TFA serving as the proton source. Hydrogen evolution was detected by headspace gas chromatography (HS-GC), occurring simultaneously with product formation (Fig. 6B).

Methods
General procedure for the photoelectrocatalytic trifluoromethylation of C(sp2)–H bonds with trifluoroacetates
A 10 mL ElectraSyn vial equipped with a stirring bar was charged with the corresponding substrate (0.5 mmol, 1 equiv), NaO2CCF3 (408 mg, 3.0 mmol, 6 equiv), Fe(OTf)2 (17.8 mg, 0.05 mmol, 10 mol%), 4,4’-dimethoxy-2,2’-bipyridine L1 (10.6 mg, 0.05 mmol, 10 mol%), and TBAPF6 (387 mg, 1.0 mmol, 2 equiv.). The electrodes RVC(+)/SS(-) were then inserted, and the vial was closed with an IKA screw-cap. The hole of the screw-cap was closed with a septum, and the vial was evacuated and backfilled with nitrogen with the aid of a needle, and this procedure was repeated three times. Against a positive N2 flow, dry MeCN (5 mL) and 50 µL of TFA were added via a syringe. Additional degassing with N2 flow for 3 min was carried out in the reaction mixture. The reaction was stirred (650 rpm) under potentiostatic conditions (i.e. constant voltage = 2.06 V) using ElectraSyn 2.0 while irradiated with a 390 nm Kessil LED, at 3 cm, and cooled down using a fan. After 24–48 h, the electrodes were rinsed with Et2O or EtOAc (10 mL), the reaction was quenched with saturated aqueous NaHCO3 solution (2 mL) and transferred to a separating funnel. The two phases were separated, and the organic layer was washed with a saturated aqueous NaHCO3 solution (2 × 15 mL), then with brine (15 mL) and dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure, the crude mixture was purified by flash column chromatography on a silica gel column to afford the trifluoromethylated product. For products that are partially soluble in water, the reaction was quenched with Na2CO3 (54 mg), and the crude mixture was filtered through celite. After solvent removal under reduced pressure, the mixture was directly purified by flash column chromatography.

General procedure for scale-up trifluoromethylation reactions
An oven-dried 100 mL Schlenk tube was equipped with a stirring bar and charged with the corresponding (hetero)arene (5 mmol, 1 equiv), NaO₂CCF₃ (4.1 g, 30 mmol, 6 equiv), Fe(OTf)₂ (178 mg, 0.5 mmol, 10 mol%), 4,4’-dimethoxy-2,2’-bipyridine (L1, 106 mg, 0.5 mmol, 10 mol%), and TBAPF₆ (3.87 g, 10 mmol, 2 equiv). All reagents were added under open-air conditions. The reticulated vitreous carbon (RVC) anode (50 × 25 × 3 mm) and stainless steel (SS) cathode (50 × 25 × 1.7 mm) were then inserted, and the vial was sealed with a perforated septum. The Schlenk tube was evacuated and back-filled with argon three times. Against a positive argon flow, degassed dry MeCN (50 mL) was added via syringe. The reaction was stirred (650 rpm) under constant potential electrolysis (CPE, Ecell = 2.06 V), while irradiated with 405 nm light (EvoluChem LEDs from HepatoChem®) at a distance of 3 cm. After 70 hours, the electrodes were rinsed with EtOAc (10 mL), and the crude mixture was transferred to a 250 mL separatory funnel. The organic phase was washed with a saturated NaHCO₃ solution (30 mL). After phase separation, the aqueous layer was extracted twice with EtOAc (20 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The crude product was purified by automated flash column chromatography on silica gel.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "The manuscript entitled “Dual-Role Iron Species in Photoelectrocatalytic Radical Trifluoromethylation with Trifluoroacetates”\nreports a photoelectrocatalytic protocol for C(sp²)–H trifluoromethylation using readily available trifluoroacetates as CF₃\nsources. The authors propose that in situ–generated Fe species play a “dual role” as both photo- and electrocatalysts,\nenabling decarboxylation and catalyst turnover without stoichiometric oxidants. In my view, this work represents an\nincremental rather than a conceptual advance over existing Fe-LMCT and electrophotocatalytic trifluoromethylation\nchemistry, and therefore does not meet the novelty and impact criteria for Nature Communications.\n1. The combination of Fe-based LMCT photochemistry with electrochemical oxidation has already been demonstrated in\nseveral recent studies (e.g., Campbell et al., Science 2024, 383, 279; Chen et al., Science 2024, 384, 670; Qi et al., J. Am.\nChem. Soc. 2023, 145, 24965). The current work does not introduce a clearly distinct mechanistic paradigm or reactivity\nprinciple beyond these precedents.\n2. The authors’ previous report (Angew. Chem. Int. Ed. 2024, e202311984) already established Fe-LMCT\nphotodecarboxylation of trifluoroacetates. The present study essentially replaces the chemical oxidant (K2S2O8) with\nanodic oxidation to complete the catalytic cycle. While this modification improves atom economy, it constitutes an expected\noptimization rather than a conceptual breakthrough. Moreover, Motornov et al. (Angew. Chem. Int. Ed. 2025, 64,\ne202504143) have employed a similar iron catalyst in photoelectrochemical catalysis with a broader substrate scope.\n3. The mechanistic analysis is limited to cyclic voltammetry and UV–vis spectroscopy. No direct or quantitative evidence\nsupports the coexistence of distinct Fe species responsible for photo- and electrocatalytic functions. Operando or time-\nresolved studies would be necessary to substantiate the proposed dual-catalyst mechanism.\n4. The substrate scope largely overlaps with known photoredox and electrophotocatalytic CF3-introduction protocols. The\nfunctionalization of a few drug-like molecules (e.g., caffeine, melatonin) is insufficient to raise the overall impact to the level\nexpected for Nature Communications.", "reviewer_2": "In this work, Francisco Juliá-Hernández et al. report a very elegant strategy for the photoelectrocatalytic radical\ntrifluoromethylation of arenes using easily accessible alkali trifluoroacetate salts and TFA. This approach is highly powerful\nand could have a significant impact on the pharmaceutical and agrochemical industries by providing a more sustainable\nroute to fluorinated molecules. This study builds upon the authors’ 2024 Angewandte Chemie paper, in which they used a\nstoichiometric oxidant for a Minisci-type trifluoromethylation reaction. Clearly, the present work represents a greener\napproach, as it solves a long-standing problem in nucleophile cross-coupling: the use of stoichiometric amounts of reactive\nand aggressive oxidants, which often limit functional group tolerance and the overall reaction scope.\nThe authors provide an elegant solution to this issue by employing dual iron electrocatalys and photocatalysis via a LMCT\n(ligand-to-metal charge transfer). They found that a “ligand-free: iron trifluoroacetate species acts as a photocatalyst,\ngenerating the trifluoromethyl radical via light-induced charge-transfer homolysis and decarboxylation. Meanwhile,\ntris(bipyridine)-coordinated iron serves as an electron mediator in the electrocatalytic step.\nThe authors present thorough mechanistic studies supported by UV-Vis spectroscopy, cyclic voltammetry (CV), and\nchronoamperometry, as well as hydrogen detection, all of which are discussed in detail in the manuscript and the Supporting\nInformation (SI). The SI is of good quality and complete.\nI strongly recommend the publication of this article, as it will be an excellent contribution for the readers of Nature\nCommunications.\nMinor comments and suggestions:\n-In Figure E6c, please correct the spelling of “voltajes” (should be “voltages”).\n-I would also like the authors to comment and discuss how the pyridyl radical, generated after the addition of the\ntrifluoromethyl radical, undergoes oxidation, rearomatization, and proton release. Does this process occur directly at the\nelectrode surface, or is the iron(III)L3 complex again the oxidant in this step?\n-Additionally, I suggest that the authors discuss the reaction's efficiency at different ratios of the iron; L is used, as this will\nnaturally affect the balance between “ligand-free” iron and tris(bipyridine) iron species.\n-Finally, what is the effect of the bipyridine ligand structure (e.g., tert-butyl, Me or unsubtituted bypy) on the electron mediator\nproperties?", "reviewer_3": "In this communication, Fernández-Garcia et. al. report a photoelectrocatalytic methodology for the decarboxylation of cheap\nand abundant TFA using Fe catalysis, producing trifluoromethyl radicals that may be harnessed for the trifluoromethylation\nof (hetero)arenes. This work is a continuation of their 2024 ACIE manuscript (Angew. Chem. Int. Ed. 2024, 63, e202311984;\nRef. 11 in the current work) in which the main advance is moving away from a chemical oxidant (K2S2O8) toward\nelectrochemical oxidation. Thus, this is the most distinguishing point of the paper. It certainly is not a big leap to do so but\nthere are a few notable points. While photoelectrocatalysis has previously been demonstrated in Fe-mediated\nfluoroalkylation from fluoroalkyl carboxylates (Ackermann, Angew. Chem. Int. Ed. 2025, 64, e202504143, ref. 40 in the\ncurrent work), the current work is distinguished by perhaps broader applicability towards electron-rich functionalities, as well\nas a potentially unique reaction mechanism. The demonstrated reaction scope appears nearly identical to the author’s prior\nwork (ref. 11), although the tolerance of electron-rich functionality (substrate 2) is notable under electrochemical conditions\nwhere anodic overoxidation is a possibility. In light of the above points, I recommend publication after addressing the\nfollowing comments, which mainly concern 1) clarification of the reaction mechanism and 2) differentiation of the\nmethodology from prior work.\n1. The redox features in the cyclic voltammograms are reported vs a Ag/AgCl reference. The authors are encouraged to\nreport the potentials vs ferrocene or SCE instead, as these values are more utilized and easily comparable in non-aqueous\nsystems.\n2. The authors state: “whereas the redox signals corresponding to complex II remained stable, displaying a higher anodic\nthan cathodic current, suggestive of electrocatalytic behavior.” In reference to Figure S20. Upon inspection of Figure S20, it\nappears the CV was slightly misinterpreted. Peak anodic and peak cathodic currents should not be read from absolute value\non the y-axis. Please do some reading in the most rudimentary electrochemical textbooks to properly interpret the CVs.\nWhen reading from the absolute values, the peak anodic current of the last scan (dark orange line) is 25 µA and the peak\ncathodic current is –11 µA, which is perhaps why the authors made the above statement. However, the baseline in the\nforward wave is about 5 mA while that of the reverse wave is ca. 9 mA, meaning that the peak anodic current is 20 µA and\ncathodic current –20 µA when read from these values, indicating a fully reversible wave, as expected for species II.\nAbsolutely no evidence for electrocatalysis can be gleaned from this CV behavior. These are the types of sloppy mistakes\nthis field is prone to … electrochemistry is a field unto itself. It needs to be done properly even if this is an “organic”\nmanuscript.\n3. The assignment of species III in the CVs is ambiguous. It’s irreversibility and similarity to a CV of Fe(OTf)2 + NaO2CCF3\nsuggest it is a TFA ligated Fe species, but a few questions remain. Figure 2B should include concentrations of analytes in the\nfigure caption or figure legend. If the orange trace and green trace are equimolar Fe concentrations, why does the orange\ntrace feature a boosted III redox wave? Figure S20 shows that this wave diminishes significantly upon cycling, suggesting\nthat the chemical step following oxidation is depleting the precursor to III overtime. Can the authors also cycle a CV of\nFe(OTf)2 + NaO2CCF3 similarly to Figure S20? Does the redox wave at –0.35 V also diminish in intensity? If equimolar\namounts of Fe and TFA are used, does the addition of L1 truly boost the current associated with III in the first scan, as Figure\n2B suggests? This would mean that there is some Fe species in solution that contains both TFA and L1.\n4. The above point is convoluted by the fact that the authors observe near quantitative formation of II via beer-Lambert\nanalysis, ruling out Fe species that contain both TFA and L1. If this is true, it is unclear why L1 would boost the anodic\ncurrent of III on the first scan, as no IV is present in solution yet to mediate the oxidation of III to V. The claim that quantitative\nII is formed suggests that adding too much L1 should completely shut off reactivity, as no Fe would be left to ligate to TFA.\nIt does not appear that the authors included an optimization of L1 concentration, unless I am mistaken. If 30 mol% L1 or\ngreater is employed, all the Fe should be sequestered as II, and the yield should drop. Can the authors demonstrate this?\nRecent work published on the rxiv (https://doi.org/10.26434/chemrxiv-2025-djp0r) showcases TFA decarboxylation from\nwell-defined (dien)FeTFA complexes. It is possiblre that the photoactive species can still contain a mixture of TFA and bpy\nligands. This, of course, would be supported by the presence of product even when employing, say, 50 mol% ligand.\n5. Notably, the authors demonstrate that Ackermann’s conditions (ref 40) result in 0 percent yield on substrate 2, showcasing\nthe current methodology’s tolerance towards more electron-rich substrates. However, the authors attribute this to the role L1\nplays in the proposed mechanism. Is it possible that L1 simply serves to decrease the required oxidation potential to access\nFe(III)? Thus, the yield is 0 under Ackermann’s conditions due to direct oxidation of 2 at the anode. Ackermann\ndemonstrates successful triufluoromethylation of caffeine without a ligand, which is harder to oxidize. Under the current\nconditions, if L1 is excluded, can caffeine still be engaged? If not, this is likely due to the low cell potential (2.06 V), if this is\nraised, or constant current electrolysis is utilized, I assume caffeine can be engaged without L1. Please perform this\nexperiment.\n6. The use of mediators instead of L1 restores reactivity, including non Fe-containing mediators such as magic blue; this is a\nnotable result. However, species III is still easier to oxidize at an electrode than these mediators, so it is unclear as to why\nthe harder to oxidize species would serve as an electron shuttle. A separate hypothesis is that the redox mediator may help\nto oxidize arene radical intermediates in solution to the cation, which facilitates rearomatization after radical addition\nfollowing proton loss.\n7. Altogether, the mechanistic hypothesis proposed in Figure 2D is perhaps plausible, but many uncertainties remain. To\nme, it is clear that L1 ligates Fe(II), making it easier to oxidize to Fe(III) which is required for LMCT. The fact that no yield is\nobserved in the absence of L1, even though no ligands are required in other work (ref. 40) is because, in this work, the\npotential at the anode is low. This helps facilitate reactions with electron-rich substrates. Presumably, the use of other\nbipyridine derivatives, or phenanthroline derivatives, can further modulate the potential required for Fe(II) oxidation. How\nare the CVs changed when more or similar electron rich bpy derivatives are used (R = NMe2, tBu, Me, etc) or when more\nelectron-poor derivatives are used (R = CF3, CO2Me, Cl, F, etc.)? Can reactivity be improved with a different ligand? If the\nrequired oxidation potential is moved too anodic with more electron poor bpy derivatives, does this completely shut off\nreactivity in the utilized potential window? Mechanistic experiments with varied bpy ligands should be carried out to provide\nmore insight into the proposed mechanism.\n8. The reaction times should be included in Figure 3.\n9. Substrates 10 and 11 do not contain sterically accessible coordinating nitrogen atoms, so the claim “Notably, the catalyst\nremained active in the presence of substrates containing potentially coordinating nitrogen atoms” is not supported.\n10. The demonstrated scope is remarkably similar to the author’s previous work (ref. 11). Compare substrate 11 (this work)\nvs 17 (ref. 11), 8 (this work) vs 19 (ref. 11), 21 (this work) vs 33 (ref.\n11), or 19 (this work) vs 29 (ref. 11). Even substrates highlighted as challenging due to their electron-rich nature (18)\nperformed equally well, if not slightly better, in ref. 11 (substrate 24). Is there any substrate or substrate class that can be\nengaged in the current methodology that is not amendable to the previous conditions employed in ref. 11? Nonetheless, it is\nunderstood that elimination of a stoichiometric oxidant increases the atom economy of the\ntransformation.\n11. The authors should check their assignment of the regioisomer depicted for substrate 12, it is more likely that the radical\naddition occurs next to the carbonyl moiety.\n12. If the redox wave for III is overlayed in Figure 6, it looks as if the yield begins to rise when accessing that couple, as\nopposed to the oxidation of the mediator. In fact, the yield plateaus even before reaching the E1/2 of Fe(II)L13 to Fe(III)L13.\nThe yield at 0.5 V is also very comparable to the yield at 0.8 V, even though the current displayed under these two\nconditions are very different. This speaks to some of the remaining mechanistic ambiguity highlighted above. Please\naddress.", "reviewer_author_response": "“Dual-Role Iron Species in Photoelectrocatalytic Radical Trifluoromethylation with\nTrifluoroacetates”\n(manuscript number NCOMMS-25-80469)\nPoint-by-point Response to the Reviewers’ Comments\nFirst, we would like to thank the reviewers for their valuable feedback and insightful questions,\nwhich have prompted us to further refine the mechanistic understanding of our transformation.\nIn response, we have expanded our mechanistic investigations by extending the electrochemical\nand spectroscopic studies to include conditions in the presence of trifluoroacetic acid (TFA).\nWe have found that, in addition to supplying protons to close the electrochemical circuit through\nH evolution at the cathode, TFA also contributes to the electrochemical stabilization of certain\n2\niron species generated under the reaction conditions. The presence of TFA alter the shape of the\ncyclic voltammogram of a mixture of Fe(OTf) , L1 and sodium trifluoroacetate (molar ratio\n2\n1:1:60), giving rise to a new reversible redox couple at –0.1 V (vs. Fc+/Fc) in addition to the\nsignals associated with the [Fe(L1) ]2+/3+ system previously detected under basic conditions.\nanalyses, this newly observed reversible redox couple, which remains electrochemically stable\nover 50 CV scans, has been assigned to ligated Fe-trifluoroacetate species II. Further\nelectrochemical studies conducted under illumination revealed that the redox couple II/V is\nalso photoactive. These findings, along with the complementary data now incorporated into\nboth the revised manuscript and the Supplementary Information, have enabled us to refine our\noriginal mechanistic proposal, in which an electrocatalytic cycle synergistically converges with\nan Fe-mediated LMCT photodecarboxylation process through two plausible pathways. Under\nreaction conditions, intermediate II is generated, which can be oxidized at the anode to form\nthe corresponding Fe(III) species V. This intermediate serves a dual function: 1) upon visible-\nlight excitation, V can facilitate LMCT photodecarboxylation, producing trifluoromethyl\nradicals and regenerating species II through coordination with sodium trifluoroacetate\n(pathway A); and 2) alternatively, V may act as a redox catalyst, promoting the single-electron\noxidation of non-ligated Fe species I in solution, thereby generating Fe(III) intermediates (IV),\nwhich also contribute to photodecarboxylation (pathway B). Although intermediate V is\nphotoactive, its evolution might be slow enough to compete with a fast electron transfer with\nintermediate I in solution. This behavior contrasts sharply with the recent study on\nphotoelectrochemical fluoroalkylation (excluding trifluoromethylation), where Fe(II)\n1\ncarboxylate intermediates showed reversible cyclic voltammograms without ancillary ligands,\nhighlighting the unique speciation of trifluoroacetates (Angew. Chem. Int. Ed. 64, e202504143\n(2025)). Additionally, the need for TFA to stabilize species II and V distinguishes the CF₃-\nradical generation mechanism from our prior, in which trifluoroacetate photodecarboxylation\noccurred under basic conditions (Angew. Chem. Int. Ed. 63, e202311984 (2024)).\nThe discussion of the updated mechanistic proposal has been added to the revised manuscript,\nincluding the following new version of Figure 2.\nA. Catalyst speciation: simultaneous in situ formation of both photoactive species and redox catalysts\nO redox catalysts\n2+\nOMe N\nNaO CF3\nN N\nFe(OTf) 2 + N OMe [Fe(O 2 CCF3) m ](2-m)+ + [FeII(L1)n(O2CCF3)(HO2CCF3)]+ + N FeII N\nN + TFA N\nL1 MeCN I II III\nphotoactive species upon oxidation\nB. Effect of the addition of TFA C. Cyclic voltammetry measurements D. Photostability of the iron species\nin the presence of TFA in solution\nE. Mechanistic proposal\ne– cathode\nanode 1/ H\n2 2\nH+ R\n[FeIII(L1)n(O2CCF3)(HO2CCF3)]2+ O CF 3\nV CF3\n[FeII] O NaO2CCF3 H+\nPath A Path B I e–\ne– LMCT electrocatalysis\ncatalysis\nLMCT\nE1/2 -0.10 V LMCT\nEp/2 +0.10 V catalysis\nLMCT R\nCF\nO\nNaO2CCF3\nCF3\n[FeIII] O R\nH\n[FeII(L1)n(O2CCF3)(HO2CCF3)]+ IV\nII\nO - CO2\nF\nO CF3 F F\n– No product formation was detected in the absence of L1, indicating that catalytic turnover\nof species I is not efficient at the anode.\n– In the absence of L1, reactivity could be restored upon addition of redox catalysts with\nsimilar electrochemical properties as that of species V, as for example ferrocene. This\nindicates that species V may act as redox mediators facilitating I to IV oxidative turnover.\nThis observation also highlights the ability of non-ligated Fe(III) trifluoroacetate\nintermediates (IV) to promote photodecarboxylation under acidic conditions, as previously\nsupported by theoretical calculations (Nat. Comm. 15, 6115 (2024)).\nExperimental evidence supporting pathway A:\n– Detection of a new reversible wave in the cyclic voltammogram under reaction conditions\nupon addition of TFA. Analysis of CV data from various combinations of the reaction\ncomponents indicates that this new Fe species (II) likely contains both L1 and\ntrifluoroacetate ligands. Corresponding ions have also been observed by in situ HRMS.\n– The reversible redox couple at –0.1 V (vs. Fc+/Fc), involving species II and V, has shown\nto be photoactive in CV experiments upon irradiation.\n– Catalytic trifluoromethylation was detected even at high ligand L1 loadings (30-50 mol%),\nwhere the concentration of non-ligated Fe species is expected to be minimal. This suggests\nthat ligated Fe(III) trifluoroacetate species play also a role in promoting\nphotodecarboxylation.\nAll data summarized and discussed in this introduction are provided in the revised\nSupplementary Information.\nWe believe that this comprehensive mechanistic hypothesis provides a more accurate\nrepresentation of the processes occurring under reaction conditions and accounts for all the\nexperimental data we have obtained.\nThe manuscript entitled “Dual-Role Iron Species in Photoelectrocatalytic Radical\nTrifluoromethylation with Trifluoroacetates” reports a photoelectrocatalytic protocol for\nC(sp²)–H trifluoromethylation using readily available trifluoroacetates as CF₃ sources. The\nauthors propose that in situ–generated Fe species play a “dual role” as both photo- and\nelectrocatalysts, enabling decarboxylation and catalyst turnover without stoichiometric\noxidants. In my view, this work represents an incremental rather than a conceptual advance over\nexisting Fe-LMCT and electrophotocatalytic trifluoromethylation chemistry, and therefore does\nnot meet the novelty and impact criteria for Nature Communications.\n1. The combination of Fe-based LMCT photochemistry with electrochemical oxidation has\nalready been demonstrated in several recent studies (e.g., Campbell et al., Science 2024, 383,\n279; Chen et al., Science 2024, 384, 670; Qi et al., J. Am. Chem. Soc. 2023, 145, 24965). The\ncurrent work does not introduce a clearly distinct mechanistic paradigm or reactivity\nprinciple beyond these precedents.\nUnfortunately, I am afraid our perspective regarding the mechanistic paradigm of our\ntransformation compared to the chemistry reported in these works differs from the\nconcerns highlighted by this reviewer. The transformations developed by the groups of\nNocera, Xuan & Mo and Wu represent very elegant and outstanding studies on the\nphotoelectrochemical trifluoromethylations of organic substrates using trifluoroacetates\nor trifluoroacetic acid, as we have highlighted in the main text. The group of Nocera used\nsilver salts to generate perfluoroalkyl radicals through the direct oxidation of the silver\nspecies at the electrode. The group of Xuan & Mo nicely engineered a WO photoanode,\n3\nenabling the selective oxidation of trifluoroacetates through an ion shielding electrode.\nThe group of Jie Wu pioneered the direct oxidation of TFA at the anode to generate the\ntrifluoromethyl radical. However, neither of these studies addresses Fe-based LMCT\nphotochemistry. We would argue that our reactivity concept, which involves dual-role Fe\nactive species, provides a complementary approach to these works.\n2. The authors’ previous report (Angew. Chem. Int. Ed. 2024, e202311984) already established\nFe-LMCT photodecarboxylation of trifluoroacetates. The present study essentially replaces the\nchemical oxidant (K2S2O8) with anodic oxidation to complete the catalytic cycle. While this\nmodification improves atom economy, it constitutes an expected optimization rather than a\nconceptual breakthrough.\nsustainable transformations, replacing a chemical oxidant with anodic oxidation is far\nfrom trivial. We hope that the more extensive mechanistic study presented in the revised\nmanuscript clarifies this point. As highlighted in the introduction of this letter, the role of\nTFA is far from innocuous, because it significantly alters the catalyst's speciation under\nreaction conditions, facilitating a successful transformation. The necessity of TFA to\nelectrochemically stabilize species II and V further distinguishes the CF₃-radical\ngeneration mechanism from our prior work, in which trifluoroacetate\nphotodecarboxylation was carried out under basic conditions, suggesting that a different\nreactivity pathway may have been operative in that case.\nMoreover, Motornov et al. (Angew. Chem. Int. Ed. 2025, 64, e202504143) have employed a\nsimilar iron catalyst in photoelectrochemical catalysis with a broader substrate scope.\nI believe our perspective on this matter also differs from the reviewer’s statement. Based\non our new experimental data, which include CV, UV-Vis spectroscopy and in situ HRMS\nstudies, we propose that our transformation operates through an intricate\nphotoelectrocatalytic manifold. In our system, the ligand plays a critical role in enabling\nthe catalyst to achieve the proper speciation, providing photoactive species that facilitate\ndecarboxylation, and redox catalysts that mediate oxidative turnover of non-ligated iron\nintermediates. In the absence of the ligand, no Fe species exhibiting reversible CV are\ndetected, and no reaction is observed in the absence of a redox mediator. While the\nreaction described by Motornov et al. proves effective for various fluoroalkylation\nreactions (including a single example of trifluoromethylation), it contrasts sharply with\nour findings. Their study demonstrates Fe carboxylate intermediates with reversible CV\nin the absence of ancillary ligands, underscoring the unique speciation of Fe\ntrifluoroacetates in the presence of TFA. Our reactivity concept has enabled the\ntrifluoromethylation of electron-rich, easily oxidizable substrates such as pyrroles,\nindoles, and electron-rich simple arenes. In contrast, when applying the method\ndeveloped by Motornov et al. to these substrates, we were unable to obtain the\ncorresponding trifluoromethylated products (see SI, page 56). This highlights the broader\nscope of our approach and its orthogonality to existing methodologies.\n5\n3. The mechanistic analysis is limited to cyclic voltammetry and UV–vis spectroscopy. No\ndirect or quantitative evidence supports the coexistence of distinct Fe species responsible for\nphoto- and electrocatalytic functions. Operando or time-resolved studies would be necessary to\nsubstantiate the proposed dual-catalyst mechanism.\nIn the revised manuscript and Supplementary Information, we have conducted a series of\nextensive and complementary experiments to support our more comprehensive\nmechanistic proposal. This updated study now includes a new set of control experiments,\ncyclic voltammetry measurements under varying conditions (including irradiation),\nas well as additional UV-Vis spectroscopic data and in situ HRMS analyses. Together,\nwe\nbelieve these provide stronger and more compelling evidence for the validity of our\nproposed mechanistic hypothesis.\n4. The substrate scope largely overlaps with known photoredox and electrophotocatalytic CF3-\nintroduction protocols. The functionalization of a few drug-like molecules (e.g., caffeine,\nmelatonin) is insufficient to raise the overall impact to the level expected for Nature\nCommunications.\nThe trifluoromethylation reaction is of central significance in numerous applied contexts\nand has therefore been the subject of extensive investigation. Although radical\ntrifluoromethylation using classical reagents (e.g., Togni and Langlois) is well\nestablished, we argue that the deployment of trifluoroacetates or trifluoroacetic acid as\ntrifluoromethylating agents for the derivatization of C(sp²)–H bonds remains\ncomparatively underexplored. To our knowledge, only a limited number of studies, most\nnotably those reported by the groups of Nocera, Wu, and Mo, which we have discussed\nin the text, have demonstrated such reactivity. In most cases, the scope of our\ntransformation is broader than that of theses methodologies. Our protocol is compatible\nnot only with electron-deficient and electron-neutral substrates but also with more\nchallenging electron-rich (hetero)arenes, which are typically susceptible to oxidative\ndegradation. A quick survey of our reaction scope reveals at least 12 structurally diverse\nscaffolds bearing distinct substitution patterns, including the synthesis of trifluridine (one\nof the top-selling small-molecule pharmaceuticals globally) and the successful\nfunctionalization of at least four drug-like substrates.\nIn this work, Francisco Juliá-Hernández et al. report a very elegant strategy for the\nphotoelectrocatalytic radical trifluoromethylation of arenes using easily accessible alkali\ntrifluoroacetate salts and TFA. This approach is highly powerful and could have a significant\nimpact on the pharmaceutical and agrochemical industries by providing a more sustainable\nroute to fluorinated molecules. This study builds upon the authors’ 2024 Angewandte Chemie\npaper, in which they used a stoichiometric oxidant for a Minisci-type trifluoromethylation\nreaction. Clearly, the present work represents a greener approach, as it solves a long-standing\nproblem in nucleophile cross-coupling: the use of stoichiometric amounts of reactive and\naggressive oxidants, which often limit functional group tolerance and the overall reaction scope.\nWe appreciate the reviewer’s comments recognizing the novelty and impact of our work.\nThe authors provide an elegant solution to this issue by employing dual iron electrocatalys and\nphotocatalysis via a LMCT (ligand-to-metal charge transfer). They found that a “ligand-free:\niron trifluoroacetate species acts as a photocatalyst, generating the trifluoromethyl radical via\nlight-induced charge-transfer homolysis and decarboxylation. Meanwhile, tris(bipyridine)-\ncoordinated iron serves as an electron mediator in the electrocatalytic step. The authors present\nthorough mechanistic studies supported by UV-Vis spectroscopy, cyclic voltammetry (CV), and\nchronoamperometry, as well as hydrogen detection, all of which are discussed in detail in the\nmanuscript and the Supporting Information (SI). The SI is of good quality and complete.\nWe thank the reviewer for acknowledging our efforts to elucidate the mechanism\nunderlying this transformation. As noted in the introduction of this letter, we have\nexpanded our mechanistic studies by extending our electrochemical and spectroscopic\nanalyses to include conditions in the presence of trifluoroacetic acid (TFA). These studies\nrevealed iron species bearing ligand L1 and trifluoroacetate groups that are\nelectrochemically stabilized by TFA. Notably, these species may serve a dual function in\nthe reaction by promoting photodecarboxylation and facilitating redox turnover of non-\nligated iron trifluoroacetate intermediates. Consequently, we propose a revised\nmechanistic framework involving two plausible productive pathways, each consistent\nwith our experimental observations. All new data is summarized in the revised\nSupplementary Information and discussed in the revised manuscript.\nthe readers of Nature Communications.\nMinor comments and suggestions:\n-In Figure E6c, please correct the spelling of “voltajes” (should be “voltages”).\nThis has been amended.\n-I would also like the authors to comment and discuss how the pyridyl radical, generated after\nthe addition of the trifluoromethyl radical, undergoes oxidation, rearomatization, and proton\nrelease. Does this process occur directly at the electrode surface, or is the iron(III)L3 complex\nagain the oxidant in this step?\nWe thank the reviewer for their valuable comments and suggestions. Indeed, following\nthe addition of the CF₃ radical, the resulting cyclohexadienyl-type radical undergoes\noxidation, proton release, and rearomatization. The efficiency of the oxidation step may\nvary depending on the nature of the substrate. In the revised manuscript, we have included\nthe possibility that [Fe(L1) ]3+ species could mediate the oxidative rearomatization in the\n3\nbulk of the solution, in addition to direct oxidation at the anode.\n-Additionally, I suggest that the authors discuss the reaction's efficiency at different ratios of\nthe iron; L is used, as this will naturally affect the balance between “ligand-free” iron and\ntris(bipyridine) iron species.\nWe appreciate the reviewer’s suggestion. In line with our updated mechanistic proposal,\ndecarboxylation can occur both from ligated Fe trifluoroacetate species (V) and from non-\nligated intermediates (IV), the latter of which was initially proposed in the first version\nof the manuscript. This conclusion stems from an extensive investigation of Fe speciation\nin the presence of TFA, which revealed the formation of ligated Fe trifluoroacetate species\nthat were found to be photoactive. Accordingly, when performing the\nphotoelectrocatalytic trifluoromethylation under optimized conditions, but with increased\nloading of L1 (30 and 50 mol%), we observed favorable reactivity, which likely results\nfrom the preferential formation of ligated species, such as II, which favored pathway A\nin our revised mechanistic proposal. Interestingly, when using 50 mol% of L1, the yield\nof the product was lower, likely due to the increased formation of Fe trisbipyridine-type\n8\nspecies (III), which are not directly involved in the decarboxylation of trifluoroacetates.\nThese experiments have been included in the revised Supplementary Information.\nFe(OTf) (10 mol%)\nO TFA (1.3 equiv)\nH CF\n+ 3\nNaO CF 3 nBu 4 NPF 6 (2 equiv)\nMeO OMe MeCN, 390 nm MeO OMe\n6 equiv [RVC (+) / SS(-)]\nE = 2.06 V\ncell\nentry L1 CF -yield (bis)\n3\n1 10 mol % 76%\n2 30 mol % 90%(9)\n3 50 mol% 36%\n-Finally, what is the effect of the bipyridine ligand structure (e.g., tert-butyl, Me or unsubtituted\nbypy) on the electron mediator properties?\nAs outlined in the introduction of this letter, the mechanistic pathway for our\nphotoelectrocatalytic trifluoromethylation reaction is more complex than initially\nanticipated, involving ligated Fe trifluoroacetate species that act as bifunctional catalysts.\nThese species both serve as redox mediators, facilitating the turnover of non-ligated Fe\ntrifluoroacetate intermediates, and promote photodecarboxylation. In response to the\nreviewer’s suggestion, we tested several electronically distinct bipyridine-type ligands\nand studied Fe speciation via cyclic voltammetry. However, none of the tested ligands\nresulted in more reactive conditions. Given the complexity of the reaction pathway, it is\nchallenging at this stage to fully rationalize the observed trends solely based on the\nelectronic properties of the ligands. This is due to the fact that each ligand class likely\nleads to distinct speciation, with intermediates that exhibit varying reactivity toward\nphotodecarboxylation and different redox potentials. We have included the relevant data\nin the revised Supplementary Information.\n9\nentry deviation yield of 2\nFe(OTf) (10 mol%) 1 L1 76%\nO TFA (1.3 equiv)\nH + CF 3 3 L3 52%\nNaO CF 3 nBu 4 NPF 6 (2 equiv) 4 L4 0%\nMeO OMe MeCN, 390 nm MeO OMe 5 L5 46%\n6 equiv [RVC (+) / SS(-)]\nE = 2.06 V 2\ncell\nMeO OMe MeO C CO Me\n2 2\nN N\nN N N N\nL1 L2 L3\nMe 2 N NMe 2 F 3 C CF 3 tBu tBu\nN N N N N N\nL4 L5 L6\nCV study with L1:\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) [grey trace]; (ii) Fe(OTf) (10 mM) and\n2 2\nNaO CCF (600 mM) [green trace], (iii) Fe(OTf) (10 mM) and L1 (10 mM) [blue trace], (iv)\n2 3 2\nFe(OTf) (10 mM), L1 (10 mM) and NaO CCF (600 mM) [orange trace]. Every independent\n2 2 3\nmeasurement was done in the presence of trifluoroacetic acid (TFA, 130 mM).\nCyclic voltammograms of: (i) Fe(OTf) (10 mM), L2 (10 mM) and TFA (130 mM) [blue trace];\n2\n(ii) Fe(OTf) (10 mM), L2 (10 mM), NaO CCF (600 mM) and TFA (130 mM) [purple trace].\n2 2 3\nCV study with L3:\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) and L3 (10 mM) [black trace]; (ii) Fe(OTf) (10\n2 2\nmM), L3 (10 mM) and TFA (130 mM) [blue trace]; (iii) Fe(OTf) (10 mM), L2 (10 mM),\n2 3\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) and L4 (10 mM) [black trace]; (ii) Fe(OTf) (10\n2 2\nmM), L4 (10 mM) and TFA (130 mM) [blue trace]; (iii) Fe(OTf) (10 mM), L4 (10 mM),\n2 3\nCV study with L5:\n60\n50\n40\n30\n20\n10\n0\n-10\n-20\n-30\n-40\n-1 -0,8 -0,6 -0,4 -0,2 0 0,2 0,4 0,6 0,8 1 1,2\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) and L5 (10 mM) [black trace]; (ii) Fe(OTf) (10\n2 2\nmM), L5 (10 mM) and TFA (130 mM) [blue trace]; (iii) Fe(OTf) (10 mM), L5 (10 mM),\n2 3\n12\n)Aµ(\ntnerruc\nFeF+eL(5OTf)2+ L5 (1:1)\nFeF+eL(5O+TTFfA)2+ L5 + TFA (1:1:13)\nFeF+eL(5O+NTaf)T2F+A L5 + NaO2CCF3 + TFA (1:1:60:13)\n-0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1.0\nPotential (V vs FC+/Fc0)\nCV study with L6:\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) and L6 (10 mM) [black trace]; (ii) Fe(OTf) (10\n2 2\nmM), L6 (10 mM) and TFA (130 mM) [blue trace]; (iii) Fe(OTf) (10 mM), L6 (10 mM),\n2 3\nIn this communication, Fernández-Garcia et. al. report a photoelectrocatalytic methodology for\nthe decarboxylation of cheap and abundant TFA using Fe catalysis, producing trifluoromethyl\nradicals that may be harnessed for the trifluoromethylation of (hetero)arenes. This work is a\ncontinuation of their 2024 ACIE manuscript (Angew. Chem. Int. Ed. 2024, 63, e202311984;\nRef. 11 in the current work) in which the main advance is moving away from a chemical oxidant\n(K2S2O8) toward electrochemical oxidation. Thus, this is the most distinguishing point of the\npaper. It certainly is not a big leap to do so but there are a few notable points. While\nphotoelectrocatalysis has previously been demonstrated in Fe-mediated fluoroalkylation from\nfluoroalkyl carboxylates (Ackermann, Angew. Chem. Int. Ed. 2025, 64, e202504143, ref. 40 in\nthe current work), the current work is distinguished by perhaps broader applicability towards\nelectron-rich functionalities, as well as a potentially unique reaction mechanism. The\ndemonstrated reaction scope appears nearly identical to the author’s prior work (ref. 11),\nalthough the tolerance of electron-rich functionality (substrate 2) is notable under\nelectrochemical conditions where anodic overoxidation is a possibility. In light of the above\npoints, I recommend publication after addressing the following comments, which mainly\nconcern 1) clarification of the reaction mechanism and 2) differentiation of the\nmethodology from prior work.\nWe would like to take this opportunity to thank this reviewer for his/her valuable\nfeedback, which has been instrumental in enhancing the impact of our work. The\nelucidation of a more comprehensive mechanistic hypothesis now provides a more\naccurate representation of the processes occurring under the reaction conditions. This has\nbeen summarized at the beginning of this letter, and it has also been incorporated into the\nrevised manuscript and Supplementary Information.\n1. The redox features in the cyclic voltammograms are reported vs a Ag/AgCl reference. The\nauthors are encouraged to report the potentials vs ferrocene or SCE instead, as these values are\nmore utilized and easily comparable in non-aqueous systems.\nFerrocene has been used to report cyclic voltammograms in both the revised manuscript\nand Supplementary Information.\n14\n2. The authors state: “whereas the redox signals corresponding to complex II remained stable, displaying a higher anodic\nthan cathodic current, suggestive of electrocatalytic behavior.” In reference to Figure S20. Upon inspection of Figure S20, it\nappears the CV was slightly misinterpreted. Peak anodic and peak cathodic currents should not be read from absolute value\non the y-axis. Please do some reading in the most rudimentary electrochemical textbooks to properly interpret the CVs.\nWhen reading from the absolute values, the peak anodic current of the last scan (dark orange line) is 25 µA and the peak\ncathodic current is –11 µA, which is perhaps why the authors made the above statement. However, the baseline in the\nforward wave is about 5 mA while that of the reverse wave is ca. 9 mA, meaning that the peak anodic current is 20 µA and\ncathodic current –20 µA when read from these values, indicating a fully reversible wave, as expected for species II.\nAbsolutely no evidence for electrocatalysis can be gleaned from this CV behavior. These are the types of sloppy mistakes\nthis field is prone to … electrochemistry is a field unto itself. It needs to be done properly even if this is an “organic”\nmanuscript.\nWe sincerely regret this misinterpretation. This explanation is no longer in the manuscript\nas the mechanistic investigation has been further improved.\n3. The assignment of species III in the CVs is ambiguous. It’s irreversibility and similarity to a CV of Fe(OTf)2 + NaO2CCF3\nsuggest it is a TFA ligated Fe species, but a few questions remain. Figure 2B should include concentrations of analytes in the\nfigure caption or figure legend. If the orange trace and green trace are equimolar Fe concentrations, why does the orange\ntrace feature a boosted III redox wave?\nWe thank the reviewer for these comments. In Fig. 2B of the original submission, the total\niron concentration for both orange and green curves was not the same. Indeed, at\nequimolar concentrations, this boost is no longer observed:\n2 2\nNaO CCF (600 mM) [green trace], (iii) Fe(OTf) (10 mM) and L1 (10 mM) [blue trace], (iv)\n2 3 2\nFe(OTf) (10 mM), L1 (10 mM) and NaO CCF (600 mM) [orange trace]. Every independent\n2 2 3\nmeasurement was done in the presence of trifluoroacetic acid (TFA, 130 mM).\nFigure S20 shows that this wave diminishes significantly upon cycling, suggesting that the\nchemical step following oxidation is depleting the precursor to III overtime. Can the authors\nalso cycle a CV of Fe(OTf)2 + NaO2CCF3 similarly to Figure S20? Does the redox wave at –\n0.35 V also diminish in intensity?\nWe performed this experiment and observed that the redox wave diminished in intensity\nin the absence of TFA, with the redox wave now occurring at 0.15 V vs Fc+/Fc.\nSequential cyclic voltammograms of Fe(OTf) (10 mM) + NaO CCF (600 mM).\n2 2 3\nassociated with III in the first scan, as Figure 2B suggests? This would mean that there is some\nFe species in solution that contains both TFA and L1.\nWhen equimolar amounts of Fe(OTf) and sodium trifluoroacetate are employed, the\n2\naddition of L1 results in the formation of a complex mixture, consisting of Fe(OTf) ,\n2\n[Fe(L1) ]2+ and solvated Fe trifluoroacetate species, as observed in the cyclic\n3\nvoltammogram.\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) and NaO CCF (10 mM) [black trace]; (ii)\n2 2 3\nFe(OTf) (10 mM), NaO CCF (10 mM) and L1(10 mM) [red trace].\n2 2 3\nIn any case, as noted in the introduction of this letter, we have expanded our mechanistic\nstudies by extending our electrochemical and spectroscopic analyses to include conditions\nin the presence of trifluoroacetic acid (TFA). These studies revealed iron species bearing\nligand L1 and trifluoroacetate groups that are electrochemically stabilized by TFA.\nNotably, these species may serve a dual function in the reaction by promoting\nphotodecarboxylation and facilitating redox turnover of non-ligated iron trifluoroacetate\nintermediates. Consequently, we propose a more comprehensive mechanistic framework\ninvolving two plausible productive pathways, each consistent with our experimental\nobservations. This has been summarized at the beginning of this letter, and it has also\nbeen incorporated into the revised manuscript and Supplementary Information.\n17\n4. The above point is convoluted by the fact that the authors observe near quantitative formation\nof II via beer-Lambert analysis, ruling out Fe species that contain both TFA and L1. If this is\ntrue, it is unclear why L1 would boost the anodic current of III on the first scan, as no IV is\npresent in solution yet to mediate the oxidation of III to V.\nWe greatly appreciate these suggestions, which have prompted us to reevaluate the\nmechanistic investigation in the presence of trifluoroacetic acid. In the presence of TFA,\nthe formation of the trisbipyridine-type iron species has been calculated to be less than\n23%. Therefore, it is highly plausible that Fe species containing both L1 and\ntrifluoroacetate ligands are formed in significant concentrations, as suggested by the\nreviewer. Indeed, the corresponding ions have also been observed by in situ HRMS. The\nnew experimental data have been added to the revised Supplementary Information and\ndiscussed in the main text.\nThe claim that quantitative II is formed suggests that adding too much L1 should completely\nshut off reactivity, as no Fe would be left to ligate to TFA. It does not appear that the authors\nincluded an optimization of L1 concentration, unless I am mistaken. If 30 mol% L1 or greater\nis employed, all the Fe should be sequestered as II, and the yield should drop. Can the authors\ndemonstrate this? Recent work published on the rxiv (https://doi.org/10.26434/chemrxiv-2025-\ndjp0r) showcases TFA decarboxylation from well-defined (dien)FeTFA complexes. It is\npossiblre that the photoactive species can still contain a mixture of TFA and bpy ligands. This,\nof course, would be supported by the presence of product even when employing, say, 50 mol%\nligand.\nOnce again, we would like to thank this reviewer for the comments, which have been key\nin directing our revised mechanistic investigation. In line with our more comprehensive\nmechanistic proposal, decarboxylation can occur both from ligated Fe trifluoroacetate\nspecies (V) and from non-ligated intermediates (IV), the latter of which was initially\nproposed in the first version of the manuscript. This conclusion stems from an extensive\ninvestigation of Fe speciation in the presence of TFA, which revealed the formation of\nligated Fe trifluoroacetate species that were found to be photoactive. Accordingly, when\nperforming the photoelectrocatalytic trifluoromethylation under optimized conditions,\nbut with increased loading of L1 (30 and 50 mol%), we observed favorable reactivity,\nwhich likely results from the preferential formation of ligated species, such as II and III,\n18\nwhich favored pathway A in our revised mechanistic proposal. Interestingly, when using\n50 mol% of L1, the yield of the product was lower, likely due to the increased formation\nof Fe trisbipyridine-type species, which are not directly involved in the decarboxylation\nof trifluoroacetates. These experiments have been included in the revised Supplementary\nInformation.\nFe(OTf) (10 mol%)\nO TFA (1.3 equiv)\nH CF\n+ 3\nNaO CF 3 nBu 4 NPF 6 (2 equiv)\nMeO OMe MeCN, 390 nm MeO OMe\n6 equiv [RVC (+) / SS(-)]\nE = 2.06 V\ncell\nentry L1 CF -yield (bis)\n3\n1 10 mol % 76%\n2 30 mol % 90%(9)\n3 50 mol% 36%\n5. Notably, the authors demonstrate that Ackermann’s conditions (ref 40) result in 0 percent\nyield on substrate 2, showcasing the current methodology’s tolerance towards more electron-\nrich substrates. However, the authors attribute this to the role L1 plays in the proposed\nmechanism. Is it possible that L1 simply serves to decrease the required oxidation potential to\naccess Fe(III)? Thus, the yield is 0 under Ackermann’s conditions due to direct oxidation of 2\nat the anode. Ackermann demonstrates successful triufluoromethylation of caffeine without a\nligand, which is harder to oxidize. Under the current conditions, if L1 is excluded, can caffeine\nstill be engaged? If not, this is likely due to the low cell potential (2.06 V), if this is raised, or\nconstant current electrolysis is utilized, I assume caffeine can be engaged without L1. Please\nperform this experiment.\nExperiments using caffeine as the substrate were performed in the absence of L1, under\nconstant cell potential, and at a constant current of 4 mA, resulting in very low yields of\nthe corresponding trifluoromethylated caffeine (15% and 2%, respectively). These results\nindicate that caffeine cannot be effectively engaged under these conditions, suggesting\nthat our reaction pathway differs significantly from the one operating under Ackermann's\nconditions. The data have been included in the revised Supplementary Information.\nMe N N H + O TFA (1.3 equiv) Me N N\nO N N NaO CF 3 nB M u 4 e N C P N F , 6 3 ( 9 2 0 e n q m uiv) O N N CF 3\nMe 6 equiv [RVC (+) / SS(-)] Me\nentry conditions CF -yield\n3\ncell\n2 i = 4.0mA 2%\n6. The use of mediators instead of L1 restores reactivity, including non Fe-containing mediators\nsuch as magic blue; this is a notable result. However, species III is still easier to oxidize at an\nelectrode than these mediators, so it is unclear as to why the harder to oxidize species would\nserve as an electron shuttle. A separate hypothesis is that the redox mediator may help to oxidize\narene radical intermediates in solution to the cation, which facilitates rearomatization after\nradical addition following proton loss.\nWe completely agree with the reviewer in this comment. Indeed, in our revised\nmechanism, we propose that species V, containing both L1 and trifluoroacetate ligands,\nwith an E at –0.1 V (vs. Fc+/Fc), may play a role in mediating the oxidation of non-\n1/2\nligated Fe trifluoroacetate species (I) with E at +0.1 V (vs. Fc+/Fc). Additionally, we\np/2\nfound that, in the absence of L1, ferrocene can mediate this oxidation, as its cyclic\nvoltammogram closely resembles that of species V. In the case of Fe trisbipyridine-type\ncomplexes or acetylferrocene, which exhibit reversible redox couples with oxidation\npotentials greater than those of non-ligated Fe trifluoroacetate intermediates, but within\nthe range of the applied potential, their role may be related to facilitating the\nrearomatization of the resulting cyclohexadienyl-type radicals after CF₃ addition in\nsolution. The efficiency of the oxidation step may vary depending on the substrate. In the\nrevised manuscript, we have included the possibility that [Fe(L1) ]3+ species could\n3\nmediate the oxidative rearomatization in the bulk of the solution, in addition to direct\noxidation at the anode. The role of magic blue, which is harder to oxidize compared to\nthe other redox mediators used, under reaction conditions without L1, remains difficult\nto clarify. While magic blue could be involved in photoinduced events, its precise role in\nthe transformation remains speculative.\n20\n7. Altogether, the mechanistic hypothesis proposed in Figure 2D is perhaps plausible, but many\nuncertainties remain. To me, it is clear that L1 ligates Fe(II), making it easier to oxidize to\nFe(III) which is required for LMCT. The fact that no yield is observed in the absence of L1,\neven though no ligands are required in other work (ref. 40) is because, in this work, the potential\nat the anode is low. This helps facilitate reactions with electron-rich substrates. Presumably, the\nuse of other bipyridine derivatives, or phenanthroline derivatives, can further modulate the\npotential required for Fe(II) oxidation. How are the CVs changed when more or similar electron\nrich bpy derivatives are used (R = NMe2, tBu, Me, etc) or when more electron-poor derivatives\nare used (R = CF3, CO2Me, Cl, F, etc.)? Can reactivity be improved with a different ligand? If\nthe required oxidation potential is moved too anodic with more electron poor bpy derivatives,\ndoes this completely shut off reactivity in the utilized potential window? Mechanistic\nexperiments with varied bpy ligands should be carried out to provide more insight into the\nproposed mechanism.\nAs outlined in the introduction of this letter, the mechanistic pathway for our\nphotoelectrocatalytic trifluoromethylation reaction is more complex than initially\nanticipated, involving ligated Fe trifluoroacetate species that act as bifunctional catalysts.\nThese species both serve as redox mediators, facilitating the turnover of non-ligated Fe\ntrifluoroacetate intermediates, and promote photodecarboxylation. In response to the\nreviewer’s suggestion, we tested several electronically distinct bipyridine-type ligands\nand studied Fe speciation via cyclic voltammetry. However, none of the tested ligands\nresulted in more reactive conditions. Given the complexity of the reaction pathway, it is\nchallenging at this stage to fully rationalize the observed trends solely based on the\nelectronic properties of the ligands. This is due to the fact that each ligand class likely\nleads to distinct speciation, with intermediates that exhibit varying reactivity toward\nphotodecarboxylation and different redox potentials. We have included the relevant data\nin the revised Supplementary Information.\n21\nentry deviation yield of 2\nFe(OTf) (10 mol%) 1 L1 76%\nO TFA (1.3 equiv)\nH + CF 3 3 L3 52%\nNaO CF 3 nBu 4 NPF 6 (2 equiv) 4 L4 0%\nMeO OMe MeCN, 390 nm MeO OMe 5 L5 46%\n6 equiv [RVC (+) / SS(-)]\nE = 2.06 V 2\ncell\nMeO OMe MeO C CO Me\n2 2\nN N\nN N N N\nL1 L2 L3\nMe 2 N NMe 2 F 3 C CF 3 tBu tBu\nN N N N N N\nL4 L5 L6\nCV study with L1:\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) [grey trace]; (ii) Fe(OTf) (10 mM) and\n2 2\nNaO CCF (600 mM) [green trace], (iii) Fe(OTf) (10 mM) and L1 (10 mM) [blue trace], (iv)\n2 3 2\nFe(OTf) (10 mM), L1 (10 mM) and NaO CCF (600 mM) [orange trace]. Every independent\n2 2 3\nmeasurement was done in the presence of trifluoroacetic acid (TFA, 130 mM).\nCyclic voltammograms of: (i) Fe(OTf) (10 mM), L2 (10 mM) and TFA (130 mM) [blue trace];\n2\n(ii) Fe(OTf) (10 mM), L2 (10 mM), NaO CCF (600 mM) and TFA (130 mM) [purple trace].\n2 2 3\nCV study with L3:\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) and L3 (10 mM) [black trace]; (ii) Fe(OTf) (10\n2 2\nmM), L3 (10 mM) and TFA (130 mM) [blue trace]; (iii) Fe(OTf) (10 mM), L2 (10 mM),\n2 3\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) and L4 (10 mM) [black trace]; (ii) Fe(OTf) (10\n2 2\nmM), L4 (10 mM) and TFA (130 mM) [blue trace]; (iii) Fe(OTf) (10 mM), L4 (10 mM),\n2 3\nCV study with L5:\n60\n50\n40\n30\n20\n10\n0\n-10\n-20\n-30\n-40\n-1 -0,8 -0,6 -0,4 -0,2 0 0,2 0,4 0,6 0,8 1 1,2\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) and L5 (10 mM) [black trace]; (ii) Fe(OTf) (10\n2 2\nmM), L5 (10 mM) and TFA (130 mM) [blue trace]; (iii) Fe(OTf) (10 mM), L5 (10 mM),\n2 3\n24\n)Aµ(\ntnerruc\nFeF+eL(5OTf)2+ L5 (1:1)\nFeF+eL(5O+TTFfA)2+ L5 + TFA (1:1:13)\nFeF+eL(5O+NTaf)T2F+A L5 + NaO2CCF3 + TFA (1:1:60:13)\n-0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1.0\nPotential (V vs FC+/Fc0)\nCV study with L6:\nCyclic voltammograms of: (i) Fe(OTf) (10 mM) and L6 (10 mM) [black trace]; (ii) Fe(OTf) (10\n2 2\nmM), L6 (10 mM) and TFA (130 mM) [blue trace]; (iii) Fe(OTf) (10 mM), L6 (10 mM),\n2 3\n25\n8. The reaction times should be included in Figure 3.\nThese have been included.\n9. Substrates 10 and 11 do not contain sterically accessible coordinating nitrogen atoms, so the\nclaim “Notably, the catalyst remained active in the presence of substrates containing potentially\ncoordinating nitrogen atoms” is not supported.\nThis sentence has been removed from the revised manuscript.\n10. The demonstrated scope is remarkably similar to the author’s previous work (ref. 11).\nCompare substrate 11 (this work) vs 17 (ref. 11), 8 (this work) vs 19 (ref. 11), 21 (this work) vs\n33 (ref. 11), or 19 (this work) vs 29 (ref. 11). Even substrates highlighted as challenging due to\ntheir electron-rich nature (18) performed equally well, if not slightly better, in ref. 11 (substrate\n24). Is there any substrate or substrate class that can be engaged in the current methodology\nthat is not amendable to the previous conditions employed in ref. 11? Nonetheless, it is\nunderstood that elimination of a stoichiometric oxidant increases the atom economy of the\ntransformation.\nIn response to the reviewer’s suggestion, we have conducted additional experiments to\nfurther expand the scope of the reaction. However, at this stage, we have not been able to\nobtain the corresponding products in synthetically useful yields (>50%). Some low-\nyielding substrates are highlighted on page 30 of the Supplementary Information.\nNonetheless, we would like to emphasize that our trifluoromethylation reaction has been\nsuccessfully applied to more than 12 different (hetero)cyclic scaffolds with various\nsubstitution patterns. Furthermore, we have successfully scaled up the reactions,\nobtaining trifluoromethylated caffeine (19) and trimethoxybenzene (2) in synthetically\nuseful yields, an outcome that was not achievable under the conditions of our previous\nwork.\n26\n11. The authors should check their assignment of the regioisomer depicted for substrate 12, it\nis more likely that the radical addition occurs next to the carbonyl moiety.\nWe have isolated and fully characterized product 12. We have amended the assignment\nof the regioisomer by direct comparison with the literature data of the isolated compound.\nWe have added the characterization data to the revised Supplementary Information:\n4,6-dimethyl-5-(trifluoromethyl)-2H-pyran-2-one (12)\nMe\nF C\none (62.1 mg, 0.5 mmol). The crude mixture was purified by flash column\nchromatography on a silica gel column, using a mixture of Cyclohexane/Et O (6:4) to\n2\nprovide 12 as a white solid (49 mg, 51% yield).\nRf = 0.42 (Cyclohexane/ Et O (6:4) (v/v)).\n2\n1H NMR (600 MHz, CDCl ): δ 5.92 (s, 1H), 2.33 (q, J = 2.9Hz, 3H), 6H), 2.26 (s, 3H)\n3\nppm.\n13C NMR (151 MHz, CDCl ) δ 164.1, 158.3, 158.2, 123.3 (q, J = 274.0 Hz), 111.2 (q, J\n3\n= 31.3Hz), 108.4, 20.8 (q, J = 4.0 Hz), 19.9 ppm.\n19F NMR (376 MHz, CDCl ): δ –58.06 ppm.\n12 13 3 4\nSpectroscopic data is in agreement with previously reported literature data. (J. Cornella\net al., J. Am. Chem. Soc. 2023, 145, 25538)\n12. If the redox wave for III is overlayed in Figure 6, it looks as if the yield begins to rise when\naccessing that couple, as opposed to the oxidation of the mediator. In fact, the yield plateaus\neven before reaching the E1/2 of Fe(II)L13 to Fe(III)L13. The yield at 0.5 V is also very\ncomparable to the yield at 0.8 V, even though the current displayed under these two\nconditions are very different. This speaks to some of the remaining mechanistic ambiguity highlighted\nabove. Please address.\nis reached at an anodic potential slightly above the E₁/₂ of the Fe-trisbipy pair for caffeine\nas the substrate. This suggests that, as mentioned above, the III/VI redox pair may play\na role in the rearomatization step or in the turnover of the non-ligated Fe trifluoroacetate\nspecies in the bulk of the solution.\nGraphical overlap between: (i) the cyclic voltammetry of Fe(OTf) (10 mM), L1 (10 mM) and\n2 3\nrelationship between anode potential (E ) vs yield of product 19 (right Y-axis).\nanode\nOverall, we are grateful for the referee’s comments which have been very useful in further\nimproving the impact and presentation of our work.\n28"}, "author_response": ""}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have done careful revision and detailed response. The additional mechanistic and electrochemical studies\nsubstantially improve the clarity and rigor of the manuscript, and the revised interpretation of iron speciation and CV data is\nappropriate. Although my view that this work represents an incremental rather than conceptual advance relative to prior Fe-\nLMCT and photoelectrochemical trifluoromethylation chemistry largely remains, I acknowledge that the revised manuscript\nmore clearly differentiates this system through ligand-controlled iron speciation, the critical role of TFA, and its compatibility\nwith electron-rich substrates. I consider my major concerns addressed and recommend acceptance.", "reviewer_2": "In this resubmission, Francisco Juliá-Hernández and the co-authors have thoroughly addressed all of my questions and\ncarefully considered my suggestions. The scientific quality of the work is very high, and the results are both timely and\nimpactful.", "reviewer_3": "In response to reviewer comments, the authors of this work have drastically changed the mechanistic interpretation of the\nreaction mechanism, aligned with suggestions made in my original review of the manuscript. The effort the authors put into\nthis mechanistic reevaluation is appreciated, and in my opinion, the mechanism is sounder than the original draft. However,\ncertain questions remain. Chief among them is the role of Path B. Path B seems almost entirely irrelevant, and the reaction\ncan be purely described by Path A, which is no different than many electrophotocatalytic schemes reported in the literature.\nI agree with Reviewer #1 that the current work is an incremental advance of the authors’ prior work, with many of the defining\nprinciples of the work already having much precedent (electrochemical turnover of Fe perfluoroalkyl carboxylates\ndemonstrated by Ackermann, substrate scope identical to authors’ prior work), as I also stated in my original review. Thus,\nparamount to the novelty of this work is the proposed distinct mechanistic paradigm involving “dual-role” iron species. It\nappears to me that the authors are clinging to this mechanistic interpretation to preserve the novelty of the current work,\nbut all signs point to a normal electrophotocatalytic pathway (i.e. Path A) that is not altogether a new concept.\nIn the original draft, Path A was not discussed by the authors as a possibility. Rather, all reactivity was described to an\nelectrocatalytic turnover of I to IV (III to V in the original draft) mediated by FeL3. Many of my comments (example: comment\n#s 3, 4, 7, 12) drove after the point that reactivity could be enabled entirely by heteroleptic FeLnTFAm complexes that (i)\nundergo Fe(II)   Fe(III) redox at an electrode and (ii) undergo Fe(III)   Fe(II) redox via photochemical LMCT. With new\nexperiments, the authors now include this mechanism as Pathway A in the current work. This represents a familiar LMCT\nelectrophotocatalytic cycle, for example, identical to the scheme proposed by Nocera (Ag(I)   Ag(II) redox at an electrode and\nAg(II)   Ag(I) redox via photochemical LMCT). Pathway B remains similar to the original hypothesis, but it is not sufficiently\nsubstantiated.\n(1) Pathway B invokes chemical oxidation of I by V. inspection of the CV data shows that I is harder to oxidize than II,\nmeaning the V/II couple should not be capable of inducing oxidation of I to IV. In fact, oxidation of I is ~200 mV uphill from\noxidation of II, and practically zero oxidative current for IV/I exists at the E1/2 of V/II. Given this, why do the authors argue that\nthe IV/II couple is relevant under catalytic conditions? Furthermore, HRMS data do not even support the existence of\nligandless FeTFA salts.\n(2) Using the Nernst equation to predict how much IV (A+) will be formed … if an equivalent amount of V (Ox) is added to I\n(A), and II is (Red), the following equation describes the reaction equilibrium:\nA + Ox ⇋ A+ + Red, Keq = [A+][Red]/[A][Ox]\nThe ratio of [A+] to [A] is at equilibrium is given by:\nLog{[A+]/[A]} = 8.47∆E\nwhere ∆E is E(Ox/Red) – E(A+/A). Thus, in this case, ∆E is –0.2V, and there is subsequently approximately 50× more A in\nsolution than A+. Given this unfavorable equilibrium implied in Path B, why do the authors maintain its importance in the\noverall reaction mechanism? Of course, this Nernstian treatment assumes that both the V/II and IV/I redox couples are\nreversible, and the latter is not. Thus, this unfavorable ET could be driven by downstream irreversible chemistry involving IV,\nsuch as LMCT. But why would pathway B, in which thermodynamically unfavorable oxidation is required, be competitive\nwith Path A? LMCT quantum yields are also notoriously low, meaning this second irreversible step is not facile. The authors\nstate in their rebuttal that “although intermediate V is photoactive, its evolution might be slow enough to compete with a fast\nelectron transfer with intermediate I in solution.” Is evolution of V slow (no electrokinetics are provided), or is electron transfer\nto I fast (once again no kinetics). Thus this statement regarding the viability of Path B is purely speculative. V is most likely\nphotoactive and thus can be generated at the electrode, and therefore pathway A can account for all reactivity.\n(3) The authors state in their rebuttal that experimental evidence for Path B is that without L1, no product is generated. The\nabsence of L1 would also shut down path A, which more than likely explains the lack of reactivity. The authors also show the\nability for redox mediators to restore reactivity, but this is not relevant under catalytic conditions when L1 is present. It is\neven more irrelevant when the new ligand loading experiments are included, which conclusively show product yield even with\n50% ligand loading, conditions where ligandless FeTFA is expected to be practically nonexistent. Interestingly, it appears\nthe authors get better results when using ferrocene instead of L1 (see Fig 3). Why was this not pursued further?\nFerrocene is actually cheaper than L1 as well (by a factor of 40 based off Sigma and Ambeed prices), why not use it to mediate the\ntransformation instead of L1 when the economics and yield are strictly better?\nIn summary, in light of the above comments, I believe Path B should be discarded unless the reaction is run without L1 and\nwith redox mediators. It seems likely that, under catalytic conditions, only Path A is operative. And this path is no different\nthan standard electrophotocatalytic protocols. Path B may be operative with no ligand included, but then obviously Path A\nwould not be functioning. The title is “Dual-Role Iron species…” but Fe would only be playing a dual role if Paths A and B\nwere operative at the same time, and this is not necessary for product formation and also is not proven to be the case. The\nproposed dual-role mechanism is overcomplicated for novelty’s sake, and can be reduced to simply one integrated\nelectrophotochemical cycle (Path A).\nUnfortunately, this does decrease one of the main selling points of the paper. My original recommendation was publication if\nthe proposed reaction mechanism could be supported and if the methodology could be differentiated from prior work. Due to\nthe “dual-role” mechanism not being in play anymore, as well as the scope not being able to be expanded beyond that of the\nauthors’ own prior work (comment #10), I leave it up to the Editor to decide if this paper should be published. Regardless, the\ncurrent version of the paper should not be published unless they provide definitive proof that Pathway B is operative.", "reviewer_author_response": "“Dual-Role Iron Species in Photoelectrocatalytic Radical Trifluoromethylation with\nTrifluoroacetates”\n(manuscript number NCOMMS-25-80469A)\nPoint-by-point Response to the Reviewers’ Comments\nReviewer #1:\nThe authors have done careful revision and detailed response. The additional mechanistic and\nelectrochemical studies substantially improve the clarity and rigor of the manuscript, and the\nrevised interpretation of iron speciation and CV data is appropriate. Although my view that this\nwork represents an incremental rather than a conceptual advance relative to prior Fe-LMCT and\nphotoelectrochemical trifluoromethylation chemistry largely remains, I acknowledge that the\nrevised manuscript more clearly differentiates this system through ligand-controlled iron\nspeciation, the critical role of TFA, and its compatibility with electron-rich substrates. I consider\nmy major concerns addressed and recommend acceptance.\nWe sincerely appreciate the reviewer’s comments, which support our revised mechanistic\nproposal and recognize our efforts to improve our work.\nReviewer #2:\nIn this resubmission, Francisco Juliá-Hernández and the co-authors have thoroughly addressed\nall of my questions and carefully considered my suggestions. The scientific quality of the work\nis very high, and the results are both timely and impactful.\nWe are grateful for the reviewer’s evaluation, which has greatly helped us further enhance\nthe impact and quality of our work.\nI have the following optional comments that can improve the clarity of the work:\n1. I found the manuscript structure somewhat challenging, particularly with respect to the\nseparation of the mechanistic discussion across the scope section. I would suggest presenting\nthe mechanistic considerations together, either before or after the scope, to improve clarity and\nreadability.\nis somewhat unconventional; however, we believe it achieves a balance between\nhypothesis, mechanistic investigation and synthetic analysis. We think that positioning\nkey mechanistic experiments at the beginning of the manuscript is essential to support the\nreaction hypothesis. At the same time, moving the remaining mechanistic experiments,\ncurrently placed at the end, earlier in the text could make the mechanistic section too\ndense, before the synthetic potential of the transformation is properly addressed (another\ncentral aspect of our work). We therefore think that maintaining the current structure,\nintroducing the scope after the hypothesis while leaving the additional mechanistic\nexperiments at the end, offers the best compromise. In our opinion, this arrangement\nallows readers to engage with the work, whether interested in the mechanistic aspects or\nthe synthetic potential.\n2. At present, the mechanistic picture involves the interplay of multiple iron species that can\nundergo LMCT to generate photoactive iron trifluoroacetate species capable of delivering the\ntrifluoromethyl radical. In this context, UV-vis titration experiments could be used to quantify\nthe relative amounts of iron chelates bearing three, two, or one ligand. Did the authors explored\nthis possibility?\nWe appreciate the reviewer’s insightful and constructive suggestion. Indeed, we have\nidentified several ligated and non-ligated Fe trifluoroacetate species able to promote the\nformation of CF radicals by electrochemical measurements (CV) and in-situ HRMS.\nreaction conditions, as discussed in the manuscript. In response to the reviewer’s\nsuggestion, the quantification of the possible mono-, bis- and tris-ligated Fe species by\nUV-Vis titration experiments is not trivial. On one hand, the ligated Fe intermediates\nabsorb in overlapping regions of the spectrum (see Fig S9 and S10 in the supplementary\ninformation), which hampers their unambiguous identification. On the other hand, we\nhave been unable to isolate the corresponding discrete chelated Fe species because of\ntheir rapid equilibration in solution. Consequently, suitable pure standards are not\navailable to determine the relative abundances of the individual intermediates.\n2\n3. Importantly, reaction yields are not necessarily correlated with the rates of elementary steps.\nI therefore suggest examining the stoichiometric reaction kinetics (in the absence of electricity\nand TFA) by trapping the CF₃ radical with TEMPO, which would facilitate interpretation of the\nrelative efficiency of the various iron species involved in LMCT. For the kinetic analysis\n(e.g., by 19F NMR) of the stoichiometric system, the authors could employ Fe(OTf)3 (1 equiv,\n0.05M), CF3CO2Na (>10 equiv), and systematically vary the ligand loading (0, 1, 2 and 3\nequiv), collecting several time points at low conversion (<40%). Analysis of the resulting\nkinetic profiles could help identify which of the non-ligated, mono-ligated, or bis-bipyridine-\nligated iron species is most efficient at generating the trifluoromethyl radical.\nStudying stoichiometric reactions that involve elementary steps could provide useful\ninformation about the underlying catalytic process. In our catalytic system, we have\nshown that although a 1:1 ratio between Fe and L1 is used, this does not lead to the\nformation of a discrete mono-ligated intermediate. Instead, an equilibrium of different\niron species is formed, with TFA playing a key role in the speciation. Therefore, we think\nthat although the study of stoichiometric reactions starting from Fe(III) and different\nligand loadings would provide information about the decarboxylation process, this might\nnot be very representative of our reaction system in the absence of TFA. Additionally, we\ndo not expect CF radical trapping by TEMPO to be highly efficient under these\n3\nconditions, as shown in our previous work (Angew. Chem. Int. Ed. 2024, 63, e202311984).\nIt is also important to consider that TEMPO can act as an effective oxidant, promoting\nthe Fe(II) to Fe(III) turnover, which may lead to non-stoichiometric processes and thereby\ncomplicate the analysis. Such behavior has recently been demonstrated for ligated Fe\nspecies by Ala Bunescu and co-workers in an elegant decarboxylative oxygenation\nreaction of aliphatic carboxylic acids (Angew. Chem. Int. Ed. 2024, 63, e202403292).\nNevertheless, we believe that the reviewer’s suggestion regarding the relative efficiencies\nof the different Fe species in solution in promoting photoinduced LMCT decarboxylation\nto generate CF radicals is pertinent. We investigated the two photodecarboxylation\n3\npathways proposed in our mechanistic hypothesis by monitoring the photoreduction of in\nsitu-formed ligated and non-ligated Fe(III) trifluoroacetate species, corresponding to\nintermediates IV and V, respectively. To this end, mixtures of Fe(OTf) , NaO CCF and\n3 2 3\nTFA in acetonitrile were prepared in the presence and absence of L1, and their evolution\nunder irradiation was followed by UV-Vis absorption spectroscopy.\n(a) UV-Vis spectra of a mixture of Fe(OTf) (10 mM), NaO CCF (600 mM) and TFA (130 mM) in dry\n3 2 3\nacetonitrile, at different irradiation times (irradiation at 405 nm) [orange gradient]; (b) UV-Vis spectrum of\na mixture of Fe(OTf) (10 mM), NaO CCF (600 mM) and TFA (130 mM) [purple line].\n2 2 3\nAfter 30 minutes of irradiation, the non-ligated Fe(III) trifluoroacetate species associated\nwith intermediate IV was completely consumed, as evidenced by the disappearance of\nthe absorption band at 350 nm. Concomitantly, Fe(II) trifluoroacetate species were\nformed, as confirmed by comparison with the purple reference spectrum. The\nphotoreduction of Fe(III) to Fe(II) arises from the decarboxylative LMCT process.\n(a) UV-Vis spectra of a mixture of Fe(OTf) (10 mM), L1 (10 mM), NaO CCF (600 mM) and TFA (130\n3 2 3\nmM) in dry acetonitrile, at different irradiation times (irradiation at 405 nm) [orange gradient]; (b) UV-Vis\nspectrum of a mixture of Fe(OTf) (10 mM), L1 (10 mM), NaO CCF (600 mM) and TFA (130 mM) [purple\n2 2 3\nline].\nPhotoreduction of the ligated Fe(III) trifluoroacetate species is evidenced by the\nemergence of an absorption band in the 500–600 nm region, which is attributed to\nFe(II)/L1 intermediates based on comparison with the purple reference spectrum.\ndata up to 0.5 h, indicating the photoreduction of both Fe(III) species after 30 min.\nNotably, in the presence of L1 the LMCT photodecarboxylation proceeds much more\nslowly than for the corresponding non-ligated species, requiring approximately 20 h to\nreach completion. Taken together, this study indicates that the photodecarboxylation of\ntrifluoroacetates proceeds much more rapidly from non-ligated Fe(III) species, which are\ninvolved in path B of the proposed mechanism.\nThese new experiments and data have been incorporated into the revised supplementary\ninformation.\nOverall, as stated previously, I believe this work is of excellent quality, and I strongly\nrecommend it for publication in Nature Communications.\nWe want to take the opportunity to thank the reviewer once again for the feedback and\nsuggestions provided.\nIn response to reviewer comments, the authors of this work have drastically changed the\nmechanistic interpretation of the reaction mechanism, aligned with suggestions made in my\noriginal review of the manuscript. The effort the authors put into this mechanistic reevaluation\nis appreciated, and in my opinion, the mechanism is sounder than the original draft. However,\ncertain questions remain. Chief among them is the role of Path B. Path B seems almost entirely\nirrelevant, and the reaction can be purely described by Path A, which is no different than many\nelectrophotocatalytic schemes reported in the literature. I agree with Reviewer #1 that the\ncurrent work is an incremental advance of the authors’ prior work, with many of the defining\nprinciples of the work already having much precedent (electrochemical turnover of Fe\nperfluoroalkyl carboxylates demonstrated by Ackermann, substrate scope identical to authors’\nprior work), as I also stated in my original review. Thus, paramount to the novelty of this work\nis the proposed distinct mechanistic paradigm involving “dual-role” iron species. It appears to\nme that the authors are clinging to this mechanistic interpretation to preserve the novelty of the\ncurrent work, but all signs point to a normal electrophotocatalytic pathway (i.e. Path A) that is\nnot altogether a new concept.\nWe thank the reviewer for the suggestions and for recognizing our efforts to establish a\nmore robust mechanistic proposal.\nIn the original draft, Path A was not discussed by the authors as a possibility. Rather, all\nreactivity was described to an electrocatalytic turnover of I to IV (III to V in the original draft)\nmediated by FeL3. Many of my comments (example: comment #s 3, 4, 7, 12) drove after the\npoint that reactivity could be enabled entirely by heteroleptic FeLnTFAm complexes that (i)\nundergo Fe(II) à Fe(III) redox at an electrode and (ii) undergo Fe(III) à Fe(II) redox via\nphotochemical LMCT. With new experiments, the authors now include this mechanism as\nPathway A in the current work. This represents a familiar LMCT electrophotocatalytic cycle,\nfor example, identical to the scheme proposed by Nocera (Ag(I) à Ag(II) redox at an electrode\nand Ag(II) à Ag(I) redox via photochemical LMCT). Pathway B remains similar to the original\nhypothesis, but it is not sufficiently\nsubstantiated.\nWe appreciate the reviewer’s valuable comments. In response, we have carried out new\nkinetic experiments that, in our view, clarify the role of path B in our reaction and\n7\nhighlight the importance of ligand addition in enabling a broader reaction scope. We have\nalso provided experimental evidence supporting the presence of non-ligated Fe\ntrifluoroacetate species in solution, and their rapid photodecarboxylation under\nirradiation. We believe that these new data provide further support for the dual role of the\nligated Fe trifluoroacetate species (V) in promoting photoinduced decarboxylation and\nfacilitating the turnover of non-ligated Fe species acting as a redox mediator.\nThese new experiments have been incorporated into the second revised version of the\nmanuscript and supplementary information and are discussed below in response to the\nspecific questions raised by this reviewer.\n(1) Pathway B invokes chemical oxidation of I by V. inspection of the CV data shows that I is\nharder to oxidize than II, meaning the V/II couple should not be capable of inducing oxidation\nof I to IV. In fact, oxidation of I is ~200 mV uphill from oxidation of II, and practically zero\noxidative current for IV/I exists at the E1/2 of V/II. Given this, why do the authors argue that\nthe IV/II couple is relevant under catalytic conditions? Furthermore, HRMS data do not even\nsupport the existence of ligandless FeTFA salts.\nWe would like to thank the reviewer for a particular insightful statement in the previous\nrevision, which we found to be very helpful: “species III is still easier to oxidize at an\nelectrode than these mediators, so it is unclear as to why the harder to oxidize species\nwould serve as an electron shuttle.”. This comment prompted us to carefully reevaluate\nour mechanistic proposal through multiple additional experiments. As it is described in\nthe literature, redox mediators act as electron shuttles between the substrate and the\nelectrode. In indirect anodic oxidation, the mediator usually has a lower redox potential\nthan the substrate, enabling milder oxidative conditions with improved chemoselectivity.\nIn our proposal, mediator V has a lower redox potential than “substrate” I. Therefore,\nelectron transfer in solution occurs against a potential gradient, which is possible when a\nsubsequent thermodynamically favorable step drives the equilibrium forward. In our\nsystem, there is a 200 mV uphill gap in the mediated oxidation of species I to IV as\ndescribed by the reviewer, a process that is driven by the rapid, irreversible photoinduced\nLMCT decarboxylation at IV (as demonstrated below). There are numerous precedents\nin the literature reporting mediated redox reactions with gaps even higher than 200 mV.\n– Shannon Stahl and co-workers: J. Am. Chem. Soc. 2025, 147, 36053.\n– R. Daniel Little and co-workers: J. Org. Chem. 2013, 78, 2104.\n– Phil Baran and co-workers: J. Am. Chem. Soc. 2017, 139, 7448.\n– R. Daniel Little: J. Org. Chem. 2020, 85, 13375 (perspective).\nIn fact, we have demonstrated that ferrocene, which exhibits a cyclic voltammogram\nsimilar to that of intermediate V, acts as an efficient electrocatalyst in the\ntrifluoromethylation of substrate 1, despite the similar uphill oxidation in solution.\nMoreover, we have investigated the relative efficiencies of the different Fe species in\nsolution in promoting photoinduced LMCT decarboxylation to generate CF radicals by\n3\nmonitoring the photoreduction of in situ-formed ligated and non-ligated Fe(III)\ntrifluoroacetate species, corresponding to intermediates IV and V, respectively. To this\nend, mixtures of Fe(OTf) , NaO CCF and TFA in acetonitrile were prepared in the\n3 2 3\npresence and absence of L1, and their evolution under irradiation was followed by UV-\nVis absorption spectroscopy.\nPhotodecarboxylation of non-ligated Fe(III) trifluoroacetate species (absence of L1)\n(a) UV-Vis spectra of a mixture of Fe(OTf) (10 mM), NaO CCF (600 mM) and TFA (130 mM) in dry\n3 2 3\nacetonitrile, at different irradiation times (irradiation at 405 nm) [orange gradient]; (b) UV-Vis spectrum of\na mixture of Fe(OTf) (10 mM), NaO CCF (600 mM) and TFA (130 mM) [purple line].\n2 2 3\nwith intermediate IV was completely consumed, as evidenced by the disappearance of\nthe absorption band at 350 nm. Concomitantly, Fe(II) trifluoroacetate species were\nformed, as confirmed by comparison with the purple reference spectrum. The\nphotoreduction of Fe(III) to Fe(II) arises from the decarboxylative LMCT process.\nPhotodecarboxylation of ligated Fe(III) trifluoroacetate species (with L1)\n(a) UV-Vis spectra of a mixture of Fe(OTf) (10 mM), L1 (10 mM), NaO CCF (600 mM) and TFA (130\n3 2 3\nmM) in dry acetonitrile, at different irradiation times (irradiation at 405 nm) [orange gradient]; (b) UV-Vis\nspectrum of a mixture of Fe(OTf) (10 mM), L1 (10 mM), NaO CCF (600 mM) and TFA (130 mM) [purple\n2 2 3\nline].\nPhotoreduction of the ligated Fe(III) trifluoroacetate species is evidenced by the\nemergence of an absorption band in the 500–600 nm region, which is attributed to Fe(II)\nintermediates based on comparison with the purple reference spectrum.\ndata up to 0.5 h, indicating the photoreduction of both Fe(III) species after 30 min.\nNotably, in the presence of L1 the LMCT photodecarboxylation proceeds much more\nslowly than for the corresponding non-ligated species, requiring approximately 20 h to\nreach completion. Taken together, these results indicate that the photodecarboxylation of\ntrifluoroacetates proceeds much more rapidly from non-ligated Fe(III) species\n(intermediate IV). This observation suggests a plausible shift in the redox equilibrium\nthat overcomes the 200 mV uphill difference detected in our system, thereby providing\nsupport for pathway B of the proposed mechanism.\nFinally, we have been also able to detect non-ligated Fe trifluoroacetate species in solution\nby in-situ HRMS monitorization, providing further support to the equilibrium displayed\nin Fig. 2 in the manuscript, resulting from a 1:1 mixture of Fe(II) and L1 in the presence\nof trifluoroacetates and TFA.\nCF\nName SFG CRUDE-NEG Data File Path D:\\Projects\\SUIC\\Data\\2025\\FABIOJULIA\\SFG CRUDE-NEG.d\nSamOple ID Fe O Acq. Time (Local) 11/26/2025 11:01:55 AM (UTC+01:00)\nInstrument LCC-QFTOF Method Path (Acq) D:\\Projects\\SUIC\\Methods\\masaexacta-5-NEG.m\nMS Type O QTOF3 Version (Acq SW) 6200 series TOF/6500 series Q-TOF (11.0.221.1)\nFInj.C Vol. (ul) O 0.5 IRM Status Success\nPo3sition P1-A5 Method Path (DA) D:\\Projects\\SUIC\\Methods\\Qual\\target screening.m\nPlate Pos. Target Source Path\nOperatorC 6 F 9 FeO 6 - SYSTEM (S YSTEM) Result Summary 1 qualified (1 targets)\nCompound Details\nCpd. 1: C6 F9 Fe O6\nName Formula RT RI MassDiff (Tgt, ppm) CAS ID Source Score Algorithm\nC6 F9 Fe O6 0.258 392.8947 0.04 FBF 96.98 FBF\nSpecies m/z Score (Tgt) Score (Lib) Score (DB) Score (MFG) Score (RT)\nM- 392.8951 96.98\nCompound Spectra (overlaid)\nx104 Cpd 1: C6 F9 Fe O6; 0.258: - FBF Spectrum (rt: 0.158-0.325 min) SFG CRUDE-NEG.d\n394.8906\nM-\n3\n2.5\n2\n1.5\n1\n0.5 392 M .8 - 951 393 M .9 - 001 395 M .8 - 934 396 M .8 - 941 397 M .8 - 990\n0\n391 391.5 392 392.5 393 393.5 394 394.5 395 395.5 396 396.5 397 397.5 398 398.5 399 399.5 400 400.5 401 401.5 402 402.5\nCounts vs. Mass-to-Charge (m/z)\nSpectrum Peaks\nm/z Z Abund Diff (ppm) Height % Height % Ion Species Formula\n(Calc)\n392.8951 1 2294 -0.56 7.19 6.36 M-\n393.9001 1 286 3.58 0.89 0.43 M-\n394.8906 1 31932 0.02 100.00 100.00 M-\n395.8934 1 2968 0.28 9.30 9.02 M-\n396.8941 1 880 -0.06 2.76 1.88 M-\n397.8990 1 59 5.51 0.18 0.14 M-\nCompound ID Table\nName Formula Species RT RT Diff Mass CAS ID Source Score Score (Lib) Score (Tgt)\nC6 F9 Fe O6 M- 0.258 392.8947 FBF 96.98 96.98\nMassHunter Qual10.0\n(End of Report)\n(2) Using the Nernst equation to predict how much IV (A+) will be formed … if an equivalent\namount of V (Ox) is added to I (A), and II is (Red), the following equation describes the reaction\nequilibrium:\nA + Ox ⇋ A+ + Red, Keq = [A+][Red]/[A][Ox]\nThe ratio of [A+] to [A] is at equilibrium is given by:\nLog{[A+]/[A]} = 8.47∆E\nMassHunter Qualitative Analysis Page 1 of 1 Generated at 12:47 PM on 1/12/2026\nwhere ∆E is E(Ox/Red) – E(A+/A). Thus, in this case, ∆E is –0.2V, and there is subsequently\napproximately 50× more A in solution than A+. Given this unfavorable equilibrium implied in\nPath B, why do the authors maintain its importance in the overall reaction mechanism? Of\ncourse, this Nernstian treatment assumes that both the V/II and IV/I redox couples are\nreversible, and the latter is not. Thus, this unfavorable ET could be driven by downstream\nirreversible chemistry involving IV, such as LMCT. But why would pathway B, in which\nthermodynamically unfavorable oxidation is required, be competitive with Path A? LMCT\n12\nquantum yields are also notoriously low, meaning this second irreversible step is not facile. The\nauthors state in their rebuttal that “although intermediate V is photoactive, its evolution might\nbe slow enough to compete with a fast electron transfer with intermediate I in solution.” Is\nevolution of V slow (no electrokinetics are provided), or is electron transfer to I fast (once again\nno kinetics). Thus this statement regarding the viability of Path B is purely speculative. V is\nmost likely photoactive and thus can be generated at the electrode, and therefore pathway A can\naccount for all reactivity.\nWe thank the reviewer for the thorough evaluation of our work. While a Nernstian\ntreatment may offer a general overview of a redox equilibrium, we believe it does not\naccurately represent the situation under our reaction conditions. As the reviewer noted,\nthe Nernst equation assumes equilibrium to determine the relative concentrations of\nintermediates. However, the redox pair I/IV exhibits an irreversible CV, which challenges\nthis assumption. Moreover, the Nernst treatment imposes equal concentrations of species\nV and I, a scenario that might not reflect the actual conditions in our system and would\nbe speculative at this point.\nNevertheless, we agree that the unfavorable electron transfer could be driven by the\nirreversible photoinduced LMCT decarboxylation process at intermediate IV. To examine\nthis point more carefully, we have now experimentally demonstrated that the\nphotoreduction of IV (without L1) is complete within 30 min, whereas ligated species V\nrequires approximately 20 h (see experimental details above). This experiment indicates\nthat the photodecomposition of IV can be sufficiently rapid to drive, and effectively drain,\nthe otherwise slightly unfavorable (about 200 mV) oxidation of I by V in solution. This\nis a similar behavior observed in other mediated redox processes reported in the literature\n(see above).\nIn our view, these observations further support path B as a viable and competent\nmechanistic pathway under our optimized reaction conditions.\n(3) The authors state in their rebuttal that experimental evidence for Path B is that without L1,\nno product is generated. The absence of L1 would also shut down path A, which more than\nlikely explains the lack of reactivity. The authors also show the ability for redox mediators to\nrestore reactivity, but this is not relevant under catalytic conditions when L1 is present. It is\neven more irrelevant when the new ligand loading experiments are included, which\n13\nconclusively show product yield even with 50% ligand loading, conditions where ligandless\nFeTFA is expected to be practically nonexistent. Interestingly, it appears the authors get better\nresults when using ferrocene instead of L1 (see Fig 3). Why was this not pursued further?\nFerrocene is actually cheaper than L1 as well (by a factor of 40 based off Sigma and Ambeed\nprices), why not use it to mediate the transformation instead of L1 when the economics and\nyield are strictly better?\nWe agree with the reviewer that when using 50 mol% of L1, path A becomes more\nplausible. One advantage of the present protocol is that both pathways (A and B) can\noperate to deliver the desired products under optimized reaction conditions, when only\n10 mol% of L1 is used.\nRegarding the use of ferrocene as a redox mediator in the absence of L1, while it yielded\ngood results for the trifluoromethylation of substrate 1, its efficiency varies with other\nsubstrates. This variation might be attributed to a competitive trifluoromethylation of\nferrocene, a phenomenon we have observed in our previous trifluoromethylation work,\nwhich could reduce its overall efficiency. In fact, when ferrocene was used as a redox\nmediator in the trifluoromethylation of caffeine in the absence of L1, no product\nformation was observed. Presumably, for less electron-rich substrates such as caffeine,\nthe homoleptic tris-bipyridine-type Fe(III) intermediate (VI) could participate in\nmediating rearomatization in the bulk solution, a process consistent with the anodic\npotential vs. yield relationship observed for product 19, which plateaued around the redox\npair III/VI (Fig. 6A).\nIn summary, in light of the above comments, I believe Path B should be discarded unless the\nreaction is run without L1 and with redox mediators. It seems likely that, under catalytic\nconditions, only Path A is operative. And this path is no different than standard\nelectrophotocatalytic protocols. Path B may be operative with no ligand included, but then\nobviously Path A would not be functioning. The title is “Dual-Role Iron species…” but Fe\nwould only be playing a dual role if Paths A and B\nwere operative at the same time, and this is not necessary for product formation and also is not proven to be the case. The\nproposed dual-role mechanism is overcomplicated for novelty’s sake, and can be reduced to simply one integrated\nelectrophotochemical cycle (Path A).\nUnfortunately, this does decrease one of the main selling points of the paper. My original\nrecommendation was publication if the proposed reaction mechanism could be supported and\n14\nif the methodology could be differentiated from prior work. Due to the “dual-role” mechanism\nnot being in play anymore, as well as the scope not being able to be expanded beyond that of the\nauthors’ own prior work (comment #10), I leave it up to the Editor to decide if this paper should be published. Regardless, the\ncurrent version of the paper should not be published unless they provide definitive proof that Pathway B is operative.\nWe firmly believe that in this second revision of our work, we have provided additional\nevidence that strongly supports path B of our proposed mechanism, further clarifying the\n\"dual role\" of the in situ-generated iron species, a point that has been appreciated by\nreviewers #1 and #2.\nOverall, we greatly appreciate the reviewers' comments, as their feedback throughout the\nrevisions has encouraged us to investigate the mechanism in much greater detail.\n15"}, "author_response": ""}]

Decision letter