Copper-Catalyzed Electrochemical C-H Fluorination

Summary:

We report the systematic development of an electrooxidative methodology that translates stoichiometric C-H fluorination reactivity of an isolable Cu^III fluoride complex into a catalytic process. The critical challenges of electrocatalysis with a highly reactive Cu^III species were addressed by the judicious selection of electrolyte, F⁻ source, and sacrificial electron acceptor. Catalyst-controlled C-H fluorination occurs with a preference for hydridic C-H bonds with high bond dissociation energies over weaker but less hydridic C-H bonds. The selectivity is driven by an oxidative asynchronous proton-coupled elelctron transfer (PCET) at an electrophilic Cu^III-F complex. We further demonstrate that the asynchronicity factor of hydrogen atom transfer η can be used as a guideline to rationalize the selectivity of C-H fluorination.

Graphical Abstract

eTOC

We report the systematic development of an electrochemical method that translates stoichiometric C-H fluorination reactivity of a copper(III) fluoride complex into a catalytic process. The challenges associated with a highly reactive copper(III) species were addressed by the judicious selection of electrolyte, fluoride source, and sacrificial electron acceptor. The catalyst-controlled C-H fluorination occurs with a preference for hydridic C-H bonds with high bond dissociation energies over weaker but less hydridic C-H bonds, due to the oxidative asynchronous nature of proton-coupled electron transfer at an electrophilic Cu^III-F complex.

INTRODUCTION

Carbon-fluorine bonds endow highly desirable chemical and physical properties to materials, pharmaceuticals, and commodity chemicals.¹ An ideal approach to synthesizing fluorinated organic molecules is to directly replace ubiquitous C−H bonds with C−F bonds. The extensive efforts devoted to developing this transformation by the groups of Lectka,^2–7 Baran,⁸ Cook,^9,10 Sorensen,¹¹ Stahl,^12,13 and others^14–18 using thermal, photochemical, or electrochemical approaches underscore the importance of the aliphatic C-H bond fluorination (Figure 1A, top path). However, these methodologies all rely on expensive electrophilic F⁺ reagents such as Selectfluor or N-fluorobenzenesulfonimide (NFSI). In contrast, C_sp3-H bond fluorination reactions with abundant sources of nucleophilic fluoride (KF, CsF, TBAF, Et₃N(HF)₃) remain rare and underdeveloped.

Figure 1.

Overview of C-H fluorination. (A) Strategies for C-H fluorination with electrophilic N-F reagents, HF, or nucleophilic F⁻ sources. (B) C-H fluorination with LCu^III-F complex. (C) LCu-catalyzed C-H fluorination enabled by electrochemistry and associated challenges.

The groups of Doyle¹⁹ and Musacchio²⁰ recently reported elegant strategies for oxidative C-H fluorination with nucleophilic fluorides. These methods rely on hydrogen atom transfer (HAT) to form a carbon-centered radical that is subsequently oxidized to a carbonium ion by a photoredox catalyst (Figure 1A, middle path). This strategy of radical-polar crossover (RPC) merges two one-electron oxidation steps to form C-F bonds with simple fluoride nucleophiles. However, efficient capture of the carbonium intermediates requires a high concentration of solvated F⁻, which is achieved with superstoichiometric quantities of soluble Et₃N(HF)₃. The limitation of these methodologies to hazardous F⁻ sources can be circumvented by combining transition metal catalysts with benign but less soluble fluoride salts. The high affinity of transition metals for F⁻ facilitates the formation of transition metal fluoride complexes even at low concentrations of solvated fluoride from inexpensive salts like KF, CsF, or AgF (Figure 1A, bottom path).^21–26 For example, Groves et al. reported a rare example of catalytic C-H fluorination using a bioinspired Mn porphyrin catalysts.^27–31

We previously identified a formal copper(III) fluoride complex (LCu^IIIF, L = pyridinebiscarboxamide) that performs both HAT and fluorine atom transfer (Figure 1B).³² Despite the relatively mild potentials at which LCu^IIIF can be formed from the oxidation of [LCu^II-F]⁻ precursor (0.47 V vs. Ag⁺/Ag), the C-H fluorination reactions were limited to stoichiometric quantities of LCu^IIIF complex, and no turnover was observed in the presence of exogenous chemical oxidants. The inability to translate the reactivity of discrete Cu^III complexes to catalytic reactions is a general challenge. Although Cu^III intermediates are frequently proposed in catalytic organic transformations, most isolable Cu^III complexes are not active for catalysis and are only employed as mechanistic probes for understanding stoichiometric reactions, e.g. proton-coupled electron transfer/HAT^33–36 and C-X bond formation processes.^37–40 If the gap between stoichiometric and proposed catalytic reactivity of Cu(III) complexes can be bridged, the well-characterized reactivities of Cu^III species can serve as blueprints for developing desirable C-H bond functionalization methodologies.

Herein, we report the systematic development of an electrooxidative methodology that translates the stoichiometric C-H fluorination reactivity of an isolable Cu^III fluoride complex into a catalytic process while addressing critical limitations of electrocatalysis with Cu (Figure 1C). This strategy leverages electrochemistry as a means of controlling potentials and rates of oxidation to establish a rare example of molecular catalysis for electrochemical C-H fluorination (ECF) with simple fluoride salts.⁴¹ Translating the reactivity of a well-defined complex to catalysis allows predictable regioselectivity based on the calculation of the HAT asynchronicity factor η. Analogous to polarity matching effects,^42–44 Cu-controlled C-H fluorination occurs by an oxidative asynchronous mechanism that is selective for strong hydridic C-H bonds over weaker C-H bonds that are less hydridic.

RESULTS AND DISCUSSION

We envisioned a catalytic ECF process that involves (i) electrooxidation of [LCu^II-F]⁻ to LCu^III-F, (ii) fluorination of C-H substrates according to the established 2:1 Cu:substrate stoichiometric reactivity,³² and (iii) regeneration of the [LCu^II-F]⁻ from a metal fluoride salt (Figure 1C). Establishing this electrocatalytic methodology requires solutions to several challenges. First, the regeneration of [LCu^II-F]⁻ from LCu^II and a metal fluoride must be favorable and should occur at a high rate. High concentrations of [LCu^II-F]⁻ would ensure productive anodic reactions and mitigate oxidative reactions of other Cu complexes that lead to decomposition. Second, the reaction medium must be conducive to electrolysis but inert to highly reactive LCu^III-F intermediates and basic metal fluorides. Third, the reduction of LCu^II at the cathode must be circumvented to avoid Cu⁰ deposition in an undivided cell.⁴⁵

LCu^III-F Stability and Electrogeneration.

The key LCu^IIIF complex that mediates C-H bond fluorination was previously prepared by sequential reaction of LCu^II(MeCN) with tetrabutylammonium fluoride (TBA)F(H₂O)₃ and [NAr₃]PF₆ (Ar = 4-bromophenyl, E = 0.66 V vs. Ag/AgNO₃) in dichloromethane (DCM).³² However, electrolysis of such solutions is problematic because DCM is resistive even with high loadings of supporting electrolytes, and most ammonium electrolytes (including TBA⁺) decompose in the presence of anhydrous fluoride to release amine byproducts that undergo competitive electrooxidation. As such, our initial studies focused on identifying electrochemically-applicable solvents in which the LCu^IIIF complex is both long-lived and readily formed from a LCu^II precursor, a metal fluoride, and a chemical oxidant (Figure 2).

Figure 2.

The yield and stability of copper fluoride complexes under various conditions. ^a Yield after stirring LCu^IIMeCN with 10 eq F⁻ sources for 3 min. ^b Measured at 22 °C. See also Figure S19–S23.

We first quantified the extent of fluoride ligation to form [LCu^IIF]⁻ after just 3 minutes of stirring a combination of [LCuII], metal fluoride salt (KF or CsF), and solvent (Figure 2). Ligation reactions with CsF formed the targeted complex [LCu^IIF]⁻ in highest yields, despite the poor solubility of the fluoride source. The [LCu^IIF]⁻ complex is typically formed in good yield after the short reaction time in polar aprotic solvents (entries 2, 4, 5), while yields are lower in less polar solvents like dichloromethane (DCM, entry 1). However, the persistence of the high-valent LCu^IIIF intermediate is highest in the less polar solvents where fluoride ligation is slow. As examples, the LCu^IIIF half-life in DCM is nearly two orders of magnitude longer than in acetone (entries 1 vs 2). Propylene carbonate (PC) and acetonitrile (MeCN) are the only two solvents that support both in situ formation of [LCu^IIF]⁻ and long-lived LCu^IIIF intermediates (t_1/2 = ca. 12 mins). Together, these experiments suggest that the combination of CsF with PC or MeCN are good starting conditions for developing an electrocatalytic C-H fluorination.

ECF Reaction Development.

The identified conditions for the formation of a persistent LCu^IIIF complex were next subjected to electrolysis in the presence of organic substrates (Figure 3). Reactions containing the ligated Cu precursor LCu^IIMeCN, CsF, and THF as the C-H substrate were electrolyzed in undivided cells at a constant voltage of 3.3 V with TBAClO₄ as a supporting electrolyte in MeCN. Even with this high applied potential, the current rapidly decreased to just 0.2 mA after 20 min, resulting in just 40% yield of fluorinated product relative to added Cu (entry 1). The cell resistance in other solvents compatible with LCu^IIIF was even higher (PC, entry 2), which allowed for only 1.7 e⁻ equiv. relative to Cu to be passed. The fluorinated product formed in only 15% yield along with a significant quantity of C-H fluorinated PC as a competing product. The combination of MeCN and PC completely inhibited ECF of PC and resulted in slightly higher yields than either solvent alone but still failed to sustain currents (entry 3).

Figure 3.

ECF reaction development. See also Figure S1–S3 and Table S1–S3.

The surprisingly high resistance of these reactions was found to result from the irreversible consumption of the redox-active Cu complex by Cu plating and deposition of insoluble materials at the cathode (Figure S4). To address these limitations, we evaluated reactions with redox mediators or sacrificial electron acceptors that undergo reduction in preference to Cu complexes without interfering with the anodic reactions.⁴⁵ While reactions with ferrocenyl mediators operated at high currents (>3 mA), no product was detected (entries 4, 5; see Figure S3 for a full list of mediators). Reactions with sacrificial e⁻ acceptors (e.g., C₆Br₆, C₆Cl₆, DCM) similarly resulted in low yields (entries 6, 7, 8). The Br⁻ or Cl⁻ ions released during the reduction of these additives were found to bind LCu in preference to F⁻, and the unreactive [LCuIICl]⁻ complex could be identified by its characteristic green color during electrolysis with DCM.³²

These results guided us to evaluate fluorinated e⁻ acceptors that could decompose to generate additional fluoride. While hexabromo- or hexachlorobenzene completely inhibited the reaction (entries 7, 8), reactions with hexafluorobenzene formed the desired product in 560% yield relative to Cu. These results constitute the first evidence of electrocatalysis. Analysis of the reaction mixture after electrolysis by ¹⁹F NMR spectroscopy revealed that hexafluorobenzene was converted to a mixture of pentafluorobenzene (57% yield vs. Cu) and 2,3,4,5-tetrafluorobenzene (35% yield vs. Cu) through electroreduction and subsequent protodefluorination. We simultaneously evaluated buffered acid-base combinations that could promote the desired cathodic reactions and improve the overall conductivity of the reaction medium. Reactions performed with a collidinium-TFA (TFA = trifluoroacetic acid) mixture formed the targeted product in 930% relative to Cu (entry 13). Finally, control reactions demonstrated that CsF, electrochemistry, and the LCu^II (MeCN) complex are necessary for C-H fluorination (entries 14–17). Collectively, these results underscore the counterintuitive challenges of Cu-catalyzed electrosynthesis. Specifically, the development of this oxidative reaction primarily focused on challenges associated with cathodic chemistry.

Substrate Scope.

We next applied the developed conditions to a range of substrates to evaluate the reactivity of the system. While reactions with THF proved high-yielding, the expected trends associated with radical-based reactivity were not immediately apparent (Figure 4). In particular, substrates with weak CH bonds that are prototypical targets for radical C-H fluorination methods often resulted in lower yields than substrates with stronger C-H bonds (e.g., 8 vs 1, 87 vs. 92 kcal/mol). The chemoselectivity of this reaction is demonstrated by the fluorination reaction of 2-(4-ethylbenzyl)tetrahydrofuran. Fluorination occurs exclusively at the position alpha to oxygen (12 and 13) rather than at the benzylic site (14 and 15). This selectivity diverges from other known C-H fluorination methods that preferentially functionalize benzylic C-H bonds.^21–26,28 Intermolecular competition experiments between THF and tetrahydronaphthalene revealed similar selectivity trends where the strong C-H bonds alpha to oxygen were preferentially functionalized over the weaker benzylic C-H bonds (1 vs. 11).

Figure 4.

ECF substrate scope. ^aYields determined by ¹⁹F NMR with fluorobenzene as an internal standard. ^bconditions: 9 equiv. C₆F₆, 15 equiv. CsF, no collidine, TFA collidinium and MS, acetone instead of PC:MeCN. ^c50 mAh instead of 20 mAh.

Regioselectivity of C-H fluorination.

The rare access to an isolable and well-characterized Cu(III) complex that is the exact intermediate of a Cu-catalyzed fluorination reaction serves as a blueprint for understanding the regioselectivity in Figure 4. We hypothesized that the observed selectivities in both inter- and intramolecular competition experiments highlighted in Figure 4 are due to the high rates of HAT at C-H bonds alpha to oxygen. Accordingly, we measured the HAT rates from various organic substrates by monitoring the consumption of LCu^IIIF (Figure 5). The logarithm of resulting secondary HAT rates log(k_HAT), spreading over four orders of magnitude, were plotted against the computed driving forces of electron transfer (ΔG^o_ET, Figure S24), proton transfer (ΔG^o_PT, Figure S25), and proton-coupled electron transfer (ΔG^o_PCET, Figure 2A). The correlations between log(k_HAT) with ΔG^o_PT and ΔG^o_ET are poor (R² = 0.2184 and 0.5227). Additionally, direct electron transfer and proton transfer are both highly endergonic (ΔG^o_ET > 0.65 eV, ΔG^o_PT > 2.42 eV, Table S4), suggesting that stepwise ET-PT and PT-ET pathways are unlikely.^46–48

Figure 5.

Plot of the log of second order rate constant k_HAT of the reaction between LCu^IIIF and C-H substrates with (A) the driving force of PCET, ΔG^o_PCET (R²=0.858) and (B) ΔG^o_PCET – F|η|/2. The R² value of the first plot improves to 0.989, if THF and pthalan are excluded. Error bars are smaller than the site of the data points. See also Figure S6–S18, Table S4–S8.

In contrast, a linear correlation between log(k_HAT) vs. ΔG^o_PCET was observed (R² = 0.858, Figure 2A). However, THF and pthalan are clearly outliers. If they are excluded from the plot, the R² value of the plot improves to 0.989. We also attempted to correlate the rates of C-H activation using a linear combination of ΔG_PCET, ΔG_PT, and ΔG_ET using semiempirical models developed by Anderson and Borovik (see Figure S26, S27).^49,50 However, the correlations do not improve to more than R² = 0.858.

Notably, although the BDFE of THF is higher than toluene by 3 kcal/mol, LCu^III-F reacts faster with THF compared to toluene, suggesting that the rate of C-H activation does not follow the classical trend predicted by the Bell-Evans-Polanyi principle.⁵¹ C-H bond cleavage by high valent metal complexes is often described as PCET. However, recent work by Borovik,⁵² Anderson,⁵³ Tolman,³⁴ and Kojima⁵⁴ suggests that the basicity or redox potential of the metal complex can play a dominant role in the rate of C-H bond cleavage. Accordingly, we rationalize the higher-than-expected rates of THF and pthalan with asynchronous transition states of HAT, which could be dominated by electron transfer (oxidative asynchronous pathway) or proton transfer (basic asynchronous pathway, Scheme 1). HAT processes with greater asynchronicity are predicted to have lower activation barriers.⁵⁵

Scheme 1.

Mechanisms of PCET.

Work by Tolman and Cramer et al. demonstrated that LCu^IIIO₂CR complexes activate C-H bonds through an oxidative asynchronous process with an ET-dominated transition state (Scheme 1).³⁴ Given the similar E_1/2 of LCu^IIIF and LCu^III(O₂CAr), HAT by LCu^IIIF is expected to be oxidative synchronous as well. To consider the combined effects of classical thermodynamics of HAT and propensity for asynchronicity, Srnec argues that the barrier of asynchronous HAT process is a function of ΔG^o_PCET – F|η|/2, where ΔG^o_PCET is the driving force of HAT/PCET, F is the Faraday constant and η is the asynchronicity factors. Indeed, we found that the plot of log(k_HAT) vs. ΔG^o_PCET – F|η|/2 shows a linear correlation with R² = 0.9781 (Figure 2B). With this plot, the ether and benzylic substrates follow a unified trend. An F-test with a null hypothesis that the model with ΔG^o_PCET only is better shows a p-value of 0.02208, suggesting the strong correlation between log(k_HAT) and ΔG^o_PCET – F|η|/2 is statistically significant.⁴⁹

Due to the oxidative asynchronous nature of HAT by LCu^III species,³⁴ the reactions of LCu^IIIF with the easily oxidized ether substrates are enhanced by virtue of high η values. For example, ECF of chroman occurs exclusively at the more asynchronous α-ethereal position (η_ether = 2.69 V, η_benzylic = 2.21 V), which is the opposite of conventional selectivity predicted by BDFE values (BDFE_ether = 94.4, BDFE_benzylic = 84.8 kcal/mol, Figure 5). This approach can also be applied to rationalize the intermolecular selectivity of tetralin vs. THF. Although tetralin has a lower BDFE than THF (85.0 vs. 92.7 kcal/mol), C-H fluorination occurs preferentially at the more asynchronous substrate (η_tetraline = 1.84 V, η_THF = 2.15 V). While leveraging asynchronous effects has been touted as an appealing tool for reversing the selectivity of C-H functionalization, our work is the first demonstration of this principle. Unlike the empirical polarity matching effect,^42–44 asynchronicity calculation has quantitative prediction ability and can potentially be applied to a broader range of systems, including transition metal.

CONCLUSION

In summary, we developed an electrooxidative methodology that translates the stoichiometric C-H fluorination reactivity of a well-characterized Cu^III complex into a catalytic process. Through systematic studies of isolable Cu^II/Cu^III intermediates, we identify conditions that allow electrochemical generation of highly reactive LCu^III-F complex at the anode while preventing its decomposition at the cathode. The use of a molecular copper catalyst allows access to F radicaltype reactivity at a much lower potential (3.3 V in an undivided cell) compared to previous ECF reactions. The mild electrolysis conditions enable selective monofluorination of strong electron-rich C-H bonds over weak benzyl C-H bonds. For the first time, we demonstrate the use of asynchronous effect of HAT to override the traditional C-H activation selectivity that often trends with bond dissociation energies. The selectivity of C-H functionalization can be easily predicted by using the computed η values as a guideline. Ongoing work aims to further leverage LCu^III complexes for electrochemical C-H functionalization reactions.

Experimental Procedures

Resource Availability

Lead Contact:

Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Shiyu Zhang (zhang.8941@osu.edu).

Materials Availability:

All unique reagents generated in this study are available from the lead contact with a completed materials transfer agreement.

Data and Code Availability

All other data supporting the findings of this study are available within the article and the supplemental information or from the lead contact upon reasonable request.

Supplementary Material

1

Data S2. NMR spectra.

2

Data S3. Computational coordinates.

Highlights.

1. Electrochemistry is used to translate a stoichiometric reaction to a catalytic process

2. The fluorination reaction is selective for electron-rich C-H bonds over weak ones

3. The selectivity is rationalized by the asynchronous effect of PCET

Bigger picture statement.

Although copper(III) intermediates are frequently proposed in catalytic organic transformations, most isolable copper(III) complexes are not active for catalysis and are only employed as mechanistic probes for understanding stoichiometric reactions. We demonstrated that electrochemistry could be used to translate the stoichiometric C-H fluorination reactivity of an isolable Cu^III fluoride complex into a catalytic process. This strategy leverages control of potentials and rates of oxidation to establish a rare example of molecular catalysis for electrochemical C-H fluorination with simple fluoride salts. The Cu-mediated C-H fluorination occurs by an oxidative asynchronous proton-coupled electron transfer that is selective for strong hydridic C-H bonds over weaker C-H bonds that are less hydridic.