Electron-Transfer-Enabled Concerted Nucleophilic Fluorination of Azaarenes: Selective C–H Fluorination of Quinolines

Direct C–H fluorination is an efficient strategy to construct aromatic C–F bonds, but the cleavage of specific C–H bonds in the presence of other functional groups and the high barrier of C–F bond formation make the transformation challenging. Progress for the electrophilic fluorination of arenes has been reported, but a similar transformation for electron-deficient azaarenes has remained elusive due to the high energy of the corresponding Wheland intermediates. Nucleophilic fluorination of electron-deficient azaarenes is difficult owing to the identity of the Meisenheimer intermediate after fluoride attack, from which fluoride elimination to regenerate the substrate is favored over hydride elimination to form the product. Herein, we report a new concept for C–H nucleophilic fluorination without the formation of azaarene Meisenheimer intermediates through a chain process with an asynchronous concerted F–-e–-H+ transfer. The concerted nucleophilic aromatic substitution strategy allows for the first successful nucleophilic oxidative fluorination of quinolines.

−3 However, selective aromatic C−H bond fluorination of functionalized molecules is far from being established, in part due to a high reaction barrier associated with C−F bond formation that results from the high electronegativity of fluorine and the small ionic radius of fluoride (1.33 Å), 4 both of which make reductive elimination from metal fluorides difficult.−11 Fluorination of sixmembered azaarenes is even more challenging, and there is currently no method for a C4-selective fluorination at all. 12,13he sp 2 -hybridized nitrogen atom on electron-deficient azaarenes renders electrophilic aromatic substitution (S E Ar) difficult due to a highly unstable potential Wheland intermediate (Figure 1a). 6,13Radical aromatic substitution of azaarenes such as Minisci-type reactions can afford C−C, C−B and C−Si bonds 14−18 but not C−F bonds. 19Nucleophilic fluorination is challenging because, after fluoride addition to form a Meisenheimer intermediate, a hydride must be removed for rearomatization.Moreover, formation of the fluoride Meisenheimer intermediate is endergonic for azaarenes (Figure 1b), which would require a facile hydride elimination so that the overall barrier is not prohibitively large.Elimination of hydride from the fluoride Meisenheimer intermediate is challenging because the high-lying HOMO upon fluoride attack has overlap with the low-lying antibonding orbital of the C−F bond (σ* C−F ), which results in the weakening of the C−F bond and facilitates heterolytic cleavage back to the starting material (Figure 1b, bottom).Modern nucleophilic aromatic substitution (S N Ar) strategies to selectively attach a linchpin such as a phosphonium substituent at the C4 position of azaarenes for subsequent functionalization have found broad applications in C−H functionalization, but the strategy has not yet been extended to fluorination. 20,21−26 Here we report a new approach to overcome the fundamental challenge for cleaving the strong C−H bond without the formation of high-energy Meisenheimer intermediates and successfully apply the concept to the C−H fluorination of quinolines (Figure 1d).
Meisenheimer complexes are commonly considered intermediates in S N Ar reactions.However, in concerted nucleophilic aromatic substitutions (CS N Ar), 24,27,28 Meisenheimer complexes are transition states, in which case the formation of high-energy intermediates is avoided.Therefore, a CS N Ar fluorination may provide the opportunity to avoid the high barriers that are associated with elimination of hydride from an already high-energy Meisenheimer complex to achieve azaarene C−H fluorination.We envisioned that when the fluoride attack on a protonated azaarene was coupled to an electron transfer, C−H bond heterolytic cleavage of a radical cation to release H + would be more facile and allow a concerted process.Whether presumed F − , e − , and H + transfer are concerted depends on the driving forces of both electron transfer (ET) and proton transfer (PT) as well as the distance between the fluoride Meisenheimer complexes and e − and H + acceptors. 29,30For example, preassociation of reactants can play an important role in concerted proton-coupled electron transfer. 29,30Therefore, we attempted to generate an ion pair TEDA 2+• F − (TEDA, N-(chloromethyl)triethylenediamine) 31−35 in proximity to the protonated quinoline for potential concerted F − -e − transfer, simultaneous with deprotonation (Figure 2a, chain propagation).We have previously made use of the high electron affinity of the doubly cationic radical TEDA 2+• (12.4 eV) 31 for a chargetransfer-directed radical substitution.We therefore envisioned that TEDA 2+• F − may support an F − -e − -H + transfer (Figure 2a, A → D) and then e − transfer (D → A) chain for C−H fluorination upon further single-electron oxidation of the intermediate after F − attack and C−H cleavage.In this case, the formation of the protonated Meisenheimer intermediate could be avoided, and the challenging fluorination could become feasible.The overall two-electron reaction Ar-H + Selectfluor → Ar-F + TEDA-H 2+ would thus be achieved via two single-electron redox processes, and ET to sustain the chain process.
Chain initiation from Selectfluor by single-electron reduction to yield the TEDA 2+• F − ion pair for chain propagation requires an electron donor that fulfills the following criteria: the electron donor is strong enough to reduce Selectfluor under acidic conditions for a sufficiently high concentration of TEDA 2+• ; and the electron donor should not engage in other side reactions with Selectfluor.An appropriate species that meets both requirements could be the reduced state of protonated azaarene itself, the N-heterocyclic π-radical F 36,37 (Figure 2a, chain initiation).Our group has reported that the excitation of an ion pair acridine-H + Cl − followed by reductive quenching of its counteranion Cl − can produce a N-heterocyclic π-radical, 38 and we intended to apply the Cl − quenching process to excited-state protonated azaarene E to generate a π-radical F. The electron donor F can thus donate an electron to Selectfluor to generate TEDA 2+• F − for chain propagation.The excited-state protonated azaarene E could originate from an energy transfer (EnT) 39 between the ground-state protonated azaarene and a triplet-state photosensitizer (PS).For EnT to occur effectively, we chose xanthone as a photosensitizer due to its high triplet-state energy of E T = 73.8kcal/mol 40 and a quinoline derivative as the substrate (E T = 57.7 kcal/mol 41 for protonated quinoline) to evaluate the fluorination of 1.When HCl and Et 3 N•HCl were used as H + and Cl − donors, respectively, C4-fluorinated quinoline derivative 2 was obtained in 56% isolated yield upon irradiation with a 365 nm LED (Figure 2b).
Concerted Mechanism.Upon initiation to generate TEDA 2+• F − , fluoride-coupled electron transfer to protonated quinoline A, simultaneous with deprotonation, to generate D is associated with an activation energy of 18.3 kcal/mol (Figure 2a, chain propagation).The electron-rich π-radical D can be oxidized by Selectfluor to form the fluorinated product and regenerate TEDA 2+• F − to complete the chain, which is exergonic by 46.2 kcal/mol.
Stepwise Mechanism 1.The fluoride of TEDA 2+• F − could attack quinoline hydrochloride A to form Meisenheimer intermediate B and TEDA 2+• , followed by ET-PT or HAT of B (A → B → D).Estimation of the ET activation energy for the reaction between B and TEDA 2+• shows that there is no significant barrier (Figure 3a, ΔG ⧧ < 0.1 kcal/mol), which indicates that it is unlikely for the Meisenheimer intermediate B and TEDA 2+• to form a stable complex.An internal reaction coordinate (IRC) analysis revealed that the transition state of TEDA 2+• F − attacking quinoline hydrochloride A directly leads to the product after ET, which excludes the existence of additional maxima along the reaction path (Figure 3b).Natural bond orbital analysis (NBO) of the transition state indicates a significant charge transfer process during the C−F bond formation, suggesting that an ET is coupled with the fluoride attack (Figure 3b).The calculated HOMO (Figure 3a, bottom) of intermediate B shows that the fluoride and enamine parts have the major contribution to the HOMO, which is remote from the proton donor.The lack of HOMO contribution from the C−H bond indicates that the C−H cleavage is difficult for a traditional HAT pathway, 43,44 which would require the H + and e − to originate from the same donor group. 29,30,45tepwise Mechanism 2. A fluoride-coupled electron transfer mechanism to form a complex of dihydroquinoline radical cation 46,47 C and TEDA + , followed by a second step of deprotonation (A → C → D), could be feasible as well.Yet, we determined a kinetic isotope effect (KIE) of 1.7 from an intermolecular competition experiment with quinoline and quinoline-d 7 (Figure 3c), which indicates a PT equilibrium before the product-formation ET (D → ArF), which is consistent with a concerted F − -e − -H + mechanism (A → D) or a stepwise mechanism (A → C → D) with a reversible deprotonation.From the calculation, when Cl − or TEDA + were used as proton acceptors, the deprotonation proceeds without a significant energy barrier (Figure 3d, AfterTS, ΔG ⧧ < 0.1 kcal/ mol), which is consistent with an asynchronous concerted F −e − -H + transfer mechanism 48 from A to D.
Chain Initiation.The fluorination reaction efficiency correlates with the E T of the photosensitizers but not with their reduction potentials, which is in agreement with an EnT process to form the triplet state of protonated quinoline (Figure 3e). 39Control experiments show the important role of the Cl − counteranion and the Et 3 N•HCl additive to improve the reaction yield (Figure 3f), which could indicate a further reductive quenching process of the triplet state of protonated quinoline by Cl − .The observation of 1-chlorododecane in an intermolecular radical-trapping experiment with 1-dodecene is consistent with the formation of Cl•. 38,49According to an electrochemistry study, the additive Et 3 N•HCl (E p1/2 = +0.94V vs SCE) cannot be oxidized by ground-state protonated quinoline (E p1/2 = −1.03V vs SCE).However, the reduction of excited-state protonated quinoline (E 0−0 = 2.65 V, 50 E p1/2 * = +1.62V vs SCE) by Et 3 N•HCl is feasible.The quantum yield for fluorination of 3.5% is consistent with a back ET (BET) between N-heterocyclic π-radical F and Cl•.The fluorination reaction can be applied to small molecules with quinoline scaffolds, as shown in Figure 4.The conditions enable C−H fluorination in the presence of a range of functional groups, including esters (7, 8, 13), halogens (9, 12, 17), ketone (4), cyano (16), phosphoryl (18), alkyls (5, 7), fluoroalkyls (10,  24), amide (20), imide (14), carbamate (27), sulfonamide (19), sulfonates (20, 23) and sulfone substituents (28).−35 Some substrates (4, 5, 8, 9) exhibit yields based on recovered starting material (BRSM) greater than 80% but have only moderate yields of isolated pure products due to the incomplete reaction, likely due to product inhibition (see Supporting Information, p S15).Fluorination of unsubstituted quinoline (3) resulted in a 2:1 ratio of C4 and C2 products, slightly favoring the more electrophilic C4 site.A 4.5:1 of C4 and C2 fluorinated products was obtained in the case of 3acetylquinoline (4), owing to enhanced C4 reactivity caused by electronic effects.The C4 selectivity is inconsistent with the fluorine atom transfer mechanism due to the polarity mismatch. 14The DFT-calculated LUMOs of protonated quinoline derivatives show that C4 has the largest contribution to the LUMO, suggesting that the site selectivity of the fluorination is consistent with the quinoline in the role of the electrophile (Supporting Information, p S73).In general, the selectivity for the C4 position is moderate but can be increased if Lewis acids are used instead of protic acid, presumably to coordinate to the quinoline nitrogen, and thereby sterically disfavor the reaction at C2 (see Supporting Information, pp S22−S23).Benzoquinolines such as 6 and 21 can be fluorinated successfully.Pyridine derivatives are not suitable substrates for the energy transfer because their E T values (79.0 kcal/mol for pyridine) 40 are too high for common photosensitizers such as xanthone (E T = 73.8kcal/mol). 40However, when direct excitation conditions were applied to access triplet-state pyridine−HCl complexes, several pyridine derivatives (25, 26)  could be fluorinated successfully.
The strategy of electron-transfer-enabled concerted nucleophilic aromatic substitution provides a conceptually new approach to azaarene C−H fluorination.Our work demonstrates how ion-coupled electron transfer avoids the formation of high-energy Meisenheimer intermediates and, therefore, can provide a hypothesis for the design of efficient catalysis by coupling ion transfer with redox processes, which may serve as a novel mechanistic basis for other nucleophilic aromatic C−H functionalization.

Figure 1 .
Figure 1.(a) High-energy Wheland intermediate in the S E Ar mechanism.(b) High-energy fluoride Meisenheimer intermediate in the S N Ar mechanism.(c) C2-selective fluorination of azaarenes with AgF 2 .(d) This work: fluorination of azaarenes via concerted nucleophilic substitution.M, Meisenheimer complex; TS, transition state.

Figure 3 .
Figure 3. Mechanistic investigation.(a) Estimation of the ΔG ⧧ SET .DFT-calculated geometry and HOMO of B; isosurface value = 0.06.(b) Reaction coordinate of the fluoride-coupled electron transfer.(c) KIE from an intramolecular competition reaction.(d) Reaction coordinate of the PT.(e) Relationship between the yield of fluorination and E T of photosensitizers.(f) Effect of chloride and a chlorine-radical-trapping reaction.