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. 2026 Mar 3;6(3):1602–1616. doi: 10.1021/jacsau.5c01460

HP(O)Ph2‑Mediated Hydrodefluorination of Polyfluoro(hetero)arenes

Xue-Ying Huang †, Xian-Xian Mao ‡, Chenshu Dai ⊥, Ming-Yang Gu †, Danhua Ge †, Zhi-Liang Shen †, Kai Guo §,*, Chao-Jun Li ∥,*, Xue-Qiang Chu †,*
PMCID: PMC13014199  PMID: 41889763

Abstract

The roles of H-phosphoryl compounds [HP­(O)­R′R″] in various transformations remain insufficiently elucidated, particularly concerning their contributions to facilitating the conversion of inert chemical bonds. Herein, we report a highly selective hydrodefluorination (HDF) reaction of polyfluoro­(hetero)­aromatic compounds mediated by HP­(O)­Ph2, which does not require complex constrained phosphorus architectures or external reducing agents. Notably, H-phosphoryl compounds, especially the commercially available, bench-stable, and inexpensive HP­(O)­Ph2 used in this study, were discovered for the first time to function as both a defluorinative surrogate and an H-reagent, displaying unconventional HDF reactivity with the assistance of water. By employing this protocol, a variety of partially fluorinated (hetero)­aromatic scaffolds can be synthesized. Furthermore, the approach demonstrates excellent regioselectivity, enables postfunctionalization of complex molecules, and allows for the transformation of the resulting products into other value-added organofluorides, highlighting its potential in medicinal and organic chemistry.

Keywords: hydrodefluorination (HDF), polyfluoro(hetero)arenes, diphenylphosphine oxide, H-phosphoryl compound, C−F bond activation

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Introduction

As a privileged subclass within the organophosphorus family, phosphoryl (PO) compounds are ubiquitous in living organisms, natural products, functional materials, pharmaceuticals, and agrochemicals. These pentavalent phosphorus species not only behave as essential ligands and organocatalysts but also serve as versatile building blocks in organic synthesis and directing groups for C–H bond activation. Typically, the P­(O) moiety exhibits distinct intrinsic properties, such as thermal stability, radical scavenging capability, structural mimicry of carboxylic acid groups, and participation in hydrogen-bonding interactions, which are attributed to its high bond dissociation energy (128–139 kcal/mol), short bond length (1.475–1.490 Å), and pronounced dipole moment (4.51 D). The extensive applications of phosphoryl compounds necessitate the development of efficient and reliable methods for the introduction of a P­(O) group onto targeted molecules. Significant efforts have been invested in direct phosphorylation through the generation of nucleophilic phosphoryl anions, phosphoryl radicals, and reactive organophosphorometallic intermediates via either heterolytic or homolytic cleavage of the H–P bond in H-phosphoryl compounds [HP­(O)­R′R″] (Figure , A; role I). In this context, H-phosphites, H-phosphinates, and H-phosphine oxides serve as phosphorylating agents for the construction of new C–P bonds. Nevertheless, the roles of HP­(O)­R′R″ in various transformationswhether catalyzed by transition-metal catalysts or proceeding via metal-free pathwaysremain insufficiently elucidated, particularly regarding their contributions to facilitating conversions of inert chemical bonds.

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The roles of H-phosphine oxides in organic transformations. A H-Phosphine oxides as phosphoryl sources in the phosphorylation reactions. B Classic Atherton–Todd reaction: H-phosphine oxides serve as phosphoryl sources and dehalogenative reagents. C Unique roles of H-phosphine oxides in the functionalization of carbonyl derivatives.

The classic Atherton–Todd (A-T) reaction proceeds via nucleophilic attack of a phosphoryl anion at the C–Cl bond of tetrachloromethane (Figure , B; role II), in situ generating phosphoryl chloride intermediates, which are critical for subsequent phosphorylation of nucleophiles. Beyond the dechlorination behavior, recent studies have revealed the feasibility of H-phosphoryl compounds in deoxygenation reactions. For instance, HP­(O)­Ph2 could mediate carbonyl reductive functionalization of aldehydes/ketones by converting CO bonds into various C-element single bonds (Figure , C, i; role III). Similarly, its deoxygenative capability enabled the synthesis of benzyl phosphorus compounds from carboxylic acids (Figure , C, ii; roles I and III). In our previous work, we found that the HP­(O)­Ph2/H2O system facilitated defluorination of β-trifluoromethyl enones to produce gem-difluoroalkenes (Figure , C, iii; role IV). Especially noteworthy is the fact that the isolation of diphenylphosphinic fluoride unequivocally confirmed the defluorinative role of HP­(O)­Ph2. Very recently, an HP­(O)­Ph2-promoted formal defluorination of trifluoromethyl ketones to access difluoromethyl, monofluoromethyl, and methyl ketones was achieved through a phospha-Brook rearrangement followed by β-fluoride elimination and protonation (Figure , C, iv; formal defluorinative role). Despite the aforementioned advancements achieved thus far, HP­(O)­Ph2-involved transformations of inert chemical bonds have focused on carbonyl derivatives, with their applications in defluorinative functionalization largely limited to indirect activation of C­(sp3)–F bonds.

The prominent applications of multifluorinated arenes (ArFn, as exemplified in Figure , A) in pharmaceuticals, agrochemicals, materials science, and organic synthesis have attracted considerable attention, thereby driving the pursuit of efficient synthetic methods. Conventional fluorination strategy faces limitations when it comes to accessing polyfluoroarenes, which heavily relies on the multistep preinstallation of functional groups or the utilization of specifically arranged directing groups to control regioselectivity. Hydrodefluorination (HDF) of readily available perfluoroarenes not only offers a promising alternative entry to partially fluorinated arenes but also deepens the fundamental understanding of C–F bond activation. Over the past few decades, the potential for HDF of perfluoroarenes has been widely recognized in transition-metal-mediated/catalytic processes, − photocatalysis, − and main-group systems. − Special attention should be paid to the nucleophilic aromatic HDF of perfluoroarenes with NaBH4 reported by Weaver and coworkers. This approach represents a common method for replacing the C­(sp2)–F bond using a hydride source. However, there is still an urgent need to develop novel strategies that allow the utilization of new reagents for selective C­(sp2)–F bond functionalization.

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The significance of polyfluoroaromatic molecules and P­(I, III, or V)-catalyzed/mediated hydrodefluorination (HDF) of polyfluoro­(hetero)­arenes. A Selected polyfluoroaromatic molecules in pharmaceuticals, agrochemicals, electronic devices, and ligands. B P­(I or III)-Catalyzed hydrodefluorination (HDF) of polyfluoro­(hetero)­arenes using strong reductants (rare). C P­(III)-Mediated HDF of polyfluoro­(hetero)­arenes without reductants. D P­(V)-Catalyzed HDF of fluoroalkanes using strong reductants. E P­(V)-Mediated HDF of polyfluoro­(hetero)­arenes without reductants: a new tool for C­(sp2)–F bond functionalization (this work).

In the quest to achieve efficient functionalization of perfluoroarenes, remarkable efforts have been dedicated to devising strategies that leverage the ambiphilic nature of phosphorus-based compounds. , Among them, important studies conducted by the groups of Radosevich (Figure , B, i), Dobrovetsky (Figure , B, ii), and Mandal (Figure , B, v) have elegantly demonstrated that low-valent pnictogen systems can facilitate the HDF of polyfluoroarenes through P­(III)/P­(V) , or P­(I)/P­(III) redox cycling in a catalytic manner. Notably, these works employed complex constrained ligand architectures, with the need to enforce unusual geometries at phosphorus centers. On the other hand, catalytic HDF reactivity using simple phosphine (Figure , B, iii) and diazaphospholenes (Figure , B, iv) has also been discussed, although excessively strong reductants were still necessary for recycling the P­(III) catalysts. Inspired by García’s previous reports on the stoichiometric simple phosphine­(III)-mediated HDF of fluoroarenes without the use of transition metals or external silanes (Figure , C), we embarked on an exploration to determine whether H–P­(O)­R′R″, a simple, commercially available, bench-stable, and inexpensive pentavalent phosphorus species, could serve as a dual hydrogenative and defluorinative promoter under transition metal-free conditions in order to ensure that the HDF reaction is widely applicable. Notably, Stephan’s pioneering findings demonstrate that the Lewis acidic organofluorophosphonium P­(V) salt could catalyze HDF of fluoroalkanes (Figure , D). − In addition, the stoichiometric utilization of P­(III)-based Lewis bases in frustrated Lewis pair (FLP) chemistry has also opened up an alternative avenue for the manipulation of C­(sp3)–F bonds. − However, the phosphonium cations are generally sensitive, and FLP systems only demonstrate high levels of reactivity toward fluoroalkanes. To the best of our knowledge, the leverage of the fluorophilicity of readily available P­(V) reagents for C­(sp2)–F functionalization remains unexplored.

To date, the proposed straightforward defluorinative process initiated by P­(V)-species contains unresolved issues: (1) fluorine’s high electronegativity directs nucleophilic attack by phosphine oxide anions toward carbon rather than fluoride; − (2) fluorine substitution in chlorocarbons diminishes reactivity in A-T-type reactions; and (3) the exceptional thermodynamic stability and kinetic inertness of C­(sp2)–F bonds (BDE = 485–526 kJ/mol) hinder desired defluorinative transformations. Despite these challenges, the defluorofunctionalization of fluorocarbons holds significant promise, as it unlocks synthetic utility in traditionally inert C–F bonds and provides access to otherwise inaccessible skeletally special fluorinated architectures. , If H–P­(O) species were capable of selectively breaking C­(sp2)–F bonds in polyfluoro­(hetero)­aromatic compounds, they would significantly broaden the range of available organophosphorus defluorinative reagents. − , Herein, we report our new finding on selective HDF of polyfluoro­(hetero)­arenes in the presence of H-phosphoryl compounds [HP­(O)­R′R″] with the support of water (Figure , E). This protocol demonstrates for the first time that the sole action of H–P­(O)-species is effective in C­(sp2)–F functionalization. − This controllable approach: (1) expediently synthesizes a plethora of densely substituted oligofluoro­(hetero)­arenes devoid of transition metals and strongly reducing reagents; (2) strategically employs water as an eco-friendly, cheap, and efficient defluoroaccelerator; , (3) selectively cleaves one aromatic C­(sp2)–F bond on polyfluoro­(hetero)­arenes under mild conditions; and (4) significantly expands the reactivity paradigm of phosphoryl (PO) compounds for inert chemical bond activation. However, defluorophosphorylation and overphosphorylation of polyfluoro­(hetero)­aromatic substances with H-phosphine oxides remain a foreseeable challenge. −

Results and Discussion

Evaluation of the Reaction Conditions

Our investigation initially built on the HDF of 2,3,4,5,6-pentafluoro-4′-methoxy-1,1′-biphenyl (1a) in the presence of diphenylphosphine oxide (2a, 1.5 equiv), H2O (5 equiv), and Cs2CO3 (3 equiv) in DMSO at 100 °C for 12 h (Figure ). To our delight, the desired product 3 was obtained in 83% NMR yield, while the starting polyfluoroarene 1a remained in 11% NMR yield (entry 1). Remarkably, switching the solvent from DMSO to EtOAc, MeCN, toluene, THF, MeOH, DMA, or H2O dramatically reduced the product yield (entry 2; see Table S15 in the Supporting Information for more details). Additionally, different bases, such as NaOAc, K3PO4, Et3N, LiOH, and DABCO, were screened (entry 3). However, all of these alternatives exhibited less efficiency than Cs2CO3. Encouragingly, a highly selective generation of 3 could be achieved at 125 °C (93% NMR yield and 90% isolated yield; entry 4), and no other regioisomers or multiple hydrodefluorinated products were formed. In contrast, when the reaction temperature was decreased from 100 to 75 °C, the desired product 3 could be obtained with 77% NMR yield, and 15% NMR yield of polyfluoroarene 1a persisted (entry 5). Next, various substituted H–P­(O)-compounds, including di-p-tolylphosphine oxide (2b), bis­(4-fluorophenyl)­phosphine oxide (2c), diethyl phosphonate (2d), and ethyl phenylphosphinate (2e), were tested in place of simple 2a, but they showed lower reactivity in providing the targeted product (entry 6). These results might be attributed to the large differences in P­(O)H to P–OH tautomerization rates among these phosphorus nucleophiles, which affects their defluorinative capability [HP­(O)­Ph2 > HP­(O)­Ph­(OEt) > HP­(O)­(OEt)2]. − As expected, triphenylphosphine oxide (2f), which lacks an H–P bond within its structure, did not produce any product. Further control experiments demonstrated the irreplaceable HDF roles of H–P­(O)-compounds (entry 7) and Cs2CO3 (entry 8). Moreover, the removal of water from the reaction mixture (entry 9) and the shortening of the reaction time had significant impacts on the targeted defluorination (entry 10). Of note, the byproduct 3′, derived from direct defluorinative phosphorylation, consistently had less than 5% NMR yield in all cases.

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Optimization of reaction conditions. a Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), H2O (1.5 mmol), and Cs2CO3 (0.9 mmol) in DMSO (2 mL) at 100 °C for 12 h. b Yields were determined by 19F NMR analysis with 3-fluoro-4-methoxybenzonitrile (0.3 mmol) as an internal standard. c NMR yield of unreacted 1a. d Isolated yield.

Substrate Scope of Polyfluoro­(hetero)­aromatic Compounds and Monofluorinated Furans

With the optimized reaction conditions in hand, we turned our attention to applying the HP­(O)­Ph2-mediated HDF system to the selective replacement of strong C­(sp2)–F bonds in various polyfluoro (hetero)­aromatic and fluoroheterocyclic compounds with C–H bonds, which represents a significant means to access partially fluorinated (hetero)­aromatic scaffolds. The substrate scope with respect to a number of polyfluoroarenes was studied, as shown in Figure , A. It appeared that the site-selectivity is driven by the electrophilicity of the substrate, with excellent regioselectivities observed. The substrates bearing electron-donating (products 3–9), electron-withdrawing (products 12–17) functional groups [e.g., ether (products 3–7), halide (products 12–14), trifluoromethyl (product 15), and nitrile (products 16–17)], and heteroarenes [e.g., benzo­[d]­[1,3]­dioxole (product 20), pyridine (product 21), and thiophene (product 22)] were successfully converted into the hydrodefluorinated products in moderate to good yields. Polyaromatic products 10, 18, and 19 could be obtained in 56–84% yields. Synthetically useful groups or substituents, such as amide (products 23–24), thioether (product 25), and ether (product 26), directly attached to the polyfluoroaromatic rings were also tolerated, thus providing great flexibility for further transformations. Interestingly, perfluorinated toluene smoothly gave product 27 in 55% yield, with the C­(sp3)–F bond remaining intact. Highly selective Di-HDF occurred for perfluoro-1,1′-biphenyl (product 28) when 2-fold amounts of HP­(O)­Ph2 and Cs2CO3 were used. When (perfluoro-1,4-phenylene)­bis­(phenylsulfane) (1b) was used, unexpected defluorinated reconstructed aromatics 29a and 29b were formed. The related structures were determined by X-ray crystallographic analysis. Moreover, partial defluorination of dibenzo­[b,e]­[1,4]­dioxine (product 30) and pyridines (products 31–32) was observed under the modified conditions (Figure , B). Notably, in addition to poly­(hetero)­aromatic compounds, monofluorinated furan derivatives also proved to be suitable substrates (products 33–34). However, in the cases of simple monofluoroarenes such as 3-fluorobenzonitrile (1c) and 1-fluoro-4-methoxybenzene (1d), the reactions failed to take place (Figure , C).

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HP­(O)­Ph2-Mediated hydrodefluorination of polyfluoro­(hetero)­aromatic compounds. A Substrate scope of polyfluoroarenes. B Substrate scope of polyfluoroheterocycles and fluorofurans. C Substrate scope of simple monofluoroarenes. a Reaction conditions: polyfluoro­(hetero)­aromatic substance (0.3 mmol), 2a (0.45 mmol), H2O (1.5 mmol), and Cs2CO3 (0.9 mmol) in DMSO (2 mL) at 125 °C for 12 h. b At 50 °C. c 24 h. d Yields were determined by 19F NMR analysis with 3-fluoro-4-methoxybenzonitrile (0.3 mmol) as an internal standard. e 2a (0.75 mmol). f Cs2CO3 (1.05 mmol). g 8 h. h 0.2 mmol scale.

Synthetic Applications

Remarkably, the present HDF showed good selectivity and reactivity for the late-stage modification of complex polyfluoroaromatic substances (Figure , A), including estrone (54%; product 35), metiapine (70%; product 36), cetirizine (62%; product 37), and the pterostilbene derivative (56%; product 38). Subsequently, a 3 mmol-scale HDF reaction of polyfluoroarene 1a with 2a was carried out without significant erosion in reaction efficiency and selectivity, demonstrating excellent scalability (91% yield; Figure , B). As shown in Figure , C, the obtained product 3 was used as a versatile building block in arylation, alkenylation, iodination, bromination, and phosphorylation reactions. The corresponding fluoroarenes 39–43 were obtained in 51–99% yields, while the C­(sp2)–F bonds on the fluoroarenes were preserved under palladium catalysis or basic conditions. Furthermore, the deuterium-incorporation reaction of polyfluoroarene 1a with presynthesized 2a-D was tested, leading to product 3/3-D in 78% yield with 98% D-incorporation in the presence of DMSO-d 6 and D2O (Figure , D). Indeed, although various HDF methods of poly­(hetero)­arenes have been reported thus far, efficient defluorinative deuteration protocols using readily available reagents are still relatively scarce. − ,−

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Synthetic applications. A Late-stage modification of complex polyfluoroaromatic substances. B Scale-up of synthesis of product 3. C Further transformations of product 3. (I) Arylation of product 3 with 1-bromo-2-methoxybenzene. (II) Heck-type reaction of product 3 with tert-butyl acrylate. (III) Iodination of product 3 with perfluorobutyl iodide. (IV) Bromination of product 3 with carbon tetrabromide. (V) Reaction of product 3 with HP­(O)­Ph2. D D-Incorporation reaction of polyfluoroarene 1a.

Mechanistic Investigations

To gain more insight into the reaction mechanism of the present HP­(O)­Ph2-mediated HDF, a series of control experiments were conducted, with results illustrated in Figures and . First, performing the defluorofunctionalization of polyfluoroarene 1a in the presence of radical inhibitors [e.g., TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) and 1,1-diphenylethylene] or under dark conditions did not significantly suppress the reactions, suggesting that the radical process might be ruled out (Figure , A). Substrates exemplified in Figure further excluded an electron-transfer mechanism, in which chloride or bromide fragments should preferentially form by the electron-transfer process. In addition, the primary site selectivity appears to be governed by substrate electrophilicity. To assess the potential role of proton transfer from H–P­(O) species bypassing P-induced HDF, different low-valent phosphorus sources as good nucleophiles , or reductants were tested as alternatives to HP­(O)­Ph2 (Figure , B). While PCy3 yielded 29% of HDF product 3 alongside unreacted 1a and p-hydroxylated byproduct 3-OH (entry 1), PPh3, H3PO2, and NaH2PO2 produced no detectable HDF products (entries 2, 5, and 6; Figure , B). In the case of ClPPh2, a doublet signal (J (FP) = 943.7 Hz) at δ = −52.78 ppm was measured by 19F NMR analysis of the reaction mixture, which might be attributed to the formation of an FP­(V) species through the oxidative addition of the C­(sp2)–F bond of 1a to the P­(III) center (entry 4; Figure , B; also see Supporting Information for more details of 31P NMR analysis and HRMS analysis). Notably, HPPh2 could mediate selective defluorination, delivering 3 in 68% NMR yield without 3-OH formation (entry 3; Figure , B). These results indicate that HP­(O)­Ph2 likely functions as a multifaceted reagent rather than a sole reductant. Subsequently, control experiments to intercept potential polyfluoroaromatic carbanions, which formed after postfluoride abstraction, were conducted (Figure , C). − Adding electrophiles, such as PhCHO, I2, PhCH2Br, cyclohexene oxide, and n C4F9I, to the model reaction did not yield adducts 3-E (entries 1–5; Figure , C). Although the slightly modified reaction with n C4F9I in the presence of NaOH afforded a 2% yield of the iodinated product (entry 6; Figure , C), it is possible that it was generated by the C­(sp2)–H bond iodination after the HDF process, as shown in Figure , C, eq IV. Next, we evaluated the substituent effect of the polyfluoroarenes on the reaction rate and constructed a pseudo-Hammett plot (Figure , D). A relatively strong correlation is observed on the side where the substituent R is H, Cl, CF3, or CN, with a negative ρ value of 0.28. In contrast, a mechanistic discontinuity becomes apparent upon transition from H to the more electron-rich t Bu and OMe groups. The Hammett plot clearly shows a break, indicating a change in the reaction mechanism, which is more consistent with either asynchronous bond breaking/making or a complete stepwise process. The exact extent of bond breaking is likely determined by the substituent. According to the results depicted in Figure , E, the addition of DMSO to reactions conducted in MeCN and DCE had no impact on the reactivity, suggesting that the interaction of DMSO with polyfluoro­(hetero)­arenes for hydrodefluorination appears to be unlikely.

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Mechanistic studies. A Performing the defluorofunctionalization of polyfluoroarene 1a in the presence of radical inhibitors or in the dark. B Performing the defluorofunctionalization of polyfluoroarene 1a in the presence of low-valent P sources. C Attempts to intercept the possible polyfluoroaromatic carbanion. D Hammett plot of substituted polyfluoro­(hetero)­arenes. E The role of DMSO.

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Mechanistic studies (continued). F D-Labeling experiments. G The role of HP­(O)­Ph2 (2a) and H2O.

To clarify the proton source, deuterium-labeling experiments were performed (Figure , F; eq 1). Using 5 equiv of D2O showed no deuterium incorporation (entry 1; Figure , F), while 10 equiv of D2O delivered hydrodefluorinated product 3 (79% yield) with 27% deuterium incorporation (entry 2; Figure , F). Reaction in DMSO-d 6 (entry 3; Figure , F) and that with coadded D2O (entry 4; Figure , F) improved D-incorporation to 52% and 75%, respectively. Further addition of D–P­(O)­Ph2 (2a-D) increased deuterated 3-D formation to 78% yield with 98%-D incorporation (entry 5; Figure , F). However, reactions in nondeuterated DMSO with the combination of 2a-D/D2O or 2a-D/H2O resulted in low D-incorporation (11%-D and 0%-D, respectively; entries 6 and 7; Figure , F). Although these results contradict the conclusion that the protons in product 3 originate from H2O and/or H–P­(O)­Ph2, the D-enrichment analysis (regarding the proportion of deuterium reagents; see Supporting Information for details) provides some support. This is because 9.5% and 6.5% D-enrichment in the reagents resulted in 27% and 11% D-incorporation of the products, respectively, when D2O and/or D–P­(O)­Ph2 were used (entries 2 and 6; Figure , F; eq 1). For the reactions in DMSO-d 6, the high 93.5% and 98.6% D-enrichments led to significantly reduced D-incorporation rates of 52% and 75%, respectively (entries 3 and 4; Figure , F; eq 1). Thus, it is possible to deduce that a rapid H/D exchange between H–P­(O)­Ph2 and D2O or DMSO-d 6 occurred. This hypothesis was evaluated by deuterium-labeling experiments of H–P­(O)­Ph2. As expected, within 1 min, a moderate deuteration was detected by treating 2a in the presence of either D2O or DMSO-d 6 (Figure , F; eqs 2 and 4). Notably, at room temperature, this deuteration process achieved a 55% D-incorporation (Figure , F; eq 5). These observations align with the 52% D-incorporation observed in the reaction mixture discussed above (Figure , F; eq 1, entry 3), thereby reflecting the crucial conversion of H–P­(O)­Ph2 to D–P­(O)­Ph2. Moreover, after 12 h, the H/D exchange between H–P­(O)­Ph2 and D2O reached 99%, indicating that this step is likely rate-determining (Figure , F; eq 3). To further confirm the unique hydrodefluorinative role of H–P­(O)­Ph2, we monitored the reaction progress by NMR spectroscopy (Figure , G, 1). After 1 min, a doublet signal (J (PF) = 1017.7 Hz) at δ = 40.72 ppm was measured, which we attributed to the defluorinative product F–P­(O)­Ph2 (2a-F; CAUTION: fluorophosphoryl species might be highly toxic), resulting from the abstraction of fluorine from polyfluoroarenes by H–P­(O)­Ph2 (δ = 20.38 ppm). This elucidates the prominent defluorinative role of H–P­(O)­Ph2. As the reaction continued, both H–P­(O)­Ph2 and intermediate 2a-F were swiftly depleted. Under basic conditions, they were ultimately converted into the diphenylphosphinate anion, i.e., compound 2a-OCs (δ = 14.95 ppm). Meanwhile, the effect of water on the reaction was investigated via 19F NMR analysis of the reaction between 1a and 2a during the initial 1–17 min (Figure , G, 2). Notably, the addition of H2O (5 equiv) accelerated both the reaction rate and the yield of product 3, with this enhancement correlating with the rate of H–P­(O)/P–OH tautomerization. − The maximum yield of F–P­(O)­Ph2, 37%, was achieved at 2 min, coinciding with the consumption of polyfluoroarene 1. When bicyclic guanidine (BG)a catalyst that lowers the tautomerization barrier from 60 to 13.5 kcal/molwas employed, an even faster rate and efficient formation of 3 were determined. These findings suggest that (1) H2O might act as a promoter for H–P­(O)-to-P–OH tautomerization, and (2) tautomerization may constitute the key RDS.

Proposed Mechanism and Density Functional Theory (DFT) Calculation

Based on the above-mentioned mechanistic studies and previous literature, − ,− four plausible mechanisms are proposed (Figure ). Phosphine oxide 2a can exist in both trivalent and pentavalent forms, with a tautomeric equilibrium established between them. This equilibrium typically favors the relatively unreactive pentavalent species. By contrast, the trivalent configuration 2a′ exhibits good nucleophilicity. The tautomerization reported in the literature matches the experimental results shown in Figure : HP­(O)­Ph2 > HP­(O)­Ph­(OEt) > HP­(O)­(OEt)2. Water accelerates the prototropic tautomerism of phosphinylidenes 2a to P­(III) form 2a′; − the latter is likely the real reactive species that interacts with the C­(sp2)–F bond of the polyfluoroaromatic compounds through a five-membered transition state C. Occurrence of synergistic protonation and defluorination events involving simultaneous dissociation of C–F/O–H bonds and formation of P–F/C–H bonds directly delivers the desired HDF products after the removal of FP­(O)­Ph2 (2a-F) (pathway A). Alternatively, we cannot rule out the possibility of a phosphoryl anion (A)-mediated A-T-type defluorination, which would produce an aromatic anion E. The anion could then be rapidly protonated by water or DMSO to release HDF products (pathway B). On the other hand, P­(V)–OH species G resulting from oxidative addition of 1a to P­(III)–OH 2a′ is also a likely intermediate in the low-valent pnictogen system-promoted reaction (pathway C). − Further intramolecular proton transfer of intermediate G yields FP­(O)­Ph2 (2a-F) and HDF products. Remarkably, the combination of HP­(O)­R′R″ and H2O exhibits unconventional HDF reactivity that differs from their traditional roles in phosphorylation. Interestingly, the phosphorylation of polyfluoroarene with excessive nucleophilic phosphoryl anion could be well inhibited (pathway D). − The Hammett studies provide evidence that pathway A was inoperative. To gain a better understanding of HP­(O)­Ph2-mediated hydrodefluorination, density functional theory calculations were performed to investigate the possible insertion of the P­(III)–OH species into the C­(sp2)–F bond of polyfluoroarene 1a (Figure , see the Supporting Information for details). First, the C­(sp2)–F bond in 1a undergoes oxidative addition to phosphine oxide 2a′, forming an intermediate G through a transition state TS1 with a ΔG‡ value of 37.5 kcal/mol. Then, the desired hydrodefluorination product 3 is formed via a five-membered-ring transition state TS2, with a ΔG‡ value of 25.8 kcal/mol. This result is consistent with the stepwise process concluded from the Hammett studies. In addition, the desired transformation involving the hydrodephosphorylation of the phosphorylated species 3′ (pathway E) could be partially ruled out on the basis of the theoretical results, which have a significantly higher energy barrier [49.3 kcal/mol (Figure S3, 1) or 71.1 kcal/mol (Figure S3, 2) vs 37.5 kcal/mol (Figure S1)] and a more positive reaction Gibbs free energy [ΔG = 11.5 kcal/mol (Figure S3, 1) or −4.7 kcal/mol (Figure S3, 2) vs −41.2 kcal/mol (Figure S1) (see Figures S1–S5 in the Supporting Information for more details). The processes of P­(O) species-mediated hydrodephosphorylation of the phosphorylated polyfluoroaromatic compound 3′ are less kinetically and thermodynamically favorable than the process of HP­(O)­Ph2-mediated hydrodefluorination of polyfluoroarene 1a.

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Proposed mechanism.

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Gibbs free energy profiles for HP­(O)­Ph2-mediated hydrodefluorination of polyfluoro­(hetero)­arenes (pathway C).

Further Assessment of the Potential of H–P­(O)­Ph2 for Inert Chemical Bond Activation

Motivated by these successes, we evaluated the potential of H–P­(O)­Ph2-mediated HDF of polyfluoro­(hetero)­arenes using a catalytic amount of 2a in the presence of PhSiH3 (Figure , A). However, the desired product 3 was only obtained in 14% NMR yield, accompanied by significant decomposition of starting material 1a. Additionally, H–P­(O)­Ph2-mediated C­(sp3)–F bond activation of 2,2,2-trifluoro-1-phenylethan-1-one (44) was performed under the standard reaction conditions (Figure , B). This reaction led to the degradation of CF3COPh, along with the formation of a monodefluorinated product 45 and an undefined fluoride species (see Supporting Information for details). These findings highlight the potential of H–P­(O)-based species in activating the C­(sp3)–F bonds. In the case of 1b, which bears two phenylthiolate substituents (Figure ), H–P­(O)­Ph2 induced C–S bond cleavage, with the resulting fragments undergoing relocation on the substrate. This transformation likely proceeds via a competitive SNAr pathway involving free thiolate. To circumvent this issue, we presynthesized monophenylthiolate 46a and subjected it to the H–P­(O)­Ph2-mediated system, yielding HDF product 3 in 39% NMR yield and reconstructed product 47a in 24% NMR yield (20% isolated yield) (Figure , C, eq 1). The dual function of H–P­(O)­Ph2 not only facilitates C­(sp2)–S bond cleavage but also enables C­(sp2)–P bond scissiona process typically requiring transition metals (Figure , eq 7; see the Supporting Information for more details). Notably, the current system exhibited no reactivity toward C–O/N/C bonds in polyfluoroaromatic compounds 46b–46f (Figure , C, eqs 2–6; see the Supporting Inforamtion for more details), C­(sp2)–S bond in heterocycle 48 (Figure , D), and C­(sp2)–Br/Cl bonds in ketones 50–51 (Figure , E). Further exploration of this system’s applicability to other functional group cleavages is underway in our laboratory.

10.

10

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Further assessment of the potential of H–P­(O)­Ph2 for inert chemical bond activation. A The catalytic performance of HP­(O)­Ph2 with PhSiH3. B HP­(O)­Ph2-mediated C­(sp3)–F bond activation of 2,2,2-trifluoro-1-phenylethan-1-one. C HP­(O)­Ph2-mediated C­(sp2)–S/O/N/C bond activation of polyfluoroaromatic compounds. D HP­(O)­Ph2-mediated C­(sp2)–S bond activation of the heteroaryl ether. E HP­(O)­Ph2-mediated C­(sp2)–Br/Cl bond activation.

Conclusion

In summary, we have developed a highly selective HP­(O)­Ph2-mediated hydrodefluorination (HDF) system for polyfluoro­(hetero)­aromatic compounds. This advancement is significant because most phosphoryl [H–P­(O)] species, particularly the commercially available, bench-stable, and inexpensive pentavalent phosphorus compound HP­(O)­Ph2 used herein, overcome limitations associated with low-valent pnictogen-facilitated HDF systems. Specifically, our method eliminates the need for complex constrained P-ligand architectures and external silane additives. The key finding lies in the multifaceted roles of H-phosphine oxides, which act not only as H-reagents but also as defluorinative surrogates. The exploitation of the fluorophilicity of readily accessible H–P­(O)-reagents for C­(sp2)–F activation represents a previously unexplored reactivity paradigm, expanding the synthetic utility of phosphoryl [P­(V)] compounds for inert chemical bond transformations. This protocol demonstrates excellent scalability, enables postfunctionalization of complex molecules, and allows conversion of the resulting products into other value-added fluorinated compounds, underscoring its broad synthetic potential in medicinal and organic chemistry. In addition to promoting HDF, HP­(O)­Ph2 shows promise for C­(sp2)–S and C­(sp2)–P bond scission. Mechanistic studies and DFT calculations revealed that (1) H–P­(O)-to-P–OH tautomerization constitutes the key rate-determining step, and water acts as a potential accelerator for this process; (2) the reaction involves a sequence of oxidative addition and proton transfer processes. However, further expansion of the present method to other simple fluoroarenes and aliphatic organofluorides and mechanistic studies of the C–S/C–P bond cleavage process in the presence of HP­(O)­Ph2 are currently underway in our laboratory.

Methods

Defluorofunctionalization of Polyfluoro­(hetero)­arenes

A solution of polyfluoro­(hetero)­arene (0.3 mmol, 1 equiv), phosphine oxide 2 (0.45 mmol, 1.5 equiv), H2O (27.0 mg, 1.5 mmol, 5 equiv), and Cs2CO3 (293.2 mg, 0.9 mmol, 3 equiv) in DMSO (2 mL) was stirred at 125 °C (oil bath) for 12 h. The reaction was then quenched with a saturated NH4Cl solution (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with saturated brine twice, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (300–400 mesh) using petroleum ether/ethyl acetate (200/1–1/1) as eluent to afford the pure product.

Supplementary Material

au5c01460_si_001.pdf (12MB, pdf)

Acknowledgments

We gratefully acknowledge the financial support from the Natural Science Foundation of Gansu Province (25JRRF004), the Jiangsu Provincial University Key Laboratory of Intelligent Medical Sensing Materials and Devices, the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX25_1702; X.-Y.H.), and Nanjing Tech University.

The data underlying this study are available in the published article and its online Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c01460.

  • General information, experimental procedures, synthetic applications, mechanistic studies, DFT calculations, reaction optimization, crystal data, characterization data for products, and spectral data for all new compounds (PDF)

X.-Y.H., X.-X.M., M.-Y.G., D.G., Z.-L.S., K.G., X.-Q.C., and C.-J.L. designed, performed, and analyzed experiments. C.D. performed the DFT calculation. K.G., X.-Q.C., and C.-J.L. prepared the paper with contributions from all authors. All the authors discussed the results and commented on the paper. Correspondence and requests for materials should be addressed to K.G. (guok@njtech.edu.cn), X.-Q.C. (xueqiangchu@njtech.edu.cn), and C.-J.L. (cjli@mcgill.ca).

The authors declare no competing financial interest.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

au5c01460_si_001.pdf (12MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

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