Metal-free Photochemical Halophosphonium Salts-mediated C(sp3)-H Functionalization

Metal-free Photochemical Halophosphonium Salts-mediated C(sp3)-H Functionalization | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 30 June 2025 V1 Latest version Share on Metal-free Photochemical Halophosphonium Salts-mediated C(sp3)-H Functionalization Authors : Kaiting Sun , Chunjie Qian , Wenlu Sun , Boyang , Youyou Zheng , Xun Yang , Shuyu Huang , and Shihui Liu [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175125459.94858555/v1 229 views 235 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract A halophosphonium salts platform merges ligand-to-phosphorus charge transfer (LPCT) and hydrogen atom transfer (HAT) for metal-free C(sp 3 )-H functionalization under visible light. Cite this paper: Chin. J. Chem. 2024 , 42 , XXX—XXX. DOI: 10.1002/cjoc.202400XXX Metal-free Photochemical Halophosphonium Salts-mediated C(sp³)-H Functionalization Kaiting Sun, §a Chunjie Qian, §a Wenlu Sun, a Boyang He, a Youyou Zheng, a Xun Yang, a Shuyu Huang, a and Shihui Liu, *a a College of Medicine, Jiaxing University, 118 Jiahang Road, Jiaxing 314001, P. R. China. Keywords Halophosphonium salts | C(sp 3 )-H functionalization | Ligand-to-phosphorus charge transfer | Metal-free Comprehensive Summary Background and Originality Content Organic photocatalysis has emerged as an eco-friendly strategy in pharmaceutical investigations, offering more economical, easily prepared and structurally tunable catalysts, and less toxic and environmentally damaging [1] . In parallel development, organophosphorus compounds have gained prominence across photocatalysis owing to their exceptional electron delocalization characteristics and photophysical adaptability [2, 3] . Particularly noteworthy are phosphonium salts, whose distinctive redox activity, extended excited-state duration, and broad-spectrum visible light responsiveness position them as innovative mediators in photoredox catalytic systems for synthetic transformations [4] . Scheme 1 Phosphonium salts-mediated photocatalysis Zuo’s group pioneered the application of bisphosphonium salts in photocatalysis, achieving the intramolecular hydroalkoxylation of olefins under mild conditions [5] . The versatility of phosphonium salts in this field was further demonstrated by Liao’s group through their innovative integration into visible-light-driven reversible addition-fragmentation chain transfer polymerization [6] . Building on this mechanistic foundation, Zuo’s group developed a series of photocatalytic platforms using phosphonium salts, which enabled selective benzyl alcohol oxidation [7] , deuterium-mediated carbon-carbon bond scission [8] and stereoselective cyclohexene ring-opening [9] . Additionally, other related works such as trifluoromethylthiophosphonium salts in the photoredox catalytic hydrotrifluoromethylation and hydrotrifluoromethythiolation of unactivated alkenes [10] , deuterated alkylphosphonium salts in the photoinduced synthesis of heterocycles [11] [3+2] annulation [12] and bisphosphonium salts/oxygen cooperative catalysis for direct benzyl C-H carbonylation [13] , these research have significantly expanded the mechanistic scope of phosphonium salt-based photocatalysis ( Scheme 1A ). The strategic convergence of organocatalysis with C-H bond functionalization represents an emergent paradigm in contemporary synthesis, synergistically addressing long-standing challenges in predictability and selectivity for inert bond transformations [14] . While photoredox catalysis has dominated recent advances, the untapped potential of phosphonium salts in this domain remains conspicuously underexploited. Notably, halophosphonium salts, conventional yet versatile intermediates in Appel-type halogenation processes, offer synthetic accessibility through phosphine oxide/halogenating reagent combinations, primarily employed in alcohol functionalization ( Scheme 1B ) [15, 16] . Intriguingly, emerging insights from ligand-to-metal charge transfer (LMCT) [17] photochemistry prompt a mechanistic hypothesis: Could ligand-to-phosphorus charge transfer (LPCT) excitation modes in these phosphorus(V) species unlock novel reactivities under photoinduction regimes? Based on our research groups focus on creating innovative sustainable platforms for direct activation of organic molecules, specifically targeting energy-efficient C(sp³)-H diversification methodologies [18] . Leveraging breakthroughs in metal-free photochemical systems and our established capabilities in catalytic synthesis, we identified halophosphonium salts as multifunctional agents capable of simultaneous photocatalysis and hydrogen atom transfer (HAT) mediation. Herein, we report a visible-light-driven C(sp³)-H functionalization platform utilizing halophosphonium salts as bifunctional photoredox catalysts ( Scheme 1C ). This dual-role catalytic paradigm not only provides a complementary approach to existing systems but fundamentally expands the application scope of halophosphonium architectures, revealing their underutilized potential as modular photocatalytic frameworks in modern synthetic methodologies. Results and Discussion Optimization of reaction conditions Table 1 Optimization studies for C(sp 3 )-H alkylation a Entry Reaction conditions Yield( 3a ) b 1 Standard conditions 86% 2 XPS2 instead of XPS1 42% 3 XPS3 instead of XPS1 68% 4 XPS4 instead of XPS1 70% 5 XPS5 instead of XPS1 trace 6 XPS6 instead of XPS1 66% 7 XPS7 instead of XPS1 64% 8 XPS8 instead of XPS1 76% 9 XPS9 instead of XPS1 80% 10 XPS10 instead of XPS1 trace 11 ( n Bu) 4 N + Cl - instead of ( n Bu) 4 P + Cl - 38% 12 (Et) 4 N + Cl - instead of ( n Bu) 4 P + Cl - 30% 13 KCl instead of ( n Bu) 4 P + Cl - 13% 14 ( n Bu) 4 P + Br - instead of ( n Bu) 4 P + Cl - trace 15 No XPS1 36% 16 No ( n Bu) 4 P + Cl - 50% a Conditions employed 395 nm Leds, 1a (1.0 mmol), 2a (0.2 mmol), XPS1 (1.2 equiv.), ( n Bu) 4 P + Cl - (1.5 equiv.), anhydrous CH 3 CN (2.0 mL), the reaction mixture was degassed via freeze pump thaw (× 3 times) and refilled with N 2 , 35 o C, 19 h, unless otherwise noted. b Isolated yields were reported. c Not detected. To systematically explore the synthetic potential of halophosphonium salts, we developed a rational screening platform for rapid assessment of ligand-to-phosphorus charge transfer (LPCT) activity across diverse phosphorus centers. Initial investigations employed 4-phenyltoluene ( 1a ) and benzalmalononitrile ( 2a ) as model substrates with 1.2 equivalents of dichlorotriphenylphosphorane ( XPS1 ) and 1.5 equivalents of ( n Bu) 4 P + Cl - in acetonitrile at 35 °C. Notably, irradiation with 395 nm light for 19 hours afforded the C(sp 3 )-H alkylation product 3a in 86% isolated yield ( Table 1 , entry 1), establishing XPS1 as the optimal catalyst. Systematic evaluation of structural analogs revealed diminished efficiency when substituting XPS1 with other chlorophosphonium salts ( XPS2-XPS4 , entries 2-4). Bromophosphonium salt XPS5 proved completely inactive (entry 5), while alternative halogenating agents ( XPS6 - XPS7 with TsCl or NCS) also showed reduced yields (entries 6-7). The chlorinated analog XPS8 exhibited intermediate performance (entry 8), whereas other commercially available phosphonium salts XPS9 - XPS10 demonstrated attenuated reactivity (entries 9-10), likely due to insufficient photoredox activity for effective hydrogen atom transfer (HAT) with 1a . It was noteworthy that other chloride sources such as ( n Bu) 4 N + Cl - , (Et) 4 N + Cl - , KCl or ( n Bu) 4 P + Br - all gave 3a in lower yields (entries 11-14). Control experiments confirmed the necessity of both XPS1 and ( n Bu) 4 P + Cl - for efficient conversion (entries 15-16), while complete reaction inhibition under dark conditions (entry 17) unequivocally established the photochemical nature of this transformation. Scope of C(sp 3 )-H alkylation With the optimized reaction conditions established ( Table 1 , entry 1), we next explored the substrate scope of hydrocarbons and radical acceptors. To evaluate the generality of C(sp 3 )-H bond functionalization, we initially examined a series of benzylic C-H substrates ( Figure 1A ). Methylarenes proved to be competent substrates, delivering the corresponding products 3b - 3f in 32-71% yields. Notably, substrates bearing methoxy ( 3b , 3c ), benzyloxy ( 3d ), phenoxy ( 3e ), and phenylthio ( 3f ) groups exhibited good compatibility under the reaction conditions. For secondary benzylic C-H bonds, the reaction proceeded with a 1:1 diastereomeric ratio (d.r., 3g ). While benzylic C-H activation demonstrated feasibility, the potential of chlorophosphonium salt XPS1 to activate inert aliphatic hydrocarbons remained unclear. Such transformations are inherently challenging due to the higher bond dissociation energies (BDEs) of aliphatic C(sp 3 )-H bonds (99-105 kcal/mol) [19] . Particularly, petroleum-derived alkanes pose significant obstacles in C-H functionalization, as their highly reactive alkyl radical intermediates complicate chemoselectivity and site selectivity control. Remarkably, by fine-tuning the reaction parameters, both branched and linear alkanes were efficiently converted to target products ( 3h - 3l ) in 51-99% yields. This protocol was further extended to allylic, O- α , and N- α C(sp 3 )-H bonds, yielding products 3m - 3q with comparable efficiency. Subsequently, we investigated the scope of radical acceptors. Compared to previous systems employing XPS1 , the current conditions enabled hydroalkylation of a broader range of electron-deficient alkenes ( Figure 1B ). Arylidenemalononitriles and arylidenemalonates bearing electron-withdrawing substituents (fluoro, bromo, cyano and trifluoromethyl) were well tolerated, affording products 4a - 4f in 30-67% yields. Furthermore, azodicarboxylates underwent smooth transformation with 4-phenyltoluene ( 1a ), generating hydrazine derivatives 4g - 4h in acceptable yields (35-59%). The methodology also proved effective for 1,1-bis(phenylsulfonyl)ethylene and tosyl cyanide, furnishing products 4i and 4j , respectively. Mechanistic investigations To elucidate the reaction mechanism, we conducted systematic spectroscopic monitoring of the model reaction system ( 1a , 2a , XPS1 → 3a ). Radical trapping experiments with TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) (2.0 equiv.) or BHT (butylated hydroxytoluene) (2.0 equiv.) completely suppressed 3a formation ( Figure 2A ), with concomitant emergence of Michael adducts unambiguously confirming benzyl radical intermediacy. Complementary 31 P-NMR studies demonstrated halogen-dependent chemical shift variations of triphenylphosphine oxide (Ph 3 P=O) signals upon treatment with oxalyl chloride with different ratios of oxalyl chloride that ranged from 1:0 to 1:2 ( Figure 2B ), directly evidencing phosphine-halogen reagent interactions [16] . 31 P-NMR spectra changed as the reaction proceeded (0-6-12-19 h), real-time ultraviolet-visible (UV-vis) absorption and emission spectral analyses ( Figure 2C ) revealed that all individual components ( 1a , 2a , XPS1 ) and binary combinations exhibited solely UV-range absorption (λ < 400 nm). Notably, prolonged stirring (4–19 h) induced a distinct bathochromic shift exclusively in the complete reactant mixture, while neither isolated components nor product 3a displayed this spectral evolution, suggesting in situ generation of light-responsive species further corroborated by the intensified emission spectra and visual color transition (colorless → reflective mixture) observed through optical filters. Moreover, the kinetic isotope effect results of competitive (k H /k D = 1.9) and parallel (k H /k D = 0.5) experiments between cyclohexane and cyclohexane-D 12 at low reaction conversion suggested that the HAT process is not a rate-determining step in the catalytic cycle ( Figure 2D ). Computational investigations Integrating experimental observations with density functional theory (DFT) calculations at the B3LYP/6-31G(d) level, we propose the mechanistic pathway outlined in Figure 3 . The cycle initiates with oxalyl chloride-mediated conversion of triphenylphosphine oxide (Ph₃P=O) into commercially available halophosphonium salt XPS1 (Δ G = –20.0 kcal/mol), concomitantly producing CO and CO 2 [16] , which consistent with the results presented in Figure 2B . Photoexcitation of XPS1 ( Int1 ) under visible light overcomes the activation barrier (Δ G = +51.2 kcal/mol) to access its triplet excited state ( Int2 ). The ligand-to-phosphorus charge transfer (LPCT) process converts Int2 to Int3 with ΔG = +7.1 kcal/mol, establishing a stabilized initial state IS1 ( Int3 + 1a ) through exergonic relaxation (∆ G = –10.08 kcal/mol) [3] . Hydrogen atom abstraction by chlorine radical ( Int3 ) from 1a proceeds via transition state TS1 (ΔG‡ = +2.3 kcal/mol), yielding HCl and carbon-centered radical Int4 (∆ G = –5.34 kcal/mol) in a thermodynamically favored process, consistent with the kinetic isotope effect results in Figure 2D . Coupling of Int4 with alkene 2a initiates through IS2 ( Int4 + 2a , ∆ G = +3.31 kcal/mol) [20] , surmounting TS2 (ΔG‡ = +7.95 kcal/mol) to form radical intermediate Int5 (ΔG = –14.46 kcal/mol). Regeneration of chlorine radical ( Int3 ) occurs via HAT between Int5 and HCl ( IS3 : ∆ G = +4.78 kcal/mol; TS3 : ΔG‡ = +16.48 kcal/mol), delivering product 3a (∆ G = +10.05 kcal/mol) and recycling Int3 (∆ G = –7.51 kcal/mol). Notably, the closed-loop regeneration of Int3 enables catalytic turnover, while the exergonicity of critical steps (–5.34 to –14.46 kcal/mol) ensures irreversible progression toward product formation. The endergonic final step (∆ G = +10.05 kcal/mol) reflects thermodynamic stability of 3a , consistent with experimental isolation yields. Scope of C(sp 3 )-H chlorination and bromination Based on the mechanism studies above, the LPCT process could efficiently generate halogen radicals, which laid a foundation for further C(sp 3 )-H divergent conversions. Herein, using chlorophosphonium salts ( CPS ) [15, 16, 21] as an effective chlorinated reagent, we developed benzylic C-H chlorination with the benzylic C-H substrates, some representative alkylbenzene derivatives were examined to explore the generality of this new chloration method ( Figure 4A ). To our delight, substrates containing different functional groups on the aromatic ring were smoothly converted to the corresponding chlorides in moderate to good yields ( 5a - 5l , 32-92%). Various methylarene substituents such as 4-phenyl ( 5a ), 3-phenyl ( 5b ), 2-phenyl ( 5c ), 4-(4-acetylphenyl) ( 5d ), 4-(2-methylbenzoate) ( 5e ), 4-(2-cyanophenyl) ( 5f ), 4-benzoyl ( 5g ), 4-ester carbonyl ( 5h ) and 4-acetyl ( 5i ) were tolerated well for this transformation while nitro group was also suitable for this system albeit with low reactivity ( 5j , 32%). Moreover, substrates 5k and 5l involving thiazole and furan were also competent for this reaction (35%). Notably, our reaction system would not result in benzylic oxidation for all substrates examined above. For secondary benzylic C-H bonds, both branched and linear substituents were efficiently converted to target products ( 5m-5u ) in 30-62% yields. Additionally, the bromination of benzylic C-H bonds has been proven feasible by using bromophosphonium salts [ N -bromosuccinimide (NBS) and Cy 3 P] [22] as HAT reagents and coupling partners ( Figure 4B ). The bromination of toluene and ethylbenzene shows a high selectivity to the corresponding bromides ( 6a - 6k and 6l - 6q ) with high yields. Drug analogues such as ibuprofen methyl ester and canagliflozin intermediate can yield corresponding brominated products ( 6r and 6s ). Scope of C(sp 3 )-H fluorination Moreover, the strategy was further applied to the benzylic C-H fluorination in the presence of fluorophosphonium salts [Selectfluor and ( n Bu) 3 P] [23] ( Figure 5 ). Both primary ( 7a - 7p ) and secondary ( 7q - 7aa ) benzylic C-H bonds are tolerated, although higher conversions are noted for electronrich substrates, consistent with fluorination from a nucleophilic benzylic radical. Although direct heterobenzylic fluorination is a challenge, nitrogen-containing substrates were successfully fluorinated ( 7o , 7p ), supporting the feasibility of late-stage fluorination on pharmaceutically relevant scaffolds. Tertiary benzylic C-H bonds is typically more difficult to convert, but is tolerated under our reaction conditions ( 7ab ). Drug molecules such as celecoxib and benzbromarone can also be used using this protocol ( 7ac , 7ad ). Demonstration of C(sp 3 )-H functionalization with nucleophilic coupling partners Despite the inherent appeal of direct C(sp³)-H functionalization, existing methodologies exhibit constrained reactivity toward benzylic coupling partners. Furthermore, key nucleophiles, including primary and secondary amines as well as thiols, remain incompatible with conventional C(sp 3 )-H activation frameworks [24] . The halogenation strategy developed in this study addresses these limitations by generating transient reactive intermediates capable of undergoing nucleophilic trapping after complete consumption of halophosphonium salts in the reaction mixture. To demonstrate the generality of this approach, we applied the tandem sequence to diverse C-H substrates ( 6r , 6s ) and nucleophiles (morpholine, piperazine, KSCN, KSeCN and p -toluenethiol) ( Figure 6 ). These transformations proceeded efficiently, affording target products ( 8a - 8f ) in 73-95% isolated yields (relative to halogenated products). Notably, the observed compatibility with water ( 8g , 8h ) significantly broadens the scope of viable coupling partners beyond those accessible through traditional oxidative protocols. Conclusions In summary, we have developed a halophosphonium salts-mediated photochemical platform that synergistically integrates ligand-to-phosphorus charge transfer (LPCT) activation with hydrogen atom transfer (HAT) processes, achieving versatile C(sp³)-H functionalization under mild visible light conditions. The discovery of halophosphonium salts as dual-function reagents capable of serving as both photoredox catalysts and halogen radical reservoirs, circumventing the need for transition metals or exogenous photosensitizers. Mechanistic elucidation through combined spectroscopic, kinetic, and computational studies, revealing a closed-loop catalytic cycle involving LPCT-induced halogen radical generation and substrate-selective HAT. Broad applicability across diverse transformations including alkylation, chlorination, bromination, and fluorination, with demonstrated compatibility for late-stage modification of pharmaceutical intermediates. Experimental General Procedure of C(sp 3 )-H alkylation. To a 10 mL vial equipped with a Teflon septum and magnetic stir bar were added the corresponding C(sp 3 )-H substrate (if solid, 2.5 mmol, 5.0 equiv.), the corresponding radical acceptor (if solid, 0.5 mmol, 1.0 equiv.), XPS1 (0.6 mmol, 1.2 equiv.), and ( n Bu) 4 P + Cl - (0.75 mmol, 1.5 equiv.). The vial was sealed and placed under N 2 atmosphere, then anhydrous CH 3 CN (5.0 mL, 0.1 M), C(sp 3 )-H substrate (if liquid, 2.5 mmol, 5.0 equiv.), radical acceptor (if liquid, 0.5 mmol, 1.0 equiv.) were added into the vial via injection through the cap, the reaction mixture was degassed via freeze pump thaw (× 3 times) and refilled with N 2 . The sealed vial was placed in 395 nm Leds and irradiated for 19 hours. When the reaction finished, the reaction mixture was diluted with saturated NaHCO 3 aqueous solution, extracted with ethyl acetate (3 × 20 mL), the combined organic extracts were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel using the indicated solvent system afforded the desired product. Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.202400xxx. Acknowledgement This work was supported by National Natural Science Foundation of China (22001096), Project of Jiaxing Science and Technology Plan-Special Project for Young Scientific and Technological Talents (2023AY40031) and Qin Shen Scholar Program of Jiaxing University (CD70623026). References [1] For selected reviews of organic photocatalysis in pharmaceutical investigations, see: (a) Nicewicz, D. A.; Nguyen, T. M. 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Manuscript received: XXXX, 2024 Manuscript revised: XXXX, 2024 Manuscript accepted: XXXX, 2024 Version of record online: XXXX, 2024 The Authors Left to Right(First row): Kaiting Sun, Chunjie Qian, Wenlu Sun, Boyang He Left to Right(Second row): Youyou Zheng, Xun Yang, Shuyu Huang, and Shihui Liu Entry for the Table of Contents Metal-free Photochemical Halophosphonium Salts-mediated C(sp³)-H Functionalization Kaiting Sun, Chunjie Qian, Wenlu Sun, Boyang He, Youyou Zheng, Xun Yang, Shuyu Huang, and Shihui Liu,* Chin. J. Chem. 2024 , 42 , XXX—XXX. DOI: 10.1002/cjoc.202400XXX A halophosphonium salts platform merges ligand-to-phosphorus charge transfer (LPCT) and hydrogen atom transfer (HAT) for metal-free C(sp³)-H functionalization under visible light. Information & Authors Information Version history V1 Version 1 30 June 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords c(sp³)-h functionalization halophosphonium salts ligand-to-phosphorus charge transfer metal-free Authors Affiliations Kaiting Sun Jiaxing University View all articles by this author Chunjie Qian Jiaxing University View all articles by this author Wenlu Sun Jiaxing University View all articles by this author Boyang Jiaxing University View all articles by this author Youyou Zheng Jiaxing University View all articles by this author Xun Yang Jiaxing University View all articles by this author Shuyu Huang Jiaxing University View all articles by this author Shihui Liu [email protected] Jiaxing University View all articles by this author Metrics & Citations Metrics Article Usage 229 views 235 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Kaiting Sun, Chunjie Qian, Wenlu Sun, et al. Metal-free Photochemical Halophosphonium Salts-mediated C(sp3)-H Functionalization. Authorea . 30 June 2025. 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