Photoinduced cross-coupling of aryl halides enabled by n-tetrabutylphosphonium phthalate

Abstract

The generation and control of aryl radicals pose considerable challenges, such as highly negative reduction potentials of aryl halides and their amphiphilic character. Herein, we introduce the synergistic interplay of a three-component photoactive electron-transfer system that enables photoinduced cross-coupling of aryl halides using n-tetrabutylphosphonium phthalate as a one-electron-transfer mediator. Our method readily accommodates the formation of four different bond-forming reactions (C(sp²)–C/P/B/S). The present approach exhibits good functional group tolerance and biocompatibility with plasmids, DNase, and serum albumin, as well as great efficiency for late-stage incorporation into drug molecules, BODIPY dye, and natural compounds. Mechanistic investigations revealed the bifunctional property of n-tetrabutylphosphonium phthalate potentially through two-point non-covalent interaction to bring aryl halides and pyrrole derivatives within proximity for facilitated electron transfer.

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Introduction

Cross-coupling reactions of aryl halides are among the most explored organic transformations for rapid diversification of molecular structures, which is very relevant in the discovery and preparation of drug candidates and materials.^1,2 As such, tremendous progress has been made in the past several decades in two-electron transition-metal catalysis. As an analogy, cross-coupling of readily available aryl halides as aryl radical precursors,³ which possess amphiphilic characteristics,⁴ could offer a general and complementary approach in the construction of (hetero)aryl–(het)atom bonds. However, its utility has been hampered by procedures for the generation of aryl radicals that are laborious because of the highly negative reduction potentials of aryl halides.

Three elementary methods are used to generate aryl radicals from the corresponding halides: (i) direct photochemical homolysis of the C–halogen bond in high-energy UV (<300 nm) radiation,^5,6 (ii) halogen-atom transfer (XAT)^7,8 typically based on stoichiometric and toxic tin or silicon species as nucleophilic radical precursors, and (iii) single-electron transfer (SET) reduction of aryl halides with very strong reductants^9,10 or super electron donors^11,12 due to their highly negative reduction potential (>−2.0 V, Scheme 1A).

Scheme 1 Photoinduced cross-coupling of aryl halides via an electron transfer process.

SET to aryl halides has sparked tremendous attention due to its synthetic appeal and a formidable challenge from redox properties. Indeed, the advent of visible-light photoredox catalysis^9,13–22 and electron-primed photoredox catalysis^23,24 provides a means to realize extremely high reduction potentials under catalyst control for the generation of aryl radicals from the corresponding halides. However, these approaches commonly require a stoichiometric amount of sacrificial electron donors or cathodic reduction, as well as an exogenous photocatalyst.²⁵

In recent years, electron donor–acceptor (EDA) photochemistry has emerged as a promising alternative to visible-light-promoted SET pathways without the need for additional photosensitizers or specialized equipment.^26–31 This single-electron redox chemistry exploits the association of donor and acceptor by non-covalent interactions to produce a ground state aggregate, known as an EDA complex, resulting in a reduction in the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO–LUMO) gap and the appearance of a new charge-transfer absorption band (Scheme 1B). Photoexcitation of the colored EDA complex then triggers an intracomplex SET from donor to acceptor to generate a radical ion pair, which is capable of initiating synthetically useful radical processes. In addition to the difficulty associated with unproductive back electron transfer (BET), challenges accompanied by the intrinsic weakness of non-covalent interactions between donor and acceptor also impede the development of such a transformation.

In this context, the efficient formation of stoichiometric EDA complexes for aryl cross-coupling reactions has been reported (Scheme 1C), and involves the addition of external base, which serves to increase the electron density of the donor,^32,33 or through modification of the substrate, which affords decreased electron density of the acceptor.³⁴ Additionally, substoichiometric aminocatalysts have been used to enhance non-covalent interactions to form EDA complexes via electron-rich enamine intermediates or electron-deficient iminium ion generation.^35,36 More recently, researchers succeeded in developing EDA complex catalysis in concert to activate only one of the reacting partners;^37–39 however, most of them have been limited to specific radical precursors or stoichiometric substrates adorned with suitable redox auxiliaries (Scheme 1C).

In parallel research, multicomponent photoinduced electron transfer systems within supramolecular assemblies, in which electron donor and acceptor are covalently or non-covalently linked, have been broadly implemented to mimic electron transfer (ET) and charge separation function in photosynthetic proteins.^40–44 Conversely, multicomponent photoactive EDA complexes with the capability to simultaneously activate both reacting partners remain scarce.^43,45

König and co-workers have very recently reported that the hydrophobic effect forces two reactants to form an EDA complex on the surface of water under 365 nm light irradiation.⁴⁵ This limitation can be attributed to inherent problems from the appropriate geometrical organization of multicomponent systems, which includes cooperativity, compatibility, and kinetics. The great success in supramolecular assemblies inspired us to question whether multicomponent photoactive EDA complexes could be extended to simultaneously activate two reactants with different electron affinities, advancing the notion of enhanced substrate breadth. In particular, we were optimistic that the assemblage of a multicomponent photoactive EDA complex by logical but non-covalent interlocking of individual molecular modules might provide sufficient structural constraints to accurately control the distance and orientation between an electron donor (ED) reactant and an electron acceptor (EA) reactant. With such a complementary strategy, it might be unnecessary to provide extra adornment with chromophoric units to enhance the absorption properties of the reacting partners.

It is important to note that judicious selection of appropriate mediators to bridge the reacting partners in close proximity to each other is a very challenging endeavour, because multiple non-covalent interactions are often temperature- and solvent-sensitive and do not always have a synergistic effect on the regular stacking of chromophores.⁴⁶ In addition, the platform derived from dicarboxylic acid demonstrated a strong ability to form non-covalent interactions. We recently reported that the simultaneous use of cyclic diacyl peroxides and halide salts facilitated the direct generation of heteroatom-centered radicals and electrophilic halocyclization through spatially confined non-covalent orientation and an intramolecular carboxylate-assisted proximity effect, respectively.^47,48

Against this backdrop, we report here that utilization of n-tetrabutylphosphonium phthalate as a bifunctional one-electron-transfer mediator, which directs and accelerates the intracomplex electron transfer, provides a powerful platform for substrate generality-oriented C(sp²)–(het)atom bond cross-coupling reactions under photoinduced conditions (>100 examples) (Scheme 1D). Mechanistic investigations indicate that appropriate non-covalent bridges in a spatially confined system facilitate close positioning between aryl halides and four useful classes of trapping agents, and visible-light excitation of the resultant well-defined EDA trio then proceeds via intracomplex electron transfer to furnish the corresponding cross-coupling products. Furthermore, the mild reaction conditions and high functional group tolerance in conjunction with the presently described non-covalent assembly of a photoactive EDA trio enable the late-stage functionalization of druglike bioactive molecules as well as organic functional materials bearing an aryl halide motif, and offer great opportunity for excellent biomolecular compatibility.

Results and discussion

Optimization of the reaction conditions

To establish a proof-of-concept, we began our investigation with radical coupling of aryl halides and pyrrole derivatives by using a range of potential phthalates as one-electron-transfer mediators (Table 1). The reaction conditions were optimized by irradiating a mixture of methyl 4-iodobenzoate (1a), N-methyl pyrrole (2a), and various phthalates in dimethyl sulfoxide (DMSO) with blue light (410 nm) at room temperature. After a careful screening of cations, substituents, and used amounts of phthalates, [(n-Bu)₄P⁺]₂[(4-OMe)-C₆H₃(COO⁻)₂] was found to be the optimal choice for the process, providing the desired product 3a in 83% yield (entries 1–4). More significantly, the replacement of one equivalent of phthalate anions by two equivalents of either benzoate anion or Br⁻ led to a substantial decrease or even loss in reaction efficiency (entries 5 and 6).

Table 1 Reaction optimization^a

Entry	Phthalates or other salts	Yield^b (%)
a Reaction conditions: the mixture of 1a (0.2 mmol), 2a (50 equiv.), and phthalates (1 equiv.) in DMSO (0.1 M) under blue LED irradiation for 20 h unless otherwise stated. b Isolated yield. c Other salts (2 equiv.). d DMF instead of DMSO. e CH3CN instead of DMSO. f Phthalates (1.2 equiv.). g In the dark. N.D. = not detected.
1	(Na^+)2[(4-Me)-C6H3(COO^−)2]	2
2	(Na^+)2[(4-OMe)-C6H3(COO^−)2]	8
3	[(n-Bu)4N^+]2[(4-OMe)-C6H3(COO^−)2]	74
4	[(n-Bu)4P^+]2[(4-OMe)-C6H3(COO^−)2]	83
5	[(n-Bu)4P^+][(3-OMe)-C6H4(COO^−)]	30^c
6	[(n-Bu)4P^+](Br^−)	N.D.^c
7	[(n-Bu)4P^+]2[(4-OMe)-C6H3(COO^−)2]	50^d
8	[(n-Bu)4P^+]2[(4-OMe)-C6H3(COO^−)2]	15^e
9	[(n-Bu)4P^+]2[(4-OMe)-C6H3(COO^−)2]	90^f
10	—	N.D.
11	[(n-Bu)4P^+]2[(4-OMe)-C6H3(COO^−)2]	N.D.^g

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The results indicate that n-tetrabutylphosphonium phthalate is a crucial component, and its two-point non-covalent interactions with the two reactants might play a decisive role in visible-light-promoted pyrrole coupling reactions. For all the examined solvents (entry 4 vs. entries 7–8), it was proved that DMSO was the most effective. It was found that the use of [(n-Bu)₄P⁺]₂[(4-OMe)-C₆H₃(COO⁻)₂] (1.2 equiv.) was the most optimal in this process, and provided the desired product 3a in 90% yield (entry 9). No product formation took place in the absence of phthalate or visible-light irradiation at room temperature in control experiments (entries 10 and 11). Gram-scale reaction of 1a, 2a, and n-tetrabutylphosphonium phthalate was also performed on a 6 mmol scale, delivering the desired product 3a in 60% yield.

Substrate scope

With the availability of a three-component photoactive complex, we examined the scope of visible-light-promoted pyrrole coupling reactions with respect to various aryl halides (Scheme 2A). Electron-poor aryl halides featuring ester, ketone, aldehyde, amide, nitrile, nitro, sulfone, and trifluoromethoxy functionalities at the para-position were efficiently coupled with N-methyl pyrrole, giving rise to the desired 2-aryl-pyrroles (3a–3i) in 43–92% yields. Although electron-rich aryl chlorides and bromides exhibited lower activity in this protocol, aryl iodides with para-substituted electron-donating groups participated smoothly and furnished the corresponding 2-aryl-pyrroles (3j–3o) in moderate yields. The reaction displayed remarkable tolerance towards polar functional groups such as free anilines (3k) and benzyl alcohol (3m), demonstrating its exceptional chemoselectivity.

Scheme 2 Scope of (hetero)arylation of aryl halides. Reaction conditions: 1 (0.2 mmol), pyrrole (50 equiv.), and phthalate (1.2 equiv.) were mixed in DMSO (0.1 M) under blue LED irradiation for 20 h; isolated yield unless otherwise noted. ^a Reactions were run on a 6 mmol scale. ^b Yield is based on recovery of the starting material.

Notably, a recent report from Leonori and co-workers illustrates that EDA-initiated radical coupling of aryl halides and pyrrole derivatives is severely restricted to electron-poor aryl iodides.¹⁵ They found that electron-neutral iodobenzene as well as electron-rich p-methoxy-iodobenzene are not completely suitable coupling partners in the presence of two equivalents of traditional sacrificial electron donors (TMG, n-Bu₃N, i-Pr₂NH, and Ph₂NPMP), due to a lack of formation of expected EDA complexation. The different observations clearly suggested that our protocol undergoes a reaction pathway that is greatly distinct from those previously reported for the EDA-initiated radical coupling of aryl halides and pyrrole derivatives.

ortho-/meta-Substituted aryl halides with electron-withdrawing groups or electron-donating groups (1p–1v) reacted similarly under the present reaction conditions, while slightly lower yields were observed in some cases that were most likely due to steric encumbrance. Disubstituted aryl iodides were also amenable with the reaction, giving the desired 2-aryl-pyrroles (3w–3z) in 44–67% yields. Moreover, the reaction proved to be compatible with polycyclic aromatic iodides and valuable heteroaryl iodides, encompassing naphthalene, benzothiazole, pyridine, pyrazine, thiophene, and isoxazole (3aa–3ag). Other pyrrole derivatives such as poly-substituted pyrrole and N-phenylpyrrole were also converted to the corresponding 2-aryl-pyrroles 3ah and 3ai with yields of 41% and 35%, respectively. The moderate yields for 3ah and 3ai were attributed to lower conversions rather than overheteroarylation arising from the increased steric hindrance. Moreover, the Minisci-type couplings with pyrazine (3aj) and pyrimidine (3ak) were found to undergo single functionalization at one of the C–Br bonds. Additionally, the coupling with thiophene (3al) resulted in moderate efficiency. Furthermore, aromatic rings (3am–3ap) were also found to be compatible as coupling partners.

To showcase the practical utility and versatility of the method for expanding accessible chemical space, we explored its potential in the late-stage functionalization of complex bioactive compounds, natural products, and their derivatives (Scheme 2B). Nine substrates derived from active pharmaceutical ingredients (APIs) led to the formation of desired products 4a–4i in synthetically useful yields, indicating that this three-component strategy is appropriate for applications in medicinal chemistry.

Similarly, aryl halides containing naturally occurring alcohols, such as cholesterol, δ-tocopherol, solanesol, citronellol, phytol, and preillyl alcohol, were accommodated as coupling partners (4j–4o). D-Allofuranose and L-glutamic acid derivatives were also competent in this process (4p–4q). The attainment of late-stage functionalization, often a rare feat in EDA-initiated radical coupling reactions, highlights the chemoselectivity as well as functional group compatibility of the protocol, which would otherwise be challenging to obtain.

The above-mentioned comparative data consistently shows that aryl chlorides and bromides are less reactive than aryl iodides. Accordingly, iodo-selective cross-coupling of polyhalogenated arene 5 that contains competing C–I, C–Br, and C–Cl sites was achieved using our newly developed three-component photoactive system (Scheme 3A). This n-tetrabutylphosphonium phthalate-mediated cross-coupling also successfully afforded tricyclic heterocycle 8 in an intramolecular manifold (Scheme 3B). Furthermore, 8-substituted BODIPY derivative 10 was constructed in 35% yield (Scheme 3C), highlighting the capabilities of this protocol due to easily accessible potential dyes. Incorporating an additional pyrrole moiety at the meso-8-aryl position produces approximately 502 nm in λ_abs(max). The results can be explained by small changes toward the large dihedral angle that is defined between the meso-8-aryl group and the BODIPY core to minimize steric interactions with the 1,7-methyl groups.

Scheme 3 Further extension and biocompatibility.

Encouraged by the broad functional group tolerance and mild metal-free conditions, we set out to explore the biocompatibility of our current protocol (Scheme 3D). We used 1% agarose gel electrophoresis to assess the integrity and quality of plasmid pUC18/19 during the reaction process. Through agarose gel electrophoresis, it was observed that plasmid pUC18/19 remained stable throughout the reaction after reacting 1 hour or 20 hours. Moreover, DNase I at a concentration of 0.032 μM was introduced into the reaction mixture containing plasmid pUC18/19, and its enzymatic activity was predominantly preserved, as evidenced by agarose gel electrophoresis analysis. Lastly, the amounts of remaining bovine serum albumin (BSA) after reacting for 1 hour and 20 hours were determined as 0.89 mg mL⁻¹ (89% recovered) and 0.75 mg mL⁻¹ (75% recovered), respectively, using the bicinchoninic acid (BCA) assay, through comparison against an absorbance curve of BSA standards of varying concentrations, revealing minimal depletion in protein content.

Mechanistic studies

To gain further insights into this mechanistic possibility, various control experiments and spectroscopic studies were performed (Scheme 4). The addition of radical scavengers such as BHT and TEMPO, as well as an electron transfer scavenger such as 1,4-dinitrobenzene, to the reactions between 1a and 2a in the presence of n-tetrabutylphosphonium phthalate fully suppressed the photo-induced cross-coupling reaction (Scheme 4A), leaving the aryl halides untouched. Electron paramagnetic resonance experiments using N-tert-butyl-α-phenylnitrone (PBN) as the free radical trapping agent also support the occurrence of an electron transfer process (Fig. S11; see the ESI† for details).

Scheme 4 Mechanistic studies and plausible mechanisms.

Because hydrogen atom abstraction from various hydrogen donors by aryl radicals is rapid (k > 10⁶ s⁻¹),⁴⁹ coupling reactions of aryl radicals usually require excess amounts of radical acceptors to suppress the competitive hydrogen abstraction.³ However, the hydrodeiodination of aryl iodide 1i did not completely take place in the absence or presence of 20 equivalents of H₂O (Scheme 4B). It is also well-known that an aryl radical formed from 12 can cyclize more rapidly (k > 10⁷ s⁻¹)⁵⁰ with the ortho-butenyl substituent. We then examined the reaction of aryl halide 12 with N-methyl pyrrole and used ¹H NMR analysis to confirm that no cyclized product was formed under optimized conditions (Scheme 4C).

These results indicate that n-tetrabutylphosphonium phthalate alone does not possess the capability to directly generate aryl radicals, and that the corresponding electron transfer event occurs inside the cage of radical-ion pairs. In addition, light ON/OFF experiments suggested that light irradiation is necessary, and the contribution of the radical chain mechanism is small (Fig. S10†), as product formation was observed only during visible-light illumination. Therefore, we inferred that the assembly of a three-component photoactive EDA complex, exploiting a network of non-covalent interactions between n-tetrabutylphosphonium phthalate and the two reactants, triggers intracomplex electron transfer and subsequent in-cage C–C formation within a geometrically restricted space and in very close proximity.

To obtain direct evidence of the possible involvement of a three-component photoactive EDA complex, we turned to NMR investigation (Scheme 4D and Fig. S7†). Upon mixing aryl iodide 1i with n-tetrabutylphosphonium phthalate, minimal shifts were observed in ¹H NMR. Thus, two separate sets of ¹H NMR signals were detected at approximately 7.23 ppm with a mixture of 1i and n-tetrabutylphosphonium phthalate under both light-on and light-off conditions. Upon addition of N-methyl pyrrole to the above mixture in the dark, only one set of peaks appeared at the same position, implying the formation of a three-component complex. Further exposure of the resulting solution within the NMR tube to 410 nm blue LEDs for 4 h caused the obvious reduction of fine splitting as well as the formation of desired product 3i. However, the UV-Vis absorption spectra of a solution of each component of this reaction were recorded alone, in pairs and in trios (Scheme 4E).

No charge-transfer band was observed in the absorption spectrum of the mixture of 1a and n-tetrabutylphosphonium phthalate or 1a and 2a in DMSO. In contrast, UV–Vis measurements of the three-component photoactive complex showed a redshifted n → π* absorbance band (λ_max,n→π* = 410 nm), confirming the formation of an EDA aggregation in the ground state. The molar extinction coefficient at 410 nm is ε₄₁₀ = 4.3 cm⁻¹ M⁻¹. Specifically, only a trace amount of product was observed for the model reaction between 1a and 2a under illumination by green light (λ_max = 525 nm) and red light (λ_max = 625 nm) (Table S1,† entries 19 and 20), which probably arose due to a lack of photoexcitation of the EDA complex.

Overall, these spectroscopic analyses revealed that photoexcitation of the three-component photoactive EDA complex is responsible for this transformation. On the basis of these mechanistic studies and literature precedence,^43,45 a plausible mechanism is proposed (Scheme 4F). Initially, phthalate species (III) acts as a bifunctional mediator for one-electron transfer and induces ‘temporary intramolecularity’ that minimizes the entropic penalty associated with intermolecular reactions. This bridges the two reactants so that three-component photoactive EDA complex IV can be formed through two-point non-covalent interactions. The resulting assembly provides a highly organized environment for facilitating electron transfer.

Based on our previous research for C(sp³)–H amination reactions,⁵¹ the electrons in the β-intrinsic bond orbital (IBO) of the substrate flow to the phenyl moiety in the tunable distonic radical anion (TDRA), along with electrons from a N–H bond in the substrate that flow to the oxygen p-orbital of the remote carboxylic radical moiety in the TDRA. This suggests that there may also be electron transport channels in intermediate IV with phthalate species (III) as bridges. Therefore, upon visible-light irradiation, three-component photoactive EDA complex IV undergoes an intracomplex electron transfer and subsequent in-cage radical combination event to deliver σ-complex V and distonic radical anions VI.^47,51 Finally, hydrogen atom abstraction from σ-complex V by the distonic radical anions in VI affords the corresponding heteroarylation product VII. The contribution of the radical chain mechanism appears negligible.

Cross-coupling of aryl halides with a variety of trapping agents

Intrigued by the successful heteroarylation of aryl halides, we proceeded to investigate the generality of this strategy by employing other radical trapping agents (Scheme 5). A brief survey on the reaction of aryl halides with trialkyl phosphites^14,15 and B₂pin₂^16,22 confirmed our assumption that electron-donating and -withdrawing substituents on the aryl ring are well tolerated to give the corresponding aryl phosphonates (14a–14i, 14m–14n) and aryl boronates (15a–15k), although slightly lower yields were observed for electron-neutral and electron-rich substrates. The chemistry was also extended to bulky naphthyl halides and select heteroaryl halides (14j–14l, and 15l–15n).

Scheme 5 Various radical arylations promoted by n-tetrabutylphosphine phthalate. Reactions were run on a 0.2 mmol scale; isolated yield unless otherwise noted. ^a Without phthalate.

The borylation reactions with diboron esters derived from 2,4-dimethyl-2,4-pentanediol, (1S,2S,3R,5S)-(−)-2,3-pinanediol, neopentyl glycol, and 1,8-diaminonaphthalene delivered the corresponding phenylboronic esters in 22–38% yields under otherwise identical conditions (15o–15r). All explored thiophenols as counterparts were found to be compatible with the n-tetrabutylphosphonium phthalate-enabled multicomponent photoactive EDA system in the presence of 0.5 equivalent of Cs₂CO₃, furnishing the corresponding aryl thioethers 16a–16i in 22–67% yields.

It should be emphasized that a significantly improved yield of 16i was obtained as compared with the results in the absence of n-tetrabutylphosphonium phthalate, which is congruent with Miyake's observation,³² and validates the role of n-tetrabutylphosphonium phthalate in controlling the intracomplex electron transfer event. In addition to C–C bond construction, n-tetrabutylphosphonium phthalate as a bifunctional one-electron-transfer mediator can also be engaged in synthetically valuable aromatic C–P, C–B, and C–S bond formation to provide aryl phosphonates, aryl boronates, and aryl thioethers, respectively.

Conclusions

The study presented here highlights the potential of two-point non-covalent interactions originating from n-tetrabutylphosphonium phthalate as an electron shuttle bridge, which can be utilized to generate multicomponent photoactive EDA aggregates that are distinctive from traditional ones and to offer an effective pathway for mediating intracomplex electron transfer from four types of coupling partners to (hetero)aryl halides. While this dual activation strategy is not without limitations, the broad substrate scope and excellent functional group tolerance under mild metal-free conditions render these processes applicable for late-stage functionalization and biocompatible photochemistry. Perhaps more importantly, a combination of various non-covalent assemblies for constructing multicomponent photoactive EDA systems could be expected to facilitate the development of additional general photochemical platforms, which will provide molecules with wide structural and functional diversity. Indeed, extensions of the present approach are currently being actively pursued in our laboratory.

Author contributions

L. S. conceived the idea, guided the project, and wrote the manuscript; C. T. performed the experiments and analyzed the data.

Data availability

All data associated with this article are available from the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge the support by the National Natural Science Foundation of China (No. 22271069 and 21871067), the Guangdong Basic and Applied Basic Research Foundation (No. 2023A1515012457 and 2021A1515010190), the Shenzhen Science and Technology Program (No. GXWD20231130100539001), the Fundamental Research Funds for the Central Universities (HIT.OCEF.2021035), and the Open Project Program of the State Key Laboratory of Elemento-Organic Chemistry (No. 202009).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4qo01268b

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