Exploring ferrocene-directed photo-Fenton initiation of RAFT polymerization

Abstract

The iron-based Fenton chemistry has been used as the radical initiator in reversible addition–fragmentation chain-transfer (RAFT) polymerization. However, its practical application in polymeric materials science has been restricted due to the unmodified nature of inorganic iron and its non-functional properties. To address this, we introduce a strategy termed ferrocene-directed photo-Fenton RAFT polymerization, abbreviated as Fc-PF-RAFT, which combines visible light-controlled ferrocene-based Fenton chemistry as the initiator with the upgradation of RAFT polymerization, enabling the exploration of polymers with unique properties and structures. For demonstration, we employed ferrocenyl compounds Fc1–Fc3 in the Fc-PF-RAFT polymerization of N,N-dimethylacrylamide (DMA) in an open aqueous system. The ferrocene-directed photo-Fenton reaction facilitated the generation of dual radicals Fc-COO˙ and ˙OH, initiating well-controlled RAFT polymers with distinct end-group functionalization types: Fc-, OH-, and carboxylic acid group derived from the RAFT agent. By adjusting the role of Fc-ended functionalization in polymer evolution, we fine-tuned self-assembled morphologies, ranging from simple spherical micelles to crosslinked clusters. Notably, the selenium (Se)-containing Fc3-end group polymer underwent self-assembly driven by Se⋯N noncovalent interactions, along with phenyl and cyclopentadienyl π–π interactions, leading to the formation of hierarchical structures. As Fc3-ended functionalization increased, the driving force for self-assembly transitioned from noncovalent interactions to crystallization, as evidenced by the growth from a polymeric DMA-based corona to an Fc3-based core. This study demonstrates the impact of incorporating ferrocene into the Fenton reaction for radical generation, thereby enhancing the versatility and effectiveness of RAFT polymerization. The resulting Fc-PF-RAFT technique provides a transformative platform for the creation of advanced materials with tailored properties and structures.

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Introduction

The development of functional materials based on well-defined polymeric architectures is proving to be a highly prosperous research direction.^1–7 Researchers such as Eisenberg,⁸ Bates,⁹ and others¹⁰ have advanced our understanding of polymer morphology and its impact on material properties. To achieve controlled nano/macroassemblies for further applications, two major aspects must be addressed: precise control of the polymerization process and rational regulation of the high-order morphology. In recent years, reversible addition–fragmentation chain-transfer (RAFT) polymerization has proven to be a highly valuable tool for achieving well-defined polymer structures with narrow molecular–weight distributions.^11–15 Nevertheless, challenges remain in exploiting the synergistic RAFT approach with appropriate initiators or chain-transfer agents for homopolymerization and self-assembly technology, aiming to maximize versatility. In most cases, radical sources employed in RAFT polymerization include peroxides,¹⁶ thermal initiators,¹⁷ and photoinitiators;¹⁸ however, the full potential of radical initiators has not been realized. As a result, aqueous formulations capable of achieving higher-order morphologies via RAFT polymerization without surfactants or plasticizers are scarce.¹² This represents an active area of exploration in radical-initiating systems capable of controlling homopolymeric assemblies on-site, aiming to enhance system sustainability.

The Fenton-RAFT polymerization strategy, introduced by Qiao et al. in 2017,¹⁹ utilizes highly reactive hydroxyl radicals (˙OH) generated from the traditional Fenton reaction of free Fe²⁺ ions and hydrogen peroxide (H₂O₂) as the initiator. The approach involves an automated/programmable polymerization method that utilizes sequenced reagent injections, operates under benign reaction conditions (room temperature, aqueous solvent, air tolerance), and is compatible with a range of monomers for constructing polymers.^20–22 A survey of the literature reveals that most Fenton-RAFT polymerization studies rely on free metal ions, e.g., Fe²⁺, as the Fenton reagent, which presents challenges in the purification and isolation of Fe²⁺/Fe³⁺ ions and limitations in chemically modifying inorganic salts to fabricate higher-order assembly structures. To address these challenges, our research introduces organometallic compounds, specifically focusing on ferrocenyl derivatives as proof of concept, to provide additional functions beyond inducing polymerization while minimizing energy requirements and reducing the occurrence of side reactions in the formation of self-assembled hierarchical structures. Our ultimate goal is to develop a general organometallic-dominant photo-RAFT polymerization approach for creating functional materials with tailored properties.

Ferrocenyl compounds have been demonstrated to effectively generate ˙OH through photo-promoted Fenton chemistry.²³ Leveraging the reversible redox properties of the ferrocene unit, our group has been dedicated to incorporating ferrocenyl compounds into nanocomposites for photo-Fenton-based therapy of tumors.^24–26 Notably, organometallic ferrocene has been identified as a rigid template for self-assembly into ordered structures, as demonstrated in the pioneering work by Manners and co-workers.^27–30 Moreover, poly(ferrocenyldimethylsilane) was shown to undergo living crystallization-driven self-assembly,³¹ leading to the formation of cylindrical supermicelles. The above work served as inspiration for the rational design of ferrocenyl compounds as promising candidates for photo-RAFT polymerization and subsequent self-assembly to achieve hierarchical structures. The design offers manifold advantages stemming from the benefits of synergistic controlled polymerization and morphology regulation, which have been challenging to achieve through conventional RAFT polymerization methods. As shown in Scheme 1 and S1,† we explored ferrocene derivatives with distinct structural modifications, including ferrocenylcarboxylic acid (Fc1), ferrocenylseleno propane carboxylic acid (Fc2), and ferrocenylseleno benzyl carboxylic acid (Fc3). The UV–visible absorption spectra of Fc1–Fc3 demonstrated a notable capability for efficient absorption of visible light (Fig. S1†). Upon irradiation with blue light and in the presence of H₂O₂, these ferrocenylcarboxylic derivatives facilitated the generation of FcCOO˙ and ˙OH radicals (Fig. 1 and S2†). This initiated a well-controlled RAFT polymerization of the N,N-dimethylacrylamide (DMA) monomer in an aqueous environment. The process led to the synthesis of polymers with three distinct end-group functionalizations: a carboxylic acid end-group from the RAFT agent, a hydroxyl end-group resulting from HO˙—commonly seen in iron Fenton-RAFT polymerization—and, more importantly, an Fc-end group, unique to polymerization initiated exclusively by our Fc-PF-RAFT strategy. The introduction of selenium (Se)-containing Fc2 and Fc3 compounds into the system further enriched the functionalities of the Fc-end polymers and facilitated their self-assembly process, resulting in the formation of hierarchical architectures. The aqueous Fc-PF-RAFT approach described in this study offers significant potential for the fabrication of polymer architectures featuring robust ferrocene-end group functionalization.

Scheme 1 Schematic illustration of the exploration of ferrocene-directed photo-Fenton RAFT (Fc-PF-RAFT) polymerization, detailing the processes of radical initiation, RAFT polymerization, and the self-assembly of distinct polymers into hierarchical structures.

Fig. 1 Synthesis and characterization of ferrocene-directed photo-Fenton RAFT polymerization of DMA. (A) ¹H NMR spectra of PDMA after dialysis for 72 h; (B) GPC chromatogram of PDMA; (C) Chain extension experiments for the synthesis of pseudo-triblock copolymers with PDMA precursors with 50 and 100 repeating units (the solid lines represent precursor polymers, the dotted lines represent chain-extended products); (D) MALDI-TOF full spectrum and magnification of part of the spectrum of PDMA₁₀₀, possible chemical structures corresponding to the mass numbers. Experimental conditions for D: [DMA] = 5 M, [Fc1] = 1.25 mM, [H₂O₂] = 75 mM, [bis-TTC] = 25 mM, 460 nm light irradiation for 15 min; (E) EPR spectra of various mixtures using 5,5′-dimethyl-1-pyrroline-N-oxide (DMPO) as spin trap. The mixtures were exposed to 460 nm irradiation for 5 min before different treatments: H₂O₂ (blue line); Fc1 + H₂O₂ (black line); Fc1 + H₂O₂+ bis-TTC (yellow line); Fc1 + H₂O₂ + DMA (red line). (F–H) Chemical structures formed through the polymerization of DMA in the absence of a RAFT reagent, subsequent to the reaction of radicals FcCOO˙ (F), ˙OH (G), and the dual radicals of FcCOO˙ and ˙OH (H) with the monomer, as demonstrated by mass spectrum analysis.

Results and discussion

Ferrocene-directed initiation in aqueous Fc-PF-RAFT

Fc-PF-RAFT polymerization commenced with the water-soluble acrylamide monomer, DMA, mixed with the symmetrical water-soluble RAFT agent, bis-TTC, and radical initiator, Fc1 and H₂O₂, in the presence of air. A mixture with initial molar ratios of [DMA]/[Fc1]/[bis-TTC]/[H₂O₂] set at 200 : 0.05 : 1 : 3 yielded DP = 200. The reaction mixture was then mildly stirred under 460 nm irradiation (100 mW cm⁻²) for 15 min. The ¹H NMR analysis (Fig. 1A) of the obtained product in d⁶-DMSO revealed signals at 1.13–1.52 and 2.40–2.80 ppm, which were attributed to PDMA. The polymer displayed signals corresponding to three distinct end groups: a weak signal at 0.8–1.0 ppm attributed to the methyl protons of the bis-TTC end group, characteristic signals of the ferrocene unit at 4.55–4.73 ppm, and an OH signal at 5.03 ppm. These observations strongly suggested successful incorporation of the ferrocene unit into the polymeric chain end. Of particular significance, nearly complete monomer conversion (95.5%) was determined by comparing the relative integrals of the peaks corresponding to the methylene groups of PDMA and the monomer at 5.65–6.10 ppm. GPC analysis confirmed a low polymer dispersity index (PDI = 1.25) and number-averaged molecular weight (M_n) of 19 056 Da (Fig. 1B), which closely aligned with the theoretical value (20 082 Da, M_n,th = [DMA]/[bis-TTC] × conversion × MW_DMA + MW_bis-TTC). In the absence of Fc1, polymer formation did not occur even after a 60 minute reaction period. Conversely, in the absence of the RAFT agent, polymer formed, resulting in a physical gel (Fig. S3†). These findings suggested that Fc1-directed photo-Fenton reaction alone could induce radical polymerization independently of the RAFT agent. This underscores the critical role of Fc1 in initiating the photo-Fenton reaction necessary for polymerization, while also demonstrating that the RAFT agent, although influential in controlling polymer architecture, is not essential for the initiation of the polymerization process.

To assess the controllable chain-end livingness of our synthetic polymers, we evaluated the chain extension process utilizing PDMA with DP values of 50 (PDMA₅₀) and 100 (PDMA₁₀₀) as macro-RAFT agents. Given the symmetrical nature of the RAFT agent, the trithiocarbonate (TTC) group should be embedded at the mid-chain position of the resulting PDMA polymers. GPC chromatogram displayed a clear shift toward higher molecular-weight species (Fig. 1C), indicating successful chain extension. Specially, the symmetrical peak shape and minimal tailing toward lower molecular–weight species suggested high chain-end fidelity or vitality of the synthesized PDMA, enabling facile formation of multiblock copolymer structures. These results demonstrate the effectiveness of the chain extension process and highlight the potential for creating complex polymer architectures with chain-end functionality.

MALDI-TOF spectral analysis was further employed to demonstrate the structural fidelity of the synthesized RAFT polymers, revealing a multimodal peak series for PDMA₁₀₀ (Fig. 1D and Fig. S4†) representing predictable polymer structures ranging from 2000 to 8000 Da. In the magnified mass spectrum of PDMA₁₀₀, the main peaks labeled with “●” were assigned to PDMA products containing two hydroxyl end groups directly initiated by ˙OH. These peaks were observed with adjacent main peaks separated by the exact mass of the DMA repeating unit (99.13 g mol⁻¹). The peak series labeled with “★” corresponded to PDMA products containing two ferrocenyl ester groups, confirming the end-group functionalization by the ferrocene unit. Additionally, some subpeaks labeled with “▲” corresponded to PDMA products with two carboxylic acid end groups derived from the bis-TTC RAFT agent. Further subpeaks (labeled “■”) corresponded to Na⁺ complexes of the “▲” PDMA products. Notably, all products retained the thiocarbonylthio moiety, indicating the high livingness of the polymer chains, which was consistent with the results obtained from the chain extension experiments shown in Fig. 1C. The content of Fc1-end PDMA in the three types of end-functionalized polymers was estimated by a quantitative analysis of iron performed using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES). The approximately 4.8% content demonstrated the presence of Fc1-end group functionalized polymers.

The above NMR and MALDI analyses confirmed that, following Fc-PF-RAFT polymerization, ferrocene was not present in its free form; instead, it was functionalized onto the polymer end groups. To further investigate the initiation mechanism of Fc-PF-RAFT polymerization, spin-trapping EPR experiments were further conducted on our systems using 5,5′-dimethyl-1-pyrrololine-N-oxide (DMPO) as the trapping agent. As depicted in Fig. 1E, when H₂O₂ under irradiation was analyzed by itself with DMPO, it produced a characteristic EPR signal for the DMPO-˙OH adduct. The intensity ratio of 1 : 2 : 2 : 1 (Fig. 1E, blue line), refers to the relative intensities of the peaks in the EPR spectrum, which is typical for the DMPO-˙OH adduct in an iron-based Fenton system.³² The Fc1 + H₂O₂ photo-Fenton system resulted in a more complex EPR signal (Fig. 1E, grey line). The intensity ratio of 1 : 2 : 1 : 2 : 1 : 2 : 1 suggests a different interaction or possibly multiple radical species being trapped by DMPO. The oxidation of Fc1 with H₂O₂ involves an intramolecular electron transfer mechanism, resulting in the formation of ferrocenyl radicals.^33,34 Additionally, O–H hydrogen atom transfer of a carboxylic acid can yield a carboxyl radical.³⁵ The presence of different radical species or interactions in ferrocene-directed photo-Fenton initiation alters the resultant EPR spectrum compared to when H₂O₂ was used alone. Based on these findings, we propose that in the current photo-Fenton reaction, the oxidized Fc1, in combination with H₂O₂ under light irradiation, may undergo an intramolecular process, generating both FcCOO˙ and ˙OH radicals. When the RAFT reagent was introduced, only DMPO-˙OH signal peaks were observed in the Fc1 + H₂O₂ + bis-TTC system, with a typical intensity ratio of 1 : 2 : 2 : 1 (Fig. 1E, yellow line), indicating that FcCOO˙ radicals were likely consumed in reaction with bis-TTC. However, in the absence of the RAFT agent, the Fc1 + H₂O₂ + DMA system (Fig. 1E, red line) did not exhibit characteristic peaks analogous to those of the Fc1 + H₂O₂ system (Fig. 1E, blue line), suggesting that the FcCOO˙ and ˙OH radicals are likely acting as initiators to start a radical polymerization reaction with the DMA monomer. When these radicals reacted with the DMA monomer, they can transfer their own radical nature to the monomer, creating a carbon-centered radical.³⁶ This radical could then propagate the polymerization process by reacting with other monomer molecules, forming polymer chains. Mass spectrometry analysis further demonstrated that both FcCOO˙ and ˙OH radicals undergo radical addition to DMA monomer independently of RAFT reagents, subsequently leading to the formation of polymeric DMA (Fig. 1F–H and Fig. S5–S7†).

These results above shed light on the Fc-PF-RAFT mechanism, as illustrated in Fig. 2: (i) Fc1 induced the generation of FcCOO˙ and ˙OH radicals through a photo-Fenton reaction, thereby initiating the polymerization process. (ii) The dual radicals subsequently react with DMA monomer or bis-TTC RAFT agent, forming carbon-centered radicals crucial for essential chain growth. (iii) The activation of the RAFT agent or DMA by dual radicals distinguishes Fc-PF-RAFT polymerization from traditional methods. In contrast to ferrocene-induced radical polymerization in the absence of a RAFT reagent (Fig. S3†), the Fc-PF-RAFT strategy effectively mitigated the occurrence of uncontrollable radical chain growth polymerization.

Fig. 2 Proposed mechanism for Fc-PF-RAFT polymerization in an aqueous system at room temperature.

Control and precision of Fc-PF-RAFT polymerization

Efficient Fc-PF-RAFT polymerization relies on three key elements: radical initiation transfer (as demonstrated in Fig. 1), irradiation control, and H₂O₂ dose for radical production. Fig. 3A and B then provide insight into optimizing the influence of irradiation time and H₂O₂ dose. A conversion of 36% was achieved after irradiation for 5 min, which increased slightly upon switching off the light, reaching 44% conversion within 30 min. Subsequent irradiation recovered the rapid polymerization, reaching 90% conversion in 10 min (Fig. S8†). These results confirmed that the ferrocene-directed photo-Fenton reaction was responsible for polymerization initiation, while the RAFT agent allowed for control over polymer chain growth. Subsequently, the influence of instantaneous H₂O₂ concentration (0–100 mM) on DMA conversion at a fixed Fc1 concentration (1.25 mM) was investigated. No monomer conversion was observed without H₂O₂; however, 40.6% conversion was achieved after 15 min of light irradiation with 25 mM H₂O₂, with only a minor increase upon extension of the irradiation time. Monomer conversion increased to 72.5%/95.5%/97.5% at H₂O₂ concentrations of 50/75/100 mM after 15 min of light irradiation, respectively, obtaining near-complete monomer conversion. These results suggested that an essential ferrocenyl agent and threshold H₂O₂ concentration, assisted by a chain-transfer agent, are required to achieve near-complete monomer conversion.

Fig. 3 Polymerization kinetics characteristics influenced by varying conditions for Fc-PF-RAFT polymerization. (A) Evolution of DMA conversion with polymerization time at different H₂O₂ concentrations. (B) Evolution of DMA conversion with H₂O₂ concentration. (C) Pseudo-first-order kinetic curves with various H₂O₂ concentrations. (D) Molecular weight and polydispersity index evolution with monomer conversion at a H₂O₂ concentration of 50 mM.

Under optimal irradiation time and H₂O₂ concentration, we verified the controlled nature of the polymerization reaction by studying the relationship between conversion rate and molecular weight. The relationship between ln([M]₀/[M]_t) and polymerization time followed pseudo-first-order kinetics, with apparent propagation rate constant (k_app) values of 0.09 and 0.22 min⁻¹ at H₂O₂ concentrations of 50 and 75 mM (Fig. 3C), respectively. These kinetics results indicated that the amount of radical exhibited a quantitative dependence on the photo-Fenton reaction. Fc-PF-RAFT polymerization showed continued monomer conversion, linear growth of molecular weight, and narrow molecular-weight distribution (PDI < 1.5) (Fig. 3D and Fig. S9, 10†), indicative of controlled polymerization. At higher H₂O₂ concentration (100 mM), as shown in Fig. 3A, complete monomer conversion was achieved in 6 min, suggesting the occurrence of nonpropagative “radical costing” reactions. Thus, further experiments were performed using a ferrocenyl concentration of 1.25 mM and H₂O₂ concentration of 75 mM. When Fc1 was replaced by Se-containing compounds Fc2 or Fc3, quantitative monomer conversion (90.3%–97.1%), chain-end fidelity, tunable reaction times, and low dispersity (1.01–1.27) were maintained (Table 1). ¹H NMR analysis of the obtained products confirmed the major presence of Fc-PDMA-Fc (where Fc = Fc2 or Fc3) and coexisting compounds OH–PDMA–OH and HCOO–PDMA–COOH (Fig. S11 and S12†). The simplicity and ready availability of the experimental apparatus make this approach particularly appealing for future exploration of Fenton-RAFT polymerization.

Table 1 Summary of Fc-PDMA-Fc characteristics

Fc	DP	Conv.^a (%)	Mn,GPC^b (Da)	PDI
a Determined by ^1H NMR spectroscopy. b Determined by GPC in 0.1 mol L^−1 NaNO3 relative to PEG standards.
Fc1	25	89.5	1588	1.21
	50	98.5	5566	1.23
	100	95.4	8790	1.28
Fc2	25	91.4	1428	1.01
	50	96.2	4540	1.22
	100	95.5	6878	1.27
Fc3	25	90.3	1300	1.22
	50	97.1	4554	1.19
	100	94.1	9206	1.25

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Polymer architectures formed through Fc-PF-RAFT polymerization

Given the higher hydrophobicity of the Fc end group relative to the polymeric DMA main chain of Fc-PDMA-Fc, clustering of Fc units within the hydrophilic chain was anticipated to spontaneously promote nano/macrostructure assembly. This self-assembly process is driven by the minimization of interfacial energy, which is associated with the inherent tendency of Fc groups to aggregate and establish energetically favorable arrangements within the polymer matrix.³⁷ As the degree of DMA polymerization increases, Fc units facilitate the formation of organized assemblies through favorable hydrophobic interactions. To study the morphology of their self-assembly, three types of PDMA polymers were investigated with DP = 25, 50, and 100. After Fc-PF-RAFT polymerization of DMA, as described above, the systems were aged at 4 °C for 12 h to facilitate self-assembly in a diluted polymer concentration of 0.5 mg mL⁻¹. This aging process led to the formation of distinct polymer architectures.

Transmission electron microscope (TEM) and scanning electron microscope (SEM) were employed to characterize the size and morphology of the assemblies. No discernible morphology was observed for the Fc1-PDMA-Fc1 polymers (DP = 25, 50, 100) after aging, similar to the behavior of free homopolymer PDMA. This lack of observable morphology was attributed to the absence of interaction between the PDMA chain and Fc1. By contrast, stepwise morphological changes were observed after aging when using Se-containing Fc2 as the Fenton reagent (Fig. 4A–C). Specifically, Fc2-PDMA₂₅-Fc2 exhibited spherical micelles with a diameter of approximately 200 nm (Fig. 4A and S13†). EDX mapping confirmed the presence of various elements (C, O, Fe, N, and Se) well distributed over the particles (Fig. 4D and E). Notably, the spherical micelles connected with one another to form clusters. The TEM images revealed a morphological transition induced by longer PDMA chains, progressing from nanospheres (DP = 25) to oval platelets (DP = 50), with a mean length of 761 nm and diameter of 105 nm (Fig. 4B and S14†), and finally to nanorods (DP = 100), with an average length of 324 nm and diameter of 40 nm (Fig. 4C and S15†). This transition was attributed to a kinetic effect, wherein the increased length of the PDMA chain led to lower hydrophilicity and increased folding of chains, resulting in a larger interfacial curvature and subsequent morphological transformation.

Fig. 4 Polymer architecture of Fc2-PDMA_x-Fc2 with Fc2 : [bis-TTC] = 0.05 : 1. (A–C) SEM image of Fc2-PDMA₂₅-Fc2 (A), Fc2-PDMA₅₀-Fc2 (B), and Fc2-PDMA₁₀₀-Fc2 (C). (D) Elemental mapping of Fc2-PDMA₂₅-Fc2. (E) EDS spectrum, inset: magnified spectrum from 0 to 3.5 keV. Scale bars for panels A, B, C and D as follows: 500 nm, 1 μm, 2 μm and 100 nm, respectively.

Intriguing morphological changes were observed during Fc-PF-RAFT polymerization of the DMA system using Fc3 (containing Se and benzene units), as shown in Fig. 5. Fc3-PDMA₂₅-Fc3 formed spherical micelles, which tended to fuse into nanowires (Fig. 5A and S16†). The SEM images revealed that the mean diameter of Fc3-PDMA₂₅-Fc3 was 165 nm (Fig. S17†). However, when the DP value increased to 50, Fc3-PDMA₅₀-Fc3 formed four-armed microfans characterized by two planar ovals sharing a central axis (Fig. 5B and S18†), with a mean length of 1.29 μm and width of 664 nm (Fig. S19†) and thicker edges than the interior. Moreover, when the DP value increased to 100, Fc3-PDMA₁₀₀-Fc3 formed multiarmed sea urchin superstructures from hierarchical self-assembly, comprising 11 to 15 nanoflakes (Fig. 5C and S20†). Each flake had a mean length of 7.99 μm and width of approximately 1.54 μm (Fig. S21†). The growth of sea urchin superstructures might have followed stepwise self-assembly directed by π–π stacking of rigid ferrocene and benzene units, where planar oval structures merged to form dimeric structures along two perpendicular directions, aggregating to form the sea urchin superstructure. Additionally, the zeta potentials of the assemblies (Fig. S22†) changed from +14.2 mV for spherical micelles (DP = 25), to −1.2 mV for four-armed microfans (DP = 50), and finally to −10.4 mV for the multiarmed sea urchin superstructure (DP = 100), suggesting electrostatic stability and resistance to aggregation.

Fig. 5 Polymer architecture of Fc3-PDMA-Fc3 with Fc3 : [bis-TTC] = 0.05 : 1. (A–C) SEM images of Fc3-PDMA₂₅-Fc3 (A), Fc3-PDMA₅₀-Fc3 (B), and Fc3-PDMA₁₀₀-Fc3 (C). (D–F) SEM image of magnified image (E) of Fc3-PDMA₅₀-Fc3 with Fc3 : [bis-TTC] = 0.05 : 1 from panel (B), adjusted at pH = 2 (D), and with 1% H₂O₂ (F). Scale bars for panels A–F are as follows: 1 μm, 1 μm, 5 μm, 500 nm, 200 nm, and 1 μm, respectively.

The XPS analysis was conducted to investigate the interaction between Fc3 and the PDMA chain. The results revealed a negative shift in the Se 3d peak from 55.7 eV (Fc3) to 55.5 eV (Fc3-PDMA₅₀), along with a positive shift in the N 1s peak from 399.6 eV (Fc1-PDMA₅₀) to 400.1 eV (Fc3-PDMA₅₀). These shifts suggest the presence of a noncovalent Se⋯N bond (Fig. S23†). The four-armed microfan-like assemblies of Fc3-PDMA₅₀-Fc3 (Fig. 5E) were further subjected to treatments adjusted to pH = 2 or with 1% H₂O₂. As shown in Fig. 5D, acid treatment resulted in obvious porous flakes, likely due to acid protonation of N in PDMA disrupting the noncovalent Se⋯N bond. This caused the positively charged PDMA chains to stretch, hindering PDMA aggregation and ultimately leading to the dissociation of the “cross” assemblies into individual flakes. Alternatively, the addition of H₂O₂ completely destroyed the original morphology, resulting in amorphous fragments (Fig. 5F). The observed phenomenon was attributed to the oxidation of Se, which disrupted the noncovalent Se⋯N bond, and to the oxidation of neutral hydrophobic ferrocene, which resulted in the formation of cationic hydrophilic ferrocenium. This transformation induced electrostatic repulsion, leading to the disassembly of the π–π stacking in the ferrocene units and ultimately facilitating the release of free PDMA.^38,39

Mechanism behind self-assembled hierarchical structures via Fc-PF-RAFT polymerization

When the ratio of Fc3 was increased to Fc3 : [bis-TTC] = 0.2 : 1, Fc3-PDMA₁₀₀-Fc3 formed a nanofiber approximately 10 μm in length (Fig. 6A and S24†). The selected area electron diffraction pattern (Fig. 6B) displayed symmetric spots along the longer axis of the fiber. By comparing the crystallization data and packing diagram of free Fc3 single crystals (Fig. 6C and Table S1†), we tentatively indexed two planes with an intersection angle of 38.5°, the (208̄) and (321̄0̄) planes with interplanar spacing of 0.373 and 0.588 Å, respectively. This finding suggested that nucleation for crystallization of the nanofibers was driven by strong parallel offset π–π stacking interactions of the ferrocene and benzene units. Furthermore, the observation of EDX mappings (Fig. 6D and E) indicated that the structural integrity and composition of the nanofibers were predominantly governed by the spatial orientation and interactive forces between the ferrocene and benzene units, leading to a highly ordered crystalline structure within the Fc3 core.

Fig. 6 Polymer architecture of Fc3-PDMA₁₀₀-Fc3 with Fc3 : [bis-TTC] = 0.2 : 1. (A) TEM image; (B) selected area electron diffraction patterns confirming crystallinity; (C) X-ray crystallography diffraction of Fc3; (D) EDX mapping image; (E) EDS spectrum, inset: magnified spectrum from 0 to 3 keV. Scale bars for panels A, B and D are as follows: 2 μm, 5 nm⁻¹ and 1 μm, respectively.

Based on the morphological results discussed above, we propose that incorporation of the Fc3 functional group into the end of PDMA is vital for the formation of self-assembled hierarchical structures. The successive morphological evolution observed in Fc3-PDMA-Fc3 agreed with the literature findings that two-dimensional platelets were thermodynamically preferred and low unimer solubility could yield kinetically trapped one-dimensional assemblies.⁴⁰ As illustrated in Fig. 7, the self-assembly of Fc3-PDMA-Fc3 polymers into hierarchical structures could be attributed to several factors: (1) core–corona structures formed with hydrophobic Fc3 as the core and PDMA chains as hydrophilic stabilizers located on the surface; (2) Se(Fc2/Fc3)⋯N(DMA) noncovalent interactions and parallel offset π–π stacking of the ferrocene (Fc2/Fc3) and phenyl moieties (Fc3) organized the PDMA to form the corona; (3) a high [Fc3] : [bis-TTC] ratio provided essential nucleation sites for Fc3 crystallization, thereby inducing growth along the longitudinal direction; (4) the decreased hydrophilicity of long PDMA chains led to a large interfacial curvature, which in turn regulated morphological transformation.⁴¹

Fig. 7 Schematic illustration of the self-assembly process of Fc-PF-RAFT polymer chains into hierarchical structures.

The current study elucidates novel roles for ferrocene in the realm of polymeric materials, showcasing that strategically designed ferrocenyl compounds are pivotal not only for enabling the aqueous Fc-PF-RAFT polymerization to synthesize functional polymers but also for promoting the on-site formation of hierarchical assemblies, thereby enhancing the sustainability of the system. The proposed mechanism, which is thoroughly outlined in this investigation, could provide a robust framework for understanding and harnessing noncovalent interaction-driven homopolymeric self-assembly. This understanding paves the way for the deliberate engineering of hierarchical structures that could lead to advancements in material science and potential applications in various technological fields.

Conclusions

We have presented a Fc-PF-RAFT polymerization approach, which merges the robust chemistry of ferrocenyl Fenton initiation with the precision of RAFT polymerization. Through the utilization of ferrocenyl compounds Fc1–Fc3 in RAFT polymerization of DMA in an open aqueous system, we successfully demonstrated the generation of dual radicals Fc-COO˙ and ˙OH via the ferrocene-directed photo-Fenton reaction. These radicals initiated well-controlled RAFT polymerization, yielding polymers with distinct end-group functionalization types, including Fc-, OH-, and carboxylic acid- end group derived from the RAFT agent. By varying the composition of distinct end groups in the resulting polymers, we were able to finely adjust their structural morphologies, ranging from simple spherical micelles to crosslinked clusters. Particularly noteworthy was the observation that as Fc-ended functionalization increased, the Se-containing Fc3-ended polymer underwent self-assembly driven by Se⋯N noncovalent interactions, in conjunction with phenyl and cyclopentadienyl π–π interactions, leading to the formation of hierarchical structures. This transition from noncovalent interactions to crystallization was evidenced by the transformation from a polymeric DMA-based corona to an Fc3-based core, underscoring the pivotal role of Fc-ended functionalization in the evolution of polymer structure. Our study highlights the significance of integrating ferrocene into the photo-Fenton reaction for radical generation, thereby enhancing the versatility and efficacy of RAFT polymerization. The developed Fc-PF-RAFT technique offers a promising broad implication in the realm of polymeric materials science.

Author contributions

S. J. conceived the idea. X. Y. Z., L. Z. and S. J. directed the project. X. Y. Z., X. L. W., C. B. P., S. Y. Z., Y. T. L. performed the experiments. W. J. and L. H. conducted the data analysis. L. Z. and S. J. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Data availability

The data for this article, including all figures and tables in both the manuscript and ESI,† are available upon request from the authors.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work is funded by the National Natural Science Foundation of China (Grant No. 22175090 and 22374075) and the Primary Research & Development Plan of Jiangsu Province (BE2021712). The authors would like to thank Dr Yufei Jiang from the State Key Laboratory of Coordination Chemistry at Nanjing University for her assistance with MALDI-TOF-MS testing, and Xing Zhu from Soochow University Analysis and Testing Center for his assistance with TEM testing.

References

1. Y. Mai and A. Eisenberg, Self-assembly of block copolymers, Chem. Soc. Rev., 2012, 41, 5969–5985.
2. S. Ganda and M. H. Stenzel, Concepts, fabrication methods and applications of living crystallization-driven self-assembly of block copolymers, Prog. Polym. Sci., 2020, 101, 101195.
3. E. Blanco, H. Shen and M. Ferrari, Principles of nanoparticle design for overcoming biological barriers to drug delivery, Nat. Biotechnol., 2015, 33, 941–951.
4. Y. Gao, D. Zhou, J. Lyu, S. A. Bilalis, Q. Xu, B. Newland, K. Matyjaszewski, H. Tai and W. Wang, Complex polymer architectures through free-radical polymerization of multivinyl monomers, Nat. Rev. Chem., 2020, 4, 194–212.
5. G. Polymeropoulos, G. Zapsas, K. Ntetsikas, P. Bilalis, Y. Gnanou and N. Hadjichristidis, 50th anniversary perspective: polymers with complex architectures, Macromolecules, 2017, 50, 1253–1290.
6. T. Pelras, C. S. Mahon, Nonappa, O. Ikkala, A. H. Gröschel and M. Müllner, Polymer nanowires with highly precise internal morphology and topography, J. Am. Chem. Soc., 2018, 140, 12736–12740.
7. J. Wan, B. Fan, K. Putera, J. Kim, M. M. Banaszak Holl and S. H. Thang, Polymerization-induced hierarchical self-Assembly: from monomer to complex colloidal molecules and beyond, ACS Nano, 2021, 15, 13721–13731.
8. G. Rizis, T. G. M. van de Ven and A. Eisenberg, Homopolymers as structure-driving agents in semicrystalline block copolymer Micelles, ACS Nano, 2015, 9, 3627–3640.
9. C. M. Bates and F. S. Bates, 50th anniversary perspective: block polymers-pure potential, Macromolecules, 2017, 50, 3–22.
10. M. Antonietti and S. Förster, Vesicles and liposomes: a self-assembly principle beyond lipids, Adv. Mater., 2003, 15, 1323–1333.
11. S. Perrier, 50th anniversary perspective: RAFT polymerization—a user guide, Macromolecules, 2017, 50, 7433–7447.
12. Y. Lee, C. Boyer and M. S. Kwon, Photocontrolled RAFT polymerization: past, present, and future, Chem. Soc. Rev., 2023, 52, 3035–3097.
13. N. G. Engelis, A. Anastasaki, G. Nurumbetov, N. P. Truong, V. Nikolaou, A. Shegiwal, M. R. Whittaker, T. P. Davis and D. M. Haddleton, Sequence-controlled methacrylic multiblock copolymers via sulfur-free RAFT emulsion polymerization, Nat. Chem., 2017, 9, 171–178.
14. F. D'Agosto, J. Rieger and M. Lansalot, RAFT-mediated polymerization-induced self-assembly, Angew. Chem., Int. Ed., 2020, 59, 8368–8392.
15. J. Wan, B. Fan and S. H. Thang, RAFT-mediated polymerization-induced self-assembly (RAFT-PISA): current status and future directions, Chem. Sci., 2022, 13, 4192–4224.
16. S. Eggers and V. Abetz, Hydroperoxide traces in common cyclic ethers as initiators for controlled RAFT polymerizations, Macromol. Rapid Commun., 2018, 39, 1700683.
17. Z. Zhang, X. Zhu, J. Zhu and Z. Cheng, Thermal polymerization of methyl (meth)acrylate via reversible addition-fragmentation chain transfer (RAFT) process, Polymer, 2006, 47, 6970–6977.
18. L. Shen, Q. Lu, A. Zhu, X. Lv and Z. An, Photocontrolled RAFT polymerization mediated by a supramolecular catalyst, ACS Macro Lett., 2017, 6, 625–631.
19. A. Reyhani, T. G. McKenzie, H. Ranji-Burachaloo, Q. Fu and G. G. Qiao, Fenton-RAFT polymerization: an “On-Demand” chain-growth method, Chem. – Eur. J., 2017, 23, 7221–7226.
20. A. Reyhani, H. Ranji-Burachaloo, T. G. McKenzie, Q. Fu and G. G. Qiao, Heterogeneously catalyzed Fenton-reversible addition–fragmentation chain transfer polymerization in the presence of air, Macromolecules, 2019, 52, 3278–3287.
21. A. Reyhani, M. D. Nothling, H. Ranji-Burachaloo, T. G. McKenzie, Q. Fu, S. Tan, G. Bryant and G. G. Qiao, Blood-catalyzed RAFT polymerization, Angew. Chem., Int. Ed., 2018, 57, 10288–10292.
22. J. Fan, C. Li, X. Guo and Y. Deng, Methylene blue sensitized photo Fenton-like reaction for rapid RAFT polymerization in aqueous solution, Polym. Chem., 2023, 14, 773–783.
23. Z. Tang, P. Zhao, H. Wang, Y. Liu and W. Bu, Biomedicine meets Fenton chemistry, Chem. Rev., 2021, 121, 1981–2019.
24. J. Zhou, X. Zhu, Q. Cheng, Y. Wang, R. Wang, X. Cheng, J. Xu, K. Liu, L. Li, X. Li, M. Hu, J. Wang, H. Xu, S. Jing and L. Huang, Ferrocene functionalized upconversion nanoparticle nanosystem with efficient Near-Infrared-light-promoted Fenton-like reaction for tumor growth suppression, Inorg. Chem., 2020, 59, 9177–9187.
25. T. Zhou, Q. Cheng, L. Zhang, D. Zhang, L. Li, T. Jiang, L. Huang, H. Xu, M. Hu and S. Jing, Ferrocene-functionalized core–shell lanthanide-doped upconversion nanoparticles: NIR light promoted chemodynamic therapy and luminescence imaging of solid tumors, Chem. Eng. J., 2022, 438, 135637.
26. T. Zhou, S. Zhang, L. Zhang, T. Jiang, H. Wang, L. Huang, H. Wu, Z. Fan and S. Jing, Redox ferrocenylseleno compounds modulate longitudinal and transverse relaxation times of FNPs-Gd MRI contrast agents for multimodal imaging and photo-Fenton therapy, Acta Biomater., 2023, 164, 496–510.
27. P. A. Rupar, L. Chabanne, M. A. Winnik and I. Manners, Non-centrosymmetric cylindrical micelles by unidirectional growth, Science, 2012, 337, 559–562.
28. H. Qiu, Z. M. Hudson, M. A. Winnik and I. Manners, Multidimensional hierarchical self-assembly of amphiphilic cylindrical block comicelles, Science, 2015, 347, 1329–1332.
29. H. Qiu, Y. Gao, C. E. Boott, O. E. C. Gould, R. L. Harniman, M. J. Miles, S. E. D. Webb, M. A. Winnik and I. Manners, Uniform patchy and hollow rectangular platelet micelles from crystallizable polymer blends, Science, 2016, 352, 697–701.
30. J. Cai, C. Li, N. Kong, Y. Lu, G. Lin, X. Wang, Y. Yao, I. Manners and H. Qiu, Tailored multifunctional micellar brushes via crystallization-driven growth from a surface, Science, 2019, 366, 1095–1098.
31. L. MacFarlane, C. Zhao, J. Cai, H. Qiu and I. Manners, Emerging applications for living crystallization-driven self-assembly, Chem. Sci., 2021, 12, 4661–4682.
32. W. Guo, T. Li, Q. Chen, J. Wan, J. Zhang, B. Wu and Y. Wang, The roles of wavelength in the gaseous toluene removal with OH from UV activated Fenton reagent, Chemosphere, 2021, 275, 129998.
33. L. S. Hernández-Muñoz, M. A. González-Fuentes, B. R. Díaz-Sánchez, R. Fragoso-Soriano, C. Vázquez-López and F. J. González, Covalent modification of carbon surfaces with ferrocene groups through a self-mediated oxidation of tetrabutylammonium salts of ferrocene-carboxylic acids, Electrochim. Acta, 2012, 63, 287–294.
34. D. E. Ramírez-Chan, J. I. Palacios-Ramírez, R. Fragoso-Soriano and F. J. González, Spontaneous decarboxylation of ferrocenecarboxylate using 1,4-benzoquinone as oxidant: application to the chemical grafting of glassy carbon surfaces, ChemistrySelect, 2022, 7, e202202453.
35. C. G. Na, D. Ravelli and E. J. Alexanian, Direct decarboxylative functionalization of carboxylic acids via O–H hydrogen atom transfer, J. Am. Chem. Soc., 2020, 142, 44–49.
36. L. Chen, J. Duan, P. Du, W. Sun, B. Lai and W. Liu, Accurate identification of radicals by in situ electron paramagnetic resonance in ultraviolet-based homogenous advanced oxidation processes, Water Res., 2022, 221, 118747.
37. X. Zhang, X. Dai, L. Gao, D. Xu, H. Wan, Y. Wang and L.-T. Yan, The entropy-controlled strategy in self-assembling systems, Chem. Soc. Rev., 2023, 52, 6806–6837.
38. X. Li, Y. Gao, C. E. Boott, D. W. Hayward, R. Harniman, G. R. Whittell, R. M. Richardson, M. A. Winnik and I. Manners, “Cross” supermicelles via the hierarchical assembly of amphiphilic cylindrical triblock comicelles, J. Am. Chem. Soc., 2016, 138, 4087–4095.
39. Y. Yi, S. Fa, W. Cao, L. Zeng, M. Wang, H. Xu and X. Zhang, Fabrication of well-defined crystalline azacalixarene nanosheets assisted by Se⋯N non-covalent interactions, Chem. Commun., 2012, 48, 7495–7497.
40. J. R. Finnegan, X. He, S. T. G. Street, J. D. Garcia-Hernandez, D. W. Hayward, D. W. R. L. Harniman, R. M. Richardson, G. R. Whittell and I. Manners, Extending the scope of “living” crystallization-driven self-assembly: well-defined 1D micelles and block comicelles from crystallizable polycarbonate block copolymers, J. Am. Chem. Soc., 2018, 140, 17127–17140.
41. D. Li, X. Chen, M. Zeng, J. Ji, Y. Wang, Z. Yang and J. Yuan, Synthesis of ABn-type colloidal molecules by polymerization-induced particle-assembly (PIPA), Chem. Sci., 2020, 11, 2855–2860.

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4py00517a

‡ These authors contribute equally.

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