RAFT Step-Growth Polymerization via ‘Grafting Through’

Abstract

Graft polymers with degradable backbones and precisely tunable side chains are highly desirable for advanced functional materials, particularly in biomedical and stimuli-responsive systems. Herein, we report a versatile strategy to synthesize degradable graft polymers via a reversible addition–fragmentation chain transfer (RAFT) step-growth polymerization approach using bifunctional poly­(methyl acrylate) (PMA) macromonomers and a bifunctional vinyl monomer. The polymerization proceeds through an A₂ + B₂-type polymerization mechanism, wherein the steric hindrance from macromonomers is effectively alleviated by incorporating a small-molecule RAFT agent as a comonomer. The resulting graft copolymers exhibit tailorable side-chain lengths and tunable rheological properties. Notably, the polymer backbones feature dual stimuli-responsive degradability enabled by xanthate and ester linkages, allowing stepwise degradation via aminolysis and hydrolysis. Furthermore, RAFT functionalities embedded in the backbone allow postpolymerization chain expansion, offering control over both the backbone architecture and graft density. This work provides a modular and robust platform for engineering degradable graft polymers with programmable architectures and multifunctionality suitable for applications in drug delivery and smart materials.

Introduction

Graft polymers have emerged as versatile materials with broad applications in supersoft elastomers, additive manufacturing, electronic storage, and biomedical devices. − The dense grafting of side chains onto a linear backbone imparts unique molecular architectures and exceptional material properties. Steric congestion among the side chains induces backbone extension, resulting in highly stretched conformations and reduced chain entanglements. Consequently, graft polymers exhibit moduli significantly lower than those of their linear analogues and tend to migrate spontaneously to surfaces and interfaces in polymer blends. There are three principal synthetic strategies for graft polymers: grafting-through, grafting-from, and grafting-to. These approaches enable stepwise construction of brush-like architectures with tunable control over both backbone and side-chain structures. Among them, living/controlled polymerization techniques are particularly powerful, affording precise regulation of the molecular weight, molecular weight distribution (MWD), and macromolecular architecture. For instance, ring-opening metathesis polymerization (ROMP), − catalyzed by Grubbs catalysts, is widely used in grafting-through strategies involving the polymerization of macromonomers. Reversible deactivation radical polymerization (RDRP), on the other hand, is frequently used in grafting-from approaches to grow side chains from initiator sites along a preformed backbone.

In recent years, graft polymers featuring stimuli-responsive degradability have attracted growing interest for biomedical applications such as drug delivery. − For example, Verduzco and co-workers developed degradable bottlebrush polymers bearing a dithiolane backbone. Their method involved the synthesis of α-lipoic acid (LA)-functionalized macromonomers via atom transfer radical polymerization (ATRP), followed by light-induced ring-opening polymerization through a grafting-through approach. Later, Matyjaszewski and co-workers introduced a reversible addition–fragmentation chain transfer (RAFT) copolymerization strategy involving LA and acrylate-based inimers, followed by ATRP-based grafting-from polymerization to yield degradable graft polymers with improved control over both backbone and side-chain structures.

RAFT step-growth polymerization offers an alternative route to construct degradable graft polymers. − This strategy exploits RAFT single unit monomer insertion (RAFT-SUMI) reactions between a chain transfer agent (CTA) and a vinyl monomer to form the backbone, followed by RAFT chain-growth polymerization to graft side chains from the pendant RAFT moiety in each repeat unit (Figure A). This strategy effectively combines some benefits of RAFT polymerization with the step-growth approach, enabling precise control over the side-chain structure and facilitating backbone degradability. For example, You and co-workers developed dual stimuli-responsive degradable graft polymers by incorporating silyl ethers and disulfide linkages into the monomers used for RAFT step-growth polymerization. Alternatively, the RAFT step-growth via Z-group approach embeds the thiocarbonylthio group into the polymer backbone, while the R group is positioned in the side chain of each repeat unit (Figure B). This enables subsequent RAFT chain-growth polymerization to produce multiblock vinyl polymers. Inspired by this approach, we envisioned a strategy wherein a bifunctional macroCTA synthesized via RAFT chain-growth polymerization serves as a macromonomer for subsequent RAFT step-growth polymerization with a bifunctional vinyl monomer. This design enables graft polymer synthesis via the grafting-through strategy (Figure C). Leveraging RAFT polymerization, the molecular weights and structures of the macromonomers are well-controlled. Additionally, the ester units in the bifunctional vinyl monomer and xanthate groups in the backbone impart dual stimuli-responsive degradability, offering potential for applications such as drug delivery and hydrogen sulfide (H₂S) release.

1.

RAFT step-growth polymerization.

Results and Discussion

To ensure an efficient RAFT-SUMI reaction for subsequent RAFT step-growth polymerization, the structures of RAFT agents and bifunctional vinyl monomers should be designed appropriately. Here, we choose the combination of a bifunctional xanthate (DiEPCP) and a vinyl ester-type bifunctional monomer (divinyl adipate, DiVA) for the conceptual validation. Methyl acrylate (MA) was used for the RAFT polymerization at first step to prepare the macromonomers, which will maintain the same structure of R group (e.g., the secondary ester structure) in the CTA after polymerization. A series of poly­(methyl acrylate) (PMA) with varying molecular weights were synthesized via thermally initiated RAFT polymerization of MA in the presence of DiEPCP. As summarized in Figure S1, PMA samples with number-average molecular weights (M _n) of 1100 (Đ = 1.05), 2400 (Đ = 1.31), and 5100 (Đ = 1.39) were obtained within 1 h (namely PMA_1.1k, PMA_2.4k, and PMA_5.1k, respectively), demonstrating efficient polymerization and reasonable control over MWD. These PMAs were subsequently used as macromonomers in an A₂ + B₂-type RAFT step-growth polymerization with DiVA under 405 nm LED irradiation via a photoiniferter RAFT mechanism. − The extent of the reaction (p) was monitored by ¹H NMR spectroscopy, where the consumption of vinyl groups and xanthate segments in unreacted monomers was tracked. As shown in Figure A, the p value rapidly increased to 0.64 within 4 h, followed by a gradual increase to 0.83 after 24 h. Near-quantitative formation of the SUMI adduct was observed, consistent with a step-growth polymerization mechanism. The polymerization was also monitored via size exclusion chromatography (SEC). As shown in Figure B,C, the molecular weights of the resulting polymers were lower than the theoretical values, indicating that steric hindrance imposed by the macromonomers inhibited the formation of higher molecular weight graft polymers, even with tails found in SEC curves. This phenomenon becomes more markedly when using PMA with higher molecular weights (e.g., the PMA_2.4k and PMA_5.1k), exhibiting much lower p values and molecular weights after 24 h (Entries 1–3, Table ). To alleviate the steric hindrance, we conducted a RAFT step-growth copolymerization using a mixture of PMA and DiEPCP with a fixed molar ratio of [PMA + DiEPCP]₀:[DiVA]₀ = 1:1. As shown in Figures S3–S8, ¹H NMR monitoring of the polymerization kinetics revealed equal consumption of the RAFT groups and vinyl group, indicating the occurrence of the SUMI reaction. Moreover, as shown in Figure S4, the consumption of DiEPCP can be tracked by the integration of peak b’, while the consumption of PMA was determined from the overall consumption of RAFT groups (peaks d and d’) after subtracting the DiEPCP contribution. As summarized in Table S4, the consumption rates of DiEPCP and PMA were found to be comparable, indicating a random copolymerization process. Furthermore, by adjusting the molar ratio of PMA to DiEPCP, a series of random copolymers with tunable compositions were obtained (entries 4–6, Table ). Higher final p values and increased molecular weights were achieved with greater DiEPCP content, which was attributed to reduced steric hindrance. To further tune the degree of polymerization of the side chains (DP_SC) in the graft polymers, we explored the copolymerization of DiVA with PMA_5.1k and a ternary system composed of [PMA_2.4k]₀:[PMA_5.1k]₀:[DiEPCP]₀:[DiVA]₀ = 0.5:0.5:1:2. This copolymerization also successfully yielded graft copolymers, as evidenced by the data presented in Entries 7 and 8 of Table . The linear viscoelastic behavior of the obtained graft polymers with varied DP_SC values was investigated using a rotational rheometer. As shown in Figure , the intrinsic viscosity increased with the proportion of PMA_2.4k (Figure A) and with longer side chains (Figure B). This trend can be attributed to an increase in the Kuhn length of the polymer backbone, likely resulting from enhanced intermolecular interactions between the longer side chains.

2.

RAFT step-growth polymerization of PMA_2.4k and DiVA with [PMA_2.4k]₀:[DiVA]₀ = 1:1 under a 405 nm LED at 25 °C. (A) Kinetic analysis of the RAFT step-growth polymerization; (B) evolution of the experimental M _n, M _w, and M _z values determined by SEC and the p calculated from 1H NMR data plotted with theoretical molecular weight averages; and (C) SEC traces of the obtained polymers at different time points.

1. RAFT Step-Growth Polymerization of PMA, DiEPCP, and DiVA for 24 h with Different Molar Ratios under a 405 nm LED at 25 °C.

entry	condition	p	M n,SEC	M w,SEC	Đ
1	[PMA1.1k]0:[DiVA]0 = 1:1	0.90	5500	9800	1.77
2	[PMA2.4k]0:[DiVA]0 = 1:1	0.83	4800	9800	2.04
3	[PMA5.1k]0:[DiVA]0 = 1:1	0.63	5800	15,300	2.62
4	[PMA2.4k]0:[DiEPCP]0:[DiVA]0 = 0.75:0.25:1	0.87	5400	11,500	2.15
5	[PMA2.4k]0:[DiEPCP]0:[DiVA]0 = 0.5:0.5:1	0.93	6000	15,000	2.48
6	[PMA2.4k]0:[DiEPCP]0:[DiVA]0 = 0.25:0.75:1	0.95	7800	16,700	2.13
7	[PMA5.1k]0:[DiEPCP]0:[DiVA]0 = 0.5:0.5:1	0.91	8500	16,000	1.88
8	[PMA2.4k]0:[PMA5.1k]0:[DiEPCP]0:[DiVA]0 = 0.5:0.5:1:2	0.90	9200	18,400	2.00

^aDetermined by ¹H NMR.

^bDetermined by THF SEC with an RI detector (calibration with poly­(methyl methacrylate) standards).

3.

Intrinsic viscosity curves of graft polymers with (A) different proportions of PMA_2.4k and (B) different side-chain lengths.

One notable advantage of the RAFT step-growth polymerization via Z-group approach is the incorporation of RAFT functionalities into the polymer backbone. This allows subsequent main chain degradation through RAFT group cleavage and enables chain expansion via RAFT chain-growth polymerization. To explore this, we first subjected the synthesized graft polymers to aminolysis with propylamine. Complete cleavage of xanthate moieties was achieved within 15 min. As shown in Figure A,B, the SEC traces revealed a significant shift to lower molecular weights, corresponding to the PMA macromonomers and DiEPCP fragments. Notably, the degraded product from the graft polymer containing more DiEPCP exhibited an increased peak intensity at lower molecular weight, which can be assigned to DiEPCP, further confirming the copolymer composition (Figure S11). Moreover, ¹H NMR spectra of the degraded product revealed disappearance of proton signals adjacent to the RAFT terminals and emergence of proton signals adjacent to nitrogen (Figure S12), indicating the degradation of the backbone triggered by propylamine. Next, we examined a second degradation step by hydrolyzing the ester bond introduced via DiVA with a 5 wt % KOH solution, resulting in an additional shift in the SEC trace toward lower molecular weights (Figure C), confirming successful hydrolysis. ¹H NMR spectra of (PMA)_n after hydrolysis showed the disappearance of proton signals adjacent to the ester group (Figure S12), further confirming the degradation. This dual-step, stimulus-responsive degradation offers promising utility in complex drug delivery systems where precise release profiles are required.

4.

Original (A), aminolysis (B) and hydrolysis (C) of the graft polymer (Entry 5, Table ).

Finally, we demonstrated chain expansion of the graft polymer using vinyl acetate (VAc) via photoiniferter RAFT polymerization under 405 nm LED light. As shown in Figure , SEC traces revealed a clear shift to higher molecular weights after chain expansion, with M _n increasing from 5500 to 34,000. Following aminolysis, a miktoarm star polymer was generated, containing two PVAc arms and two PMA arms. The measured M _n of 5100 closely matched the theoretical value (M _n,th = M _n,PMA + [VAc]₀/[xanthate]₀ × M _VAc × Conv. % = 5700), validating both the chain expansion and aminolysis processes.

5.

Chain expansion and aminolysis of the graft polymer. (A) SEC trace of the brush polymer prepared at the molar ratio of [PMA_1.1k]₀:[DiVA]₀ = 1:1. (B) SEC trace of (PMA)_n after chain expansion at the molar ratio of [VAc]₀:[xanthate]₀ = 100:1, and the conversion of this reaction was 54.3%. (C) SEC trace of (PMA)_n after aminolysis at the molar ratio of [propylamine]₀:[xanthate]₀ = 10:1.

Conclusions

In summary, we have developed a synthetic strategy for degradable graft polymers by combining RAFT step- and chain-growth polymerization. By employing bifunctional PMA macromonomers and a bifunctional vinyl monomer (DiVA), we successfully synthesized graft copolymers through an A₂ + B₂-type step-growth mechanism. The steric hindrance inherent to macromonomers was mitigated through the incorporation of small-molecule comonomers (DiEPCP), enabling access to higher degrees of polymerization and tunable side-chain lengths. The resultant graft polymers exhibited structure-dependent viscoelastic properties and dual-stimuli-responsive degradability via aminolysis and hydrolysis, providing a proof-of-concept for environmentally or biologically triggered polymer degradation. Additionally, the embedded RAFT functionalities allowed for further chain expansion via photoiniferter RAFT polymerization, enabling the synthesis of miktoarm star polymers after further aminolysis. This synthetic platform opens new opportunities for the design of advanced polymeric materials with responsive degradability and structural precision, with potential applications in controlled drug delivery and stimuli-responsive systems.

Experimental Section

Materials

Methyl acrylate (MA, 99%, Aldrich, Shanghai, China), vinyl acetate (VAc, 99%, Aldrich, Shanghai, China), and divinyl adipate (DiVA, AR, Energy Chemical) were passed through a neutral alumina column prior to use. Bis­[2-(2-hydroxyethoxy)­ethyl] ether (C₅H₉BrO₂, 99%, Aladdin), ethyl-2-bromopropionate ethyl acetate (C₃HBr₂O, 97%, Aladdin), propylamine (C₃H₉N, 98%, Macklin), dichloromethane (DCM, 99%, Qiangsheng), hexane (99%, Qiangsheng), ethanol (99%, Qiangsheng), acetone (99%, Qiangsheng), tetrahydrofuran (THF, 99%, Qiangsheng), carbon disulfide (CS₂, 99.9%, Alfa Aesar), 2,2’-azobis­(2-methylpropionitrile) (AIBN, 98%, Energy Chemical), 1,1,2,2-tetrachloroethane (C₂H₂Cl₄, 98%, Macklin), and potassium hydroxide (KOH, 98%, Qiangsheng) were used as received.

Instrumentation

Nuclear magnetic resonance (NMR) spectrum was recorded on a Bruker 300 MHz NMR instrument using CDCl₃ or DMSO-d ₆ as the solvent and tetramethylsilane as an internal standard.

The number-average molecular weight (M _n) and MWD (Đ) of polymers were determined by TOSOH HLC-8320 SEC equipped with refractive index and UV detectors using two TSKgel SuperMultiporeHZ-N (4.6 × 150 mm) columns arranged in series, and it can separate polymers in the molecular weight range 500–1.9 × 10⁵ g mol^–1. THF was served as the eluent with a flow rate of 0.35 mL min^–1 at 40 °C. SEC samples were injected using a TOSOH HLC-8320 SEC plus auto sampler. Data acquisition was performed using EcoSEC software, and molecular weights were calculated with poly­(methyl methacrylate) (PMMA) standards. No correction factors were applied.

The 405 nm LED light source used in polymerization (λ_max = 405 nm, 60 mW cm^–2) was purchased from Zhong Shan Tian Dou Electric Factory.

Viscosity was determined by an RS6000 Rotational Rheometer instrument from THERMO SCIENTIFIZ, using 10 Hz as the frequency and 0.1 mm as the distance.

Synthesis of Ethyl 2-((Ethoxycarbonothioyl)­thio)­propanoate (DiEPCP)

Bis­[2-(2-hydroxyethoxy)­ethyl] ether (3.88 g, 20 mmol) was dissolved in 100 mL of THF in a 250 mL round-bottom flask. Potassium hydroxide (2.81 g, 50 mmol) was added dropwise, and the resulting mixture was stirred for 30 min. Carbon disulfide (3.05 g, 40 mmol) was then added dropwise while the reaction mixture was cooled with an ice–water bath. After the addition, the ice bath was removed, and the mixture was stirred at room temperature for 4 h. Subsequently, ethyl 2-bromopropionate (7.24 g, 40 mmol) was added, and the reaction mixture was stirred for 12 h. The reaction mixture was filtered to remove the white precipitate, and the filtrate was concentrated under reduced pressure. The residue was washed with saturated brine (200 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to afford the product as a yellow oil (4.58 g, 41.9%). ¹H NMR (CDCl₃, 300 MHz) δ: 4.72–4.39 (m, 2 H), 4.20 (qd, J = 6.4, 1.3 Hz, 1 H), 3.85 (t, J = 5.3 Hz, 1 H), 3.68 (s, 3 H), 1.58 (s, 1 H), 1.28 (t, J = 6.3 Hz, 2 H).

Synthesis of Poly­(methyl acrylate) (PMA)

A mixture of DiEPCP (200 mg, 0.4 mmol), methyl acrylate (860 mg, 10 mmol), and AIBN (6 mg, 0.04 mmol) was placed in a dry Schlenk tube equipped with a three-way stopcock. The content was degassed by three freeze–pump–thaw cycles and purged with nitrogen. The Schlenk tube was placed in a 70 °C oil bath for 1 h. The resulting polymer was precipitated in petroleum ether. Monomer conversion was determined by ¹H NMR spectroscopy. Number-average molecular weight (M _n) and MWD (Đ) were determined by SEC.

Procedure for Step-Growth Polymerization Using DiVA and PMA

PMA_2.4k was taken as an example. A mixture of DiVA (16 mg, 0.08 mmol), PMA (200 mg, 0.08 mmol), and TCE (0.16 mL) was placed in a dry Schlenk tube equipped with a three-way stopcock. The content was degassed by three freeze–pump–thaw cycles and purged with argon. Then, the Schlenk tube was placed under light irradiation of a 405 nm LED at 25 °C for 24 h. At predetermined time intervals, small aliquots were taken using a syringe for analysis. The final polymer was precipitated in a petroleum ether. Monomer conversion was determined by ¹H NMR spectroscopy. M _n, M _w, M _z , and Đ were determined by SEC.

Theoretical Number-Average, Weight-Average, and Z-Average Molecular Weight

Theoretical number-average molecular weight (M _n,th), weight-average molecular weight (M _w,th), and Z-average molecular weight (M _z,th) were calculated as described by Flory for linear step-growth polymerization:

$$M_{\mathrm{n},\mathrm{th}}=M_0\frac{1}{1-p}$$

$$M_{\mathrm{w},\mathrm{th}}=M_0\frac{1+p}{1-p}$$

$$M_{\mathrm{z},\mathrm{th}}=M_0\frac{1+4p+p^2}{1-p^2}$$

M ₀ is the molecular weight of average molecular weight of A ₂ (DiVA) and B ₂ (PMA) comonomers.

Aminolysis of (PMA)_n

(PMA)_n (Entry 7, Table ) was taken as an example. (PMA)_n (500 mg 0.059 mmol) was dissolved in THF (1 mL) in a dry Schlenk tube. Propylamine (120 mg, 2 mmol) was then added, and the mixture was stirred for 15 min. The molar ratio between the xanthate group and propylamine is 1:10. The resulting polymer was precipitated in petroleum ether. M _n and Đ were determined by SEC.

Hydrolysis of (PMA)_n

Taking (PMA)_n after aminolysis (Figure B) as an example. (PMA)_n after aminolysis (200 mg 0.0625 mmol) was dissolved in THF (1 mL) in a dry Schlenk tube. A 5 wt % aqueous potassium hydroxide solution was added, and the mixture was stirred for 4 h. The resulting polymer was precipitated in petroleum ether. M _n and Đ were determined by SEC.

Chain Expansion of (PMA)_n Using VAc

A mixture of PMA (entry 1, Table ) (550 mg, 0.1 mmol) and VAc (1.72 g, 20 mmol) was placed in a dry Schlenk tube equipped with a three-way stopcock. The content was degassed by three freeze–pump–thaw cycles and purged with nitrogen. Then, the Schlenk tube was placed under the light irradiation of 405 nm LED at 25 °C for 1 h. The resulting polymer was precipitated in petroleum ether. Monomer conversion was determined by ¹H NMR spectroscopy. M _n and Đ were determined by SEC.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acspolymersau.5c00084.

• Detailed experimental procedures; characterization methods; supplementary figures (Figures S1–S6); and supplementary tables (Tables S1–S15) (PDF)

CRediT: Wenjie Mao data curation, investigation, writing - original draft.

The authors declare no competing financial interest.