Multi‑Stimuli‑Responsive Poly(N‑vinylamide) Copolymers: Controlled Aggregation in Aqueous Media via Thermal and Photonic Triggers

Background

In polymer science, integrating multi‑stimuli responsiveness—such as thermo‑redox, thermo‑salt, or thermo‑pH—is essential for advanced applications [1–3]. Lower critical solution temperature (LCST) behaviour has been extensively studied, and combining it with photo‑responsive moieties, notably azobenzene derivatives, yields polymers capable of precise environmental control [17–22]. Controlled aggregation of such polymers in aqueous solutions is a prerequisite for applications ranging from targeted drug release to supramolecular recognition [23–29].

Poly(N-vinylamide) derivatives, first synthesized via a novel route for poly(N-vinylacetamide) (PNVA) [30], have proven versatile: PNVA is amphiphilic [32], PNVIBA is thermosensitive [33], and PNVF serves as a polycation precursor [34]. Importantly, PNVF can be hydrolysed under alkaline conditions to generate cationic poly(N-vinylamine) without releasing toxic amines [34], and it remains stable under UV irradiation [35]. Despite these advantages, research on poly(N-vinylamide) derivatives lags behind that on poly(acrylamide) analogues [36–38] due to the low reactivity of unconjugated vinyl monomers. This study addresses this gap by synthesizing a methoxyethyl‑substituted monomer to improve hydrophilicity and then incorporating photo‑responsive azobenzene units to achieve dual responsiveness.

Methods

Materials

N-vinylformamide (NVF) was obtained from Tokyo Chemical Industry Co., Ltd. (Japan) and distilled prior to use. Sodium hydride (NaH) 60% in oil, 1,2‑dibromoethane, 4-(phenylazo)phenol, and anhydrous tetrahydrofuran (THF) were sourced from Tokyo Chemical Industry Co., Ltd. (Japan). Anhydrous N,N‑dimethylformamide (DMF), acetone, toluene, ethyl acetate, magnesium sulfate, azobisisobutyronitrile (AIBN), and hexane were purchased from NACALAI TESQUE, INC. (Japan) and Wako Pure Chemical Industries Ltd. (Japan). Diethyl ether was obtained from AZBIO CORP. (Japan).

Polymerization

The copolymer poly(N-vinylformamide-co-NOENVF) (1) was prepared by free‑radical copolymerization: MOENVF (1.03 g, 8 mmol), NVF (0.14 g, 2 mmol), toluene (5 mL), and AIBN (0.044 g, 0.25 mmol) were mixed in a 50 mL glass flask, purged with nitrogen for 2 min, then heated to 60 °C for 24 h. The mixture was cooled, precipitated in 500 mL diethyl ether, washed twice, and vacuum‑dried at 30 °C for 12 h, yielding 0.69 g (59 % yield).

To introduce azobenzene units, 0.20 g of polymer 1 and 0.4 mmol NaH (0.011 g) were dissolved in DMF (1 mL) at 100 °C under nitrogen. After 15 min, 1‑bromoethane azobenzene (0.4 mmol, 0.12 g) was added, followed by 12 h stirring. Water (1 mL) and additional DMF (2 mL) were then added, and the mixture was precipitated in 500 mL acetone. The product, poly(N-vinylformamide-co-MOENVF-co-NVFazo) (2), was recovered by centrifugation and dried at 30 °C for 12 h, giving 0.29 g (43 % yield).

Measurements

Size‑exclusion chromatography (SEC) was performed on a Chem NAV system (JASCO) with polystyrene standards at 40 °C using DMF as the eluent. Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on a JEOL JNM‑ECX 400 (400 MHz). Light transmittance versus temperature was monitored on a Shimadzu UV‑2600. UV irradiation (330 nm, 300 W Xenon lamp) was applied for 10 min. Dynamic light scattering (DLS) was conducted with a Malvern ZEN3600 Zetasizer Nano ZS (633 nm laser).

Results and Discussion

Polymer 1 was successfully synthesized in 59 % yield. Its composition matched the feed ratio (NVF:MOENVF = 20:80) as confirmed by ¹H NMR integration. Polymer 2 was obtained in 43 % yield; NMR indicated that ~72 % of NVF units were converted to azobenzene‑bearing NVFazo, yielding an average of four azobenzene groups per chain (M_n ≈ 4000).

SEC traces (Fig. 2) revealed a single broad peak for 1, whereas 2 displayed a broadened profile with a high‑molecular‑weight shoulder, reflecting the heterogeneity introduced by azobenzene grafting. UV detection at 500 nm (Fig. 2d) confirmed that the high‑MW shoulder arose from azobenzene‑rich fractions, consistent with π–π interactions promoting aggregation.

Temperature‑dependent light transmittance (Fig. 3) showed that 1 remained transparent across 20–90 °C, indicating its hydrophilic nature. In contrast, 2 exhibited a ~10 % decrease in transmittance, evidencing temperature‑driven aggregation driven by hydrophobic and π–π interactions.

DLS measurements (Fig. 4, Table 2) revealed that 2 formed 210 nm nanoparticles at 20 °C and 250 nm at 60 °C. UV‑irradiated 2 (2’) formed 330 nm aggregates at 60 °C but remained below detection limits at 20 °C. The larger size of 2’ is attributed to trans‑azobenzene conformations enhancing π–π stacking, while cis‑isomers at lower temperatures reduce aggregation.

Conclusions

We have demonstrated a facile route to synthesize dual‑responsive poly(N-vinylamide) copolymers that aggregate in a controlled manner via thermal and photonic stimuli. Polymer 2 forms distinct nanoparticle assemblies (210–330 nm) depending on temperature and UV exposure, highlighting the pivotal roles of hydrophobic and π–π interactions as well as azobenzene isomerism. This platform offers a promising foundation for smart delivery systems where aggregation size can be tuned on demand.

Abbreviations

AIBN:

Azobisisobutyronitrile

LCST:

Lower critical solution temperature

MOENVF:

N-Methoxyethyl-N-vinylformamide

NVFazo:

4-(2‑N-Vinylformamide)ethoxyazobenzene

PNVA:

Poly(N-vinylacetamide)

PNVF:

Poly(N-vinylformamide)

PNVIBA:

Poly(N-vinylisobutylamide)