One-pot catalyst-switching synthesis of thermoresponsive amphiphilic diblock copolymers consisting of poly(N,N-diethylacrylamide) and biodegradable polyesters

Abstract

A method for the syntheses of thermoresponsive amphiphilic diblock copolymers through sequential organocatalyzed polymerizations of vinyl-based and lactone-based monomers using group transfer polymerization (GTP) and ring-opening polymerization (ROP), respectively, is described. The organocatalysts were switched between the two polymerization stages and all syntheses could be conducted in a one-pot manner. The polymerization systems directly produced diblock copolymers composed of poly(N,N-diethylacrylamide) and biodegradable polyesters (poly(ε-caprolactone), poly(trimethylene carbonate), and poly(L-lactide) in various content ratios. Aqueous solutions of the obtained block copolymers below their cloud point temperatures (T_cp) were carefully characterized, revealing a close relationship among the structures of the block copolymers, T_cp, and micellar forming properties below the T_cp.

---

Introduction

Amphiphilic copolymers modified with hydrophobic groups self-assemble in water to form nano aggregates, such as micelles and vesicles that have three-dimensional structures, such as spheres and rods.^1–4 The morphology of these aggregates is highly dependent on the molecular design of the amphiphilic copolymer and is determined by the primary polymer structure, including the structural properties and balance of hydrophilic and hydrophobic moieties, composition, chain length, and chain configuration.^5,6 Amphiphilic copolymers with different linkage structures between hydrophilic and hydrophobic moieties are designated as block copolymers with hydrophilic and hydrophobic chains linked in series, graft copolymers with hydrophilic main chains and hydrophobic side chains, or random and alternating copolymers of hydrophilic and hydrophobic side chains.^7–10 The development of precision polymerization techniques, controlled/living radical polymerization (CLRP) as a representative example, has enabled facile syntheses of a variety of block copolymers.^11–13 For example, many amphiphilic block copolymers with poly(N-isopropylacrylamide) (PNIPAm) as a thermoresponsive segment have been designed and synthesized using appropriate CLRPs, such as nitroxide mediated polymerization, metal catalyzed atom transfer radical polymerization, and reversible addition–fragmentation chain transfer polymerization.^14–19 Poly(N,N-disubstituted acrylamide)s are thermoresponsive, and poly(N,N-diethylacrylamide) (PDEAm) is commonly used in the synthesis of various thermoresponsive architectures, including block copolymers, graft copolymers, cyclic polymers, and star-shaped polymers using CLRP or controlled/living anionic polymerization.^20–24 We have reported that the organocatalytic group transfer polymerization (GTP) of acrylamide monomers using silyl ketene acetal (SKA) and silyl ketene aminal (SKAm) is a reliable synthetic method for obtaining well-defined polyacrylamides. Furthermore, we developed a new GTP method without relying on SKA and SKAm initiating agents, i.e., the hydrosilylation-promoted GTP of acrylamide monomers using a Lewis acid of B(C₆F₅)₃ and a hydrosilane (R₃SiH).²⁵ Additionally, an α-end functionalized polyacrylamide was synthesized by the hydrosilylation-promoted GTP of acrylamide monomers using B(C₆F₅)₃ and functionalized methacrylamide as a latent initiator.²⁶

Since Hedrick et al. reported the living ring-opening polymerization (ROP) of lactide to a well-defined polylactide using 4-dimethylaminopyridine as an organocatalyst, many developments have been reported for the organocatalytic ROP reaction in terms of applicable monomers, organocatalyst types, and controlled/living systems.²⁷ Cyclic ethers, such as ethylene oxide (EO) and glycidyl ether, cyclic esters, such as δ-valerolactone (δ-VL), ε-caprolactone (ε-CL), and L-lactide (L-LA), and cyclic carbonates rare commonly studied biocompatible and biodegradable monomers for ROP.^28–32 There are many types of organocatalysts, including imidazoles, amines, amidines ammonium salts, phosphonium and phosphazene bases, and N-heterocyclic carbenes.^33–36 We reported that diphenyl phosphate (DPP) is an effective organocatalyst for controlled/living ROP of δ-VL, ε-CL, and trimethylene carbonate (TMC), but is a poor catalyst for ROP of L-LA.^37–39 Hadjichristidis et al. used phosphazene base t-Bu-P₂ to improve the applicable monomer limitations and successfully produced copolymers with various block combinations by the t-Bu-P₂-catalyzed ROPs of EO, δ-VL, ε-CL, TMC, and L-LA.^40–44

Here we report the “one-pot catalyst-switching” method for synthesizing amphiphilic diblock copolymers without separating the first block segment using two different controlled/living addition polymerization methods, GTP and ROP, by switching to the appropriate organocatalyst for each polymerization (Scheme 1).^45–50 The one-pot synthetic pathway is described as follows: (1) equimolar amounts of MAm-OTBDMS and Me₂EtSiH using B(C₆F₅)₃ for 1,6-hydrosilylation yields the SKAm^Me2Et-OTBDMS initiator. (2) Me₃SiNTf₂-catalyzed GTP of DEAm using SKAm^Me2Et-OTBDMS yields PDEAm-OTBDMS. (3) Deprotection of PDEAm-OTBDMS using tetra-n-butylammonium fluoride (TBAF) in the polymerization system yields macroinitiator PDEAm-OH. (4) Lastly, switching the catalyst from Me₃SiNTf₂ to t-Bu-P₂ enables the ROPs of cyclic esters initiated by PDEAm-OH to synthesize PDEAm-block-polyesters (PDEAm-b-PEs). Thermoresponsive behaviors of the resulting PDEAm-b-PEs were evaluated by measuring the cloud-point temperature (T_cp) and the aggregation properties below and above the T_cp are discussed in terms of changes in the hydrodynamic radius (R_h).

Scheme 1 One-pot catalyst-switch syntheses of PDEAm-b-PEs by the controlled/living GTP and ROP using B(C₆F₅)₃ and t-Bu-P₂, respectively.

Experimental

Materials

N-(2-tert-Butyldimethylsiloxyethyl)-N-methylmethacrylamide (MAm-OTBDMS) was prepared according to the previously reported method.²⁶ Dry tetrahydrofuran (99.5%) and dimethylethylsilane (Me₂EtSiH; 99.5%) were purchased from Kanto Chemical, Co., Inc. (Tokyo, Japan). N,N-Diethylacrylamide (DEAm) was purchased from Tokyo Chemical Industry Co., Ltd (TCI; Tokyo, Japan) and used after distillation over CaH₂ under reduced pressure. Tris(pentafluorophenyl)borane (B(C₆F₅)₃) was purchased from TCI and was used after purification by recrystallization from n-hexane at −30 °C. 1-tert-Butyl-2,2,4,4,4pentakis(dimethylamino)-2λ⁵,4λ⁵-catenadi(phosphazene) (t-Bu-P₂) was purchased from Sigma-Aldrich (St Louis, MO, USA). Extra dry dichloromethane (>99.5%; water content, <50 ppm) delivered over molecular sieves was purchased from Energy Chemicals Co., Inc. (Anhui, China). All other reagents were used as received without further purification.

Measurements

¹H NMR spectra were recorded by Bruker Avance III HD 500. Polymerization solutions were prepared in a Mikrouna glove box equipped with a gas purification system (molecular sieves and copper catalyst) and a dry argon atmosphere (H₂O, O₂, <1 ppm). Moisture and oxygen contents in the glove box were monitored by sensors MK-XTR-100 and MK-OXSEN-1, respectively. Number-average molecular weights (M_n,SEC) and size distribution (Đ) of the polymers were measured by size exclusion chromatography (SEC) at 60 °C using an Agilent high performance liquid chromatography system (1260 Infinity II) in N,N-dimethylformamide (DMF) containing lithium chloride (0.01 mol L⁻¹) at the flow rate of 1.0 mL min⁻¹ using Agilent Polar Gel-M (exclusion limit, 2 × 10⁴ g mol⁻¹) and Polar Gel-M (exclusion limit, 4 × 10⁶ g mol⁻¹) columns (7.5 × 300 mm; average bead size, 5 μm). Cloud-point measurements were performed on ultraviolet–visible (UV-vis) spectrophotometer (Jasco V-770, Tokyo, Japan) equipped with a Jasco CTU-100 temperature-controller. The path length was 10 mm and temperature was increased at a rate of 1 °C min⁻¹. Changes in transmittance with temperature were recorded u at a wavelength of 500 nm. Hydrodynamic radius (R_h) of the obtained polymers was analyzed using a Dyna Pro Nanostar® (Wyatt Technology, Sant Barbara, Ca, USA).

One-pot synthesis of PDEAm-b-PEs with catalyst-switching

A typical procedure for the synthesis of PDEAm-b-PCL is described as follows: in a glove box under an argon atmosphere, B(C₆F₅)₃ (25.5 mg, 50.0 μmol) was added to a solution of MAm-OTBDMS (56.5 mg, 0.22 mmol) and Me₂EtSiH (26.4 μL, 0.20 mmol) in 0.95 mL of CH₂Cl₂ in a round-bottom flask at room temperature. After stirring the reaction solution for 12 h, an aliquot was removed from the reaction mixture and the quantitative formation of SKAmMe₂Et-OTBDMS was confirmed by ¹H NMR. DEAm (1.27 g, 10.0 mmol) and CH₂Cl₂ (4.75 mL) were added to the round bottom flask, and then 0.1 mL of Me₃SiNTf₂ in CH₂Cl₂ (10.0 μmol, 0.1 mol L⁻¹) was added to catalyze GTP. After 30 min, PDEAm₅₀-OTBDMS was obtained. Quantitative consumption of DEAm was confirmed using ¹H NMR measurements of aliquots taken from the polymerization mixture. To deprotect PDEAm₅₀-OTBDMS, 3.0 mL of tetrabutylammonium fluoride (TBAF) in THF (3.0 mmol, 1.0 mol L⁻¹) was added to the round-bottom flask, and the entire mixture was stirred for 36 h. This solution became the stock solution of PDEAm₅₀-OH (0.20 mol) with an M_n,SEC of 6.2 kg mol⁻¹ and a Đ of 1.08. In a separate test tube, PDEAm-OH stock solution (2.0 mL, 40 mmol) was mixed with a solution of ε-CL (228.2 mg, 2.0 mmol) in toluene (0.2 mL), and then t-Bu-P₂ (36.8 mg) was added to catalyze ROP. After 12 h, the crude polymer was purified by precipitation with cold hexane to afford PDEAm₅₀-b-PCL₅₀ as a white solid with an M_n,SEC of 12.3 kg mol⁻¹ and a Đ of 1.10. Similarly, ROP of trimethylene carbonate (TMC, 204.2 mg, 2.0 mmol) using a stock solution of PDEAm-OH (2.0 mL, 40 mmol) yielded PDEAm₅₀-bPTMC₅₀ with a M_n,SEC of 11.2 kg mol⁻¹ and a Đ of 1.17 and also L-lactide (L-LA, 288.2 mg, 2.0 mmol) yielded PDEAm₅₀-b-PLLA₅₀ with an M_n,SEC of 12.5 kg mol⁻¹ and Đ of 1.17.

Results and discussion

Formation of functional SKAm initiator

Scheme 1 shows the one-pot synthesis of PDEAm-b-PEs using two controlled/living polymerizations, GTP and subsequent ROP, using the appropriate organocatalysts for each polymerization stage. To prepare the SKAm initiator, a small excess of latent initiator should be used to avoid the presence of free hydrosilane in the reaction mixture. We applied the B(C₆F₅)₃-catalyzed hydrosilylation of MAm-OTBDMS with Me₂EtSiH ([MAm-OTBDMS]₀/[Me₂EtSiH]₀/[B(C₆F₅)₃]₀ = 1.1/1.0/0.25) in CH₂Cl₂ to yield a SKAm initiator possessing a tert-butyldimethylsilyl (TBDMS)-protected hydroxyl group (SKAm^Me2Et-OTBDMS). The formation of SKAm was confirmed by ¹H NMR spectroscopy of the hydrosilylation product compared with those of Me₂EtSiH and MAm-TBDMS, as shown in Fig. 1. In Fig. 1c, the hydrosilylation product displayed signals attributed to the dimethylethylsilyl group of Me₂EtSiH (white triangles in Fig. 1a) signals attributed to the TBDMS group of MAm-TBDMS (black triangles in Fig. 1b). Additionally, the vinyl group signals in MAm-TBDMS (white circles in Fig. 1b) were not observed while methyl group signals appeared at 0.76 ppm. These results confirm that the B(C₆F₅)₃-catalyzed hydrosilylation of MAm-TBDMS with Me₂EtSiH lead to quantitative formation of SKAm^EtMe2-TBDMS, and the reaction solution was used as the stock solution for subsequent GTP.

Fig. 1 ¹H NMR spectra of (a) Me₂EtSiH, (b) MAm-TBDMS, and (c) the hydrosilylation product measured in CDCl₃.

Synthesis of α-end hydroxyl functionalized PDEAm

In the GTP of DEAm with [DEAm]₀/[SKAm^Me2Et-OTBDMS]₀ = 50, Me₃SiNTf₂ was used as the organocatalyst. DEAm was quantitatively polymerized to afford a poly(N,N-diethylacrylamide) with an OTBDMS-protected hydroxyl group (PDEAm-OTBDMS). Fig. 2a displays the ¹H NMR spectrum of PDEAm₅₀-OTBDMS showing signals for methylene protons at 2.39–2.80 ppm (white circles) together with –NCH₂CH₃ group signals at 0.95–1.33 ppm (black squares). After deprotecting PDEAm₅₀-OTBDMS to PDEAm₅₀-OH using tetrabutylammonium fluoride (TBAF), a very small portion divided from the polymerization mixture was purified to isolate and characterize PDEAm₅₀-OH. As shown in Fig. 2b, the PDEAm₅₀-OH proton signals due to the TBDMS group of PDEAm₅₀-OTBDMS (black triangles in Fig. 2a) have completely disappeared. Table S1† lists the polymerization results. The targeted PDEAm₅₀-OH obtained had a SEC-measured M_n,SEC of 6.2 kg mol⁻¹ and low Đ of 1.08 that well agreed with calculated number-average molecular weights (M_n,calcd) of 6.4 kg mol⁻¹. Similarly, for GTP using [DEAm]₀/[SKAm^Me2Et-OTBDMS]₀ of 30–90, the obtained PDEAmOHs possessed the targeted SEC-measured M_n along with low Đs, as shown in Fig. 3a.

Fig. 2 ¹H NMR spectra of (a) PDEAm-TBDMS, (b) PDEAm-OH, and (c) PDEAm-b-PCL in CDCl₃.

Fig. 3 SEC traces of PDEAm_x-OH and PDEAm_x-b-PCL_y in CDCl₃: (a) x/y = 30/70, (b) x/y = 40/60, (c) x/y = 50/50, (d) x/y = 60/40, (e) x/y = 70/30, (f) x/y = 80/20, and (g) x/y = 90/10.

Synthesis of PDEAm-b-PEs

We planned the preparation of PDEAm_x-b-PEs_y in which x and y denote the degree of polymerizations for the PDEAm and PEs segments (DPx and DPy, respectively). Three types of polyesters (PEs) were selected as the second segments of block copolymers, including poly(ε-caprolactone) (PCL), poly(trimethylene carbonate) (PTMC), and poly(L-lactide) (PLLA). Table 1 lists the result of the second polymerizations. For a representative example, PDEAm₅₀-OH was used as the macroinitiator for the ROP of ε-caprolactone (ε-CL) using t-Bu-P₂ as the polymerization organocatalyst. After the polymerization with a [PDEAm₅₀-OH]₀/[ε-CL]₀ of 50 for 24 h, ε-CL was quantitatively consumed and the resulting copolymer structure was confirmed by ¹H NMR. Signals corresponding to the methylene protons of the PCL segment along with the PDEAm segment were observed at 1.38, 1.65, 2.31, and 4.06 ppm (black and white triangles in Fig. 2c), indicating PDEAm_x-b-PCL_y was successfully produced. The M_n,SEC of 12.3 kg mol⁻¹ agreed well with the M_n,calcd of 12.0 kg mol⁻¹ and Đ was the low value of 1.10. We prepared seven samples of well-defined PDEAm_x-b-PCL_y copolymers in total with diverse DPx/DPy ratios as shown in Fig. 3.

Table 1 One-pot synthesis of PDEAm-b-PCL by ROP of ε-CL using PDEAm-OH as the macroinitiator and t-Bu-P₂ as the organocatalyst^a

Sample code	[ε-CL]0/[PDEAm-OH]0	M n,calcd ^b/kg mol^−1	M n,SEC (Đ)^c/kg mol^−1
a PDEAm-OH, 0.20 mmol; [ε-CL]0, 1.0 mol L^−1; solvent, CH2Cl2; room temperature; argon atmosphere; polymerization time, 24 h; monomer conversion determined by ^1H NMR in CDCl3, >99%. b M n,calcd = (MW of PDEAm-OH) + [ε-CL]0/[PDEAm-OH]0 × (monomer conversion) × (MW of ε-CL) + (M.W. of H) × 2. c Determined by SEC calibrated against poly(methyl methacrylate) standards.
PDEAm30-b-PCL70	70	11.7	11.8 (1.13)
PDEAm40-b-PCL60	60	11.8	11.5 (1.11)
PDEAm50-b-PCL50	50	12.0	12.3 (1.10)
PDEAm60-b-PCL40	40	12.1	12.0 (1.12)
PDEAm70-b-PCL30	30	12.2	12.8 (1.17)
PDEAm80-b-PCL20	20	12.4	13.2 (1.07)
PDEAm90-b-PCL10	10	12.6	13.9 (1.11)

---

In place of ε-CL, trimethylene carbonate (TMC) or L-lactide (L-LA) were used as the second monomers to afford the corresponding block copolymers, and ¹H NMR spectroscopy was used to confirm the structures (Fig. S3†). In total, 14 additional samples of PDEAm-b-PTMC and PDEAm-b-PLLA, block copolymers formed from PTMC and PLLA, were prepared with targeted molecular weights (Tables S2 and S3,† respectively) and narrow Đs (Fig. S1 and S2,† respectively).

In the ¹H NMR spectra of PDEAm-b-PEs, the molecular weight of PE was difficult to determine because of the overlap of the PDEAm and PE absorptions. However, the synthesis of PDEAm-b-PE was performed by the ROP of cyclic ester monomers using a PDEAm-OH with a known molecular weight, which was beforehand prepared in a one-pot polymerization system, as a macroinitiator. Moreover, all cyclic ester monomers were quantitatively consumed, and the SEC traces of the resulting PDEAm-b-PEs were clearly shifted toward high molecular weight region compared to PDEAm-OH, with their Đs ranging from 1.07 to 1.20 smaller. From these results, we concluded that PDEAm-b-PE was synthesized as designed. For the sample code of PDEAm_x-b-PCL_y, x and y values are used an initial molar ratio of [MAm-OTBDMS]₀/[DEAm]₀/[ε-CL, TMC, or L-LA]₀.

Thermoresponsive properties

We prepared a total of 21 PDEAm_x-b-PEs_y samples, including PDEAm_x-b-PCL_y, PDEAm_x-b-PTMC_y, and PDEAm_x-b-PLLA_y, with diverse DPx/DPy ratios of 90/10, 80/20, 70/30, 60/40, 50/50, 40/60, and 30/70. Unexpectedly, all of the obtained copolymers were water-soluble at room temperature, even hydrophobic PEs-enriched PDEAm₃₀-b-PEs₇₀. On the other hand, all solutions became turbid upon heating, indicating that these PDEAm_x-b-PEs_y copolymers were thermoresponsive. Fig. 4 shows the plots of optical transmittance at 500 nm as a function of temperature (cloud point curves) for the aqueous solutions of PDEAm_x-b-PEs_y copolymers. Table 2 lists the T_cp values determined from Fig. 4. Fig. 5 shows the plots of T_cp values against the DPx values for the PDEAm_x-b-PEs_y systems together with those for the PDEAm_x-OH starting homopolymer system (T_cps are listed in Table S1†). A trend can be observed for T_cps: PDEAm_x-OH > PDEAm_x-b-PCL_y > PDEAm_x-b-PTMC_y ≈ PDEAm_x-b-PLLA_y. This result could be expected because the introduced PEs units were hydrophobic, which decrease the T_cp values compared to that for starring PDEAm_x-OH.^51–54 The dependence of T_cp on the DPx was very small for the PDEAm_x-OH system and only ranged from 49.9 °C to 53.8 °C. Contrastingly, the dependence was noticeable in the PDEAm_x-b-PCL_y system where T_cp increased from 35.5 °C to 5 °C with increasing DPx content from 30% to 90%. This trend was also observed for the other PDEAm_x-b-PEs_y systems where the T_cps increased from 29.7 °C to 36.1 °C and from 25.2 °C to 38.1 °C for the PDEAm_x-b-PTMC_y and PDEAm_x-bPLLA_y systems, respectively. Addition thermoresponsive trends were revealed upon closer examination of PDEAm_x-b-PEs_y within their respective PEs series.

Fig. 4 UV-vis absorption spectra in water (3 g L⁻¹) at different temperatures of PDEAm-b-PEs: (a) PDEAm_x-b-PCL_y, (b) PDEAm_x-b-PTMC_y, and (c) PDEAm_x-b-PLLA_y.

Fig. 5 Dependence of T_cp on DPx for PDEAm_x-OH (Δ), PDEAm_x-b-PCL_y (○), PDEAm_x-bPTMC_y (□), and PDEAm_x-b-PLLA_y (◊).

Table 2 T _cp and R_h of PDEAm-b-PEs

Sample code	T cp ^a	R h ^b/nm
		25 °C	55 °C
a Determined by UV–vis measurements in water (3 g L^−1). b Determined by dynamic light scattering (DLS) measurements in water (3 g L^−1).
PDEAm30-b-PCL70	35.5	112.0	436.8
PDEAm40-b-PCL60	36.0	114.2	434.0
PDEAm50-b-PCL50	39.0	110.4	400.8
PDEAm60-b-PCL40	42.2	110.2	337.6
PDEAm70-b-PCL30	44.1	102.3	322.1
PDEAm80-b-PCL20	47.5	99.7	314.5
PDEAm90-b-PCL10	50.8	98.0	266.2
PDEAm30-b-PTMC70	29.7	238.5	720.5
PDEAm40-b-PTMC60	30.5	227.7	675.3
PDEAm50-b-PTMC50	31.0	221.0	629.7
PDEAm60-b-PTMC40	32.9	197.0	607.5
PDEAm70-b-PTMC30	34.7	171.4	531.8
PDEAm80-b-PTMC20	35.9	168.4	515.4
PDEAm90-b-PTMC10	36.1	163.9	480.0
PDEAm30-b-PLLA70	25.2	494.6	1431.0
PDEAm40-b-PLLA60	27.3	480.0	1259.0
PDEAm50-b-PLLA50	31.5	478.8	823.1
PDEAm60-b-PLLA40	32.4	454.9	745.5
PDEAm70-b-PLLA30	35.2	421.9	686.6
PDEAm80-b-PLLA20	37.1	412.5	678.1
PDEAm90-b-PLLA10	38.1	386.0	524.6

---

The ¹H NMR spectra for a series of PDEAm_x-b-PEs_y copolymers in D₂O were measured at different temperatures to characterize their phase transition behaviors.^55,56Fig. 6 displays the ¹H NMR spectra for PDEAm₃₀-b-PCL₇₀ (T_cp = 35.5 °C) at 30, 35, and 40 °C in D₂O. Focusing on the signals attributed to the PCL (black and white triangles) and PDEAm segments (black and white squares), at 30 °C, we expected that signals due to the PDEAm segments would appear, while those for the PCL segments would not be observed because molecular motion of the protons in the hydrophobic PCL segments should be significantly suppressed by their hydrophobic interactions. However, we obtained clear signals for both PDEAm and PCL segments. A possible interpretation of this result is that the hydrophobic interactions among the PCL segments were not very strong. This hypothesis may be supported in the forthcoming discussion. For the measurements at 35 °C and 40 °C, nearly all the PCL and PDEAm peaks disappeared. At temperatures higher than T_cp, PDEAm_x-b-PCL_y aggregates to precipitate out, resulting in loss of sample signals since the copolymer has left the solution phase. Similar results were obtained for the PDEAm_x-b-PTMC_y and PDEAm_x-b-PLLA_y systems (Fig. S4†).

Fig. 6 ¹H NMR spectra of PDEAm₃₀-b-PCL₇₀ measured at 30, 35, and 40 °C in D₂O.

To provide reliable insights into the phase transition behavior, we performed dynamic light scattering (DLS) measurements at 25 °C (Fig. S5, S7, and S9†) and 55 °C (Fig. S6, S8, and S10†). The DLS measurements confirmed that all of PDEAm-b-PEs copolymers exist as particles in aqueous solutions at both 25 °C and 55 °C, while their average R_h values varied significantly depending on the measurement temperature and the resulting thermoresponsive structures (Table 2). Fig. 7a and b display plots of the observed R_h on DP_x for a series of PDEAm_x-b-PEs_y's measured at 25 °C and 55 °C, respectively. A general result is that the R_h values at 25 °C (98.0–494.6 nm) are significantly smaller compared to those at 55 °C (266.2–1431.0 nm). Another observed trend was that the R_h values increased in the order of PDEAm_x-b-PCL_y < PDEAm_x-b-PTMC_y ≪ PDEAm_x-b-PLLA_y.

Fig. 7 Dependence of R_h on DP_x for PDEAm_x-b-PCL_y (○), PDEAm_x-b-PTMC_y (□), and PDEAm_x-b-PLLA_y (◊) measured in water at: (a) 25 °C and (b) 55 °C.

Examining each sample individually, the measurements at 25 °C (below T_cp) indicate that PDEAm_x-b-PCL_y exists as particles with a R_h of 98.0–114.2 nm (Fig. S5†). Notably, the particle size was somewhat larger if the morphology of the aggregate was a distinct core–shell micelle structure, indicating that PDEAm_x-b-PCL_y existed as an aggregate with a randomly mixed micelle structure morphology below its T_cp. This hypothesis would be consistent with the discussion from the NMR section where the molecular motions for the hydrophobic PCL segments were not significantly restricted. The R_h at 25 °C increased with increasing DPx in PDEAm_x-b-PCL_y. The measurements at 55 °C (above T_cp) indicated that each R_h significantly increased in the range of 266.2 nm to 436.8 nm (Fig. S6†). Notably, the distributions in the particle sizes appear broader. These results support that PDEAm_x-b-PCL_y exists as a large hydrophobic cluster-like structure composed of thermoresponsive PDEAm segments and hydrophobic PCL ones above T_cp.

Similar results were obtained for the PDEAm_x-b-PTMC_y system: the R_h values ranged from 136.9 nm to 238.5 nm at 25 °C and increased to range from 480.0 nm to 720.5 nm at 55 °C. For the PDEAm_x-b-PLLA_y system, the observed particle size increases were the most significant. The R_h values ranged from 386 nm to 494.6 nm at 25 °C and increased significantly to range from 524.6 nm to 1259.0 nm at 55 °C. We would like to emphasize this featured result: that the R_h in the PDEAm_x-b-PLLA_y system was considerably larger than those of PDEAm_x-bPCL_y and PDEAm_x-b-PTMC_y at 25 °C. Therefore, PDEAm_x-b-PLLA_y formed larger and looser aggregates within these three kinds of PDEAm_x-b-PEs_y copolymers.

Conclusion

A series of PDEAm_x-b-PEs_y (PDEAm_x-b-PCL_y, PDEAm_x-b-PTMC_y, and PDEAm_x-bPLLA_y) were synthesized using the one-pot catalyst-switching method where organocatalytic GTP and ROP can be performed sequentially in the same reaction vessel by simply changing the organocatalyst. This synthetic method encourages the broadening of thermoresponsive polymer architecture libraries composed from vinyl polymers and aliphatic biodegradable polymers. In total, 21 PDEAm_x-b-PEs_y samples with different DP_x/DP_y ratios were carefully characterized in water, providing insights into their T_cp values. A small but crucial conclusion from characterization studies performed below T_cp was that PDEAm_x-b-PEs_y copolymers seem to exist as randomly mixed loose micellar aggregates and not distinct core–shell micelle structures. Notably, PDEAm_x-b-PLLA_y formed larger and looser aggregates within the three types of PDEAm_x-b-PEs_y copolymers studied, thus leading to lower T_cp temperatures.

Conflicts of interest

There are no conflicts to declare.

References

1. Y. Zhao, T. Bai, Q. Shao, S. Jiang and A. Q. Shen, Polym. Chem., 2015, 6, 1066–1077.
2. D. Wang, H. Ren, X. Wang and X. Wang, Macromolecules, 2008, 41, 9382–9388.
3. S. J. T. Rezaei, M. R. Nabid, H. Niknejad and A. A. Entezami, Int. J. Pharm., 2012, 437, 70–79.
4. J. Mao, X. Ji and S. Bo, Macromol. Chem. Phys., 2011, 212, 744–752.
5. N. Toshikj, J. J. Robin and S. Blanquer, Eur. Polym. J., 2020, 127, 109599.
6. J. Sun, S. Fransen, X. Yu and D. Kuckling, Polym. Chem., 2018, 9, 3287–3296.
7. Y. Shao, Y. G. Jia, C. Shi, J. Luo and X. X. zhu, Biomacromolecules, 2014, 15, 1837–1844.
8. H. Y. Lee, S. H. Park, J. H. Kim and M. S. Kim, Polym. Chem., 2017, 8, 6606–6616.
9. R. Tang, W. Ji and C. Wang, Macromol. Biosci., 2010, 10, 192–201.
10. A. L. Brocas, M. Gervais, S. Carlotti and S. Pispas, Polym. Chem., 2012, 3, 2148.
11. L. Yao, L. Yu, L. Li and J. Kou, J. Phys.: Conf. Ser., 2020, 1575, 012161.
12. G. Barouti, K. Jarnouen, S. Cammas-Marion, P. Loyer and S. M. Guillaume, Polym. Chem., 2015, 6, 5414–5429.
13. S. Imai, Y. Hirai, C. Nagao, M. Sawamoto and T. Terashima, Macromolecules, 2018, 51, 398–409.
14. D. Zehm, A. Laschewsky, H. Liang and J. P. Rabe, Macromolecules, 2011, 44, 9635–9641.
15. W. H. Binder, D. Gloger, H. Weinstabl, G. Allmaier and E. Pittenauer, Macromolecules, 2007, 40, 3097–3107.
16. G. Lu, X. Jiang, Y. Li, X. Lv and X. Huang, RSC Adv., 2015, 5, 74947–74952.
17. C. Lv, Z. Zhang, J. Gao, J. Xue, J. Li, J. Nie, J. Xu and B. Du, Macromolecules, 2018, 51, 1013610149.
18. K. Y. Cho, J. W. Choi, S. H. Lee, S. S. Hwang and K. Y. Baek, Polym. Chem., 2013, 4, 2400.
19. J. Škvarla, J. Zedník, M. Šlouf, S. Pispas and M. Štěpánek, Eur. Polym. J., 2014, 61, 124–132.
20. R. Freitag, T. Baltes and M. Eggert, J. Polym. Sci., Part A: Polym. Chem., 1994, 32, 3019–3030.
21. M. Kobayashi, S. Okuyama, T. Ishizone and S. Nakahama, Macromolecules, 1999, 32, 6466–6477.
22. A. Narumi, S. I. Sato, X. Shen and T. Kakuchi, Polym. Chem., 2022, 13, 1293–1319.
23. S. Kikuchi, Y. Chen, E. Ichinohe, K. Kitano, S. Sato, Q. Duan, X. Shen and T. Kakuchi, Macromolecules, 2016, 49, 4828–4838.
24. J. Li, S. Kikuchi, S. Sato, Y. Chen, L. Xu, B. Song, Q. Duan, Y. Wang, T. Kakuchi and X. Shen, Macromolecules, 2019, 52, 7207–7217.
25. S. Kikuchi, Y. Chen, K. Kitano, K. Takada, T. Satoh and T. Kakuchi, Polym. Chem., 2015, 6, 6845–6856.
26. S. Kikuchi, Y. Chen, K. Kitano, S. Sato, T. Satoh and T. Kakuchi, Macromolecules, 2016, 49, 3049–3060.
27. F. Nederberg, E. F. Connor, M. Möller, T. Glauser and J. L. Hedrick, Angew. Chem., Int. Ed., 2001, 40, 2712–2715.
28. T. He, Y. Wang, A. Narumi, L. Xu, S. I. Sato, X. Shen and T. Kakuchi, Polymers, 2021, 13, 3873.
29. K. Makiguchi, T. Satoh and T. Kakuchi, J. Polym. Sci., Part A: Polym. Chem., 2011, 49, 3769–3777.
30. T. Kitayama, H. Yamaguchi, T. Kanzawa and T. Hirano, Polym. Bull., 2000, 45, 97–104.
31. T. Horváth, K. Marossy and T. J. Szabó, J. Therm. Anal. Calorim., 2021, 147, 2221–2227.
32. X. Wang, S. Cui, Z. Li, S. Kan, Q. Zhang, C. Zhao, H. Wu, J. Liu, W. Wu and K. Guo, Polym. Chem., 2014, 5, 6051–6059.
33. C. Thomas and B. Bibal, Green Chem., 2014, 16, 1687–1699.
34. S. Liu, C. Ren, N. Zhao, Y. Shen and Z. Li, Macromol. Rapid Commun., 2018, 39, 1800485.
35. I. Jain and P. Malik, Eur. Polym. J., 2021, 150, 110412.
36. S. Tempelaar, L. Mespouille, O. Coulembier, P. Dubois and A. P. Dove, Chem. Soc. Rev., 2013, 42, 1312–1336.
37. K. Makiguchi, T. Satoh and T. Kakuchi, Macromolecules, 2011, 44, 1999–2005.
38. K. Makiguchi, Y. Ogasawara, S. Kikuchi, T. Satoh and T. Kakuchi, Macromolecules, 2013, 46, 1772–1782.
39. K. Makiguchi, S. Kikuchi, K. Yanai, Y. Ogasawara, S. Sato, T. Satoh and T. Kakuchi, J. Polym. Sci., Part A: Polym. Chem., 2014, 52, 1047–1054.
40. R. A. Alshumrani and N. Hadjichristidis, Polym. Chem., 2017, 8, 5427–5432.
41. J. K. Palacios, J. Zhao, N. Hadjichristidis and A. J. Müller, Macromolecules, 2017, 50, 9683–9695.
42. H. Alamri, J. Zhao, D. Pahovnik and N. Hadjichristidis, Polym. Chem., 2014, 5, 5471–5478.
43. J. Zhao, D. Pahovnik, Y. Gnanou and N. Hadjichristidis, Polym. Chem., 2014, 5, 3750–3753.
44. J. Zhao, D. Pahovnik, Y. Gnanou and N. Hadjichristidis, Macromolecules, 2014, 47, 3814–3822.
45. V. Ladelta, J. D. Kim, P. Bilalis, Y. Gnanou and N. Hadjichristidis, Macromolecules, 2018, 51, 2428–2436.
46. H. Alamri and N. Hadjichristidis, Polym. Chem., 2016, 7, 3225–3228.
47. J. Zhao and N. Hadjichristidis, Polym. Chem., 2015, 6, 2659–2668.
48. J. Zhao, D. Pahovnik, Y. Gnanou and N. Hadjichristidis, J. Polym. Sci., Part A: Polym. Chem., 2014, 53, 304–312.
49. M. S. Zaky, G. Guichard and D. Taton, Macromol. Rapid Commun., 2022, 43, 2200395.
50. M. Liu, B. Wang, L. Pan, X. H. Liu and Y. S. Li, Polym. Chem., 2022, 13, 3451.
51. S. S. Patil and P. P. Wadgaonkar, J. Polym. Sci., Part A: Polym. Chem., 2017, 55, 1383–1396.
52. B. Lu, L. Li, L. Wei, X. Guo, J. Hou and Z. Liu, RSC Adv., 2016, 6, 50993–51004.
53. H. Ajiro, Y. Takahashi and M. Akashi, Macromolecules, 2012, 45, 2668–2674.
54. Y. S. Jo, D. K. Kim and M. Muhammed, J. Mater. Sci.: Mater. Med., 2004, 15, 1291–1295.
55. T. He, Y. Wang, A. Narumi, L. Xu, S. I. Sato, X. Shen and T. Kakuchi, Polym. Chem., 2021, 12(17), 2580–2591.
56. J. Li, S. Mizutani, S. I. Sato, A. Narumi, O. Haba, S. Kawaguchi, M. Kikuchi, T. Kakuchi and X. Shen, Polym. Chem., 2020, 11(13), 2346–2359.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3py00195d

---