Thermally Responsive Unimolecular Nanoreactors from Amphiphilic

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Thermally Responsive Unimolecular Nanoreactors from Amphiphilic Dendrimer-Like Copolymer Prepared via Anionic Polymerization and Cross Metathesis Reaction Ke Zheng, Jie Ren, and Junpo He* The State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, China Downloaded via NOTTINGHAM TRENT UNIV on August 29, 2019 at 22:24:37 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

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ABSTRACT: Amphiphilic dendrimer-like polymers are expected to be promising candidates as micro containers or carriers due to their much larger size in relative to regular dendrimers. In the present study, we synthesize amphiphilic dendrimer-like copolymers possessing interior poly(styrene) segments and peripheral poly(ethylene oxide) (PEO) segments through iterative anionic polymerization, hydrosilylation, coupling, followed by olefin cross-metathesis with a PEO macromonomer bearing acrylic terminus (denoted as PEGMEA480). The molecular weight of the resulting dendrimer-like copolymer, G3-g-PEO2900, is as large as 2.16 × 106, with number of outer PEO arms up to 2900, and the average diameter 32.8 nm in solution. The behavior of the dendritic product as unimolecular micelles is investigated, using dynamic light scattering (DLS) and pyrene probing, together with the thermal responsiveness arising from the low critical solution temperature (LCST) of PEO segments. The amphiphilic dendrimer-like copolymers are used as nanoreactors for the nucleophilic displacement of benzyl halide by KSCN and the hydrolysis reaction of benzyl halide, in which significant increases in the reaction yields are observed. More interestingly, the nanoreactor can be regulated activation-and-deactivation due to thermoresponsiveness of peripheral PEO segments, and the dendritic nanoreactor is recyclable for at least 7 times.

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INTRODUCTION Dendrimers are good candidates for nanoreactors that afford specific microenvironments for various reactions.1−5 This is a benefit from the unique characters of dendrimers such as multiplicity of the functional groups, spherical molecular conformation and the voids in the interior of specifically engineered molecules.6−9 Dendrimer-based nanoreactors catalyze organic reactions in two manners, i.e., either as the catalyst carrier or as the substrate carrier. In the former, catalysts can be covalently attached to the core, to the branch units, or to the peripheral units of the dendrimers.10−12 Noncovalent encapsulation of catalyst molecules and catalytic nanoparticles by dendrimers has also been implemented in organic reactions and polymerizations.13−15 Many relevant studies have reported enhanced catalytic activity and selectivity due to dendritic effect such as site-isolation, multivalency, and space confinement.11,16 On the other hand, dendrimers were also used as substrate carrier for organic reactions. In these cases, © XXXX American Chemical Society

dendrimers were utilized to provide a favorable microenvironment for the reaction in an unfavorable reaction media.17−24 Usually, amphiphilic dendrimers were utilized for this purpose in a similar way to that of traditional surfactants, yet with much better recyclability.19−24 Obviously, one of the advantages is to adapt reactions in organic solvent into aqueous phase, thus reducing volatile organic compounds (VOC) in the chemical engineering process. Dendrimer-like polymers are a unique class of dendrimers in which the branch points of successive generations are interlinked with polymer segments.25−29 They exhibit molecular structure similar to regular dendrimers,7,30 such as the presence of a central core and multiplicity of branch points and terminal functionalities, yet are more tunable on the molecular Received: May 4, 2019 Revised: August 7, 2019

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DOI: 10.1021/acs.macromol.9b00920 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

(98%, TCI), and 18-crown-6 (99%, Adamas) were used as received. Calcium hydride (CaH2, 99%), toluene (99%), chlorotrimethylsilane (99%), and anhydrous methanol (99%) were purchased from National Pharmaceutical and used as received. Chlorodimethylsilane (98%, Aldrich) was distilled under the protection of argon before use. Tetrahydrofuran (THF) and toluene (both from National Pharmaceutical) were refluxed over CaH2 and distillated from n-BuLi on the vacuum line before use. Styrene (St, Adamas, 99%) and 4-vinylbenzyl chloride (TCI, 90%) were distilled over CaH2 and stored at −20 °C. Styrene (40 mL) was distilled over MgBu2 solution (10 mL) on the vacuum line. Platinum (0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex solution (Karstedt’s catalyst, Pt ∼2%, in xylene) and second generation Hoveyda-Grubbs catalyst (HGII) were purchased from Aldrich and used as received. Poly(ethylene glycol) methyl ether acrylate (PEGMEA480, average Mn = 480, the DP of poly(ethylene glycol) segment is approximately 9) was purchased from Aladdin and used as received. Poly(styrene-b-ethylene oxide) (denoted as PS-bPEO, Mn = PS (3800)-b-PEO (6500), Mw/Mn = 1.07) was purchased from Polymer Source, Inc. and used as received. p-(3′-Butenyl) styrene (BSt) was synthesized according to the previous reports44,45 and was distilled in the presence of CaH2 under reduced pressure prior to polymerization. Measurements. 1H NMR measurements were performed on a Bruker (400 MHz) NMR instrument, using CDCl3 as the solvent and tetramethylsilane as interior reference. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) was carried out on a Voyager DE-STR MALDI-TOF mass spectrometer equipped with a 337 nm nitrogen laser. First, A 10 μL sample solution (10 mg/mL in THF), 10 μL dithranol solution (20 mg/mL in THF), and 2.0 μL silver trifluoroacetate solution (10 mg/ mL in THF) were mixed. Then, 0.5 μL mixed solution was dropped onto a plate and dried at room temperature. Mass spectra were obtained in the reflector mode using an acceleration voltage of 20 kV. Two gel permeation chromatography (GPC) systems were used for the measurement of apparent molecular weight, one system using THF as the eluent for analysis of dendrimer-like products, G1, G1-gnBu, G2, G2-g-nBu, G3-g-BSt3060, while the other one using DMF as the eluent for amphiphilic product, G3-g-PEO2900. In the former, samples were passed through three TSK gel columns (G1000HXL, G2500HXL, and G4000HXL) in series with eluent flow rate 1.0 mL/ min and narrow disperse poly(styrene)s as the standards. In the latter, samples were passed through two Agilent columns (PolarGel-M and PolarGel-L) in series with DMF flow rate 1.0 mL/min. Narrow disperse PMMAs were used as calibration standards. Absolute molecular weight (Mw,MALLS) was obtained by multiangle laser light scattering (MALLS), which was performed on DAWN HELEOS in the online mode (GPC-MALLS). The dn/dc value was determined by Optilab rEX in the off-line mode. Fourier transform infrared spectroscopy (FT-IR) was performed on a Thermofisher Nicolet 6700 Fourier Transformation Infrared Spectrometer (potassium bromide pellet). Dynamic light scattering (DLS) experiments were carried out on dynamic and static light scattering instrument with the ALV/CGS-3 compact goniometer system (ALV, Langen, Germany) equipped with a multi-τ digital correlator (ALV-7004) and a He−Ne laser light source (λ = 632.8 nm). Cryogenic transmission electron microscopy (cryo-TEM) was carried out on a Gatan cryo-holder operating at −170 °C and FEI Tecnai G2 20 Twin TEM at 200 kV. The freezing specimen was prepared by placing one drop (0.2 μL) of polymer solution on a copper grid coated with superthin carbon film, and the redundant liquid was removed by filter paper. Then, the grid was quickly plunged into liquid ethane (approximately −170 °C). Finally, it was placed into a cryo-holder and transferred to the TEM instrument. The fluorescence emission spectra were obtained using a PTI QM40 luminescence spectrophotometer using pyrene as probe, and the wavenumber of exciting light is 339 nm. The concentration of pyrene in final solution was 5 × 10−7 mol/L, and the solutions were stirred overnight before measurement. UV−vis absorption and transmittance experiments were performed on a PerkinElmer UV− vis spectrophotometer (Lambda 750, path length: 10 mm) equipped with a thermostatically regulated bath. To obtain temperature-

level to further affect their properties, including chemical composition of polymer segments, number of peripheral functional groups, density of branching, size of the molecules and the interior cavity.25 For example, the molecular weight of dendrimer-like polymers can be as high as tens of millions at medium generations, resulting in diameters of up to tens of nanometers, which is remarkably larger than the regular dendrimers.31−34 Thus, dendrimer-like polymers covers a wider range of sizes, which would be beneficial for the application as functional materials. The synthesis of dendrimerlike polymer has been performed either through divergent or convergent method, among which the former being dominant due to significant steric hindrance in the latter.25,26,29 In the divergent method, the polymer segment can be formed either by “grow-from” or “attach-to” approaches, depending on the polymerization mechanism, i.e., usually atom transfer radical polymerization (ATRP), ring opening polymerization, or living anionic polymerization.35−37 Particularly, amphiphilic dendrimer-like copolymers with layered structures were synthesized by introducing hydrophobic segment, such as poly(styrene) and poly(L-lactide) (PLLA), and hydrophilic segment such as poly(ethylene oxide) (PEO), poly(acrylic acid) (PAA), poly(2-vinylpyridine) (P2VP), and poly(p-hydroxylstyrene).32,33,38−43 These amphiphilic dendrimer-like copolymers can be used as unimolecular micelles as demonstrated by a number of studies.40−43 Nevertheless, they have never been used as nanoreactors for organic reactions. In a previous report, we prepared amphiphilic dendrimerlike polymers composed of inner dendritic poly(styrene) and outer poly(p-hydroxystyrene) (derived from hydrolysis of poly(p-tert-butoxystyrene)) part and studied its property as unimolecular micelle.43 The synthesis used epoxidation of the double bond of polyisoprene segment and subsequent anionic coupling for chain branching. However, this process formed undesired hydroxyl groups and exhibited low reactivity for less active living chains, which was disadvantageous for the application of the products as unimolecular micelles and nanoreactors. In this contribution, we synthesize an amphiphilic dendrimer-like copolymer of styrene and ethylene oxide through a new route involving iterative divergent process involving anionic polymerization, hydrosilylation, chlorosilane coupling, and olefin metathesis reaction. The resulting product possesses a dendritic poly(styrene) core and a dense PEO shell, which respectively constitute 35 and 65% weight fraction of the molecule. Although the molecule is not a perfect dendritic structure, the attachment of the polymer segment occurs in a statistical way, and the branch points are evenly distributed within the molecule. The final product shows narrow distribution with large number (2900) of PEO segments to form the dense shell; thus, the leakage of the substrate or catalyst can be greatly reduced or avoided. The product behaves as nonionic unimolecular micelle in aqueous phase and is used as effective thermally responsive nanoreactors for organic reactions by taking advantage of the thermal responsiveness of PEO segments.

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EXPERIMENTAL SECTION

Materials. n-Butyllithium (n-BuLi; 2.5 mol/L solution in hexane, Aldrich), sec-butyllithium (sec-BuLi; 1.3 mol/L solution in cyclohexane, Aldrich), di-n-butylmagnesium (MgBu2; 1.0 mol/L in heptane, Aldrich), allylmagnesium chloride solution (1.0 mol/L in THF, Adamas), pyrene (98%, J&K), 1,3,5-tris(bromomethyl)benzene B

DOI: 10.1021/acs.macromol.9b00920 Macromolecules XXXX, XXX, XXX−XXX

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SiCl260. The chlorosilyl moieties in G2-g-SiCl260 were deactivated using n-BuLi, yielding G2-g-nBu for characterization (conversion of 1butene type CC double bond in G2 is higher than 99%; G2-g-nBu, Mn, GPC = 1.40 × 105, Đ: 1.34). For the last grafting reaction, PBStLi homopolymer was prepared (Arm3: PBSt, Mn,theo = 2.36 × 103, Mn,GPC = 2.60 × 103, Đ = 1.04, Mn,MALDI = 2.74 × 103, theoretical average formula: sec-BuBSt14.56−Li+, actual average formula: sec-Bu-BSt16.97−Li+). A solution of G2-g-SiCl260 (1.0 g, approximately 1.1 mmol Si−Cl groups) in 10 mL toluene was mixed with the solution of PBStLi (approximately 1.4 mmol in 60 mL solution), and the reaction stood for 30 min at approximately −45 °C before adding 1 mL of n-BuLi solution (2.5 mol/L) to deactivate unreacted chlorosilyl moieties. Finally, the remaining anions were terminated by methanol. The product (Mn,theo = 9.56 × 105) was obtained by fractionation in toluene/methanol, precipitation in methanol and dried under vacuum. G3-g-BSt3060, yield: 70%, Mn,GPC = 2.10 × 105, Đ = 1.31, Mw,MALLS = 7.45 × 105, coupling efficiency: 70%. Synthesis of Amphiphilic Dendrimer-Like Copolymer (G3g-PEO2900). First, G3-g-BSt3060 (0.3 g, approximately 1.2 mmol butenyl double bond), dry CH2Cl2 (5 mL), and poly(ethylene glycol) methyl ether acrylate (1 mL, 2.4 mmol, the DP of poly(ethylene glycol) is approximately 9) were mixed in a Schlenk flask. The solution was degassed using three freeze−pump−thaw cycles and then backfilled with argon gas. Subsequently, second generation Hoveyda-Grubbs catalyst (10 mg) was added to the flask. After stirring for 6 h at 40 °C, the reaction was quenched by adding 20 μL of ethyl-vinyl ether. Finally, the reaction mixture was dialyzed against methanol, condensed using rotary evaporator, and dried under vacuum to afford the product G3-g-PEO2900 (Mn,theo = 2.21 × 106). Yield: 93% (conversion of 1-butene type CC double bond in G3-gBSt3060 is approximately 95%; G3-g-PEO2900, Mn,GPC = 3.53 × 105, Đ = 1.25, Mw,MALLS = 2.16 × 106). Nucleophilic Displacement of Benzyl Halide by KSCN. G3-gPEO2900 aqueous solution (5 mL, 4 mg/mL) and benzyl chloride (200 μL, 1.74 mmol) were added to a 10 mL round-bottom flask. The mixture was placed in a water bath (25 °C) and stirred (200 rpm) for 12 h before the adding of KSCN (0.203 g, 2.09 mmol). After the reaction for designated periods (Table S1), the product was extracted by diethyl ether. For the nucleophilic displacement of benzyl bromide by KSCN, the experiment was carried out in a same process as above. The amounts of benzyl bromide and KSCN are 200 μL (1.68 mmol) and 0.196 g (2.02 mmol), respectively. The blank experiments were performed with a similar procedure except in the absence of nanoreactor. It should be noted that PS-b-PEO cannot be dissolved in water directly. The aqueous solution was prepared by dissolving PS-b-PEO in THF followed by dialysis against water. Hydrolysis Reaction of Benzyl Halide in Alkaline Aqueous Solution. Benzyl chloride (200 μL, 1.74 mmol) and G3-g-PEO2900 aqueous solution (5 mL, 4 mg/mL) were added to a 10 mL roundbottom flask. The mixture was placed in a water bath (25 °C) and stirred (200 rpm) for 12 h before the adding of KOH (0.117g, 2.09 mmol). After the reaction for designated periods, the product was extracted by diethyl ether. For the thermoresponsive hydrolysis experiment, the reaction mixture was taken out at predetermined time intervals for 1H NMR characterization, and the sampled mixture was immediately injected into liquid nitrogen for quenching the reaction at once. It should be noted that the most important step for this experiment is the fast adjustment of reaction temperature. Therefore, we prepared four water baths, which were kept at 0, 60, 70, and 99 °C, respectively. After sampling at 70 °C, the flask was first transferred into 0 °C water bath for quickly decreasing the temperature. After the temperature was reduced to 60 °C, the flask was immediately transferred into 60 °C water bath for reaction. Similarly, after sampled at 60 °C, the flask was first transferred into 99 °C water bath for quickly increasing temperature. After the reaction temperature increased to 70 °C, the flask was immediately transferred into 70 °C water bath.

dependent optical transmittance curve, G3-g-PEO2900 aqueous solution was placed in the spectrophotometer and heated or cooled at a rate of 0.2 °C/min. The absorption of solution at λ = 560 nm was recorded every 30 s. Synthesis of Living Block Copolymer (PBSt-b-PSLi) and 3Arm Star-Like Polymer (G1). The anionic polymerization was carried out in a round-bottom flask connected to a vacuum/argon line, under an overpressure of argon gas and with magnetic stirring. First, the flask was dried by six cycles of evacuating/heating with hot air/argon-purging. Then 50 mL of THF, 100 mL of toluene, and 2.8 mL of BSt (15.9 mmol) were added with dry syringes. After the flask was placed in a bath kept at approximately −45 °C, the polymerization was induced by adding 1.5 mL sec-BuLi solution (1.3 mol/L, 1.95 mmol). BSt was polymerized for 20 min, yielding PBStLi (theoretical average formula: sec-Bu-BSt8.15−Li+). A small amount solution was sampled and terminated by degassed anhydrous methanol for characterization (PBSt, Mn,theo = 1.35 × 103, Mn,GPC = 1.66 × 103, Đ = 1.12, Mn,MALDI = 1.69 × 103, actual average formula: sec-Bu-BSt10.30−Li+). For the synthesis of living block copolymer, 16.8 mL of St solution (hexane was introduced during distillation over MgBu2 solution, VSt/Vhexane = 4/1, molar amount of St: 117.3 mmol) was added to the reaction flask and the mixture was stirred for 1 h, yielding PBSt-b-PSLi (Arm1, Mn,theo = 9.62 × 103, Mn,GPC = 1.02 × 104, Đ = 1.05, Mw,MALLS = 8.8 × 103, theoretical average formula: secBu-BSt10.30-b-St76.17−Li+, actual average formula: sec-Bu-BSt10.14-bSt68.31−Li+). Finally, the flask was cooled to approximately −80 °C before adding a solution of 1,3,5-tris(bromomethyl)benzene (0.1 g, 0.28 mmol) in dry THF (5 mL). The reaction stood for 30 min and was terminated by methanol. The purified G1 (Mn,theo = 2.65 × 104) was obtained by fractionation using toluene/methanol, and precipitation in methanol. G1, Yield: 64%, Mn, GPC = 2.98 × 104, Đ = 1.18, Mw,MALLS = 2.92 × 104. Hydrosilylation. A flask was dried by three cycles of evacuating/ heating with hot air/argon-purging. G1 (1.2 g, approximately 1.4 mmol 1-butene type CC), toluene (50 mL), and Karstedt’s catalyst solution (0.1 mL, Pt ∼2%) were mixed in the flask. A small amount of chlorotrimethylsilane (0.8 mL, 6.3 mmol) were added to remove the possible impurities which can quench chlorosilane moieties. Then, chlorodimethylsilane (0.7 mL, 6.3 mmol) was added, and the reaction was kept at 60 °C for 24 h. The reaction mixture was distilled to remove toluene, residual chlorotrimethylsilane, and unreacted chlorodimethylsilane under vacuum. The obtained viscous solid was redissolved in dry toluene, and the distillation process being repeated to ensure the complete removal of small molecular organosilanes. The hydrosilylated product, G1-g-SiCl30, was finally dissolved in dry toluene and encapsulated in a glass ampule for storage. For characterization, the product was reacted with excessive n-BuLi to deactivate the reactive Si−Cl group. The resulting more stable product, G1-g-nBu, was analyzed by 1H NMR and GPC (conversion of 1-butene type CC double bond in G1 is higher than 99%; G1-gnBu, Mn, GPC = 3.00 × 104, Đ = 1.20). Synthesis of Third Generation Dendrimer-Like Copolymer (G3-g-BSt3060). In a similar process as in Arm 1, sequential polymerization of BSt and St resulted in the formation of PBSt-bPSLi (Arm2; PBSt in Arm2, Mn,theo = 1.35 × 103, Mn,GPC = 1.69 × 103, Đ = 1.11, Mn,MALDI = 1.61 × 103, theoretical average formula: sec-BuBSt8.15−Li+, actual average formula: sec-Bu-BSt9.82−Li+. Arm 2, Mn,theo = 9.63 × 103; Mn, GPC = 1.01 × 104, Đ = 1.06, Mw,MALLS = 8.6 × 103, theoretical average formula: sec-Bu-BSt9.82-b-St72.41−Li+, actual average formula: sec-Bu-BSt9.82-b-St67.11−Li+). Then, a solution of G1-g-SiCl30 (1.0 g, approximately 1.2 mmol Si−Cl groups) in toluene (10 mL) was added to the solution of PBSt-b-PSLi (1.5 mmol in 120 mL solution), and the reaction stood 30 min before adding 1 mL of nBuLi solution (2.5 mol/L) to deactivate unreacted chlorosilyl moieties. Finally, the remaining anions were terminated by degassed anhydrous methanol. The purified second generation dendrimer-like copolymer (G2, Mn,theo = 2.87 × 105) was obtained by fractionation using toluene/methanol and precipitation in methanol. Yield: 72% (Mn,GPC = 1.29 × 105, Đ = 1.29, Mw,MALLS = 2.54 × 105, coupling efficiency: 87%). Repeating the hydrosilylation process afforded G2-gC

DOI: 10.1021/acs.macromol.9b00920 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Scheme 1. Synthetic Route of an Amphiphilic Dendrimer-Like Copolymer

Figure 1. (A) GPC curves monitoring the synthesis of dendrimer-like G3-g-BSt3060 (THF was used as eluent). The samples are purified by removing excess precursor Arms, as shown in the inset; (B) GPC curves of (a) PEGMEA480 as arm precursor and (b) G3-g-PEO2900 which was purified by dialysis in methanol (DMF was used as GPC eluent).

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The hydrolysis experiments of benzyl bromide were carried out in a same process as hydrolysis of benzyl chloride. The amounts of benzyl bromide and KOH are 200 μL (1.68 mmol) and 0.113 g (2.02 mmol), respectively. The blank experiments were performed with a similar procedure except in the absence of nanoreactor.

RESULTS AND DISCUSSION

Synthesis and Characterization of Amphiphilic Dendrimer-Like Copolymer. The methodology for the synthesis of amphiphilic dendrimer-like copolymer in the D

DOI: 10.1021/acs.macromol.9b00920 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

Figure 2. (A) 1H NMR spectra (in CDCl3) monitoring the synthesis of dendrimer-like G3-g-BSt3060 and (B) 1H NMR spectrum (in CDCl3) of target dendrimer-like polymer, G3-g-PEO2900 (* signal of residual protons of 1-butene type double bond, −CH2−CHCH2).

Figure 1 shows the GPC chromatograms of dendrimer-like copolymers after separation of the excessive precursor arm (as shown in the inset). It is clear that the elution curves of the product G1, G2, and G3-g-BSt3060 shift to higher molecular weight sides while keeping relatively narrow molecular weight distributions. The GPC measured molecular weight of G3-gBSt3060 is as high as 2.10 × 105. The high molecular weight is a consequence of large number of polymer segments constituting the dendritic products. It should be point out that molecular weight distributions (Đ) by GPC are only apparent values in relative to narrow disperse linear polystyrene standards. The uncertainty arises not only from the highly branched structure, but also from the imperfections of the dendrimer-like polymers. Fortunately, it is still meaningful in determining the molecular weight distribution (or more rigorously hydrodynamic volume distribution) among dendrimer-like molecules. It is very useful to monitor the residual of the grafting arms and possible intermolecular cross-linking. In the above process, the short PBSt segment actually played the role of branching points, at which the theoretical ramification number was dependent on the number of vinyl groups of PBSt segment, the yield of hydrosilylation reaction and the coupling reaction. The degree of polymerization (DP) of PBSt segments of Arm 1, Arm 2 and Arm3, measured by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS; Figure S2), was 10, 10, and 17, respectively, which are in close agreement with the results measured by GPC shown in Figure S3. This indicates that the branching factor, or ramification number, of each PBSt

present study is based on iterative coupling reactions of living anionic poly(styrene) with chlorosilane at the preceding generations, which has been introduced via hydrosilylation of the multiple terminal vinyl moieties, followed by covalently attaching multiple PEO segments through metathesis reaction at the peripheral parts. This unique process enables fast increase of the molecular weight and densely grafting PEO at the periphery. As shown in Scheme 1, a living diblock copolymer, poly(p-(3′-butenyl)styrene)-b-polystyrenyllithium (PBSt-b-PSLi; Arm 1), was prepared via sequential anionic polymerization of BSt and styrene (St) initiated by secbutyllithium (sec-BuLi; molar ratio BSt: St ≈ 1:7). The styrenic double bond was selectively polymerized while butenyl remained unreacted (Figure S1). The resulting PBSt-b-PSLi was coupled with 1,3,5-tris(bromomethyl)-benzene to form a 3-arm star polymer (G1) in a quantitative way. The butenyl groups in G1 was then converted into Si−Cl groups via reaction with chlorodimethylsilane (HSiMe2Cl). The resultant G1-g-SiCl30, containing overall ca. 30 Si−Cl and ca. 10 on each arm, was used to react with the same type of the diblock copolymer PBSt-b-PSLi (Arm 2) and subsequently subject to hydrosilylation to form second generation dendrimer-like polymer G2-g-SiCl260. Coupling of Si−Cl with a living homopolymer, PBStLi (Arm 3), yielded the third generation product G3-g-BSt3060. Finally, the target amphiphilic dendrimer-like copolymer, G3-g-PEO2900, was synthesized through the olefin cross-metathesis reaction between poly(ethylene glycol) methyl ether acrylate (Mn = 480, denoted as PEGMEA480) and the vinyl groups of the butenyl at the periphery of G3-g-BSt3060. E

DOI: 10.1021/acs.macromol.9b00920 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Table 1. Characterization of Precursor Arms and Dendrimer-Like Polymer Products samples

Mn,GPCa × 10−3

Mw,GPCa × 10−3 Mw,MALLSb × 10−3

Arm1 (PBSt-b-PS) G1 Arm2 (PBSt-b-PS) G2 Arm3 (PBSt) G3-g-BSt3060 G3-g-PEO2900

10.2

10.7

8.8

1.05

29.8 10.1

35.3 10.7

29.2 8.6

1.18 1.06

3

3

4.0

128.5 2.6 209.6 352.9

166.2 2.7 275.5 441.7

253.9 2.7 744.6 2157.0

1.29 1.04 1.31 1.25

30

26

10.1

8.2

0.812

260 3060

180 2900

16.3 23.3

15.8 22.5

0.969 0.966

Đc

Narm,theod

Narm,obs.e

RHf (nm) Rgg (nm)

Rg/RH

dn/dch (mL/g)

[η]wi (mL/g)

0.1898

6.7

0.1913 0.1895

12.8 6.6

0.1867 0.1811 0.1817 0.0702

25.3 3.9 23.2 12.7

a

Determined by GPC. bDetermined by GPC-MALLS. cCalculated from GPC curves. dTotal number of Si−Cl groups in its preceding generation. Calculated from the equation Narm,obs. = (Mw,MALLS (Gn) − Mw,MALLS (Gn-1))/Mw (Arm (n)). fDetermined by dynamic light scattering at a fixed angle of 90° in THF. gDetermined by static light scattering in THF. hdn/dc values of polymers are measured in THF and that of G3-g-PEO2900 in DMF. i[η]w was measured by online viscometry detector connected to GPC. e

Figure 3. (A) DLS results of G3-g-PEO2900 in water with different concentration (c = 0.01−10 mg/mL), (B) DLS results of G3-g-PEO2900 in different solvents (c = 5 mg/mL), and (C) cryo-TEM image of G3-g-PEO2900 in water (c = 1.0 mg/mL). The DLS traces are in intensity, and the measured solution were filtered (average pore size of the nylon membrane is 800 nm).

segment can be up to 1 → 10 or 17 instead of usual 1 → 2 in regular dendrimer synthesis. In order to examine the hydrosilylation efficiency, chlorosilyl moieties in G1-g-SiCl30 and G2-g-SiCl260 were deactivated with n-BuLi to form more stable G1-g-nBu and G2-g-nBu for the convenience of characterization. Figure 2 shows 1H NMR spectra of the starting material and the resulting product. Before hydrosilylation, the vinylic protons show signals at δ = 5.0 and 5.9 ppm. After the reaction these signals disappeared for both deactivated products by n-BuLi, indicating nearly complete conversion of the pendent vinyl groups. In addition, no cross-linking reaction was observed in the hydrosilylation reaction (Figure S4). The high efficiency of the coupling reaction between chlorosilane and anionic species was well documented in the literature.46 In the present study, although the reaction was nearly completed within 5 min, each coupling step was allowed to stand for 30 min with at least 1.2-fold excess of the living polymer chain to Si−Cl group in order to reach high grafting efficiencies. However, the coupling reaction suffered from steric hindrance (vide infra). The dendritic products were also characterized using GPC coupled with multiangle laser light scattering (MALLS) detector. As shown in Table 1, the molecular weights measured by light scattering, Mw,MALLS, are remarkably larger than those measured by GPC, indicative the highly branched structure. The number of arms was estimated to be Narm,obs. = 3, 26, and 180 for G1, G2, and G3-g-BSt3060, respectively, from measured molecular weights of the dendritic products, the grafting arms

and the preceding generations. In comparison with the corresponding theoretical values, Narm,theo = 3, 30, and 260, it was found that the grafting efficiency decreased from G1 to G3-g-BSt3060, which was attributed to the steric hindrance caused by overcrowding of the peripheral segments in the precursor. Nevertheless, the molecular weight distributions were narrow in spite of the imperfection presence. This could be a consequence of evenly statistical grafting of the arms to the peripheral part of the precursors. It should be noted that, after the coupling reaction, the remaining chlorosilyl moieties in dendritic product were deactivated by n-BuLi so as to prevent intra- and intermolecular cross-linking. The iterative process led to the preparation of G3-g-BSt3060, a dendrimer-like polymer with poly(styrene) skeleton and 180 PBSt segments, or 180 × 17 = 3060 vinyl groups at the peripheral part. Poly(ethylene glycol) methyl ether acrylate (Mn = 480) was readily grafted onto G3-g-BSt3060 by olefin cross-metathesis reaction, affording an amphiphilic dendrimerlike copolymer with dense hydrophilic shell, G3-g-PEO2900. The cross-metathesis reaction was performed with an excess of PEGMEA480, and the product was characterized using 1H NMR, FT-IR, and GPC-MALLS. As shown in Figure 2B, after grafting 6 h, the signal at δ = 5.0 ppm corresponding to vinylic protons almost disappeared, while a new signal at δ = 3.6 ppm for protons of PEO chains was observed. In FT-IR spectra of G3-g-BSt3060 and G3-g-PEO2900 (Figure S5), the absorption peak at 3076 cm−1, ascribed to stretch vibration mode of  C−H bonds in pendent vinyl groups, disappeared after the F

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Macromolecules olefin cross-metathesis reaction, while the stretching vibration peaks of CO and C−O bonds in PEGMEA480 emerged at 1720 and 1109 cm−1, respectively. Meanwhile, the pendent vinyl groups in G3-g-BSt3060 were transformed into CHR CHR inner double bonds in G3-g-PEO2900, as evidenced by the shift of the stretch vibrational peak from 1640 to 1653 cm−1.47,48 It should be pointed out that GPC system using THF as eluent is not suitable for measurement of the dendritic copolymer, G3-g-PEO2900, due to possible adsorption of the sample in the column. Thus, direct comparison between GPC profiles of G3-g-BSt3060 and the copolymer is impossible. Figure 1B shows the GPC curve of G3-g-PEO2900 using DMF as the eluent with the equipment of a MALLS detector. The sample was purified by dialysis in methanol to remove the PEGMEA480. A monomodal distribution was observed. From the results of light scattering in Table 1, it is concluded that an amphiphilic layered structural dendrimer-like copolymer of styrene and EO was synthesized with molecular weight of approximately 2.16 × 106 (Mw,MALLS) and relatively low polydispersity index 1.25. The copolymer bears 2900 PEO segments at the periphery which constitute ca. 65% weight percentage of the dendritic molecule. Unimolecular Micelle Behavior for G3-g-PEO2900 in Solution. The dendrimer-like copolymers as synthesized is a model globular molecule with a hydrophobic core and hydrophilic shell in selective solvent. G3-g-PEO2900 was readily soluble in water, a selective solvent for PEO segment, forming clear solution yet with Tyndall effect. The behavior of the product as unimolecular micelle was investigated in aqueous solution using dynamic light scattering (DLS) and cryo-TEM. The results are presented in Figure 3. Figure 3A shows that the hydrodynamic radius, RH, of G3-gPEO2900 is nearly unchanged with unimodal distribution in a wide concentration range from 0.01 to 10 mg/mL, indicating that the dendrimer-like copolymer existed as individual molecule in water.43 Furthermore, no change was observed over 12 months in the micelle solution stored at ambient temperature (Figure S6). Figure 3B shows that the sizes of the molecules are very close in water and in methanol (also a selective solvent for PEO segment). Interestingly, when toluene was added into the aqueous solution, RH became larger due to the encapsulation of toluene in the core of the molecular micelle. In THF, the size of micelle further increased because THF is a good solvent for both PS and PEO segments.49 Cryo-TEM was employed to visualize the morphology of dendrimer-like molecules. The sample was prepared by dropping aqueous solution of G3-g-PEO2900 onto superthin carbon film supported by copper grid, the excess solution being removed by filter paper, then the specimen being rapidly frozen with liquid ethane. It was reported that this method avoided shrink and aggregation of the unimolecular micelle during water evaporation.43,50 Cryo-TEM graph in Figure 3C shows scattered particle with regularly spherical shape and the average diameter 32 nm, which is in good agreement with hydrodynamic diameter (DH) determined by DLS (33.8 nm). The fluorescence of pyrene depends on the polarity of the microenvironment and is frequently used as a probe for the measurement of critical micelle concentration (CMC).51−53 In the present study, the ratio of intensities of first and third emission peaks of pyrene, I1/I3, was measured for aqueous solutions of dendrimer-like copolymers. Figure 4 depicts the

Figure 4. Emission spectra of pyrene (5 × 10−7 mol/L) in water with increasing concentration of G3-g-PEO2900.

values of I1/I3 against concentration. While a typical value of 1.84 was observed in water, similar to that in the literature,21 the ratio of I1/I3 dropped to 1.40−1.44 and was independent of polymer concentration to as low as 5.0 mg/L. The latter is slightly larger than those previously measured in hydrophobic microenvironment, indicating that the pyrene molecules may stay at the interface of PS and PEO in the aqueous solution.54,55 It is well-known that polymers containing oligo- or polyethylene glycol segments exhibit lower critical solution temperature (LCST) behavior due to reversible formation and destruction of hydrogen bonds between PEG units and water by changing temperature.56−59 The thermoresponsive behavior of G3-g-PEO2900 was easily observed as the clear aqueous solution became turbid when heating and in turn back to be transparent when cooling. Figure 5 is the results of measured

Figure 5. Temperature-dependent optical transmittance of G3-gPEO2900 aqueous solution (c = 5 mg/mL). The temperature is increased or decreased at 0.2 °C/min with the initial temperature of 50 °C.

transmittance monitored at λ = 560 nm against temperature. When the temperature was raised from 50 to 70 °C at a rate of 0.2 °C/min, the transmittance of the aqueous solution was quickly decreased to nearly zero at 65 °C. The reverse process from 70 to 50 °C resulted in almost 100% transmittance at 64 °C with negligible hysteresis. Both transitions were completed within 1 °C. These sharp transitions are a consequence of high grafting density of PEO chains at the periphery of unimolecular micelle.60 The heating and cooling cycle can be repeated for at least ten times without loss of reversibility. G

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Macromolecules The heating and cooling process was also monitored using DLS measurement. As shown in Figure S7, the RH of G3-gPEO2900 was ∼16 nm, and was nearly constant below the LCST. After reaching the LCST, the RH value dramatically increased, indicating intermolecular aggregation.61,62 On cooling, the RH value returned to 16 nm. Figure S8 shows the DLS results of G3-g-PEO2900 before heating and after cooling (first heating to 70 °C and then cooling back to 25 °C). No difference was observed between their particle size distribution curves. The LCST behavior of G3-g-PEO2900 can be utilized to tightly encapsulate and remove organic molecules from solution. As a demonstration, Nile red, a hydrophobic dye, was encapsulated by the dendritic copolymer to form a stable clear solution which was pink in color (Figure 6b). Upon

Scheme 2. Nucleophilic Displacement of Benzyl Halide by KSCN (1) and Hydrolysis of Benzyl Halide (2) in Aqueous Solution Accelerated by Nanoreactors, G3-g-PEO2900

media where KSCN was dissolved. These two reactants may react at the interface of PS and PEO. Figure 7 shows kinetics of nucleophilic displacement of benzyl chloride and bromide by KSCN in different reaction solutions. It is clear that the reaction rate for displacement of benzyl halide by KSCN in nanoreactor aqueous solution is the highest among systems using dendrimer-like polymer, 18-crown-6 (which can chelate K+ of KSCN), and PS-b-PEO (Mn: PS (3800)-b-PEO (6500), Mw/Mn = 1.07), demonstrating highest catalytic ability of unimolecular nanoreactor. Next, the reusability of the unimolecular micelle as the nanoreactor was studied. After the displacement reaction, the products were completely extracted by using diethyl ether, while G3-g-PEO2900 remained in water phase and reused for the next cycle of reaction. In this way, the nanoreactor was recycled at least 7 times while keeping high activity in the reaction of benzyl chloride with KSCN (Figure S17). After 8 recycles, a slight decrease in yield was observed, possibly due to unavoidable loss of nanoreactors during the process of extraction. The second reaction is the hydrolysis reaction of benzyl chloride in alkaline aqueous solution. As shown in Figure 8, no obvious hydrolysis of benzyl chloride occurred in aqueous KOH solution even after 24 h, due to the limited contact interface. On the other hand, the hydrolysis efficiency was significantly promoted by the addition of G3-g-PEO2900, reaching to 95% conversion for 24 h. Moreover, the hydrolysis rates of benzyl chloride in alkaline solution are higher for systems with a dendrimer-like nanoreactor than that using 18crown-6 or linear diblock copolymer (Figure S18). Similar results were obtained for the hydrolysis of benzyl bromide with however a small amount of benzyl ether as side product (Table S3, Figures S19 and S20). Furthermore, Diels−Alder reaction between maleic acid and cyclopentadiene in nanoreactor was observed to be much faster than that without nanoreactor (Figure S21). Stimuli-responsive dendrimers have been synthesized by introducing functionalities or fragments which are responsive to external stimulation such as changes in temperature, pH, redox potentials, light, enzyme, and ultrasound.64,65 These functional dendrimers have shown promising applications in various fields including targeted drug delivery,65 sensors,66 nanocarriers,67 etc. However, the study of the stimuliresponsiveness of dendrimers to control the reaction within the dendritic structure is still scarce. To our knowledge, there is only one paper that reported a modified poly(propyleneimine) dendrimer with poly(N-isopropylacrylamide) (PIPAAm) that acts as a temperature-sensitive nanoscopic capsule to catalyze the oxidative coupling of 2mercaptoethanol.68

Figure 6. Optical snapshots and UV/vis spectra of Nile red solutions: (a) in pure water, 25 °C; (b) in 10 mg/mL G3-g-PEO2900 aqueous solution, 25 °C; (c) in 10 mg/mL G3-g-PEO2900 aqueous solution, 70 °C; (d) after filtration above LCST.

increasing the temperature to above LCST, the clear solution turned into opaque (Figure 6c) due to the aggregation of the unimolecular micelle. The opaque dispersion can be either filtrated to completely remove the organic dye (Figure 6d) or cooled to below LCST to form the transparent solution again (Figure 6b). These results clearly demonstrated that the unimolecular micelle is able to be used as a molecular container in aqueous phase.63 Amphiphilic Dendrimer-Like Copolymers as Thermally Responsive Nanoreactors. The above results on encapsulation and thermoresponsiveness of the amphiphilic dendrimer-like copolymer indicates that G3-g-PEO2900 may be used as unimolecular nanoreactors for organic reactions. To explore the possibility, two reactions using hydrophilic and hydrophobic agents were carried out in aqueous media (Scheme 2). The first example was a nucleophilic displacement of benzyl halide by KSCN. In this reaction, both benzyl chloride and bromide were not soluble in water, while KSCN was watersoluble. The reaction employed unimolecular micelle as a carrier of hydrophobic benzyl chloride or bromide in aqueous H

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Figure 7. Kinetics of nucleophilic displacement of (A) benzyl chloride and (B) benzyl bromide by KSCN in different reaction solutions (as indicated in the figure; conversion for benzyl halide, lines for guidance). Conditions: 5 mL of water, 10 mL of round-bottom flask, stir at the speed of 200 rpm, 25 °C, the dosage of nanoreactor and other phase transfer catalyst (18-crown-6 and PS-b-PEO) is 20 mg. The conversion was obtained by 1H NMR (Figures S9−16, Tables S1 and S2). For panel A, the amount of benzyl chloride and KSCN are 200 μL (1.74 mmol) and 0.203 g (2.09 mmol), respectively; For panel B, the amount of benzyl bromide and KSCN are 200 μL (1.68 mmol) and 0.196 g (2.02 mmol), respectively.

Figure 9. Activation/deactivation of hydrolysis reaction of benzyl chloride in nanoreactors, G3-g-PEO2900, by changing the temperature. (Conditions: 5 mL water, 10 mL round-bottom flask, stir at the speed of 200 rpm; the amount of benzyl chloride and KOH are 200 μL (1.74 mmol) and 0.117 g (2.09 mmol), respectively. The amount of nanoreactor is 20 mg. The conversion is calculated from 1H NMR results, as shown in Figure S22 and Table S4.)

1

Figure 8. H NMR results of hydrolysis of benzyl chloride in KOH aqueous solution in the absence of nanoreactors for 24 h (a) and in the presence of G3-g-PEO2900 for 4 h (b), 16 h (c) and 24 h (d), respectively. (Conditions: 5 mL water, 10 mL round-bottom flask, stir at the speed of 200 rpm; the amount of benzyl chloride and KOH are 200 μL (1.74 mmol) and 0.117 g (2.09 mmol), respectively. The amount of nanoreactor is 20 mg.)

aggregation of the unimolecular nanoreactor. The shrinkage of PEO and aggregation of unimolecular micelles reduced the water/organic interface. As a result, the reaction rate was sharply dropped, even though the reaction temperature was higher. When the reaction temperature was again decreased below LCST, the aggregates dissociated into unimolecular micelle with PEO parts being hydrated and thus the nanoreactor being activated. Despite a few cycles of activation/deactivation, the reaction progressed to completion to reach the final yield of >99%.

The use of external stimuli to regulate the activity of nanoreactor provides opportunity to manipulate reaction temporally.69−72 Motivated by the intense thermoresponsiveness of G3-g-PEO2900, we investigated the possibility of using this amphiphilic dendrimer-like copolymer as a thermally responsive nanoreactor, in which the catalytic activity can be controlled by temperature. As shown in Figure 9, the hydrolysis reaction of benzyl chloride underwent a repetitive process of temperature change between 60 and 70 °C, with LCST being 65 °C. The reaction readily proceeded at lower temperature whereas nearly halted at higher temperature. Therefore, an alternating activation/deactivation control over the reaction was achieved by simply heating and cooling the system. We propose a reaction way for the temperature dependent activation/deactivation process based on the conformation and morphology of dendrimer-like copolymers in aqueous solution. As shown in Scheme 3, at the temperature lower than LCST, the nanoreactor was soluble and PEO periphery was highly hydrated in reaction media, allowing reactants to easily contact with each other. At the temperature higher than LCST, however, PEO segments shrunk and desolvated, leading to

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CONCLUSIONS An amphiphilic dendrimer-like copolymer containing poly(styrene) inner and PEO outer segments is successfully synthesized through divergent anionic grafting and olefin cross metathesis reactions. The metathesis reaction is highly efficient without causing intermolecular cross-linking, which facilitates construction of a densely grafted PEO shell. The resulting product, G3-g-PEO2900, exists as discrete molecules in dilute solution, as indicated by DLS and cryo-TEM results. The individual molecules behave as unimolecular micelles which can efficiently encapsulate hydrophobic organic molecules in aqueous solutions. The dense PEO shell endows I

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Scheme 3. Proposed Reaction Pathway for (A) Accelerating Reaction by Amphiphilic Dendrimer-Like Copolymer in Aqueous Solution and (B) Activation/Deactivation of Nanoreactor Based on LCST of the Densely Grafted Peripheral PEO Segments of Nanoreactors

and Professor Redouane Borsali, who had many helpful discussions in this work.

the unimolecular micelles thermal responsiveness which undergoes sharp transition around LCST of PEO segments. G3-g-PEO2900 is used as nanoreactors for promoting organic reaction, such as nucleophilic displacement of benzyl halide and the hydrolysis of benzyl chloride, the latter exhibiting activation or deactivation by changing the temperature below or above the LCST, respectively. Therefore, it is concluded that a thermally responsive unimolecular organic nanoreactor with high reusability is thus accomplished.

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(1) Astruc, D.; Boisselier, E.; Ornelas, C. Dendrimers Designed for Functions: From Physical, Photophysical, and Supramolecular Properties to Applications in Sensing, Catalysis, Molecular Electronics, Photonics, and Nanomedicine. Chem. Rev. 2010, 110, 1857− 1959. (2) Caminade, A.-M.; Ouali, A.; Laurent, R.; Majoral, J.-P. Catalysis Within Dendrimers. In Effects of Nanoconfinement on Catalysis. Fundamental and Applied Catalysis; Poli, R., Ed.; Springer: Cham, 2017; pp 173−207. (3) Crooks, R. M.; Zhao, M.; Sun, L.; Chechik, V.; Yeung, L. K. Dendrimer-Encapsulated Metal Nanoparticles: Synthesis, Characterization, and Applications to Catalysis. Acc. Chem. Res. 2001, 34, 181− 190. (4) Liang, C.; Fréchet, J. M. J. Applying Key Concepts from Nature: Transition State Stabilization, Pre-concentration and Cooperativity Effects in Dendritic Biomimetics. Prog. Polym. Sci. 2005, 30, 385−402. (5) Ornelas, C. Brief Timelapse on Dendrimer Chemistry: Advances, Limitations, and Expectations. Macromol. Chem. Phys. 2016, 217, 149−174. (6) Newkome, G. R.; Shreiner, C. Dendrimers Derived from 1→3 Branching Motifs. Chem. Rev. 2010, 110, 6338−6442. (7) Vögtle, F.; Richardt, G.; Werner, N. Dendrimer Chemistry: Concepts, Syntheses, Properties and Applications; Wiley-VCH: Weinheim, Germany, 2009. (8) Tomalia, D. A. Birth of a New Macromolecular Architecture: Dendrimers as Quantized Building Blocks for Nanoscale Synthetic Polymer Chemistry. Prog. Polym. Sci. 2005, 30, 294−324. (9) Jansen, J. F. G. A.; de Brabander-van den Berg, E. M. M.; Meijer, E. W. Encapsulation of Guest Molecules into a Dendritic Box. Science 1994, 266, 1226−1229. (10) Liu, L.; Breslow, R. Dendrimeric Pyridoxamine Enzyme Mimics. J. Am. Chem. Soc. 2003, 125, 12110−12111. (11) Breinbauer, R.; Jacobsen, E. N. Cooperative Asymmetric Catalysis with Dendrimeric [Co(salen)] Complexes. Angew. Chem., Int. Ed. 2000, 39, 3604−3607.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.9b00920.

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REFERENCES

Additional 1H NMR spectra, MALDI-TOF MS spectra, GPC curves, FT-IR spectra, DLS results, and reusability of the nanoreactor (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Junpo He: 0000-0001-7754-1479 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was subsidized by the National Natural Science Foundation of China (Grant No. 21474016). We also thank the funding of Senior Visiting Scholarship of the State Key Laboratory of Molecular Engineering of Polymers (16FHJ08 and 18FGJ01) to support the visits of Professor Akira Hirao J

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