Synthesis and Aqueous Solution Properties of Novel Sugar

Biomacromolecules 2003, 4, 1746-1758

1746

Synthesis and Aqueous Solution Properties of Novel Sugar Methacrylate-Based Homopolymers and Block Copolymers Ravin Narain and Steven P. Armes* School of Chemistry, Physics and Environmental Science, Sussex University, Falmer, Brighton, East Sussex, BN1 9QJ United Kingdom Received May 29, 2003; Revised Manuscript Received July 29, 2003

We report the facile preparation of a range of novel, well-defined cyclic sugar methacrylate-based polymers without recourse to protecting group chemistry. 2-Gluconamidoethyl methacrylate (GAMA) and 2-lactobionamidoethyl methacrylate (LAMA) were prepared directly by reacting 2-aminoethyl methacrylate with D-gluconolactone and lactobionolactone, respectively. Homopolymerization of GAMA and LAMA by atom transfer radical polymerization (ATRP) gave reasonably low polydispersities as judged by aqueous gel permeation chromatography. A wide range of sugar-based block copolymers were prepared using nearmonodisperse macroinitiators based on poly(ethylene oxide) [PEO], poly(propylene oxide) [PPO], or poly(e-caprolactone) [PCL] and/or by sequential monomer addition of other methacrylic monomers such as 2-(diethylamino)ethyl methacrylate [DEA], 2-(diisopropylaminoethyl methacrylate [DPA], or glycerol monomethacrylate [GMA]. The reversible micellar self-assembly of selected sugar-based block copolymers [PEO23-GAMA50-DEA100, PEO23-LAMA30-DEA50, PPO33-GAMA50, and PPO33-LAMA50] was studied in aqueous solution as a function of pH and temperature using dynamic light scattering, transmission electron microscopy, surface tensiometry, and 1H NMR spectroscopy. Introduction Polymers containing pendent sugar groups (sometimes known as glycopolymers) have received considerable attention over the last two decades.1-5 The carbohydrate moieties are highly hydrophilic and hence impart water-solubility. Moreover, synthetic sugar polymers are emerging as potentially important materials for the study of carbohydrateprotein interactions.6-9 They are also expected to serve as new nonionic polymeric surfactants, surface modifiers and hydrogels.10-12 Well-defined sugar-based homopolymers and diblock copolymers have been traditionally prepared via living ionic polymerization.13-15 However, this approach necessitates protection of all of the hydroxy groups, which is both atom-inefficient and inevitably adds two steps to the synthesis of well-defined glycopolymers. This disadvantage, along with the rigorously anhydrous conditions required for ionic polymerizations, means that such syntheses are usually not commercially viable. An alternative direct route to sugar polymers based on ring-opening metathesis polymerization (ROMP) has been recently described by Strong and Kiessling,5 but this approach suffers from the limited range of commercially available comonomers that are available for the construction of well-defined sugar-based diblock copolymers. The recent discovery16 of living radical polymerization chemistries such as atom transfer radical polymerization (ATRP) has allowed the design of a wide range of new controlled-structure copolymers. For example, a number of well-defined sugar polymers have been prepared by * To whom correspondence should be addressed. Fax: +1273-677196. Tel: +1273-678650. E-mail: [email protected].

ATRP.17-20 However, despite the well-documented tolerance of ATRP toward functional groups, most examples still involve a protection/deprotection strategy.17-19 Amphiphilic copolymers have been widely studied because of their interesting properties such as surface activity and micelle formation. Micellar self-assembly in aqueous solution has received increasing attention from various research groups.21-28 The aggregation behavior of stimulus-responsive diblock copolymers is of particular interest to our group.29-32 For example, micellization of biocompatible diblock copolymers in aqueous solution is a promising route to nanosized drug delivery vehicles for biomedical applications.32 In some cases, these diblock copolymers have been shown to be either thermo-responsive or pH-responsive, which offers the possibility of the triggered release of hydrophobic drugs. Following our two recent communications,21,22 we now report in full the direct synthesis of a wide range of controlled-structure, sugar methacrylate-based diblock copolymers via ATRP. First, derivatization of 2-gluconamidoethyl methacrylate (GAMA) and 2-lactobionamidoethyl methacrylate (LAMA) was readily achieved under mild conditions by the reaction of 2-aminoethyl methacrylate with either D-gluconolactone and lactobionolactone, respectively (see Scheme 1). Then various well-defined macro-initiators were utilized for the homopolymerization and block copolymerization of GAMA and LAMA without recourse to protecting group chemistry (see Schemes 2 and 3). Sequential monomer addition of GAMA with several methacrylic monomers, including LAMA, was also achieved. Finally, the reversible micellization of selected block copolymers in aqueous solution was examined by 1H NMR spectroscopy,

10.1021/bm034166e CCC: $25.00 © 2003 American Chemical Society Published on Web 08/23/2003

Novel Sugar Methacrylate-Based Polymers

Biomacromolecules, Vol. 4, No. 6, 2003 1747

Scheme 1. Synthesis of GAMA and LAMA from the Reaction of 2-Aminoethyl Methacrylate with D-Gluconolactone and Lactobionolactone, Respectively

Scheme 2. Reaction Scheme for the Block Copolymerization of GAMA with DEA Using a PEO-Based Macroinitiator via ATRP in Methanol at 20 °C

dynamic light scattering (DLS), surface tensiometry, and transmission electron microscopy (TEM) studies. Experimental Section Materials. 2-(Diethylamino)ethyl methacrylate (DEA) was obtained from Aldrich. Glycerol monomethacrylate (GMA) was donated by Ro¨hm, Germany. 2-(Diisopropylamino)ethyl

methacrylate (DPA) was purchased from Scientific Polymer Products, U.S.A. These monomers were purified in turn by treatment with basic alumina to remove inhibitor and then stored at -20 °C prior to use. Copper(I) bromide, 2,2′bipyridine (bpy), 2-bromoisobutyryl bromide, triethylamine, D-gluconolactone, and poly(-caprolactone) (PCL; Mn ) 2,000, Mw/Mn ) 1.60) were purchased from Aldrich and used as received. Poly(propylene oxide) (PPO; Mn ) 2,000; Mw/

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Biomacromolecules, Vol. 4, No. 6, 2003

Narain and Armes

Scheme 3. Homopolymerization of LAMA via ATRP in 3:2 Methanol/Water Mixtures or NMP at 20 °C using an Aldehyde-Functionalized Initiator (Ald-Br)

Mn ) 1.15) and two monohydroxy-capped poly(ethylene oxide)s (PEO; Mn ) 1,000 and Mn ) 5,000; Mw/Mn < 1.10 in each case) were kindly donated by Cognis Performance Chemicals (Hythe, U.K.) and were used without further purification. N-Methyl-2-pyrrolidone (NMP) and methanol were also purchased from Aldrich and were both HPLC grade. The water used in all syntheses was both deionized and doubly distilled. Synthesis of 2-Aminoethyl Methacrylate (AMA). This precursor is commercially available from Aldrich in its hydrochloride salt form, but its “technical grade” purity is only 90%, which was considered too low for the present study. Thus, AMA was synthesized in-house as follows. Ethanolamine hydrochloride (65.0 g, 0.67 mol), methacryloyl chloride (100 mL, 0.96 mol), and hydroquinone (0.50 g) were mixed together in a three-necked round-bottomed flask fitted with a condenser. The mixture was then heated in an oil bath to 93-95 °C under nitrogen atmosphere. The heterogeneous mixture of the molten salt and methacryloyl chloride was stirred vigorously for 1 h at this temperature. The hydrogen chloride evolved during this highly exothermic reaction was removed by passing through an alkaline solution. A homogeneous viscous yellowish brown solution was obtained, which was stirred for a further 2 h at a lower temperature (70-75 °C). The mixture was then allowed to cool to around 40 °C and THF (150 mL) was added. This solution was then added slowly to cold n-pentane (600 mL) and the creamy white precipitate that was formed was isolated by filtration, washed well with n-pentane, and dried under vacuum. The crude product was recrystallized using a 7:3 ethyl acetate/2-propanol mixture and isolated in its hydrochloride salt form in 70% yield. Synthesis of D-Gluconamidoethyl Methacrylate (GAMA). D-Gluconolactone (10 g, 56.2 mmol) was dissolved in methanol (100 mL). 2-Aminoethyl methacrylate hydrochloride (16.0 g, 96.6 mmol) and hydroquinone (0.10 g) were added, followed by triethylamine, and this reaction mixture was stirred for 5 h at 20 °C. It was then concentrated under vacuum and precipitated into either excess 2-propanol or dichloromethane. This step removed the triethylammonium chloride salt, which remained soluble. The crystalline creamy-white precipitate of crude GAMA monomer was then filtered off, washed several times with 2-propanol followed by n-pentane, and then dried under vacuum. Characterization of the GAMA monomer by both 1H and 13C NMR (see

Figure 1) and also high-resolution mass spectroscopy (Bruker Daltonics APE III ESI spectrometer operating in ionization mode; calculated mass for the M + 1 parent ion was 308.1340, found 308.1341) confirmed its high purity. The overall monomer yield was ∼75%. Synthesis of 2-Lactobionamidoethyl Methacrylate (LAMA). Lactobionic acid was first converted to the corresponding lactobionolactone. This was achieved by dissolving lactobionic acid (25.0 g) in anhydrous methanol (150 mL) at 50 °C, followed by vacuum distillation. This reaction was repeated at least twice until the acid precursor was fully converted to the lactone. This process can also be catalyzed by the addition of a small amount of trifluoroacetic acid. Lactobionolactone (10.0 g, 29.4 mmol) was first dissolved in methanol at 40 °C and then cooled to room temperature before the addition of 2-aminoethyl methacrylate hydrochloride (10.0 g, 60.4 mmol), triethylamine (10.0 mL), and hydroquinone (0.25 g). The mixture was stirred for 5 h, concentrated by rotary evaporation and precipitated into either 2-propanol or dichloromethane. Characterization of the LAMA monomer by both 1H and 13C NMR (see Figure 2) and also high-resolution mass spectroscopy (Bruker Daltonics APE III ESI spectrometer operating in ionization mode; calculated mass for the M + 1 parent ion was 470.1868, found 470.1860) confirmed its high purity. The white solid formed was filtered, washed with 2-propanol, dried under vacuum, and isolated in 78% yield. Preparation of Macroinitiators. The macroinitiators were prepared by esterification of the terminal hydroxy groups of the monohydroxy-capped poly(ethylene oxide) [PEO; DPn ) 45; Mn ) 2,000, Mw/Mn ) 1.10], monohydroxy-capped poly(propylene oxide) [PPO; DPn ) 33; Mn ) 2,000, Mw/ Mn ) 1.10], and dihydroxy-capped poly(-caprolactone) [PCL; DPn )18; Mn ) 2,000, Mw/Mn ) 1.60] using 2-bromoisobutyryl bromide, as described previously.33 The two poly(alkylene oxide)-based precursors were donated by Cognis Performance Chemicals (Hythe, U.K.) and the PCL precursor was purchased from Aldrich and used as received. The PEO-Br, PPO-Br, and Br-PCL-Br macroinitiators were each characterized using 1H NMR spectroscopy and MALDI-TOF mass spectroscopy, respectively. Degrees of esterification were estimated to be greater than 95% in each case. Typical Synthesis of Br-PCL-Br Macroinitiator. Dihydroxy-terminated poly(-caprolactone) (20.0 g, 10.0


Figure 1. Assigned 1H (upper) and

13C


NMR (lower) spectra for the 2-gluconamidoethyl methacrylate (GAMA) monomer.

mmol) was dissolved in dry toluene (150 mL), followed by the addition of triethylamine (5.0 mL, excess). Excess 2-bromoisobutyryl bromide (9.30 g, 40.6 mmol) was then added dropwise to this solution, which was stirred at 40 °C under nitrogen for 24 h. Then the solution was concentrated and THF was added. The triethylammonium bromide salt that precipitated was filtered off, and the filtrate was again concentrated under reduced pressure. The poly(-caprolactone) macroinitiator was then precipitated into excess methanol. The resulting white solid was washed with methanol, dried under vacuum, and obtained in 85% yield. Synthesis of Aldehyde-Functionalized Initiator (AldBr). 4-hydroxybenzaldehyde (5.0 g, 41 mmol) was dissolved in anhydrous THF (200 mL) in a three-necked round-bottom flask followed by the addition of excess triethylamine (10

mL). The resulting solution was cooled in ice, and 2-bromoisobutyryl bromide (6.0 g, 48.7 mmol) was added slowly from a dropping funnel. The reaction was quite exothermic, and a white precipitate of triethylammonium chloride was observed. After stirring the mixture for 4 h, the white precipitate was filtered off, and the remaining solution was concentrated under vacuum. A cream yellow precipitate was recovered, which was washed with n-pentane and dried under vacuum. Yield ∼ 80%. General Polymerization Protocols. Typical Protocol for the Homopolymerization of GAMA with PEO23-Br Via Methanolic ATRP at 20 °C. GAMA (2.00 g, 6.5 mmol) was heated to 40 °C to aid its dissolution in methanol (4.0 mL). The PEO23-Br initiator (0.130 g, 0.013 mmol, target DPn ) 50) was then added and this solution was purged with

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Figure 2. Assigned 1H (upper) and

13C

Narain and Armes

(lower) NMR spectra for the 2-lactobionamidoethyl methacrylate (LAMA) monomer.

nitrogen for 10 min. Copper(I) bromide (0.018 g, 0.013 mmol) and two equivalents of bpy (0.040 g, 0.026 mmol) were added and the resulting dark brown solution was stirred under a nitrogen atmosphere. The extent of polymerization was monitored by 1H NMR. High conversion (>97%) was achieved after 15 h at 20 °C. GPC data for this PEO23GAMA50 diblock copolymer indicated an Mn of 11,400 and an Mw/Mn of 1.23. The spent ATRP catalyst was removed by passing the reaction solution through a column packed with basic alumina. The methanol was removed under vacuum and the white polymer was redissolved in water and freeze-dried overnight. The isolated yield of purified PEO23GAMA50 homopolymer was 78%. The same protocol was

used for ATRP syntheses in either water or water/methanol mixtures except that the GAMA did not require heating for dissolution under these conditions. The reaction times required for high conversions were significantly reduced in the presence of water. Typical Protocol for the Homopolymerization of LAMA Via ATRP at 20 °C in a 3:2 Methanol/Water Mixture. LAMA (2.00 g, 4.26 mmol) was heated to 60 °C to aid its dissolution in 3:2 methanol/water (12.0 mL). PEO23-Br initiator (0.085 g, 0.085 mmol, target DPn ) 50) was then added, and this solution was purged with nitrogen for 10 min. Copper(I) bromide (0.012 g, 0.085 mmol) and two equiv. of bpy (0.026 g, 0.170 mmol) were added and the resulting dark brown


solution was stirred under a nitrogen atmosphere. The extent of polymerization was monitored by 1H NMR; high conversions (>95%) were achieved after 3 h at 20 °C. GPC analysis [using mixed-B PLgel columns and DMF as eluent at 70 °C; refractive index detector and poly(methyl methacrylate) calibration standards] of the PEO23-LAMA50 diblock copolymer indicated an Mn of 23 400 and an Mw/Mn of 1.10. The spent ATRP catalyst was removed by passing the reaction solution through a column packed with basic alumina. The methanol was removed under vacuum, and the aqueous copolymer solution was freeze-dried overnight. The isolated yield of the purified copolymer was 73%. The same protocol was used for ATRP syntheses conducted in either water or NMP. The reaction time required for 95% conversion was reduced to around 0.50 h in pure water. Preparation of the PPO33-GAMA50 Diblock Copolymer. GAMA (2.0 g, 6.5 mmol) was dissolved in a 9:1 methanol/ water mixture. Then the PPO33-Br initiator (0.26 g, 0.13 mmol) was added and the solution was degassed via nitrogen purge. After 10 min, the Cu(I)Br catalyst (0.019 g, 0.13 mmol) and bpy (0.040 g, 0.26 mmol) were added in turn to the reaction solution, which turned dark brown and became more viscous. After the required polymerization time, the solution was exposed to air and diluted with methanol, which led to aerial oxidation of the ATRP catalyst. The resulting blue solution was treated with basic alumina to remove the spent ATRP catalyst and the clear solution was concentrated using a rotary evaporator. Finally, water was added to the viscous solution, which was freeze-dried overnight to obtain white polymer. Preparation of GAMA15-PCL18-GAMA15 Triblock Copolymers. Bifunctional poly(-caprolactone) macroinitiator (0.43 g, 0.21 mmol) was first dissolved in a 4:1 2-propanol/ water mixture at 40 °C. GAMA (2.00 g, 6.50 mmol) was then added, and the solution was degassed via nitrogen purge. Copper(I) bromide (0.060 g, 0.42 mmol) and bpy (0.130 g, 0.84 mmol) were added in turn, and the resulting dark brown solution was stirred under nitrogen at room temperature. Purification of this reaction solution was achieved using the same protocol as described above for the PPO33-GAMA50 diblock copolymer. Preparation of PEO23-GAMA50-DEA100 Triblock Copolymer. GAMA (2.00 g, 6.5 mmol) and PEO23-Br (0.13 g, 0.13 mmol) were first co-dissolved in methanol (10 mL) at 40 °C. The clear solution was cooled to room temperature and then purged with nitrogen for about 15 min. Cu(I)Br (0.020 g, 0.14 mmol) and bpy (0.043 g, 0.28 mmol) were then added to the degassed solution, which turned dark brown. The solution became progressively more viscous, indicating the onset of the polymerization. The GAMA conversion was monitored by 1H NMR, and after more than 95% conversion had been achieved in 8 h, DEA (2.41 g 13.0 mmol) in degassed methanol was added. This reaction solution was then stirred for a further 12 h. The viscous brown solution was finally diluted with methanol and immediately turned blue because of the aerial oxidation of Cu(I) to Cu(II). A clear colorless solution was obtained after treatment with basic alumina. The solvent was removed


under vacuum, and the copolymer was redissolved in water and freeze-dried overnight. The yield was ∼80%. Preparation of PEO23-GAMA30-GMA60 Triblock Copolymer. GAMA (2.00 g, 6.54 mmol) and PEO23-Br (0.22 g, 0.22 mmol) were co-dissolved in methanol (10 mL) at 40 °C. The clear solution was cooled to room temperature and then purged with nitrogen for about 15 min. Cu(I)Br (0.020 g, 0.14 mmol) and bpy (0.043 g, 0.28 mmol) were then added to the solution, which turned dark brown. The reaction solution was stirred for 6 h, followed by the addition of the second monomer GMA (2.09 g, 13 mmol) in degassed methanol (2 mL). After stirring for a further 8 h, the viscous polymerizing solution was quenched by dilution with methanol, resulting in a color change from dark brown to blue. This reaction mixture was treated with basic alumina, and the solvent was removed under vacuum. The resulting triblock copolymer was redissolved in water and freeze-dried overnight. The yield was ∼81%. Preparation of PEO23-LAMA30-GAMA30 Triblock Copolymer. LAMA (2.00 g, 4.26 mmol) and PEO23-Br (0.14 g, 0.14 mmol) were co-dissolved in degassed NMP (10 mL). Cu(I)Br (0.02 g, 0.14 mmol) and bpy (0.043 g, 0.28 mmol) were then added to the solution. The resulting dark brown solution was then stirred for 5 h under a nitrogen atmosphere. A solution of GAMA (1.30 g, 4.26 mmol) in degassed NMP (3 mL) was added, and the reaction solution was stirred for a further 5 h. The resulting viscous solution was then added to a stirred solution of excess 2-propanol. The blue precipitate was isolated by filtration and washed several times with 2-propanol to remove residual NMP. The moist copolymer was then dissolved in water and passed through a basic alumina column to remove the copper catalyst. The clear colorless solution was concentrated and freeze-dried overnight. The yield was ∼68%. Preparation of Ald-LAMA25-GMA60 Diblock Copolymer. LAMA (2.00 g, 4.26 mmol) and Ald-Br (0.046 g, 0.17 mmol) were co-dissolved in degassed NMP (10 mL). Cu(I)Br (0.02 g, 0.14 mmol) and bpy (0.043 g, 0.28 mmol) were then added to the solution. The resulting dark brown solution was stirred for 5 h under a nitrogen atmosphere. A solution of GMA (2.83 g, 17.6 mmol) in degassed NMP (2 mL) was added and stirred for a further 5 h. The resulting viscous solution was then slowly added to a 10-fold excess of THF with continuous stirring. The resulting blue precipitate was isolated by filtration, redissolved in water, treated with basic alumina, and concentrated prior to freeze-drying overnight. The yield was ∼72%. Polymer Characterization. Molecular weights and molecular weight distributions were assessed by gel permeation chromatography (GPC) in both aqueous and DMF eluents. The following three GPC protocols were used in this work. Aqueous GPC at Neutral pH. This protocol was used for the GAMA homopolymers. Chromatograms were recorded using a Viscotek instrument equipped with a Viscotek TSK alpha-3000 column, 0.10 M sodium nitrate/0.01 M sodium dihydrogen phosphate eluent (pH 7) at a flow rate of 1.0 mL min-1 at 35 °C using a refractive index detector. Calibration was achieved using a series of near-monodisperse poly(ethylene oxide) standards.

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Table 1. Summary of the Synthesis Parameters and Molecular Weight Data for the Homopolymerization of GAMA by ATRP in Protic Media at 20 °C

expt. no.

ATRP solvent composition

reactiona time (h)

initiator type

target DPnb

yieldc (%)

Mnd

Mw/Mnd

1 2 3 4 5 6 7 8

methanol methanol 9:1 methanol/H2O 3:2 methanol/H2O H2O methanol methanol methanol

15 15 6.0 3.0 0.50 15 15 15

PEO23-Br PEO23-Br PEO23-Br PEO23-Br PEO23-Br PEO23-Br PEO113-Br PEO7-Br

30 50 50 50 50 100 50 50

72 65 74 78 78 80 75 71

8300 11 400 12 000 12 600 13 400 18 000 16 000 10 000

1.19 1.23 1.28 1.48 1.82 1.37 1.19 1.15

copper levele (ppm) 0.8 1.6 0.9 1.7 6.8 12.8

a Reaction time to reach at least 97% conversion as determined by 1H NMR studies. b Target degree of polymerization. c Final yield obtained after purification using basic alumina to remove the spent ATRP catalyst. d Determined using aqueous GPC [0.20 M sodium nitrate and 0.01 M sodium dihydrogen phosphate as eluent at pH 7 with poly(ethylene oxide) calibration standards]. e Copper content of purified solid polymer determined by inductively coupled plasma atomic emission spectrometry.

Aqueous GPC at Low pH. Chromatograms for the GAMADEA diblock copolymers were obtained using a Viscotek TSK G5000 PWXL column at 30 °C in conjunction with an ERC-7515A refractive index detector. The eluent used was 0.50 M acetic acid/0.30 M sodium sulfate (approximately pH 2) at a flow rate of 1.0 mL min-1. Calibration was achieved using near-monodisperse poly(2-vinylpyridine) standards. DMF GPC. This protocol was used for selected homopolymers and block copolymers. Chromatograms were obtained from RAPRA, U.K. The equipment comprised a Waters 150 CV instrument fitted with two 30 cm (10 micron) Mixed Bed-B PLgel columns operating at 80 °C with a refractive index detector. DMF containing 0.01 M lithium bromide was used as the eluent at a flow rate of 1.0 mL min-1. Calibration was achieved using a series of nearmonodisperse poly(methyl methacrylate) standards. Aqueous Solution Properties. Dynamic light scattering (DLS) studies were performed using a Brookhaven Instruments Corporation BI-200SM goniometer equipped with a BI-9000AT digital correlator using a solid-state laser (125 mW, λ ) 532 nm) at a fixed scattering angle of 90°. The intensity-average hydrodynamic diameter (Dh) and polydispersity, µ2/T2, of the micelles were obtained by cumulants analysis of the experimental correlation function. All 1H and 13 C NMR spectra were recorded using a Bruker Avance DPX 300 MHz spectrometer (operating at 75 MHz for 13C spectra). 1 H NMR spectra of micelles were recorded in dilute solution at copolymer concentrations that were comparable to those used in the DLS studies. Block compositions were calculated from spectra recorded in either D2O or CD3OD. The kinetics of GAMA and LAMA homopolymerization were also determined using D2O or CD3OD by comparing the vinyl signals at δ 5.0-6.0 to either the methacrylate backbone at δ 0.5-1.2. In addition, d6-DMSO or CDCl3 were also used to record NMR spectra for the various (macro)initiators and monomers. Surface tension measurements on selected diblock and triblock copolymers were obtained using a Kru¨ss Tensiometer K10ST instrument. The copolymer concentration was typically 0.5 w/v %. The solution pH was adjusted by adding small quantities of either 2 M NaOH or 1 M HCl. The surface tension of pure water was periodically recorded

during these experiments and was found to be approximately 71 mN m-1 at 20 °C. Results and Discussion Monomer Syntheses. GAMA and LAMA were readily synthesized in reasonably high yields in methanol at 20 °C by the reaction of AMA with D-gluconolactone and lactobionolactone, respectively (see Scheme 1). The addition of triethylamine to neutralize the AMA‚HCl adduct was essential: no reaction occurred in the absence of this base. In situ neutralization was preferred because AMA is relatively unstable: the free amine can attack the carbonyl group in an internal rearrangement that generates 2-hydroxyethyl methacrylamide. In view of this unwanted side-reaction, a 2-fold excess of AMA was used in these monomer syntheses: both excess AMA and any 2-hydroxyethylmethacrylamide that might be formed were removed during the selective precipitation of the target monomer in 2-propanol. DGluconolactone is a relatively cheap, commercially available starting material obtained from the oxidation of D-glucose, whereas lactobionolactone had to be prepared in-house from lactobionic acid. GAMA and LAMA were characterized by 1 H and 13C NMR (see Figures 1 and 2 for the fully assigned spectra) and both monomers were confirmed to be of high purity. Although GAMA is easier to prepare than LAMA, the latter monomer is potentially more interesting because in principle it allows molecular recognition applications to be examined. This is an essential prerequisite for many biomedical applications and also certain industrial applications, e.g., cotton recognition in laundry formulations. Homopolymerizations. GAMA and LAMA were homopolymerized in turn by ATRP at 20 °C in both protic media (either methanol, water or methanol/water mixtures for GAMA; water or methanol/water mixtures for LAMA) and NMP (LAMA only) to produce controlled-structure sugar methacrylate polymers using a range of ATRP (macro)initiators15 in combination with a Cu(I)Br/2bpy catalyst (see Tables 1 and 2). When pure methanol was used as solvent, dissolution of the GAMA monomer required heating to 40 °C prior to the addition of the initiator and copper catalyst. The highly hydrophilic nature of LAMA rendered it insoluble in pure methanol and hence polymerization of this monomer



Table 2. Summary of the Synthesis Parameters and Molecular Weight Data for the Homopolymerization of LAMA by ATRP at 20 °C

entry no.


reactiona time (h)

initiator type

target DPn

yieldb (%)

Mnc

Mw/Mnc

1 2 3 4 5 6 7 8 9 10 11 12

H2O H2O 3:2 methanol/H2O NMP 3:2 methanol/H2O 3:2 methanol/H2O NMP 3:2 methanol/H2O NMP 3:2 methanol/H2O 3:2 methanol/H2O NMP

0.50 0.50 3.0 4.0 3.0 4.0 4.0 3.0 4.0 3.0 3.0 4.0

PEO23-Br PEO113-Br PEO23-Br PEO23-Br PEO113-Br PEO113-Br PEO113-Br PPO33-Br PPO33-Br Ald-Br Ald-Br Ald-Br

50 100 50 50 50 100 50 30 50 30 50 30

74 75 68 65 63 67 70 64 63 71 75 68

34 800 28 800 23 400 22 500 25 300 32 300 23 200 12 500 18 900 10 000 19 200 8600

1.60 1.78 1.10 1.24 1.26 1.20 1.24 1.22 1.26 1.17 1.19 1.22

copper contentd (ppm) 7 8 17 3 23 26

a Reaction time to reach at least 95% conversion as determined by 1H NMR studies. b Final yield obtained after purification using basic alumina to remove the spent ATRP catalyst. c Determined using DMF GPC [0.01 M LiBr and poly(methyl methacrylate) as calibrants]. d Copper content of the solid purified polymer as determined by inductively coupled plasma atomic emission spectroscopy [ICP-AES].

was conducted in either a 3:2 methanol/water mixture or NMP. The target DPn’s were varied from 30 to 100. 1H NMR analysis of the polymerizing solution indicated conversions of more than 95% but the final isolated yields varied from 65 to 80%, indicating some polymer adsorption onto the basic alumina. Kinetic studies were conducted on the homopolymerization of GAMA and LAMA at 20 °C. In the case of GAMA, the rate of polymerization was substantially faster in water and methanol/water mixtures compared to pure methanol under the same conditions (see Table 1 and Figure 3). The evolution of Mn was linear with conversion, polydispersities remained relatively narrow throughout the polymerization and GPC analyses indicated monomodal chromatograms in all cases. The best living character was achieved in pure methanol, which also gave the slowest polymerizations. Higher polydispersities were obtained as the water content was increased, with an Mw/Mn as high as 1.82 being obtained for ATRP syntheses conducted in pure water. We have recently reported similar results for a range of methacrylic monomers.34-36 It is likely that the Cu-Br bond in the Cu(I)2bpy catalyst has some ionic character in aqueous media, which would most likely reduce the efficiency of the de-activation step and lead to increased radical-radical annihilation and hence premature chain termination. Alternatively, the terminal C-Br bond on the polymer chain-ends may be prone to hydrolysis. There is also some evidence for progressively reduced control (i.e., higher polydispersities) as the target DPn was increased from 30 to 100, as is generally expected for ATRP syntheses (compare entries 1, 2, and 6 in Table 1). Analysis of the purified GAMA homopolymers by inductively coupled plasma atomic emission spectroscopy [ICP-AES] as described previously32 indicated relatively low levels of residual copper (95%) were achieved in both sets of syntheses. The residual copper contents of the purified LAMA homopolymers were determined by ICP-AES and ranged from 3 to 26 ppm (see Table 2). 1 H NMR studies confirmed that high conversions (>95%) and first-order kinetics with respect to LAMA monomer were obtained in 3:2 methanol/water mixtures (see Figure 4). A self-blocking (chain extension) experiment was also carried out for LAMA under these conditions (see Figure 5a). Increasing the target DPn from 30 to 60 led to a doubling of the Mn, as expected. The polydispersity of the chain-extended LAMA homopolymer increased slightly but remained low at 1.25, indicating good living character. Preparation of Sugar Methacrylate-Based Block Copolymers. A summary of the various sugar methacrylatebased diblock copolymers and triblock copolymers is given in Tables 3 and 4. For example, in Table 3, the ATRP of GAMA using a PEO-based macroinitiator was allowed to proceed to high conversion in methanol (>90-95%), followed by the addition of the second methacrylic monomer (either GMA, DEA, or DPA). Such one-pot syntheses were found to be both effective and convenient. However, the polydispersity of the final triblock was usually slightly higher than its diblock precursor, which suggested that some termination may occur under monomer-starved conditions. On the other hand, chain extension of a PEO23-GAMA50 diblock copolymer with GMA resulted in a clear shift in the molecular weight distribution curve and the polydispersity of the final PEO23-GAMA50-GMA60 remained relatively

Figure 5. (a) DMF GPC traces obtained for a self-blocking (chain extension) experiment of the homopolymerization of LAMA via ATRP at 20 °C in a 3:2 methanol/water mixture. Note the doubling of molecular weight and retention of low polydispersity as the target DPn was increased from 30 to 60. (b) DMF GPC traces obtained for the chain extension of PEO23-GAMA50 with GMA to give a PEO23GAMA50-GMA60 triblock copolymer.

low at 1.29 (see Figure 5b). It is noteworthy that both of the DPA-based triblock copolymers proved to be water-insoluble at pH 7 after purification because of the relatively high hydrophobic character of the DPA block. In recent unpublished work, we have obtained similar results with various DPA-based block copolymers. Indeed, only highly hydrophilic blocks comprising monomers such as 2-methacryloyloxyethyl phosphorylcholine appear to be sufficient to render DPA-based block copolymers soluble at neutral pH.32 The GAMA-PCL-GAMA syntheses were conducted in 4:1 IPA/water mixtures in order to ensure adequate solubility of the relatively hydrophobic PCL-based macroinitiator, which was insoluble in methanol. In the case of the PPOGAMA diblock and the GAMA-PCL-GAMA triblock syntheses, the PPO and PCL macroinitiator efficiencies appeared to be very high, because no unreacted PPO or PCL could be isolated after attempted purification (the final copolymer was washed with excess THF for 24 h at 20 °C, which should extract any unreacted PPO33-Br or BrPCL18-Br macroinitiator). Details of four well-defined LAMA-based block copolymers are summarized in Table 4, including one example of a LAMA-GAMA block copolymer. In principle, this copolymer could have been synthesized in a 3:2 methanol/ water mixture, but the ATRP of GAMA is not particularly well controlled under these conditions (see entry 4 in Table 1). Instead, the copolymer synthesis was conducted in NMP, which led to a relatively narrow polydispersity of 1.28.



Table 3. Summary of Synthesis Parameters and Molecular Weight Data for GAMA-Based Diblock and Triblock Copolymers Prepared via ATRP at 20 °C in Either Methanol or 4:1 Isopropanol/Water Mixtures block copolymer composition


yielda (%)

Mnb

Mw/Mn

solubility in waterc

PEO23-GAMA50 PEO113-GAMA50 PEO23-GAMA30-DEA60 PEO23-GAMA30-DEA80 PEO23-GAMA50-DEA100 PEO23-GAMA50-GMA60 PEO23-GAMA30-GMA60 PEO23-GAMA30-DPA80 PEO23-GAMA30-DPA60 PPO33-GAMA50 PPO33-GAMA30 PPO33-GAMA20 GAMA15-PCL18-GAMA15 GAMA50-PCL18-GAMA50

methanol methanol methanol methanol methanol methanol methanol methanol methanol methanol methanol methanol 4:1 IPA/H2O 4:1 IPA/H2O

75 76 75 73 80 79 81 75 74 75 79 74 82 78

11 400 16 000 27 400 17 200 37 600 25 200 19 500

1.23 1.19 1.29 1.28 1.37 1.29 1.32

23 000 15 500 12 850 14 500 24 600

1.11 1.22 1.23 1.15 1.12

yes yes yes yes yes yes yes no no yes yes no yes yes

a Final yield obtained after purification using basic alumina to remove the spent ATRP catalyst. The actual NMR conversions were close to 95%. Determined by GPC using DMF containing 0.01 M LiBr at 70 °C and calibrated with poly(methyl methacrylate) standards except entries 1 and 2, which were analyzed by aqueous GPC [0.20 M sodium nitrate and 0.01 M sodium dihydrogen phosphate as eluent at pH 7 with poly(ethylene oxide) calibration standards]. c At pH 7 and 20 °C. b

Table 4. Summary of the Synthesis Parameters and Molecular Weight Data for the Block Copolymerization of LAMA with Other Methacrylic Comonomers by ATRP at 20 °C copolymer type

solvent composition

PEO23-LAMA30-DEA50 Ald-LAMA25-DEA50 PEO23-LAMA30-GAMA30 Ald-LAMA25-GMA60

3:2 methanol/water 3:2 methanol/water NMP NMP

The aqueous solution behavior of six block copolymers selected from Tables 3 and 4, namely, PEO23-GAMA50DEA100, PEO23-LAMA30-DEA50, PPO33-GAMA50, PPO33LAMA50, GAMA50-PCL18-GAMA50, and GAMA15PCL18-GAMA15, was investigated by dynamic light scattering (DLS), transmission electron microscopy (TEM), 1H NMR spectroscopy, and surface tensiometry. Regardless of the solution conditions, the two GAMA-PCL18-GAMA triblock copolymers (entries 14 and 15 in Table 3) always formed large aggregates of around 120-150 nm diameter in aqueous solution because of the permanently hydrophobic character of the central PCL block. In contrast, certain sugar methacrylate diblock and triblock copolymers proved to be stimulus-responsive, i.e., they could be dissolved molecularly but underwent reversible micellar self-assembly on adjusting the solution pH or temperature. More specifically, the PEO23-GAMA50-DEA100 and PEO23-LAMA50-DEA50 triblocks proved to be pH-responsive and the PPO33GAMA50 and PPO33-LAMA50 diblocks exhibited thermoresponsive behavior. Their aqueous solution properties are discussed in turn below. Micellar Self-Assembly of pH-Responsive Block Copolymers. DEA homopolymer is a weak polybase with a pKb of around 6.7 and is insoluble in neutral or alkaline aqueous solution. Below pH 7, it is soluble as a weak cationic polyelectrolyte because of protonation of the DEA residues. In the case of the two PEO23-GAMA50-DEA100 and PEO23-LAMA30-DEA50 triblock copolymers, the DEA block leads to pH-induced self-assembly. Thus both triblocks were molecularly dissolved below pH 7 because of protonation of the DEA residues and underwent micellar self-

Mn of LAMA homopolymer

Mn of final block copolymer

Mw/Mn of final block copolymer

11 400 10 600

17 900 17 300 21 200 18 100

1.34 1.30 1.28 1.29

10 100

assembly at or above pH 7. Figure 6 shows the 1H NMR spectra of the PEO23-LAMA30-DEA50 triblock copolymer at acidic, neutral, and alkaline pH, respectively. As expected, the strong signal at δ ∼ 0.5-1.0 due to the protonated DEA residues observed in acidic solution became attenuated (and shifted downfield to δ ∼ 1.0-1.5) at neutral pH, before disappearing completely at pH 10 as the DEA block became hydrophobic and less mobile within the micelle cores. Similar NMR results (not shown) were obtained for the PEO23GAMA50-DEA100 triblock copolymer. The copolymer surface activity was also dependent on the solution pH (see Figure 7). Above pH 7, the DEA block is relatively hydrophobic and hence strongly adsorbed at the air-water interface. Below pH 7, the DEA residues become protonated and copolymer desorption from the interface occurred, resulting in low surface activity. Thus, the PEO23GAMA30-DEA60 and PEO23-GAMA30-DEA60 triblocks behave as pH-responsive polymeric surfactants above the pKa of the DEA. It is noteworthy that increasing the DPn of the DEA block from 60 to 80 at a fixed DPn of 30 for the central GAMA block led to a small reduction in the limiting surface tension of the triblock copolymer (see Figure 7). More importantly, the behavior of the Ald-LAMA25-DEA50 diblock copolymer was qualitatively different to that of the two PEO-GAMA-DEA triblocks. The critical pH for modulation of the former’s surface activity was shifted by approximately one pH unit from around pH 7 (approximately the pKa of the conjugate acid form of DEA homopolymer) to around pH 6 (see Figure 7). This indicates that the DEA chains in the Ald-LAMA25-DEA50 diblock copolymer are more weakly basic than anticipated. Based on our previous

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Narain and Armes

Figure 6. 1H NMR spectra (D2O) of a PEO23-LAMA30-DEA50 triblock copolymer at pH 2.5, 7, and 10, respectively. The triblock was initially dissolved molecularly in DCl/D2O and then the solution pH was adjusted using NaOD. Note the progressive attenuation of the DEA signals as this block becomes more deprotonated.

Figure 7. (a) Surface tension vs pH curves for 0.50 w/v % aqueous solutions of the PEO23-GAMA30-DEA60 (b) and PEO23-GAMA30DEA80 (9) triblock copolymers and the Ald-LAMA25-DEA50 diblock copolymer (O).

experience, the pH-induced surface activity and micellization behavior of a range of weak polyelectrolytes (both polybases and polyacids) usually correlates very well with the relevant pKa or pKb values of the pH-responsive chains.29,30,32 At present, we have no satisfactory explanation for this surprising observation: further work is in progress to clarify this issue. Finally, it is noteworthy that the periphery of the micelles formed by the Ald-LAMA25-DEA50 diblock copolymer at or above neutral pH are decorated with aldehyde groups derived from the Ald-Br initiator (see Scheme 2). In principle, these functional groups should facilitate conjugation of the micelles with biologically active motifs, as described by Kataoka and co-workers.38 This is an important advantage for cell targeting applications.

Figure 8. Variable temperature 1H NMR spectra (D2O) recorded for the PPO33-GAMA50 diblock copolymer at 5, 10, 25, and 35 °C, respectively.

Micellar Self-Assembly of Thermo-Responsive Diblock Copolymers. Below 5 °C, the PPO33-GAMA50 diblock copolymer was molecularly dissolved, as judged by its relatively low scattered light intensity. At around the cloud point for the PPO block,37 near-monodisperse micelles (polydispersity ) 0.15) of around 50 nm were formed at 20 °C. No significant size difference was obtained at various scattering angles (30-150°), which suggests that these aggregates are approximately spherical. Their relatively large size compared to conventional micelles is best explained by the hydrated nature of the PPO block in the micelle cores. This interpretation is supported by variable temperature 1H NMR studies of the same diblock dissolved in D2O, see Figure 8. The PPO signal at 1.45 ppm is clearly visible at lower temperatures but becomes progressively more attenuated at higher temperatures due to the gradual dehydration



Figure 9. Surface tension vs temperature curves for 0.50 w/v % aqueous solutions of the PPO33-GAMA50 (b) and PPO33-LAMA50 (O) diblock copolymers at pH 7. According to DLS studies both diblock copolymers were molecularly dissolved at 5 °C but formed PPO-core micelles above 15 °C, which corresponds approximately to the cloud point of the PPO block.

of the PPO block (resulting from its reduced hydrogen bonding interaction with the surrounding water molecules). On the other hand, in contrast to the pH-responsive micelles, the PPO signal always remains visible. This suggests that the PPO-core micelles remain partially hydrated. Finally, temperature-induced micellar self-assembly is completely reversible: on cooling the hot diblock copolymer solution, rapid dissociation of the micelles occurs. The PPO33-LAMA50 diblock copolymer also exhibited thermo-responsive behavior, as expected. It dissolved molecularly at 2 °C but was only weakly surface-active at this temperature, because both blocks are well solvated. Variable temperature 1H NMR studies of the PPO33-LAMA50 diblock (not shown) produced essentially the same results as those depicted in Figure 8 for the PPO33-GAMA50 diblock copolymer. Surface tension vs temperature plots are shown in Figure 9. Above approximately 20 °C, the PPO chains become adsorbed at the air/water interface and the surface tension is lowered. Very similar limiting surface tensions of around 37 mN m-1 were obtained for the PPO33-LAMA50 and PPO33-GAMA50 diblock copolymers. Dynamic light scattering studies indicated that the PPO33-LAMA50 diblock formed PPO-core micelles with an intensity-average diameter of approximately 38 nm at 20 °C. Finally, a TEM image of PPO33-LAMA50 copolymer micelles adsorbed onto a carboncoated copper grid at 20 °C is shown in Figure 10. The mean number-average micelle diameter was estimated to be around 50 nm. Given that the intensity-average diameter of these micelles in aqueous solution is around 38 ( 7 nm, the larger TEM diameter suggests that the adsorbed micelles are somewhat flattened on the grid. Similar spreading effects have been recently reported for other diblock copolymer micelles.30,39 Conclusions The synthesis of two new sugar methacrylate monomers, GAMA and LAMA, has been achieved under mild conditions

Figure 10. Transmission electron micrograph depicting PPO33LAMA50 diblock copolymer micelles prepared at 20 °C. The average particle diameter is around 50 nm, which suggests some spreading of these micelles on the TEM grid. Scale bar is 0.50 µm.

without recourse to protecting group chemistry. ATRP was exploited for the direct synthesis of a range of well-defined GAMA-based homopolymers and diblock copolymers in protic media at 20 °C. Poor living character was obtained in water, but controlled polymerization of GAMA was achieved in either pure methanol or a 9:1 methanol/water mixture. Reduced control, as evidenced by a higher polydispersity (Mw/Mn ) 1.48), was obtained in a 3:2 methanol/water mixture. Unfortunately, the cyclic sugar monomer, LAMA, proved to be insoluble in pure methanol. However, controlled polymerizations with low polydispersities (Mw/Mn e 1.26) were achieved in both a 3:2 methanol/water mixture and also NMP at 20 °C, although the latter solvent precluded the use of NMR to study polymerization kinetics. Good blocking efficiencies were obtained with both GAMA and LAMA, which enabled the synthesis of a range of well-defined, stimulus-responsive sugar-based diblock and triblock copolymer surfactants with predictable aggregation behavior in aqueous solution. For example, PPO33-GAMA50 and PPO33-LAMA50 diblocks exhibited very similar thermoresponsive aggregation behavior at elevated temperatures. On the other hand, unexpected qualitative differences were observed for at least one pH-responsive block copolymer: the critical micellization pH for a LAMA25-DEA50 diblock copolymer differed by at least one pH unit compared to a PEO23-GAMA30-DEA60 triblock (and all other DEA-based block copolymers reported to date). Acknowledgment. EPSRC is thanked for postdoctoral funds to support R.N. (GR/R29260). Rohm (Germany) and Cognis Performance Chemicals (Hythe, U.K.) are thanked for their kind donation of GMA monomer and the monohydroxy-capped PEO and PPO precursors, respectively. Mr. P. D. Iddon is thanked for his assistance in preparing some of the figures for this paper.

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BM034166E

Synthesis and Aqueous Solution Properties of Novel Sugar

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