Direct synthesis and aqueous solution properties of well-defined cyclic sugar methacrylate polymers

Article abstract of DOI:10.1021/ma034321h

The direct synthesis and aqueous solution properties of well-defined cyclic sugar methacrylate polymers were presented. The first step in the sugar monomer synthesis involved the preparation of lactobionolactone from lactobionic acid. The residual copper contents of the purified sugar polymers were determined by inductively coupled plasma atomic emission spectroscopy.

Full text of DOI:10.1021/ma034321h

Macromolecules 2003, 36, 4675-4678
4675
Dir ect Syn th esis a n d Aqu eou s Solu tion
P r op er ties of Well-Defin ed Cyclic Su ga r
Meth a cr yla te P olym er s
Ra vin Na r a in a n d Steven P . Ar m es*
School of Chemistry, Physics and Environmental Science,
Sussex University, Falmer, Brighton,
East Sussex, BN1 9QJ , UK
Received March 14, 2003
Revised Manuscript Received May 14, 2003
In tr od u ction . The exploitation of carbohydrates as
F igu r e 1. Synthesis of LAMA monomer by the ring-opening
reaction of 2-aminoethyl methacrylate with lactobionolactone
at 20 °C.
a renewable resource in polymer synthesis has been of
1
increasing interest. Moreover, synthetic carbohydrate
polymers can exhibit specific interactions with lectins
2
-5
and proteins.
Improved synthetic routes and control
In addition, both poly(ethylene oxide)-based [PEO-
Br] and poly(propylene oxide)-based [PPO-Br] macro-
initiators were employed; these were prepared as pre-
over copolymer architecture have become important
6
-8
objectives for a number of biomedical applications.
1
3
A wide range of well-defined, tailor-made polymers have
recently been prepared by various research groups using
viously reported. The homopolymerization of LAMA
was investigated in water, methanol/water mixtures,
and N-methyl-2-pyrrolidinone (NMP). The results are
summarized in Table 1. Because of its highly hydrophilic
nature, solubility problems were encountered for LAMA
in pure methanol. Hence the dipolar aprotic solvent
NMP was preferred for polymerizations conducted in
the absence of water. In unpublished work we have
recently established that a range of methacrylic mono-
mers can be polymerized by ATRP in NMP with good
control and low polydispersities (M /M < 1.30). As
9
atom transfer radical polymerization (ATRP). Because
of its radical nature, ATRP is tolerant of many func-
1
0
tional groups. The ATRP of various sugar monomers
has been investigated in recent years, but perhaps
surprisingly, most examples concern the (co)polymeri-
zation of protected sugar monomers. We have recently
reported the synthesis of controlled-structure sugar
methacrylate polymers by ATRP without the use of
protecting group chemistry.11 D-Gluconolactone was
reacted with 2-aminoethyl methacrylate in methanol at
w
n
shown in Table 1, the homopolymerization of LAMA
using both the PEO-based macroinitiators and the Ald-
Br initiator afforded low polydispersities and proceeded
to high conversions (>95%) in either a 3:2 methanol/
water mixture or NMP. The spent ATRP catalyst was
removed by treatment with basic alumina, followed by
freeze-drying of the concentrated aqueous polymer
solution. The final yield was 60-75%, indicating that
some polymer had adsorbed onto the alumina. For
syntheses conducted in NMP, the viscous reaction
mixture was first precipitated into 2-propanol and
redissolved in water prior to treatment with basic
alumina. The residual copper contents of the purified
sugar polymers were determined by inductively coupled
plasma atomic emission spectroscopy (ICP-AES) and
ranged from 3 to 26 ppm (Table 1).
2
0 °C to produce a ring-opened monomer, 2-gluconami-
doethyl methacrylate (GAMA). The ATRP of GAMA was
reasonably well controlled in both methanol and metha-
nol/water mixtures at 20 °C. Herein we report the facile
preparation of a second class of controlled-structure
sugar polymers without recourse to protecting group
chemistry. Moreover, in this case the cyclic sugar ring
is preserved during synthesis, which is a significant
advantage if molecular recognition applications are
sought.
Resu lts a n d Discu ssion . The first step in the sugar
monomer synthesis involves the preparation of lacto-
bionolactone from lactobionic acid. This was achieved
by dissolving the latter in dry methanol at 50 °C,
followed by vacuum distillation in the presence of a
catalytic amount of trifluoroacetic acid. This process was
repeated twice to ensure complete conversion of the acid
precursor to the lactobionolactone. The isolated dried
product was then reacted with 2-aminoethyl methacry-
late hydrochloride in methanol at room temperature for
Inspecting Table 1, the homopolymerization of LAMA
in pure water was rapid and not controlled (M /M >
w
n
1.50). In contrast, relatively low polydispersities (M /
w
M < 1.30) were obtained in both 3:2 methanol/water
n
mixtures and also NMP, suggesting reasonably good
5
h in the presence of triethylamine (see Figure 1 and
control under these conditions. The kinetics of polym-
erization were first-order with respect to LAMA up to
85% conversion using the Ald-Br initiator (see Support-
ing Information). Self-blocking (chain extension) experi-
ments were conducted in a 3:2 methanol/water mixture
at 20 °C. An initial degree of polymerization of 30 was
targeted, and a LAMA homopolymer was obtained with
an Mn of 12 150 [vs poly(methyl methacrylate) stan-
dards] and an M /M of 1.21 after 95% conversion
(Figure 3). On addition of a second batch of LAMA
monomer (overall target degree of polymerization ) 60),
the Mn approximately doubled to 22 400 as expected,
and the Mw/Mn remained narrow at 1.25. These results
indicate that this homopolymerization is reasonably well
Supporting Information). The reaction solution was
concentrated and poured into a large excess of cold
2
-propanol with vigorous stirring. The resulting white
crystalline powder was isolated by filtration and dried
under vacuum. 2-Lactobionamidoethyl methacrylate
1
(
LAMA) was obtained in 78% yield; analysis by H NMR
and high-resolution mass spectroscopy confirmed its
high purity (see Supporting Information). Polymeriza-
tion of LAMA was achieved using an aldehyde-func-
tionalized ATRP initiator12 (Ald-Br; Figure 2).
w
n
*
Corresponding author: Tel + 44 1273-677196, Fax + 44 1273
6
78650, e-mail S.P.Armes@sussex.ac.uk.
1
0.1021/ma034321h CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/31/2003

4
676 Communications to the Editor
Macromolecules, Vol. 36, No. 13, 2003
F igu r e 2. Homopolymerization of LAMA via ATRP in 3:2 methanol/water mixtures or NMP at 20 °C using an aldehyde-
functionalized initiator (Ald-Br).
Ta ble 1. Syn th esis P a r a m eter s a n d Molecu la r Weigh t Da ta for th e Hom op olym er iza tion of LAMA by ATRP in Va r iou s
Med ia a t 20 °C
ATRP solvent
composition
reactiona
time (h)
initiator
type
target
DPn
conversiona
(%)
copper
content (ppm)
Mnb
Mw/Mnb
c
entry no.
1
2
3
4
5
6
7
8
9
H2O
H2O
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-Brd
50
100
50
50
50
100
50
30
50
30
>95
>95
>95
34 800
28 800
23 400
22 500
25 300
32 300
23 200
12 500
18 900
10 000
19 200
8 600
1.60
1.78
1.10
1.24
1.26
1.20
1.24
1.22
1.26
1.17
1.19
1.22
3:2 MeOH/H2O
NMP
3:2 MeOH/H2O
3:2 MeOH/H2O
NMP
3:2 MeOH/H2O
NMP
3:2 MeOH/H2O
3:2 MeOH/H2O
NMP
7
8
>95
>95
17
>95
3
23
1
1
1
0
1
2
>95
>95
Ald-Br
50
30
26
Ald-Br
a
1
b
Reaction time to reach at least 95% conversion as determined by H NMR studies. Determined using DMF GPC [0.01 M LiBr and
c
PMMA as calibrants]. Copper content of the solid purified polymer as determined by inductively coupled plasma atomic emission
spectroscopy [ICP-AES]. Aldehyde-functionalized initiator.
d
low surface activity at pH 3 (Figure 4a). The periphery
of these LAMA-corona, DEA-core micelles contains
aldehyde groups derived from the Ald-Br initiator. In
principle, this should facilitate conjugation with biologi-
1
4
cally active motifs. Finally, a PPO33-LAMA50 diblock
copolymer (see entry 9 in Table 1) exhibited thermore-
sponsive behavior. It dissolved molecularly at 2 °C and
was only weakly surface-active at this temperature since
both blocks are well-solvated (Figure 4b). Above the
cloud point of the PPO block at approximately 15 °C,15
the diblock copolymer becomes surface-active due to
adsorption of the PPO chains at the air/water interface.
F igu r e 3. Self-blocking (chain extension) experiment for 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 a low polydispersity as the target
degree of polymerization is increased from 30 to 60.
1
Variable temperature H NMR studies confirmed re-
duced solvation of the PPO block at higher temperature
(see Supporting Information), and dynamic light scat-
tering studies indicated the formation of PPO-core
micelles with an intensity-average diameter of 38 ( 7
nm diameter at 20 °C. Above ambient temperature, the
surface activity of the LAMA-PPO diblock copolymer
increases progressively, with a limiting surface tension
controlled. The blocking efficiency of LAMA monomer
was also studied by sequential monomer addition with
other methacrylates such as glycerol monomethacrylate
(
GMA), 2-(diethylamino)ethyl methacrylate (DEA), and
GAMA in either a 3:2 methanol/water mixture or NMP.
A series of novel diblock and triblock copolymers with
polydispersities ranging from 1.28 to 1.34 were obtained
-
1
of 37 mN m being achieved at 40 °C (Figure 4b).
In summary, a range of novel well-defined sugar
methacrylate polymers has been synthesized by ATRP
without recourse to protecting group chemistry. This is
a significant extension of our earlier work in this area
since the sugar rings are preserved in the final copoly-
mer structures, which should facilitate a wider range
of applications. Use of an aldehyde-functionalized initia-
tor allows the construction of sugar methacrylate-
functionalized diblock copolymer micelles by reversible
pH-induced micellar self-assembly. The periphery of
these new micelles contains potential conjugation sites,
which should facilitate cell-targeting applications. An
example of thermoresponsive polymeric surfactant be-
(
Supporting Information). Two types of LAMA-based
stimuli-responsive diblock copolymers were prepared.
The Ald-Br initiator was used to prepare a pH-
responsive LAMA25-DEA50 diblock (Mn ) 17 300, Mw/
Mn ) 1.30) that was characterized by 1H NMR and
surface tension (see Supporting Information). As ex-
pected, this copolymer was molecularly dissolved below
pH 7 (due to protonation of the DEA residues) but
formed micelles above pH 7 (disappearance of DEA
1
signals observed by H NMR). This pH-reversible mi-
cellar self-assembly was further confirmed by the ob-
servation of high surface activity at pH 10.5 but only

Macromolecules, Vol. 36, No. 13, 2003
Communications to the Editor 4677
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 mL), and hydroquinone (0.25
g). The mixture was stirred for 5 h, concentrated by
rotary evaporation, and precipitated into either 2-pro-
panol or dichloromethane. The white solid formed was
filtered, washed with 2-propanol, and dried under
vacuum. Yield ∼ 78%.
c. A Typ ica l P r otocol for th e Hom op olym er iza -
tion of LAMA via ATRP a t 20 °C in a 3:2 Meth a n ol/
Wa ter Mixtu r e. 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 (0.09 g, 0.085 mmol,
target degree of polymerization ) 50) was then added,
and this solution was purged with nitrogen for 10 min.
Copper(I) bromide (0.01 g, 0.085 mmol) and 2 equiv of
2
,2′-bipyridine (0.03 g, 0.170 mmol) were added, and the
resulting dark brown solution was stirred under a
nitrogen atmosphere. The extent of polymerization was
1
monitored by H 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 PMMA as calibration
standards) of the LAMA homopolymer 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
polymer solution was freeze-dried overnight. The iso-
lated yield of the LAMA homopolymer was 73%. The
same protocol was used for ATRP syntheses in either
water or NMP. The reaction time required for 95%
conversion was significantly reduced to around 0.50 h
in pure water.
F igu r e 4. (a) Surface tension vs pH curve obtained for a
0
.50% (w/v) aqueous solution of the Ald-LAMA25-DEA50
diblock copolymer. (b) Surface tension vs temperature curve
for a 0.50% (w/v) aqueous solution of the PPO33-LAMA50
diblock copolymer at pH 7. According to DLS studies, this
diblock copolymer is molecularly dissolved at 5 °C and formed
PPO-core micelles above 15 °C, which corresponds approxi-
mately to the cloud point of the PPO block.
Ack n ow led gm en t. EPSRC is thanked for providing
postdoctoral support for R.N. (GR/R29260).
havior is also described.
Exp er im en ta l Section . a . Syn th esis of 2-Am in o-
eth yl Meth a cr yla te (AMA). Ethanolamine hydrochlo-
ride (65.0 g, 0.67 mol), methacryloyl chloride (100 mL,
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization. This material is available free of
charge via the Internet at http://pubs.acs.org.
0
.96 mol), and hydroquinone (0.50 g) were mixed in a
three-necked round-bottom flask fitted with a con-
denser. The mixture was then heated in an oil bath to
Refer en ces a n d Notes
(
1) (a) Wulff, G.; Schmid, J .; Venhoff, T. Macromol. Chem. Phys.
996, 14, 259. (b) Okada, M. Prog. Polym. Sci. 2001, 26, 67.
(c) Narain, R.; J hurry, D.; Wulff, G. Eur. Polym. J . 2002,
8, 273. (d) Wulff, G.; Schmidt, H.; Zhu, L. Macromol. Chem.
9
3-95 °C under a nitrogen atmosphere. The heteroge-
1
neous mixture of the molten salt and methacryloyl
chloride was stirred vigorously for 1 h at this temper-
ature; this reaction was highly exothermic. The hydro-
gen chloride gas evolved during the process was re-
moved 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
3
Phys. 1999, 200, 1619.
2) Kobayashi, K.; Tshuchida, A. Macromolecules 1997, 30,
(
2
016.
(3) Lee, Y. C.; Lee, R. T. Neoglycoconjugates: Preparation and
Application; Academic Press: San Diego, 1994.
4) Kobayashi, A.; Goto, M.; Kobayashi, K.; Akaike, T. J .
Biomater. Sci. Polym. Ed. 1994, 6, 325.
(
(
5) (a) Nagahori, N.; Nishimura, S.-I Biomacromolecules 2001,
2
, 21. (b) Strong, L.; Kiessling, L. L. J . Am. Chem. Soc. 1999,
121, 6193.
(
600 mL), and the creamy white precipitate that was
(6) Labeau, M.; Cramail, H.; Deffieux, A. Macromol. Chem.
Phys. 1998, 199, 335.
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. Yield ∼ 70%.
(
(
(
7) Chen, Y. M.; Wulff, G. Macromol. Chem. Phys. 2001, 202,
3
273.
8) Wang, J .; Tomito, I.; Endo, T. Macromolecules 2001, 34,
4294.
9) (a) Patten, T. E.; Xia, J .; Abernathy, T.; Matyjaszewski, K.
Science 1996, 272, 866. (b) Matyjaszewski, K.; Xia, J . Chem.
Rev. 2001, 101, 2921. (c) Kamigaito, M.; Ando, T.; Sawa-
moto, M. Chem. Rev. 2001, 101, 3689.
b. Syn th esis of 2-La ctobion a m id oeth yl Meth -
a cr yla te (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 process was repeated at least twice
until the acid was fully converted to the lactone. This
process can also be catalyzed by the addition of a small
(10) (a) Ohno, K.; Tsujii, Y.; Fukuda, T. J . Polym, Sci., Part A:
Polym. Chem. 1998, 36, 2473. (b) Chen, Y. M.; Wulff, G.
Macromol. Chem. Phys. 2001, 202, 3426. (c) Ejaz, M.; Ohno,
K.; Tsujii, Y.; Fukuda, T. Macromolecules 2000, 33, 2870.
(d) Chen, Y. M.; Wulff, G. Macromol. Rapid Commun. 2002,
23, 59.

4
678 Communications to the Editor
Macromolecules, Vol. 36, No. 13, 2003
(
11) Narain, R.; Armes, S. P. Chem. Commun. 2002, 2776.
(14) Nagasaki, Y.; Okada, T.; Scholz, C.; Iijima, M.; Kato, M.;
(12) Haddleton, D. M.; Waterson, C. Macromolecules 1999, 32,
Kataoka, K. Macromolecules 1998, 31, 1473.
8
732.
(
15) Liu, S.; Armes, S. P. Angew. Chem. Int. Ed. 2001, 40, 2328.
(
13) J ankova, K.; Chen, X. Y.; Kops, J .; Batsberg, W. Macromol-
ecules 1998, 31, 538.
MA034321H