Linear-hyperbranched graft-copolymers via grafting-to strategy based on hyperbranched dendron analogues and reactive ester polymers

Article abstract of DOI:10.1021/ma300972v

The synthesis of hyperbranched polyglycerol dendron analogues with precisely one focal amino functionality (H₂N-hbPG) and their use for the synthesis of linear-hyperbranched graft-copolymers in a grafting-to approach is reported. By use of N,N-

Full text of DOI:10.1021/ma300972v

Article
pubs.acs.org/Macromolecules
Linear-Hyperbranched Graft-Copolymers via Grafting-to Strategy
Based on Hyperbranched Dendron Analogues and Reactive Ester
Polymers
†
,‡
†
†,‡
†
†
†,
Christoph Schu
̈
ll, Lutz Nuhn, Christine Mangold, Eva Christ, Rudolf Zentel, and Holger Frey *
†
Institute of Organic Chemistry, Johannes Gutenberg-University Mainz (JGU), Duesbergweg 10-14, D-55128 Mainz, Germany
‡Graduate School Materials Science in Mainz (MAINZ), Staudingerweg 9, D-55128 Mainz, Germany
*
S Supporting Information
ABSTRACT: The synthesis of hyperbranched polyglycerol dendron
analogues with precisely one focal amino functionality (H N-hbPG)
2
and their use for the synthesis of linear-hyperbranched graft-
copolymers in a grafting-to approach is reported. By use of N,N-
dibenzyl tris(hydroxylmethyl) aminomethane as a novel initiator for
the ring-opening multibranching polymerization of glycidol, dendron
analogues with one focal amino functionality of molecular weights
−1
ranging from 500 to 15000 g mol and narrow to moderate
polydispersities (M /M = 1.2−1.9) were synthesized, as confirmed
w
n
by NMR and SEC. After removal of the benzyl protective groups, the
accessibility and selective transformation of the focal amino group was
demonstrated by NMR and MALDI−ToF MS. H N-hbPG was then selectively grafted to a linear reactive ester polymer
2
backbone, poly(pentafluorophenol methacrylate) (PPFPMA), to obtain linear polymers with highly branched side chains of high
−
1
molecular weights (M > 126 kg mol ) and low polydispersities (M /M = 1.1−1.3), as shown by SEC. Successful attachment
n
w
n
19
of the hyperbranched polyether structure to the linear backbone was confirmed by F NMR and fluorescence spectroscopy. The
modular approach introduced bears some analogy to the convergent dendrimer synthesis and describes the first linear-
hyperbranched graft-copolymers prepared in a grafting-to approach, resulting in hyperbranched brush-type polymers with the
highest molecular weight reported to date.
INTRODUCTION
molecular weight polyglycerol brush-type polymers with linear
or perfectly branched side chains via the grafting-through
■
Combining specific functionality and polymer architecture is
6
−8
method.
Still, only few works have dealt with synthesis
important for the generation of novel materials for future
1
strategies toward “imperfect” DenPols, i.e., linear-hyper-
applications. The combination of linear and dendritic or
9
,10
branched graft-copolymers.
Recently, the so-called “hyper-
hyperbranched polymers results in novel multifunctional
polymers with unusual topologies. The objective of this
work is (i) the synthesis of novel hyperbranched polyglycerol
hbPG) dendron analogues and (ii) their use for the generation
2
grafting” strategy was employed to synthesize linear-hyper-
branched graft-copolymers based on a linear poly(4-hydroxy
11
styrene) core and hyperbranched polyglycerol side-chains.
(
However, to the best of our knowledge, no grafting-to strategy
has been applied to date for the preparation of such
hyperbranched brush-type polymers. This approach would
permit to synthesize the linear backbone and the hyper-
branched side chain individually, that is in a modular approach
that would permit tailoring of the side-chain density.
of linear-hyperbranched graft-copolymers, based on a linear
poly(pentafluorophenol methacrylate) (PPFPMA) backbone in
a grafting-to approach.
Linking linear and branched polymer architectures gives
access to complex, multifunctional polymer architectures.
Dendronized polymers (DenPols), i.e., linear polymers with
perfectly branched dendron side chains, are a well-established
class of macromolecules for a variety of potential applica-
Dendrons are perfectly branched dendrimer segments with a
1
2
single focal functional group. They permit orthogonal
functionalization of either one focal or multiple terminal
dendritic end-groups. While in most cases monodisperse
dendrons or dendrimers are only available in demanding
multistep syntheses, hyperbranched polymers can usually be
3
,4
tions. The sterically demanding side chains force the linear
backbone into a cylindrical conformation, leading to “molecular
objects” of extremely high molecular weight and defined
5
orientation. In a so far sparsely studied alternative approach,
well-defined hyperbranched side chains might be attached to a
linear backbone. It still remains an intriguing issue, whether
hyperbranched side chains might as well lead to a stretching of
the linear backbone. Several works presented syntheses of low
Received: May 15, 2012
Revised: July 3, 2012
©
XXXX American Chemical Society
A
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Figure 1. Schematic representation of the synthesis of linear-hyperbranched graft copolymers via grafting-to strategy.
1
3,14
synthesized in one reaction step,
representing an imperfect
alcohols to form stable amides is a key feature for attachment of
alternative to dendrons. Hyperbranched polyglycerol (hbPG) is
obtained by ring-opening multibranching polymerization
the hbPG dendron analogues to PPFPMA without cross-
linking.
21
(
ROMBP) of glycidol in a broad range of molecular weights
In the current work, we present the synthesis of hbPG
dendron analogues containing exactly one focal amino group,
accessible by three synthesis steps using a trifunctional initiator.
The polymers have been characterized by NMR spectroscopy,
SEC and MALDI−ToF MS. Moreover, the first synthesis of a
linear-hyperbranched graft-copolymer based on poly-
(pentafluorophenol methyacrylate) (PPFPMA) and hbPG
side chains in a novel grafting-to approach is described (Figure
1). Furthermore, it was demonstrated that after grafting of
hbPG to PPFPMA, residual PFP-repeat units can be selectively
addressed without further work-up after the first coupling step.
This was achieved by adding an excess of 2-hydroxypropyl-
amine to convert residual PPFPMA repeat units into
biocompatible poly(2-hydroxy propylamide) (PHPMA). The
novel grafting-to approach gives novel complex polymer
architectures that are valuable for potential biomedical
applications.
−1
(
500−700 000 g mol ) with moderate to narrow polydisper-
1
5,16
sities (M /M = 1.3−1.8).
applications.
and is considered for a variety of
w
n
1
7,18
In earlier works of our group, various initiators
were incorporated as cores for the synthesis of hbPG, but to
date only low molecular weight photoactive or nonfunctional
19
2
0
cores have been used as initiators for the synthesis of hbPG
by ROMBP.
In a different approach, we coupled linear-hyperbranched
block copolymers based on linear poly(ethylene glycol) with a
single amino-functionality and a hyperbranched polglycerol
2
1
block to biotin. In elegant works, the groups of Haag and
Zimmerman presented stepwise constructed, perfectly
23
22
branched polyglycerol dendrons with focal amine or alkyne2
functionalities, demonstrating use as soluble supports for dyes
4
25
or for surface functionalization. Haag and co-workers used a
dibenzyl-protected amino compound for the synthesis of hbPG
dendron analogues, which were used as building blocks for
unimolecular dye transporters. In the current work, we
introduce a novel trifunctional amine-based initiator for the
ROMBP of glycidol that leads to exactly one focal amine
functionality at the hbPG scaffold.
The reactive backbone precursor polymers for our grafting-to
approach can be synthesized via controlled radical polymer-
ization, affording well-defined materials with narrow poly-
dispersity and high reactivity. One of the most frequently used
techniques that gives access to a variety of reactive monomers is
26
EXPERIMENTAL SECTION
Materials. All reagents were purchased from Acros Organics or
Sigma-Aldrich and used as received, unless otherwise stated. Glycidol
■
and diglyme were freshly distilled from CaH prior to use. Anhydrous
2
THF and 1,4-dioxane were freshly distilled from a sodium/potassium
mixture. 2,2′-Azobis(isobutyronitrile) (AIBN) was recrystallized from
diethyl ether and stored at −7 °C.
Instrumentation. 1H NMR and 13C spectra were recorded at 300
and 75 MHz, respecttively, on a Bruker AC300 and were referenced
1
9
internally to residual proton signals of the deuterated solvent.
F
2
7,28
RAFT (reversible addition chain transfer) polymerization.
NMR spectra were recorded on a Bruker 400 MHz FT NMR
spectrometer. For size exclusion chromatography (SEC) measure-
ments in tetrahydrofuran (THF) a PU 1580 pump, an auto sampler
AS1555, a UV-detector UV 1575 (detection at 254 nm) and an RI-
detector RI 1530 from JASCO were used. Columns were obtained
We chose poly(pentafluorophenyl methacrylate) (PPFPMA) as
a well-established reactive ester polymer. This material can be
conveniently synthesized by RAFT with controlled molecular
weights and low polydispersity and shows selective reactivity
toward primary amines.
block was used to obtain well-defined polymer architectures or
2
from MZ-Analysentechnik: MZ-Gel SDplus 10 Å and MZ-Gel SDplus
2
9,30
In various works, this building
6
1
0
Å. Calibration was carried out with polystyrene standards
purchased from Polymer Standard Services (PSS). For SEC
measurements in DMF (containing 0.25 g/L of LiBr), an Agilent
1100 series was used as an integrated instrument including a PSS Gral
3
1,32
for biomedical applications.
PPFPMA repeat units toward amines in the presence of
The selective reactivity of the
B
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Scheme 1. Three-Step Synthesis Strategy for Hyperbranched Polyglycerol Dendron Analogues (H N-hbPG) Bearing One Focal
2
Amino Functionality
6
4
2
column (10 /10 /10 Å porosity) and RI as well as UV detector.
Calibration was achieved with poly(ethylene glycol) standards
provided by PSS. UV−vis spectra were recorded using a Jasco V-
Synthesis of PhNHCSNH-hbPG. A 25 mg sample of H N-hbPG
2
was dissolved in 1 mL of methanol with a catalytic amount of
triethylamine, and then two drops of phenyl isothiocyanate were
added. The mixture was shaken at 50 °C for several minutes,
concentrated, precipitated into an excess of diethyl ether, and dried
under vacuum. Yield: quantitative.
6
30 Spectrophotometer (1 cm × 1 cm quartz cell). Matrix-assisted
laser desorption and ionization time-of-flight mass spectrometry
MALDI−ToF MS) measurements were performed on a Shimadzu
Axima CFR MALDI-TOF mass spectrometer using dithranol (1,8,9-
tris(hydroxyanthracene)) or CHCA (α-Cyano-4-hydroxycinnamic
acid) as a matrix. The samples were prepared from methanol and
ionized by adding aliquots of lithium chloride or potassium triflate.
Synthesis of N,N-Dibenzyl Tris(hydroxymethyl) Amino-
methane (Bn TRIS). A mixture of 17 g of benzyl bromide (0.1
mol), 5.5 g (0.045 mol) of tris(hydroxymethyl) aminomethane, 13.8 g
of K CO (100 mmol), and 150 mL of DMF were refluxed for 24 h.
After cooling the reaction mixture to room temperature, the solution
was filtrated and DMF was removed in vacuo. Then, 300 mL of CHCl3
were added, and the organic phase was washed with water (3 × 200
mL) and saturated NaHCO solution and dried with MgSO . The
solvent was removed in vacuo, and a highly viscous, slightly yellow
liquid was obtained. The crude product mixture was purified by
recrystallization from ethyl acetate, giving a white solid of the desired
(
Synthesis of Poly(pentafluorophenol methacrylate)
PPFPMA). As an example, the synthesis of PPFPMA95 is described.
(
Pentafluorophenyl methacrylate and the chain transfer agent (CTA)
3
2
were synthesized as described recently. For a typical RAFT
polymerization, a Schlenk tube equipped with a stirring bar was
loaded with pentafluorophenyl methacrylate (PFPMA) (2.00 g; 7.93
mmol), 4-cyano-4-(phenylcarbonothioylthio)pentanoic acid (26.0 mg;
0.09 mmol) and AIBN (1.5 mg; 0.01 mmol). All compounds were
dissolved in anhydrous dioxane (2 mL). Following three freeze−
pump−thaw cycles, the tube was immersed in an oil bath at 65 °C for
about 42 h under vigorous stirring. The resulting polymer was isolated
by precipitation in hexane and centrifugation. After redissolving in few
milliliters of dioxane, this process was repeated three times. The
precipitated polymer was dried for 12 h at 40 °C under 10 mbar
vacuum affording P(PFPMA)95 (1.15 g; 58%) as a slightly red powder.
2
2
3
3
4
1
product which was dried under vacuum (yield: 80%). H NMR (300
SEC (THF, PS-Std.): M
n
= 18 000 g/mol; M
w
= 22 800 g/mol; PDI =
1
MHz, DMSO-d ): δ (ppm) = 7.28−7.02 (m, 10H, aromatic), 4.34−
1.26. H NMR (CDCl
−CH −) and 1.80−0.80 (br, 3H, −CH
MHz): δ [ppm] = 172.90 (−CO −); 143.50−141.29 (o-ArC);
3
, 300 MHz): δ [ppm] = 2.80−2.00 (br, 2H,
6
13
4
.26 (br, 3H, OH), 3.99−3.91 (4H, PhCH N), 3.55−3.45 (d, 6H,
2
). C NMR (CDCl , 75
3 3
2
1
3
CCH OH). C NMR (75 MHz, DMSO-d ): δ (ppm) = 142.6, 128.1,
2
2
6
1
39.92−139.16 (p-ArC); 136.30−135.23 (m-ArC); 124.72 (ArC−O);
52.55 (Cquat. polymer main chain); 46.05 (−CH - polymer main
chain); 18.25 (−CH , 376
polymer main chain). 19F NMR (CDCl
1
27.7, 126.0 (Carom.), 65.4 (Bn NC), 60.8 (CH OH), 53.7 (PhCH ).
2 2 2
Synthesis of N,N-Dibenzyl Tris(hydroxymethyl) Amino-
2
methane Initiated Hyperbranched Polyglycerol (Bn TRIS-
3
3
2
hbPG). For the preparation of 1 g of polymer 0.3 mol % (compared
MHz): δ [ppm] = −150.31 to −151.39 (br, 2F, o-ArF); −156.91 (br,
1F, p-ArF); −162.05 (br, 2F, m-ArF).
to the number of hydroxyl groups) of cesium hydroxide monohydrate
were added to a suspension of Bn TRIS in dry benzene. The mixture
Removal of Dithiobenzoate End Groups. Dithiobenzoate end
groups of polymers synthesized by RAFT polymerization can be
2
was stirred for 1 h at room temperature and the solvents were
subsequently removed under high vacuum at 90 °C. The initiator salt
was dissolved in diglyme and a solution of glycidol in diglyme was
added using a syringe pump at 100 °C. The highly viscous product was
dissolved in methanol, stirred with a cation exchange resin for 30 min,
33
removed according to a procedure reported by Perrier et al. For a
typical reaction, in a Schlenk tube equipped with a stir bar, PPFPMA95
(0.60 g; 0.033 mmol), and azobis(isobutyronitrile) (AIBN) (0.16 g;
0.98 mmol; 30 times excess in relation to the polymer end group)
were dissolved in 6 mL of anhydrous dioxane under nitrogen
atmosphere. The reaction mixture was kept at at 80 °C for 4 h while
stirring vigorously. When the polymer solution turned colorless, the
polymer was isolated by precipitation in a 1:1 mixture of hexane/
diethyl ether and centrifugation. After redissolving in a few milliliters
of dioxane, this process was repeated three times. The precipitated
polymer was dried for 12 h at 40 °C under 10 mbar vacuum, affording
PPFPMA95 (0.48 g; 80%) as a colorless powder. The absence of the
dithiobenzoate group was confirmed by UV−vis spectroscopy
filtrated, concentrated and precipitated into cold diethyl ether. Yields:
1
9
1
0%. H NMR (300 MHz, MeOH-d ): δ (ppm) = 7.32−7.00 (m,
4
0H, aromatic), 4.10−3.96 (br, OH), 3.83−3.40 (polyether back-
13
bone). C NMR: For detailed peak assignment of the hyperbranched
repeat units see Figure S3 (Supporting Information).
Deprotection to Hyperbranched Polyglycerol Dendron
Analogues with Exactly One Amino Group (H N-hbPG). A 0.7
g sample of Bn TRIS-hbPG was dissolved in 60 mL of methanol, and
50 mg of palladium hydroxide on charcoal (10%) was added. The
reaction vessel was flushed with hydrogen (50−80 bar) and the
reaction was allowed to stir for 72 h at room temperature. The
2
2
1
(absorption maxima at 310 and 500 nm disappear). SEC: M = 24
n
1
000 g/mol; M = 27 200 g/mol; PDI = 1.13. H NMR (CDCl , 300
w
3
solution was filtered, concentrated, and precipitated into cold diethyl
MHz): δ [ppm] = 2.80−2.10 (br, 2H, −CH −) and 1.80−0.80 (br,
2
1
13
ether. Yields: 90%. H NMR (300 MHz, MeOH-d ): δ (ppm) = 4.10−
3H, −CH ). C NMR (CDCl , 75 MHz): δ [ppm] = 172.90
4
3
3
13
3
.96 (br, OH), 3.83−3.40 (polyether backbone). C NMR: For
(−CO −); 143.50−141.29 (o-ArC); 139.92−139.16 (p-ArC); 136.30−
2
detailed peak assignment of the hyperbranched repeat units see Figure
S4 (Supporting Information).
135.23 (m-ArC); 124.72 (ArC−O); 52.55 (C polymer main chain);
quat.
46.05 (−CH − polymer main chain); 18.25 (−CH polymer main
2
3
C
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chain). 19F NMR (CDCl , 376 MHz): δ [ppm] = −150.31 to −151.39
3
hbPG141 (Table 1, no. 8), we used Bn TRIS-hbPG (Table 1,
2
4
(
br, 2F, o-ArF); −156.91 (br, 1F, p-ArF); −162.05 (br, 2F, m-ArF).
Synthesis of Poly(hb-polyglycerol methacrylamide-co-pen-
no. 1) as a macroinitiator, while for the synthesis of Bn TRIS-
2
tafluorophenol methacrylate) (P(hbPGMA-co-PFPMA)).
Table 1. Characterization Data of All Bn TRIS-hbPG and
2
PPFPMA and the corresponding amount of H N-hbPG were dissolved
2
H N-hbPG Samples
in a mixture (1:1) of dry dimethyl sulfoxide and 1,4-dioxane. After the
addition of dry triethylamine (5 equiv per PPFPMA), the reaction
mixture was stirred under argon atmosphere at 50 °C for 24 h. The
product was purified by dialysis against water or methanol and dried
by freeze-drying or in vacuo at room temperature.
2
a
b
c
d
d
no.
composition
Mn
Mn
Mn
PDI
1
2
3
4
5
6
7
8
9
Bn TRIS-hbPG4
500
900
600
1180
1410
2310
2720
3020
9600
10 800
14 880
−
420
880
1.19
1.24
1.45
1.48
1.42
1.72
1.60
1.94
1.80
1.36
1.67
1.51
1.69
2
Bn
2
Bn
2
TRIS-hbPG
8
Fluorescamine Reaction. A 16 mg sample of H N-hbPG32 were
TRIS-hbPG15
1000
1500
2500
2700
6000
10 000
15 000
1000
1230
2130
1150
1500
2100
2850
4760
6860
8280
610
2
dissolved in 0.5 mL of dry dimethyl sulfoxide after the addition of
triethylamine. A 10 mg sample of PPFMA61 in 0.5 mL of dry dioxane
was added and the reaction was stirred at 50 °C. After 24 h, a 0.5 mL
aliquot of the reaction mixture was reacted with 3.5 mL of a solution of
fluorescamine (5 mg in 50 mL of acetone) and the reaction was
quenched by adding an excess of 10 mM borate buffer. Fluorescence
spectra of the solution were measured at λex = 391 nm at room
temperature.
Bn TRIS-hbPG
2
27
Bn TRIS-hbPG
2
32
Bn TRIS-hbPG
2
36
Bn TRIS-hbPG
2
125
141
200
e
e
Bn TRIS-hbPG
2
Bn TRIS-hbPG
2
10
11
12
13
H N-hbPG8
2
H N-hbPG
−
−
−
860
2
15
H N-hbPG
1150
3910
RESULTS AND DISCUSSION
2
32
■
H N-hbPG
9420
b
2
125
A. Hyperbranched Dendron Analogues. A novel
protected, trifunctional initiator-core for the synthesis of
polyglycerol, viz. N,N-dibenzyl tris(hydroxymethyl) amino-
a
1
Determined by H NMR data. Targeted molecular weight in g
mol (for entry 10−13: calculated from H NMR data of the
corresponding protected dendron analogues). Determined by
NMR in g mol . Determined by SEC (DMF, PEG-Std.) in g mol .
Synthesized using the macroinitiator-strategy.
−
1
1
c
1
H
methane (Bn TRIS) was synthesized in one step, using benzyl
−1
d
−1
2
bromide and tris(hydroxymethyl)aminomethane (TRIS)
e
3
4
(
Scheme 1). The general concept to use benzyl protective
groups has been employed in other works where linear
functional poly(ethylene glycols) or linear-hyperbranched
hbPG200 (Table 1, no. 9), Bn TRIS-hbPG (Table 1, no. 2) was
2
8
employed. These results expand the applicability of the
macroinitiator-strategy for the controlled synthesis of high
molecular weight hbPGs from homopolymers to benzyl
protected functional dendron analogues of molecular weights
α,ω -telechelics were synthesized using monofunctional
n
2
1,35
initiators.
However, the availability of three hydroxyl
groups presented here is crucial to secure control over glycidol
polymerization and to realize low polydispersity of the
−1
36
exceeding 6000 g mol .
hyperbranched polymers. The benzyl protective groups
allow the introduction of exactly one amino functionality
under the basic conditions present in the oxy-anionic
polymerization process. To prepare the reactive initiator for
Molecular weight determination was achieved both by SEC
1
and H NMR spectroscopy. Figure 2a shows a typical SEC
diagram of Bn TRIS-hbPG with the signals of a refractive index
2
(
RI) and a UV detector. Monomodal molecular weight
the ROMBP of glycidol, the hydroxyl groups of Bn TRIS were
2
partially deprotonated (30%) using cesium hydroxide. The
benzyl protective groups increase the solubility of the
deprotonated initiator, therefore higher degrees of deprotona-
tion compared to the established and commercially available
initiator TMP (1,1,1-trimethylol propane) can be used. A high
degree of deprotonation and good solubility of the initiator at
high concentration in the reaction solvent are advantageous to
keep the ROMBP of glycidol under control. Side-reactions,
such as self-initiation of glycidol leading to low molecular
weight side-products were not observed. The high degree of
deprotonation and high concentration of the partially
deprotonated initiator in the reaction solvent favors the
incorporation of the initiator over the self-initiation of glycidol,
which would lead to the undesired formation of hbPG
homopolymers and cyclic species. Glycidol was added slowly
in high dilution at 100 °C, following the established slow
monomer-addition (SMA) procedure (Scheme 1) to give the
benzyl-protected hbPG dendron analogues (Bn TRIS-hbPG).
2
Our studies demonstrate that the direct synthesis of dendron
analogues of this type with controlled molecular weights
−1
exceeding 6000 g mol is difficult using Bn TRIS as an
2
initiator. It is known from the literature that hbPG with higher
molecular weights are difficult to synthesize because of the high
viscosity of the products and the low number of alkoxide end
groups at high degree of polymerization. This problem can be
overcome by using hbPG polymers with medium molecular
Figure 2. SEC diagrams (measured in DMF) of (a) Bn TRIS-hbPG
2
8
16
weights as macroinitiators. For the synthesis of Bn TRIS-
and (b) several Bn TRIS-hbPG samples (RI-detector signal).
2
2
D
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distributions before and after the reaction work-up and full
overlap of RI and UV detector signal resulting from the benzyl
protective groups support complete incorporation of the
initiator into the polymer structure. Deviations of molecular
weights measured by SEC from the targeted molecular weights
are a consequence of the use of linear polymer standards
deprotected dendron analogues H N-hbPG can only be
2
determined by SEC. The hydrogenation of Bn TRIS-hbPG
2
with molecular weights exceeding 10 000 g mol− (Table 1, no.
8 and no. 9) remained incomplete even after several days or
weeks of reaction time and led in some cases to bimodal
molecular weight distributions, probably due to sterically
hindered accessibility of the focal protected amino group in
the highly branched polymer structure. In addition, samples
1
(
poly(ethylene glycol) (PEG)) for the measurement of the
branched polymer structures. Figure 2b shows selected SEC
1
3
1
results for several Bn TRIS-hbPG samples (RI-detector signal).
were characterized by C NMR. Like in the H NMR
2
13
Because of the oligomer-character of Bn TRIS-hbPG (Table 1,
spectrum, in the C NMR spectrum the signals of the
protective groups can also be clearly assigned (Figure S3,
Supporting Information). Four signals at 143.2, 129.8, 129.1,
and 127.7 ppm correspond to the aromatic benzyl moiety,
while the signal at 55.7 ppm corresponds to the benzyl
methylene carbons. After catalytic hydrogenation, no signals
2
4
no. 1), the SEC curve shows individual repeat-units (degree of
polymerization = 2, 3, and 4 at the peak maximum) in high
resolution.
1H NMR spectroscopy has been used to determine the
absolute number-average molecular weights (M ) by comparing
n
1
3
the clearly distinguishable integral of the signals of the benzyl
protective groups (7.32−7.00 ppm) and the polyether
backbone (3.83−3.40 ppm) (Figure 3). For all samples good
due to the benzyl protective group were observed in the
C
NMR spectrum (Figure S4, Supporting Information). In
agreement with quantitative removal of the benzyl protective
1
13
groups shown by H and C NMR spectroscopy and taking
into account that every polymer contains exactly one initiator
molecule, as shown by SEC, the presence of exactly one focal
amino group in every hbPG dendron analogue is achieved. It
should be mentioned that in some casesdepending on the
polymer concentration during hydrogenationH N-hbPG was
2
1
obtained as acetic ammonium salt, as can be seen from H
NMR spectroscopy (Figure S7, Supporting Information).
Characterization of the H N-hbPG samples by SEC showed
2
monomodal molecular weight distributions (Figure S6,
Supporting Information) with a shift to a higher elution
volume and thereby lower relative molecular weight compared
to the protected Bn TRIS-hbPG precursors. These results are
in agreement with the removal of the protective groups. The
2
Figure 3. 1H NMR spectra (300 MHz, MeOH-d ) of Bn TRIS-
4
2
hbPG32 and H N-hbPG confirming the successful removal of the
2
32
deviation of the PDI values for H N-hbPG compared to the
2
benzyl protective groups by catalytic hydrogenation.
corresponding Bn TRIS-hbPG samples is ascribed to inter-
2
action of the amines with the column material of the SEC setup
and has been observed for other amino-functional polymers
before.
Matrix-assisted laser desorption/ionization time-of-flight
mass spectrometry (MALDI−ToF MS) is a key technique for
the end group analysis of functional polymers and has been
agreement for M with the targeted values was found. The
n
molecular weights determined by NMR are usually slightly
1
higher than the targeted values. By comparing SEC and H
NMR results, it can be deduced that the control over molecular
weight and polydispersity is maintained for the whole series of
molecular weights. Usually, the molecular weight determined
employed to monitor the structure of H
stages of the synthesis. Figure 4a shows the MALDI−ToF
spectrum of Bn TRIS-hbPG15. Two molecular weight distribu-
tion modes with a mass difference of 74.1 g mol support
quantitative incorporation of Bn TRIS as an initiator. The first
N-hbPG at various
2
1
by SEC is lower than the data obtained by H NMR
spectroscopy (Table 1). The molecular weights of branched
polymer architectures are usually slightly underestimated in
SEC due to utilization of linear polymer standards, and
resulting change in hydrodynamic volume due to the densely
packed structure. This problem becomes more significant for
2
−1
2
distribution mode corresponds to the distribution with a proton
counterion, the other one to a distribution with potassium as a
counterion. Because of the presence of amines and alcohols as
well as sample preparation in protic methanol, species with
protons as counterions are generated and detected for low
molecular weight species. As an example, the highlighted signals
in Figure 4a at m/z = 1192.0 and m/z = 1229.9 correspond to
the 12-mers of Bn TRIS-hbPG with a proton (C H O N-
Bn TRIS-hbPG samples with molecular weight exceeding 6000
2
−1
g mol (Table 1, no. 8 and no. 9). The results obtained by
NMR are more reliable and were therefore used for the
nomenclature of the Bn TRIS-hbPG samples, the index n
2
n
1
representing the degree of polymerization calculated from H
NMR data.
2
18 20
3
+
In the third step, the benzyl protective groups were removed
by hydrogenation using Pearlman’s catalyst Pd(OH)2 on
charcoal (Scheme 1) in methanol, adding catalytic traces of
(C H O ) H ·H ; calculated isotopic mass = 1192.3 Da) and
3 6 2 12 3
+
with potassium (C H O N(C H O ) H ·K ; calculated
18
20
3
3
6
2
12
3
isotopic mass = 1229.4 Da) as a counterion. The data confirm
1
acetic acid. In the H NMR spectrum of the dendron analogue
(i) the suitability of Bn TRIS as an initiator for the ROMBP of
2
H N-hbPG no signals in the aromatic region (7.32−7.00
glycidol and (ii) the incorporation of one (protected) amine
functionality per polymer into the hyperbranched dendron
2
15
ppm) were observed after hydrogenation (Figure 3). These
results evidence successful removal of the benzyl protective
group. After removal of the benzyl protective group, no
structure. Interestingly, it was found that the deprotected H N-
2
hbPG is not detectable by MALDI−ToF MS, when potassium
as counterion and dithranol (1,8-dihydroxy-10H-anthracen-9-
1
distinguishable signal of the initiator group is visible in the H
NMR spectrum. Therefore, the molecular weight of the
on) as a matrix are used, while for Bn TRIS-hbPG this
2
E
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peak at m/z = 1239.2 corresponds to the 15-mer of H N-hbPG
2
+
with lithium as a counterion (C H O N(C H O ) H ·Li ;
4
8
3
3
6
2 15
3
calculated isotopic mass = 1239.3 Da). A monomodal
molecular weight distribution with a mass difference of 74.1
Da is in agreement with quantitative removal of the benzyl
protective groups and thus the existence of a focal amino
functionality in every macromolecule. This data supports the
1
results obtained by SEC and H NMR.
Selective chemical transformation of the focal amino
functionality is crucial for the use of H N-hbPG as a building
2
block for the synthesis of complex macromolecular structures.
Because of the special structure of H N-hbPG, no α-proton is
2
localized next to the amino group, which would be necessary
for the mechanism of the ninhydrin test, a classical chemical
37
detection reaction for amines. As expected, ninhydrin tests
gave negative results for H N-hbPG, supporting the absence of
2
the α-proton next to the amino group in H N-hbPG and
2
successful incorporation of Bn TRIS as initiator into the
2
polymer structure. Another possibility for the chemical
detection of amino groups is the use of isothiocyanate
derivatives. These can be used for the selective derivatization
of amines to thioureas in the presence of alcohols (Scheme S1,
Supporting Information). The formation of the thiourea
derivative (PhNHCSNH-hbPG) of H N-hbPG using phenyl
2
isothiocyanate (PHI) was demonstrated by SEC and MALDI−
ToF MS (Figure S8, Supporting Information). A shift of the
peak maximum in the elution volume in SEC shows a change in
the hydrodynamic volume by the additional hydrophobic group
(Figure S9, Supporting Information). As a consequence of this
derivatization reaction, we observed a UV signal in SEC
resulting from the incorporation of the phenyl group into the
hbPG structure (Figure S9a, Supporting Information). A
monomodal molecular weight distribution in SEC is not in
conflict with the assumption of selective functionalization of the
focal amino group at the dendron analogue. Additionally, in the
MALDI−ToF MS spectrum, PhNHCSNH-hbPG15 shows a
single molecular weight distribution corresponding to the
Figure 4. MALDI−ToF MS spectra of (a) Bn TRIS-hbPG (matrix:
2
15
dithranol) and (b) H N-hbPG (matrix: CHCA).
2
15
procedure gives excellent results. Detailed sample preparation
studies revealed that H N-hbPG with lithium as a counterion
2
and CHCA (α-cyano-4-hydroxycinnamic acid) as a matrix is an
optimal detection mode for this type of polymer. Figure 4b
shows the MALDI−ToF spectrum of H N-hbPG . It is known
2
15
for MALDI−ToF MS that low molecular weight compounds
are more easily desorbed than high molecular weight species.
This “mass discrimination effect” leads to the observed decrease
in peak intensity (Figure 4b) for increasing molecular weight of
monofunctionalized H N-hbPG derivative (Figure S8b). The
2
−1
peaks exhibit a mass difference of 74.1 g mol related to the
glycerol repeat units. As an example, the signal of
PhNHCSNH-hbPG13 (m/z = 1260.2; C H O N S-
20
the ionized polymers. As an example, the highlighted mass
11
13
3
2
Scheme 2. Synthesis of P(hbPGMA-co-PFPMA) Linear-Hyperbranched Graft-Copolymer Using Grafting-to Strategy and
Subsequential Functionalization of Residual PFP-Repeat Units by 2-Hydroxypropylamine, Leading to P(hbPGMA-co-HPMA)
F
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+
(
C H O ) H ·K ; calculated isotopic mass = 1258.5 Da) is
3
6
2 15
3
highlighted in Figure S8b, which can be correlated to the
derivatized dendron analogue with DP = 13 and potassium as a
counterion. This proves the selective addressability of the single
amino moiety in the presence of multiple hydroxyl groups by
reaction with isothiocyanates.
B. Grafting of the Dendron Analogues to the Linear
Chains: Linear-Hyperbranched Graft-Copolymers. Line-
ar-hyperbranched graft-copolymers are promising for various
potential applications, e.g., as templates for elongated
nanostructures or as “chain analogues” of conventional
hyperbranched homopolymers, where nonfunctional low
molecular weight core-molecules are used as initiators. The
use of hbPG as a building block also opens options for polymer
therapeutics with unusual topologies, due to the excellent
Figure 5. SEC elugrams (RI-detector signal, measured in DMF) of
PPFPMA95 (red, dashed) and P((hbPG125MA) -co-PFPMA ) (black,
solid).
10
85
38
biocompatibility of polyglycerol. Pentafluorophenol esters
allow selective chemical addressing of amines in the presence of
multiple alcohols, which makes them valuable candidates for
Table 2. Characterization Data of the Linear-Hyperbranched
Graft-Copolymers
2
1
the selective functionalization of H N-hbPG at the focal amino
2
functionality (Scheme 2). By attachment of H N-hbPG to
no.
Polymer Composition
M
n
M
w
M /M
w n
2
poly(pentafluorophenol methacrylate) (PPFPMA) a novel type
of linear-hyperbranched graft-copolymer, poly(hb-polyglycerol
methacrylamide-co-pentafluorophenol methacrylate) (P-
1
2
3
4
P((hbPG MA) -co-PFPMA )
138.9
161.6
126.4
123.2
183.8
188.2
153.0
164.3
1.32
1.16
1.21
1.33
32
10
85
P((hbPG MA) -co-PFPMA )
32
30
65
P((hbPG125MA) -co-PFPMA )
10
85
(
hbPGMA-co-PFPMA) is obtained, when an excess of
P((hbPG MA) -co-PHPMA )
32 12 49
PPFPMA repeat units with respect to H N-hbPG is reacted
2
to preserve residual PPFPMA repeat units for further
functionalization. To date, no grafting-to strategy has been
applied for the synthesis of linear-hyperbranched graft-
copolymers or oligomers. In this context, it is an important
question, if the steric hindrance of the dendron analogues
impedes the coupling reaction. To shed light on this issue, we
varied the molecular weight of the linear backbone and of the
hyperbranched dendron analogues. The linear backbone
poly(pentafluorophenol methacrylate) (PPFPMA) was synthe-
sized using RAFT polymerization, enabling excellent control
over molecular weight and polydispersity. Two backbone
polymers, PPFPMA95 and PPFPMA61 3(both M /M < 1.3)
PMMA standards, as they exhibit structural analogy to
PPFPMA. All samples exhibited low polydispersity indices
(
1
M /M < 1.3) and high molecular weights in the range of
26400 to 161600 g/mol. To the best of our knowledge, no
w n
polyglycerol brushes, with linear or dendritic side chains of this
high molecular weight have been described to date. It is worth
mentioning that when comparing P((hbPG MA) -co-
3
2
10
PFPMA ) and P((hbPG MA) -co-PFPMA ) (Table 2, no.
85
32
30
65
1 and no. 2) a 3-fold increase in the number of side chains gives
only an approximate increase of 15% in the number-average
molecular weight. This is in agreement with dense packing of
the side chains at the backbone, leading to no significant
increase in hydrodynamic volume detected by SEC.
w
n
2
were synthesized as previously described and characterized in
1
13
19
detail using H, C, F NMR, and UV/vis spectroscopy as
well as SEC (Table S1 and Figure S10−S13, Supporting
Information). For the grafting-to reaction, two dendron
analogues with different molecular weights, viz. H N-hbPG
To demonstrate successful conversion of the amino
functionality in H N-hbPG in the coupling reaction, a
2
2
32
fluorescamine assay, which is commonly known from protein
39
and H N-hbPG (Table 1, no. 12 and no. 13), were used, to
biochemistry, was used. Fluorescamine selectively forms a
fluorescent derivative after reaction with primary amines. The
unreacted dye and the quenched products, e.g., by addition of
water, do not show fluorescence. Moreover, the reaction is also
applicable in organic media, such as DMSO, dioxane and
acetone and thereby makes it a valuable tool for the monitoring
2
125
show the applicability of the synthesis strategy for varying size
of the dendron analogues.
Figure 5 shows the SEC diagrams of PPFPMA95 and the
corresponding graft-copolymer P((hbPG125MA) -co-
10
PFPMA ), where 10 molecules of H N-hbPG were attached
85
2
125
to PPFPMA95. The significant shift in elution volume confirms
of the conversion of H N-hbPG when reacted with PPFPMA.
2
successful grafting of H N-hbPG to the linear PPFPMA
Figure 6 shows the fluorescence spectra of the reaction mixture
under usual reaction conditions (DMSO/dioxane = 1:1, TEA,
50 °C) with and without the addition of PPFPMA61 to 0.2
equiv of H N-hbPG per PPFPMA repeat unit after 24 h. In
2
backbone, which is supported by an increase in molecular
weight, causing an increase of the hydrodynamic radius
detected by SEC. No residual signal of remaining PPFPMA95
can be seen, which is in agreement with the assumption of
complete transformation of the reactive PPFPMA backbone as
a linear building block for the synthesis of P((hbPG125MA)10-
co-PFPMA ).
2
32
61
the spectrum of H N-hbPG, the appearance of the peak
2
maximum at λ = 469.0 nm is in correspondence with the
availability of the focal amino functionality under the selected
reaction conditions during the whole reaction time, as shown
by the formation of the fluorescent derivative of fluorescamine.
When PPFPMA61 is present in the mixture, after 24 h only a
very low intensity fluorescence signal is observable. The novel
peak maximum at λ = 489.9 nm can be explained by the
excitation of residual PPFPMA repeat units and released
pentafluorophenol. These results show successful conversion of
85
Table 2 gives an overview of linear-hyperbranched graft-
copolymers P(hbPGMA-co-PFPMA) prepared. The molecular
weight of the polyglycerol dendron analogue, the number of
dendritic segments attached to the PPFPMA backbone and the
length of the PPFPMA backbone have been varied. Molecular
weights were determined via SEC in DMF, utilizing linear
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described previously, H N-hbPG was purified as acetic
2
ammonium salt, depending on the reaction conditions during
hydrogenation. Therefore, the formation of PFP-acetate as a
low molecular weight side product due to efficient release of
pentafluorophenol can be monitored (Figure 7b, sharp signals
at −154.2 (doublet), −159.6 (triplet), and −163.8 ppm
40
(
triplet)). Moreover, the presence of acetic acid/acetate in
the reaction mixture leads to a varying degree of deprotonation
of free PFP, evident from time-correlated shift variation of free
PFP in the spectra. A proposed reaction mechanism and more
detailed 19F NMR spectra showing this phenomenon can be
found in the Supporting Information (Scheme S2, Figure S14).
In addition to the SEC data showing high molecular weight
polymers after the grafting-to reaction and the fluorescamine
Figure 6. Fluorescence spectra of H N-hbPG (black, solid) and after
2
32
reacting with PPFPMA61 (red, dashed) under standard coupling
conditions (DMSO/dioxane = 1:1, 5 equiv TEA, 50 °C, 24 h) after
addition of fluorescamine with λex = 391 nm.
assay showing the consumption of the focal amine of H N-
2
hbPG, the release of pentafluorophenol confirms amide
formation between H N-hbPG and PPFPMA.
the focal amino groups of H N-hbPG during the reaction after
2
2
To demonstrate the formation of low molecular weight PFP
ester side products and to support the preservation of the
residual PPFPMA repeat units, the reaction mixture was
quenched by adding an excess of 2-hydroxy propylamine
2
4 h, and thereby indirectly permit the determination of the
number of the hbPG side chains in the linear-hyperbranched
graft-polymer, since all H N-hbPG dendron analogues are
transformed.
2
(
Scheme 2, Figure 7c). No remaining signals resulting from the
Pentafluorophenyl esters allow precise monitoring of the
1
9
PPFPMA backbone or from PFP acetate side products were
observed. This is in correspondence with the successful
synthesis of poly(hb-polyglycerol methacrylamide-co-(2-hy-
droxy propylamine) methacrylamide) (P(hbPGMA-co-
HPMA) and the enduring addressability of residual PPFPMA
coupling reaction by F NMR spectroscopy. Therefore, not
only the reaction of H N-hbPG can be monitored, as shown by
the fluorescamine reaction, but also the reaction of PPFPMA
using F NMR spectroscopy. In a typical experiment,
PPFPMA61 and 0.2 equiv H N-hbPG compared to the PFP
repeat units were mixed in a NMR tube and spectra were
2
1
9
2
32
repeat units after attachment of H
substitution of the PFP repeat units in PPFPMA with H
N-hbPG. By only partial
N-
2
19
recorded every 6 min at 50 °C for 14 h. Figure 7a shows the F
NMR spectrum of PPFPMA61 as a reference and an additional
spectrum after a reaction time of 14 h. One can clearly observe
the decrease of the PPFPMA backbone signals from −150.31 to
2
hbPG, additional functional amines can covalently be attached
in a one-pot procedure. Both components hbPG and PHPMA
1
8,41,42
19
are highly biocompatible.
SEC, fluorescence and
F
−
151.39 ppm and at −156.91 and −162.05 ppm. This is in
NMR spectroscopy confirm the successful synthesis of a linear-
hyperbranched graft-copolymer and a novel type of polyglycer-
ol-based brush-type polymer, which may open the path for
novel complex macromolecules that are especially valuable for
biomedical applications.
agreement with the assumption of high and selective reactivity
of PPFPMA with the focal amino functionalities of H N-hbPG.
Additionally, the signals resulting from released pentafluor-
ophenol (−169.5, −171.5, and −189.0 ppm) appear. As
2
Figure 7. 19F NMR spectra (376 MHz, measured in DMSO-d /1,4-dioxane=1:1 at 50 °C) of (a) PPFPMA , (b) P((hbPG MA) -co-PFPMA )
6
61
32
12
49
after 14 h of reaction time, (c) P((hbPG MA) -co-HPMA ), after addition of an excess of 2-hydroxy propylamine (HPA).
32
12
49
H
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CONCLUSION
ACKNOWLEDGMENTS
■
■
In summary, we have presented a facile three step synthesis for
the generation of hyperbranched polyglycerol dendron
C.S. and C.M. thank the Graduate School of Excellence
Material Science in Mainz “MAINZ” (DFG/GSC 266) for
financial support and acknowledge technical assistance from
Alina Mohr. L.N. gratefully acknowledges financial support by
the Max Planck Graduate Center (“MPGC”) and the Fond der
Chemischen Industrie (“FCI”). Moreover, the authors want to
thank Dr. Mihail Mondeshki for performing the F NMR
experiments and Dipl.-Chem. Jana Leppin for help with the
fluorescence measurements.
analogues (H N-hbPG), containing exactly one focal amino
2
group by use of a trifunctional initiator (Bn TRIS). First, a new
2
initiator Bn TRIS was synthesized, followed by the slow
2
addition of glycidol to create the hyperbranched dendron
1
9
analogue with controlled molecular weights (M = 500−15 000
n
−1
g mol ) and narrow to moderate polydispersities (M /M =
w
n
1
.3−1.9). Via catalytic hydrogenation the benzyl protective
groups were removed and the amino functionality was released.
The general chemical addressability of the amino group was
verified by derivatization using low molecular weight
isothiocyanate compounds.
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AUTHOR INFORMATION
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*
1
(
Corresponding Author
E-mail: hfrey@uni-mainz.de.
Notes
(
The authors declare no competing financial interest.
I
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dx.doi.org/10.1021/ma300972v | Macromolecules XXXX, XXX, XXX−XXX