Linear-Dendritic Alternating Copolymers

Article abstract of DOI:10.1002/anie.201903402

Herein, the design, synthesis, and characterization of an unprecedented copolymer consisting of alternating linear and dendritic segments is described. First, a 4th-generation Hawker-type dendron with two azide groups was synthesized, followed by a step-growth azide-alkyne “click” reaction between the 4th-generation diazido dendron and poly(ethylene glycol) diacetylene to create the target polymers. Unequal reactivity of the functional groups was observed in the step-growth polymerization. The resulting copolymers, with alternating hydrophilic linear and hydrophobic dendritic segments, can spontaneously associate into a unique type of microphase-segregated nanorods in water.

Full text of DOI:10.1002/anie.201903402

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Linear-Dendritic Alternating Copolymers
Authors: Haotian Sun, Farihah M Haque, Yi Zhang, Alex Commisso,
Mohamed Alaa Mohamed, Marina Tsianou, Honggang Cui,
Scott M Grayson, and Chong Cheng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903402
Angew. Chem. 10.1002/ange.201903402
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http://dx.doi.org/10.1002/ange.201903402

10.1002/anie.201903402
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Linear-Dendritic Alternating Copolymers
Haotian Sun,[a] Farihah M. Haque,[b] Yi Zhang,[a] Alex Commisso,[a] Mohamed Alaa Mohamed,[a,c]
Marina Tsianou,[a] Honggang Cui,[d] Scott M. Grayson,[b] and Chong Cheng*[a]
Abstract: Herein, the design, synthesis and characterization of an
unprecedented copolymer consisting of alternating linear and
dendritic segments is described. First, a 4th-generation Hawker-type
dendron with two azide groups was synthesized, followed by a step-
growth azide-alkyne “click” reaction between the 4th-generation
diazido dendron and poly(ethylene glycol) diacetylene to create the
target polymers. Unequal reactivity of functional groups was observed
in the step-growth polymerization. The resulting copolymers, with
alternating hydrophilic linear and hydrophobic dendritic segments,
can spontaneously associate into a unique type of microphase-
segregated nanorods in water.
macromolecules with contrasting regiospecific characteristics.
They have been studied due to their novel hybrid properties for a
variety of emerging applications.[4] As reported by Fréchet and co-
workers, the first examples of L-D copolymers (Figure 1a,b) were
prepared by coupling dendrons with a single reactive focal point
to linear polymers with
a
single functional end group.[5]
Subsequently, other approaches have also been developed to
synthesize L-D copolymers, with block,[6] star,[7] or brush-like
hybrid architectures.[8] In addition, statistical copolymers have
been prepared to incorporate dendritic units randomly along the
linear backbone (Figure 1c).[9] However, synthetic methodologies
for preparing copolymers with regularly alternating linear and
dendritic segments have remained elusive. Based on the reported
properties of other amphiphilic L-D hybrid materials,[6c, 10] such L-
D copolymers with precise spacing of dendrons (Figure 1d) are
expected to exhibit unique physicochemical properties, as well as
interesting self-assembly behavior.
Polymers have been broadly used in nearly every industry
because of their versatile structure and modular properties.
Among many structural factors, branching plays a key role in
determining the macroscopic and materials’ properties of
polymers.[1] Most synthetic polymers are linear or moderately
branched, and prepared by chain or step-growth polymerizations.
In general, they have flexible conformations and are subject to
significant intermolecular forces. On the other hand, dendrimers
are macromolecules with precisely defined, highly branched
structures, and obtained by sequential reactions via divergent or
convergent synthesis.[2] As a result of their unique architecture,
dendrimers
possess
unimolecular,
three-dimensional
morphologies and weakened intermolecular interactions, leading
to enhanced solubility and miscibility with other materials.
Furthermore, dendrimers hold promise as nano-sized carriers and
reactors for a broad range of applications due to their void spaces
for encapsulation, and easily conjugated multifunctional
periphery.[2-3]
Figure 1. Schematic illustrations of L-D copolymers with a) LD-type, b) DLD-
type, c) statistical, and d) alternating (this work) structures.
Integrating these drastically different building segments,
linear-dendritic (L-D) copolymers are a class of fascinating
Herein, we describe the first report of L-D copolymers with
alternating structures in which linear polymeric segments serve
as uniform spacers between dendritic units (Scheme 1). To
achieve this, several key design features were employed. First,
dendrons having two selective reactive groups at their focal point
were reacted with complementary α,ω-difunctional linear
polymers to generate the alternating architectures. Accordingly,
the synthesis follows the principles of step-growth polymerization,
albeit employing special polymeric reactants. Second, the highly
reactive copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)
“click” reaction was chosen to construct the copolymers.[11]
CuAAC reactions of diyne with diazide has been utilized to
generate a variety of novel polymers.[12] Precedence for the step-
growth CuAAC synthesis of alternating copolymers has been
previously reported by Matyjaszewski and others,[13] but
exclusively with linear polymeric reactants. Third, taking
advantage of the efficient and orthogonal divergent synthesis of
dendrimers via repetitive thiol-ene[14] and esterification
reactions,[2e] the 4th-generation hydrophobic dendron modified
with two azide groups was designed as the dendritic reactant.
[a]
H. Sun, Y. Zhang, A. Commisso, M. A. Mohamed, Prof. M. Tsianou,
Prof. C. Cheng
Department of Chemical and Biological Engineering
University at Buffalo, The State University of New York
Buffalo, New York 14260, USA
E-mail: ccheng8@buffalo.edu
F. M. Haque, Prof. S. M. Grayson
Department of Chemistry
Tulane University
New Orleans, LA 70118, USA
M. A. Mohamed
Department of Chemistry
Mansoura University
Mansoura 35516, Egypt
Prof. H. Cui
[b]
[c]
[d]
Department of Chemical & Biomolecular Engineering
The Johns Hopkins University
Baltimore, MD 21218, USA
Supporting information for this article is given via a link at the end of
the document.
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With a molecular weight (MW) of over 8,000 Da and with 32
pendant end groups, each dendritic repeating unit represents a
novel type of alternating segment. Finally, to target amphiphilic
copolymers with a propensity for self-assembly, poly(ethylene
glycol) diacetylene (PEGDA) was selected as the linear polymeric
reactant because of the hydrophilicity of poly(ethylene glycol).
S7). In particular, according to the 1H NMR spectrum of DA-[G4]-
ene32, a 32:2 ratio of alkene to azide functionalities was verified
(Figure S7). DA-[G4]-ene32 was also analyzed by matrix-assisted
laser desorption ionization-time of flight mass spectrometry
(MALDI-TOF MS; Figure 2). The MALDI-TOF mass spectrum
revealed that the DA-[G4]-ene32 sodium adduct has a MW of
8,801.4, close to the theoretical value of 8,802.6, confirming its
molecular structure. The sample also showed a higher m/z signal
corresponding to the [M+K]+ signal, typically observed for
polyesters along with the [M+Na]+ signal. The assignment of their
different alkali cation adducts was confirmed by analyzing the
sample with either excess sodium or potassium cation (Figure S8).
There is also one lower MW signal with an observed m/z value of
~24 less than the sodium adduct. Comparing the mass spectra
from using linear and reflector modes confirmed that this is a
metastable signal resulting from the loss of N2 from either of the
two azide functionalities in the dendrimer.[15] In addition, gel
permeation chromatography (GPC) analysis showed a very
narrow monomodal peak for DA-[G4]-ene32 (MnGPC = 9,460, ƉGPC
= 1.03; Figure 3), further confirming its purity.
[DA-[G4]-ene32] + Na+
Theo: 8801.4 m/z
Exp: 8802.6 m/z
[DA-[G4]-ene32]
- N2 + Na+
[DA-[G4]-ene32]
+ K+
8740
8780
8820
8860
5500
6500
7500
8500
m/z
Figure 2. MALDI-TOF mass spectrum of DA-[G4]-ene32 with expanded
spectrum from m/z = 8725 to 8875. The spectrum was taken in positive reflector
mode.
The step-growth CuAAC reactions of PEGDA (DPnNMR = 49,
ƉGPC = 1.02; Figure S9) with DA-[G4]-ene32 were studied at room
temperature in dimethylformamide (DMF) by using different
addition approaches and molar feed ratios of reactants. Copper
(I) bromide (CuBr; 1.00 eq. relative to azide) and N,N,N’,N”,N”-
pentamethyldiethylenetriamine (PMDETA; 1.00 eq. relative to
azide) were used as catalyst and ligand, respectively.[16] The
polymerization was monitored by GPC (Figure 3c-g). The first set
of reaction trials (L/D = [PEGDA]0:[DA-[G4]-ene32]0 = 0.86) were
performed by using a syringe pump to slowly add DA-[G4]-ene32
solutions over 10 h into the reaction media. The initial intention
was to target the synthesis of the LDL-type intermediate to
minimize the formation of the LD-type intermediate, which may
possibly undergo intramolecular cyclization.[17] However,
according to GPC analysis after 46 and 120 h of reaction (Figure
3c-d), a surprisingly high amount (~50%) of unreacted DA-[G4]-
ene32 was observed in each trial, while the GPC peak of PEGDA
disappeared with the appearance of a broad multimodal GPC
peak for the resulting copolymer. Extension of reaction time did
not lead to considerable increase of the conversion of DA-[G4]-
ene32. Whereas, reaction systems with simultaneously mixed
reactants (L/D = 0.86, 1.00, and 1.28) showed the disappearance
of GPC peaks of both reactants in 46 h (Figure 3e-g; the minor
Scheme 1. Synthesis of L-D copolymers with alternating multiblock structure.
The diazido-functionalized dendron was successfully
prepared following Hawker’s approach,[2e] except that a diazido-
diene compound (Scheme S1), instead of a triene, was used as
the core molecule. Starting from this core, repetitive thiol-ene
reaction with 1-thioglycerol and esterification with 4-pentenoic
anhydride yielded precisely-defined diazido dendrimers through
the 4th-generation. The chemical structures of the diazido 4th-
generation dendrimer (i.e. DA-[G4]-ene32) and its precursors were
verified through comprehensive characterizations (Figures S1-
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GPC peaks at ~17.1 min most likely indicate cyclic copolymers
formed by intramolecular cyclization). The resulting copolymers
for all reactant ratios exhibited similar GPC traces for all one-pot
reactions corresponding to MWs higher than those for copolymers
obtained through gradual addition of the dendritic reactant. The
unexpected synthetic results above suggested unequal reactivity
of the two azide groups of DA-[G4]-ene32, presumably because
the triazole group formed by the reaction of the first azide group
can coordinate with Cu(I) and the resulting complex may
significantly boost the CuAAC reactivity of the second azide group
(see detailed discussion in SI).[18]
The resulting assemblies were characterized using transmission
electron microscopy (TEM), atomic force microscopy (AFM), and
dynamic light scattering (DLS).
Figure 4. TEM and AFM analysis of assemblies of L-D alternating copolymer
(the sample corresponding to Figure 3i): a) and b) TEM images; c) tapping mode
AFM image of an assembled nanorod; d) 3-D AFM height image of the nanorod.
Conventional TEM imaging unambiguously revealed a rod-
like morphology of the nanoscale assembles of the copolymer
(Figure 4a,b). These nanorods showed lengths ranging from 94
to 174 nm. Each individual nanorod exhibited relatively uniform
widths, ranging from 19 to 27 nm. The aspect ratios (length/width)
of these nanorods were 4.4-7.8. To elucidate the internal
molecular packing, ruthenium tetroxide was used as the staining
agent to selectively stain other structures while excluding the
polyester-based cores of the dendrons.[20] Figure 4b reveals a
clearly microphase segregated morphology with pearl necklace
bright region and peripheral dark region. The size of each “pearl”,
which was slightly smaller than the width of nanorods, is
reasonably uniform within each individual nanorod. The overall
dimensions and morphologies of these nanorods imply a two-
stage self-assembly process of the copolymer, in which spherical
micelles were intramolecularly formed, followed by their
intermolecular packing into a one-dimensional cylinder (Figures 5
and S11). Hydrophobic interactions of polyester-based dendritic
units may serve as the primary driving force for the association
process. With a low copolymer concentration, unimolecular
micelles with tight intramolecular packing of dendrons at core
domains might be formed predominantly in the first stage. For
instance, to maximize packing efficiency, a copolymer molecule
with six dendrons would possibly prefer to have the dendrons
pack in the form of a triangular antiprism.[21] The presence of
hydrophilic linear PEG segments helps to inhibit macroscopic
aggregation. However, the relatively short PEG segments of the
micelles could not form hydrophilic outer domains to fully cover
the hydrophobic dendron-based cores. To minimize interfacial
energy, micelles with similar sizes further assemble by
intermolecular packing together to minimize the exposure of their
hydrophobic cores, thereby forming nanorods. Moreover, tapping
mode AFM imaging of the copolymer assemblies also verified
Figure 3. GPC traces of a) PEGDA, b) DA-[G4]-ene32, c-g) CuAAC reaction
mixtures of PEGDA and DA-[G4]-ene32, and h-j) L-D alternating copolymer
samples.
High MW L-D alternating copolymers were isolated from the
reaction mixture by precipitation in diethyl ether. The coexistence
of both linear and dendritic segments with ~1:1 segment ratio was
verified by 1H NMR analysis based upon the comparisons of
resonance intensities of PEG methylene protons (-CH2CH2O-) at
3.60 ppm and [G4]-ene32 allyl methine protons (–CH=) at 5.80
ppm (Figure S10). GPC analysis showed that these copolymers
GPC
had a Mn
of 97,600-122,000, and dispersity (Ɖ) of 2.44-3.19,
relative to linear polystyrene standards (Figure 3h-j). According to
the ratios of MnGPC of copolymers to the sum of MnGPC of DA-[G4]-
ene32 (9,460) and PEGDA (5,140), it is estimated that the
copolymers have on average 6-7 linear and dendritic segments
respectively.
The solution self-assembly behavior of the amphiphilic L-D
alternating copolymers was studied, using a representative
copolymer sample (MnGPC = 97,600; ƉGPC = 2.44). Because both
segments are soluble in tetrahydrofuran (THF), but only the PEG
segment is water-soluble, solution self-assembly of the copolymer
was induced by slow addition of water into the THF solution of the
copolymer at room temperature, followed by THF evaporation.[19]
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these rod-like assemblies with surface heights up to ~6 nm
(Figures 4c,d, and S12). DLS analysis further confirmed the
presence of assembled nanostructures of the copolymer with a
volume-average hydrodynamic size of 290 ± 21 nm (Figure S13).
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Figure 5. Schematic illustration of self-assembly behavior of L-D alternating
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In summary, the synthesis of L-D alternating copolymers has
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systems, amphiphilic copolymers could be prepared with
alternating hydrophilic linear PEG and 4th-generation dendritic
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The authors (SMG, FMH) acknowledge NSF-CHE 1412439 for
support, and NSF-MRI 0619770 for MALDI characterization.
Keywords: alternating copolymer • click chemistry • linear-
dendritic copolymer • nanorod • self-assembly
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