Modular Toolkit of Multifunctional Block Copoly(2-oxazoline)s for the Synthesis of Nanoparticles

Article abstract of DOI:10.1002/chem.202101327

Post-polymerization modification provides an elegant way to introduce chemical functionalities onto macromolecules to produce tailor-made materials with superior properties. This concept was adapted to well-defined block copolymers of the poly(2-oxazoline) family and demonstrated the large potential of these macromolecules as universal toolkit for numerous applications. Triblock copolymers with separated water-soluble, alkyne- and alkene-containing segments were synthesized and orthogonally modified with various low-molecular weight functional molecules by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and thiol-ene (TE) click reactions, respectively. Representative toolkit polymers were used for the synthesis of gold, iron oxide and silica nanoparticles.

Full text of DOI:10.1002/chem.202101327

Communication
doi.org/10.1002/chem.202101327
Chemistry—A European Journal
Modular Toolkit of Multifunctional Block
Copoly(2-oxazoline)s for the Synthesis of Nanoparticles
Philipp Keckeis,[a] Enriko Zeller,[a] Carina Jung,[a] Patricia Besirske,[a] Felizitas Kirner,[a]
Cristina Ruiz-Agudo,[a] Helmut Schlaad,[b] and Helmut Cölfen*[a]
every chemical functionality is tolerated in cationic polymer-
izations, though this limitation can be overcome by the use of
Abstract: Post-polymerization modification provides an
elegant way to introduce chemical functionalities onto
protecting group chemistry or by suitable post-polymerization
macromolecules to produce tailor-made materials with
modification approaches. For the latter, the modification of
superior properties. This concept was adapted to well-
POxs carrying either alkyne or alkene side chains has been
defined block copolymers of the poly(2-oxazoline) family
successfully achieved using “click” chemistry,[4] namely by
and demonstrated the large potential of these macro-
copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)[5] or by
molecules as universal toolkit for numerous applications.
thiol-ene (TE)[6] reactions, respectively, profiting from high yields
Triblock copolymers with separated water-soluble, alkyne-
and mild reaction conditions. In this regard, Schubert and
and alkene-containing segments were synthesized and
coworkers introduced a multifunctional copoly(2-oxazoline)
orthogonally modified with various low-molecular weight
scaffold containing anthracene and azide termini and two
functional molecules by copper(I)-catalyzed azide-alkyne
alkene side chains for triple orthogonal click post-polymer-
cycloaddition (CuAAC) and thiol-ene (TE) click reactions,
ization modifications by Diels-Alder cycloaddition, CuAAC and
respectively. Representative toolkit polymers were used for
TE click reactions.[7] This sophisticated orthogonal coPOx system
the synthesis of gold, iron oxide and silica nanoparticles.
is complemented by our versatile toolkit enabling high degrees
of modification by equipping whole segments with the desired
functionalities. Functional POx have been applied to modify the
surface of inorganic nanoparticles,[8] however, the literature for
Multifunctional block copolymers can synergistically improve
the properties of materials, which is the reason why they are
used in all scientific disciplines from physicochemical material
science up to biological applications in the medicinal course.
Particularly, the poly(2-oxazoline) (POx) polymer family is of
great interest due to its architectural versatility, tunable polarity
and property, biocompatibility and wide range of chemical
functionalization.[1] The sequential living cationic ring opening
polymerization (CROP) of 2-oxazolines enables the synthesis of
well-defined block copolymers with predictable molar masses
(up to about 300 incorporated monomer units) and narrow
molar mass distributions of each segment.[2] Hence, a large
selection of POxs with specific properties and functionalities
can be obtained by the incorporation of 2-alkyl-2-oxazoline
monomers with different chemical side groups.[3] However, not
the grafting-onto approach is limited. Nevertheless, some
inspiring examples are available for iron oxide using phosphate
linkers,[9] silica using trimethoxysilane linkers,[10] and gold nano-
particles using thiol linkers.[11]
Herein, we combine well-established CuAAC and TE click
reactions into one universal synthetic protocol for the orthogo-
nal post-polymerization modification of triblock coPOxs aiming
to generate a modular toolkit of multifunctional polymers
(Figure 1). Specific chemical functionalities can be introduced to
the separated alkyne- and alkene-containing block segments in
order to equip the polymer segments with charges (COOH or
NH2), hydroxyl groups (OH) or fluorescence labels (Rhodamine
B), respectively, but also with chemical linkers. The latter include
the introduction of desired binding groups onto the polymer
such as thioethers (SAc), siloxanes (Si(OMe)3), catechols (Ph-
(OH)2) or carboxylates (COOH) as chemical ligands for the
interaction with different inorganic systems such as gold, metal
(-loid) hydroxides, iron oxide and other appropriate positively-
charged surfaces. Moreover, we provide straightforward recipes
for the synthesis of polymer-coated gold, iron oxide and silica
nanoparticles with help of the newly tailor-made coPOxs.
The synthetic pathway towards the modular polymer toolkit
starts with the synthesis of the functionalizable monomers 2-(4-
pentynyl)-2-oxazoline (PentynOx) and 2-(3-butenyl)-2-oxazoline
(ButenOx) (see Supporting Information, section 2).[5–6,12] The
sequential microwave-assisted CROP[13] of 2-methyl-2-oxazoline
(MeOx), PentynOx, and ButenOx in acetonitrile solution at
[a] Dr. P. Keckeis, E. Zeller, C. Jung, P. Besirske, F. Kirner, Dr. C. Ruiz-Agudo,
Prof. Dr. H. Cölfen
Physical Chemistry, University of Konstanz
Universitätstrasse 10, Box 714, 78457 Konstanz (Germany)
E-mail: helmut.coelfen@uni-konstanz.de
[b] Prof. Dr. H. Schlaad
Institute of Chemistry, University of Potsdam
Karl-Liebknecht-Strasse 24–25, 14476 Potsdam (Germany)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202101327
© 2021 The Authors. Published by Wiley-VCH GmbH. This is an open access
article under the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
°
140 C (initiator was methyl triflate and the reaction time for
every monomer was 30 min) produced a series of triblock
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Table 1. List of multifunctional triblock copoly(2-oxazoline)s obtained by
post-polymerization modification of PMeOx-PPentynOx-PButenOx with low
molecular weight azides and thiols via consecutive azide-alkyne cyclo-
addition (CuAAC) and thiol-ene (TE) reactions; numbers in parenthesis
correspond to the degrees of modification for each modification step.
Precursor
P1
CuAAC
(100%)
(80%)
TE
Product
P1-OHÀ Si(OMe)3
(55%)
(100%)
P3
P3-COOH-SAc
P3
P3
P3-OH-SAc
(100%)
(100%)
(100%)
(100%)
P3-OH-COOH
P3
P3-OHÀ Ph(OH)2
(100%)
(15%)
First post-polymerization modification: CuAAC
To guarantee orthogonality, CuAAC must be carried out first
before the TE click reaction, since thiols can react with both
alkynes (under formation of 1,2-dithio compounds)[14] and
alkenes during UV exposure following a radical pathway.
Figure 1. Schematic representation of the modular toolkit representing the
orthogonal post-polymerization modification of a poly(2-oxazoline)-based
triblock copolymer PMeOx-PPentynOx-PButenOx via azide-alkyne cycloaddi-
tion (CuAAC) and thiol-ene (TE) click reaction as well as potential systems for
nanotechnological application.
The CuAAC reaction between the triblock copolymer P3 and
6-azido-hexanoic acid was promoted by copper(II)sulfate and
ascorbic acid in a water/tert-butanol mixture (see Supporting
Information). The copper ions were afterwards removed by
dialysis against EDTA-solution, which turned out as indispen-
sable procedure to avoid a green coloration of the polymers,
that disturbs subsequent analyses. The modified copolymer was
analyzed by 1H NMR spectroscopy (Figure 2). The appearance of
the triazole proton signal at 7.8 ppm and the signal of the
neighboring methylene group at 4.4 ppm showed the success-
ful attachment of carboxylates. The degree of modification of
P3 alkyne units was found to be about 80%, by considering the
peak integrals of the vinyl and triazole protons, corresponding
to 26 carboxylate units on the PPentynOx segment.
copoly(2-oxazoline)s consisting of a hydrophilic block (PMeOx)
and two consecutive blocks with alkyne (PPentynOx) and alkene
(PButenOx) moieties (see Supporting Information, section 3).
The molecular compositions were determined by 1H NMR
spectroscopy and the dispersity by size exclusion chromatog-
raphy. Notably, the block copolymer samples exhibited some-
what higher dispersities, that is in the range of 1.2–1.4, which
can be attributed to the highly concentrated and thus viscous
reaction solutions. Exemplary two precursor samples PMeOx43-
PPentynOx11-PButenOx11 (P1) and PMeOx52-PPentynOx32-PBute-
nOx13 (P3) (were used for subsequent post-polymerization
modifications with low-molecular weight azido and thiol
molecules by orthogonal CuAAC and TE click reactions (see
Table 1 and Supporting Information, sections 4 and 5).
Second post-polymerization modification: TE
The orthogonal modification of P3 to give P3-COOH-SAc
(which was later used as surfactant for gold nanocubes, see
below) is described as representative example of the polymer
toolkit.
To attach S-(8-mercaptooctyl)ethanethioate to the PButenOx
segment, the carboxylate-modified copolymer was dissolved in
THF/methanol solution and exposed to UV irradiation (λ=
356 nm) for two days in the presence of the photoinitiator 2,2-
dimethoxy-2-phenylacetophenone (see Supporting Informa-
tion). The 1H NMR analysis of the dialyzed polymer product
suggested a quantitative modification of the 13 alkene units as
the signals of the vinyl protons at 5.05/5.86 ppm were
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to chemisorb on gold surfaces.[16] After removing non-bound
polymer by centrifugation, the AuNC-polymer composite was
analyzed with complementary structural techniques (see Fig-
ure 3 and Supporting Information, section 6.1).
UV/Vis spectroscopy indicated minute shifts of the absorp-
tion maxima from 529 to 530 nm suggesting the colloidal
stability of the AuNC-polymer composites, free of aggregation
(Figure S52).[17] Analytical ultracentrifugation (AUC) sedimenta-
tion-velocity experiments revealed a significant shift of the
AuNC sedimentation coefficient in the presence of P3-COOH-
SAc to lower values (Figure 3C, blue line). As the total particle
density decreases after the adsorption of polymer and the
friction of the polymer shell increases with respect to the initial
CPC stabilizer, the shift of the sedimentation coefficient with
otherwise unchanged distribution suggests the presence of
stable, organic polymer-coated AuNCs without aggregation.[18]
In addition, the resemblance of the sedimentation profiles
points towards the morphological conservation of the nano-
particles. Zeta-potential measurements reveal a significant
reduction of the positive value of CPC-stabilized AuNCs in the
presence of the polymer emphasizing the macromolecular
surface modification and ion complex formation between the
CPC ammonium and the polymer carboxylate (Figure 3D). This
experiment was repeated with the multifunctional block
copolymer P3-OH-SAc (PMeOx52-PPentynOx32(OH)32-PBute-
nOx13(SAc)13) having a polyhydroxyl middle segment instead of
polycarboxylate and the zeta potential stayed in the region of
40 mV as for the initial CPC-stabilized AuNCs (Figure 3D). This
shows that the block copolymer is adsorbed additionally to the
CPC stabilizer without a full ligand exchange. The AUC experi-
Figure 2. 1H NMR spectra (400 MHz, CD3OD) of A) PMeOx52-PPentynOx32-
PButenOx13 (P3), B) PMeOx52-PPentynOx32(COOH)26-PButenOx13 after attach-
ing 6-azido-hexanoic acid via CuAAC and C) PMeOx52-PPentynOx32(COOH)26-
PButenOx13(SAc)13 (P3-COOH-SAc) after attaching S-(8-mercaptooctyl)
ethanethioate via TE click reaction.
completely absent (Figure 2). Quantification of the peak inte-
grals at 2.9 ppm (À CH2-SAc) and 4.4 ppm (À CH2-triazole) con-
firmed the number of 26 attached carboxylate units, which
however excludes that the thiol reacted with residual alkyne
units. Accordingly, the final polymer P3-COOH-SAc exhibits the
chemical
structure
PMeOx52-PPentynOx32(COOH)26-PBute-
nOx13(SAc)13.
Notably, as documented in Table 1, some of the CuAAC or
TE modification reactions were not quantitative, hence were
not truly “click” reactions, for yet unknown reasons. Particularly
the
TE
reaction
with
N-(3,4-dihydroxyphenethyl)-4-
mercaptobutaneimidamide) gave a yield of just 15% corre-
sponding to two catechol groups attached to the PButenOx
segment. Nevertheless, the attachment of catechol derivatives
by a radical TE reaction is remarkable because catechols are
otherwise known and used as radical scavengers or inhibitors.
Exemplary application of the block copoly
(2-oxazoline) toolkit
Ultimately, selected polymer architectures of the POx toolkit
were applied in colloidal model systems in order to chemisorb
on gold and iron oxide nanoparticle surfaces or in the Stöber
synthesis of silica nanoparticles. Surface interaction represents a
key role for numerous nanoparticle applications focusing for
instance on particle stabilization, crystallization events, polarity
tuning, visualization, etc.
Addressing gold nanoparticles, an aqueous dispersion of
freshly synthesized, cetylpyridinium chloride (CPC) - stabilized
gold nanocubes (AuNC)[15] with an average edge length of
34 nm was mixed with an aqueous solution of P3-COOH-SAc.
The thioester (SAc) group was selected due to the known ability
Figure 3. Surface-functionalization of CPC-stabilized AuNC using P3-COOH-
SAc (PMeOx52-PPentynOx32(COOH)26-PButenOx13(SAc)13) and P3-OH-SAc
(PMeOx52-PPentynOx32(OH)32-PButenOx13(SAc)13). TEM analyses of the poly-
mer-gold nanocube composites P3-COOH-SAc (A) and P3-OH-SAc (B). AUC
sedimentation experiments (C) of CPC-stabilized AuNC (black) and AuNC-
polymer composites (P3-COOH-SAc, blue and P3-OH-SAc, red). Zeta-
potential measurement (D) of CPC-stabilized AuNC (black) and AuNC-
polymer composites (P3-COOH-SAc, blue and P3-OH-SAc, red) with
increasing total polymer concentrations.
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ments reveal identical sedimentation profiles of the two differ-
ent gold polymer conjugates (Figure 3C). This gives rise to the
conclusion that the SAc is the key to surface linkage
independent of the presence of COOH or OH groups. Moreover,
transmission electron microscopy (TEM) analysis depicts the
existence of a ring with lower contrast surrounding the AuNC in
the case of both polymers (Figure 3A and 3B) indicating the
presence of a surface coating with polymer.
Addressing iron oxide nanoparticles (IONP), the two poly-
mers P3-OH-COOH and P3-OH-Ph(OH)2 were used to modify
the surfaces of the as-synthesized IONP with a size of 9 nm, as
described by Kang et al.[19] Carboxylate and catechol function-
alities were selected due to their well-known ability to
chemisorb on Fe3O4,[20] having an isoelectric point of 6.8.[21] In
general, carboxylic[21] and catechol[22] groups were found to
adsorb stronger on iron oxide surfaces at alkaline milieu via
complexation of Fe surface atoms.[23] TEM, AUC and TGA
analysis (Supporting Information, section 6.2) suggested the
presence of polymer-coated nanoparticles with organic con-
tents of 4.5% (P3-OH-COOH) and 15.5% (P3-OH-Ph(OH)2),
respectively. The high polymer content observed with P3-OH-
Ph(OH)2 supports the very good binding ability of catechol
groups to IONPs,[24] much better than that of carboxylates, and
demonstrates the successful application of the toolkit polymers
to colloidal iron oxide.
and silica nanosystems. Therefore, the non-toxic post-function-
alized polyoxazolines bear the potential to enter various nano-
technological applications, for instance, the field of drug
delivery in terms of modifying, stabilizing and visualizing
nanoconjugates or alternatively guiding the drug loaded
micelle by a magnetic field due to attached magnetite nano-
particles. Another application would be nanomedicine where
one block is modified with a target molecule to attach to
tumors, while the second block has binders for gold or
magnetite nanoparticles, which would destroy the tumor by
light- or magnetic field-generated heat. Also, a combination of
a cholesterol-functionalized block and an acidic block could be
used to dissolve atherosclerotic plaques, as we have demon-
strated for poly-peptide-based triblock copolymers.[28]
These examples just demonstrate a small part of the
possibilities with the here developed modular toolkit, because
any combination from the following applications should be
feasible: self-assembly, templating, nanoparticle stabilization,
surface modification, scale inhibition, solubilization, staining,
drug-delivery (or more general molecular delivery) or nano-
medical applications. Ultimately, the binary orthogonal scaffold
introduced in this work could even be extended to a multi-
dimensional system applying multiple orthogonal click post-
polymerization reactions.
Finally we were addressing silica nanoparticles, which are
widely used as carrier systems in biomedical applications,[25] in Experimental Section
sensor techniques[26] or as rheological additives.[27] P1-OH-
Detailed descriptions of the synthesis of the modular polymer
Si(OMe)3 was used as a macromolecular silica precursor agent
in the Stöber-synthesis of silica nanoparticles. The hydrolysis
and condensation reaction yielded to 15 nm-sized SiO2 nano-
particles (Supporting Information, section 6.3). Dynamic light
scattering experiments showed the absence of aggregation. In
toolkit and procedures for the functionalization of inorganic nano-
particles are provided in the Supporting Information.
a more general consideration, this example presents the Acknowledgements
opportunity to produce silica particles with selected surface
functionalities (e.g. carboxy, hydroxy, amine or fluorescent
molecules) that have been attached to the block copolymer via
CuAAC.
We thank Rose Rosenberg for AUC measurements, Ann-Kathrin
Göppert for TGA measurements, Niklas Unglaube for synthetic
support, Sascha Keßler for iron oxide nanoparticles, the group
of Prof. Dr. Stefan Mecking for GC measurements, Adrian
Donner and Sebastian Sutter for ESI-MS measurements and the
particle analysis center of the SFB 1214 for DLS and zeta-
potential measurements. We are grateful about the financial
support of the Zukunftskolleg and of the University of Konstanz.
CRA thanks Deutsche Forschungsgemeinschaft SFB 1214 (proj-
ect A7). Open access funding enabled and organized by Projekt
DEAL.
In conclusion, an orthogonal system for the post-polymer-
ization modification of poly(2-oxazoline)-based triblock copoly-
mers has been developed. The two distinct segments of alkyne
and alkene blocks were subsequently modified by copper(I)-
catalyzed azide-alkyne cycloaddition (CuAAC) and thiol-ene (TE)
click reaction. Various low-molecular-weight molecules were
attached to the chemical handles pursuing specific interactions
with inorganic surfaces. Apart from CuAAC and TE, the alkyne
and alkene blocks can alternatively be modified by using Pd0-
catalyzed CÀ C cross coupling using the Sonogashira (triple
bonds) and Heck reactions (double bonds); preliminary results Conflict of Interest
are shown in the Supporting Information (section 5.3). To this
end, the triblock copolymer was equipped with functional
groups, such as carboxylates, amines, hydroxyl groups, fluores-
cent Rhodamine B, thioacetates, catechols and silanes as shown
in the overview Table S1 containing 14 examples of multifunc-
tional polymers. The combination of these specific function-
alities defines the modular toolkit for tailored specific applica-
tions, which exemplarily was demonstrated for gold, iron oxide
The authors declare no conflict of interest.
Keywords: block copolymers · click chemistry · nanoparticles ·
ring-opening polymerization · surfactants
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Manuscript received: April 14, 2021
Accepted manuscript online: April 20, 2021
Version of record online: ■■■, ■■■■
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COMMUNICATION
Polyoxazoline block copolymers
offer a wide range of possibilities for
application depending on their
molecular structure and properties.
This study introduces the huge
potential of this polyoxazoline toolkit
and demonstrates how tailor-made
toolkit polymers can be applied in
representative systems.
Dr. P. Keckeis, E. Zeller, C. Jung, P.
Besirske, F. Kirner, Dr. C. Ruiz-Agudo,
Prof. Dr. H. Schlaad, Prof. Dr. H. Cölfen*
1 – 6
Modular Toolkit of Multifunctional
Block Copoly(2-oxazoline)s for the
Synthesis of Nanoparticles