A New Versatile Water-Soluble Iniferter Platform for the Preparation of Molecularly Imprinted Nanoparticles by Photopolymerisation in Aqueous Media

Article abstract of DOI:10.1002/chem.201600750

The multi-step synthesis of a new water-soluble dithiocarbamate iniferter platform for the preparation of nanoparticles and -gels in aqueous solvents by photoinduced living-radical polymerisation is described herein. The water solubility of the dithiocarb

Full text of DOI:10.1002/chem.201600750

DOI: 10.1002/chem.201600750
Full Paper
&
Living Radical Polymerisation
A New Versatile Water-Soluble Iniferter Platform for the
Preparation of Molecularly Imprinted Nanoparticles by
Photopolymerisation in Aqueous Media
[
a]
Paolo Bonomi,* Mira Daoud Attieh, Carlo Gonzato, and Karsten Haupt*
Abstract: The multi-step synthesis of a new water-soluble
dithiocarbamate iniferter platform for the preparation of
nanoparticles and -gels in aqueous solvents by photoin-
duced living-radical polymerisation is described herein. The
water solubility of the dithiocarbamate iniferter was ach-
ieved by incorporating two unprotected glucose units into
the iniferter structure by copper(I)-catalysed azide–alkyne cy-
cloaddition (“click chemistry”). Molecularly imprinted nano-
particles (MIPs) specific for 2,4-dichlorophenoxyacetic acid
and the corresponding non-imprinted particles (NIPs) were
prepared in pure water by using the prepared iniferter as
photoinitiator. Radioligand binding tests confirmed a high
imprinting factor, and the living character of the iniferter
was demonstrated by re-initiating a second photochemical
polymerisation on the NIP nanoparticles in water by using
ethylene glycol methacrylate phosphate. Our newly synthes-
ised structure is a promising tool for iniferter-mediated pho-
topolymerisations in aqueous media for the preparation of
biocompatible nanomaterials with high potential for bio-
medical applications in a bottom-up fashion.
Introduction
sation mediated by iniferters is of particular interest. Iniferters
are a class of compound usually containing a dithiocarbamate
[3]
Biomaterials are natural or chemically synthesised materials ca-
pable of interacting with living organisms. They are often used
in medical applications, either to replace a natural function or
as drug delivery systems. Polymers and especially nanogels are
a very interesting class of materials because they can be syn-
thesised to dimensions close to those of biomacromolecules
moiety. As described by Otsu, dithiocarbamates act simulta-
neously as initiators, transfer agents and terminators and they
are retained in the formed polymers. Their versatility towards
a wide range of monomers, their tolerance of virtually any
functional group and their ability to be active without the aid
of any co-catalyst make them an excellent choice for the prep-
aration of different types of functional nanosystems. One im-
portant limitation of these molecules is, however, their low
water solubility.
[
1]
such as proteins and viruses. Among the several methods
available for preparing nanogels, controlled/living-radical poly-
merisation (CLRP) offers two important advantages: control
over the size of the material and the living character.
In fact, despite having been synthesised and studied previ-
ously for other applications, only a small number of dithiocar-
bamates, such as benzyl N,N-diethyldithiocarbamate (BDC) and
The latter is the ability to re-initiate a polymerisation process
on a pre-formed matrix without using additional initiator. This
living character of a polymerisation, which is crucial for the
post-modification of a material in a bottom-up approach, is
achieved by the initiator molecule incorporated into the initial
nanoparticles remaining active. Over the last three decades dif-
ferent types of CLRP methods have been developed, for exam-
ple, nitroxide-mediated polymerisation (NMP), transition-metal-
catalysed atom transfer radical polymerisation (ATRP), reversi-
ble addition fragmentation chain transfer (RAFT) polymeri-
[4]
its derivatives, have been used and investigated in CLRP. In
addition, only in two cases have they been utilised in the
[5]
aqueous phase. For example, Takeuchi and co-workers used
benzyl N,N-bis(carboxymethyl)dithiocarbamate for the synthe-
[6]
sis of molecularly imprinted polymers (MIPs). However, the
presence of (charged) carboxy groups may interfere with many
of the applications of MIPs because they may interact unfav-
ourably with other reagents, for example, monomers, cross-
linkers and templates.
[
2]
sation and iniferter polymerisation. For the synthesis of func-
tional polymers and nanocomposites, photochemical polymeri-
We therefore wanted to develop a more versatile iniferter
platform (Figure 1) to which different hydrophilic end groups
(
R1) can be easily attached by click chemistry. As an example,
[
a] Dr. P. Bonomi, M. D. Attieh, Dr. C. Gonzato, Prof. K. Haupt
CNRS Institute for Enzyme and Cell Engineering
Sorbonne Universitꢀs, Universitꢀ de Technologie de Compiꢁgne
CS60190, 60203 Compiꢁgne (France)
we report herein the synthesis of a new water-soluble dithio-
carbamate-based iniferter bearing unprotected glucose units
(
10; see Scheme 1) and its use for the preparation, in water, of
E-mail: paolobonomi00@gmail.com
MIP nanoparticles as synthetic receptors specific for the herbi-
cide 2,4-dichlorophenoxyacetic acid (2,4-D). We demonstrate
the living character of the polymerisation with our water-solu-
karsten.haupt@utc.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600750.
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philic group could easily be substituted for the glucose moiet-
ies by using the same chemistry. The triazole groups formed
through click chemistry have a high chemical and enzymatic
stability (even towards hydrolysis by protease and glycoami-
[11]
[12]
dase) and the reaction is environmentally friendly.
Synthesis and characterisation of the water-soluble iniferter
Figure 1. Structure of the iniferter. R1 and R1’ are hydrophilic moieties and
R2 can also be varied, allowing, for example, attachment to a surface or la-
belling.
The multi-step synthesis involved the preparation of two main
building blocks: (tert-butoxycarbonyl)dipropargylamine (2) and
peracetylated b-d-glucopyranosyl azide 5, as shown in
Scheme 1. Compound 2 was prepared by treating the com-
mercially available propargylamine with di-tert-butyl dicarbon-
ate to give N-(tert-butoxycarbonyl)propargylamine (1) as
a light-brown solid, which was treated with propargyl bromide
in the presence of sodium hydride to give the product 2 in
ble iniferter by post-functionalisation of the pre-formed materi-
al.
[13]
Results and Discussion
a highly satisfactory yield (>70%). Next, commercially avail-
able b-glucose pentaacetate 3 was quantitatively converted
into its a-chloride derivative 4 by using titanium(IV) chloride
Rational design of a new water-soluble iniferter
[14]
Dithiocarbamate iniferters are known as initiators for con-
(TiCl ), as described in the literature. Sodium azide was sub-
4
[
3]
trolled/living radical polymerisation (CLRP). Although a great
number of such molecules have been synthesised for different
sequently used to convert 4 into the b-azide derivative 5 in
a yield of 70% by a modified version of a published proce-
[
4]
[15]
1
purposes, such as metal-chelating agents, few examples bear-
ing hydrophilic moieties have been used as radical initiators in
dure. The H NMR spectrum confirmed the transformation
through the expected upfield shift of the anomeric proton to
d=4.63 ppm and an increase in the coupling constant (J) to
[
5]
aqueous conditions. Our new water-soluble dithiocarbamate
iniferter (10) bears two hydrophilic moieties, namely glucose,
linked to a central nitrogen atom through two triazole groups
[16]
8.9 Hz. The intermediates 2 and 5 were connected by means
of a copper(I)-catalysed azide–alkyne cycloaddition reaction to
give intermediate 6 bearing the two 1,4-regioisomers of the
(Scheme 1). Glucose was chosen as a model substituent to im-
[17]
prove the water solubility of the molecule and for its high po-
tential in biological applications. The importance of protein
glycosylation in a large variety of cellular recognition processes
1,2,3-triazole moieties in high yield. This intermediate had
not yet been described in the literature and for this reason
was fully characterised by MS and NMR spectroscopy (see Fig-
ures S1–S3 in the Supporting Information). In particular, the 1,4
regioselectivity of the cycloaddition was confirmed by the typi-
(
enzyme trafficking, cellular migration, cancer metastasis and
[
7–10]
immune functions) is well known.
However, another hydro-
Scheme 1. Multistep synthesis of iniferter 10.
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cal large positive d Àd values (ca. 24 ppm) for the triazole
the H NMR spectrum of 10 (Figure 2 and Figure S9 in the Sup-
porting Information) show two singlets at d=8.28 and
8.23 ppm for the two aromatic protons of the two triazole
rings, whereas in the completely deprotected precursor 7 they
were fused into a unique singlet. In the aromatic region we
find two doublets at d=7.33 and 7.22 ppm, with a J coupling
constant of 8.2 Hz, which indicates a 1,4-substituted benzene
ring. Integration of the signals further confirmed the structure,
perfectly matching the 2:1 ratio between the protons of the
benzene ring and triazole units. The doublet at d=5.63 ppm,
with a J coupling constant of 9.2 Hz, originates from the two
anomeric protons of the two glucose units (they are not affect-
ed by the loss of symmetry and therefore they are still equiva-
lent) and, once again, the integration is in accord with the
structure of the molecule as well as for the remaining peaks.
The two doublets at d=5.47 and 5.41 ppm, with a strong J
coupling constant of 15.0 Hz (typical of two geminal protons
C4
1
C5
3
[18]
carbon atoms in the C NMR spectrum (see Figure S2).
Subsequently, compound 6 was fully deprotected under
acidic conditions to generate intermediate 7, a secondary
amine suitable for further reaction with carbon disulfide. It was
decided to perform the hydrolysis at this stage of the synthetic
pathway because any basic or acidic deprotection would be
impossible later without causing the decomposition of the di-
[
19]
thiocarbamate moiety to be introduced.
Acidic conditions
were preferred over basic for the deprotection to avoid the
formation of sodium acetate, which would have made the pu-
rification process, by flash chromatography, more complicated.
The full deprotection of 6 afforded 7 in a yield of 47%. Inter-
mediate 7 had not yet been described in the literature and
was therefore fully characterised by MS and NMR spectroscopy
(see Figures S4–S6 in the Supporting Information). Mass spec-
trometry (ESI-MS, see Figure S6) validated the synthesis show-
3
ing the presence of the expected signal at m/z=504.2049. We
on an sp carbon), and the traceable broad singlet at d=
then introduced the dithiocarbamate moiety by using CS and
5.13 ppm, which overlaps the peak of water, are related to the
protons of the two methylene groups at the a position with
respect to the central nitrogen atom. The methylene unit at
the 4-position of the benzene ring is described by a singlet at
d=4.51 ppm. The remaining protons are those of the two glu-
cose moieties, the methyl ester group and the methyl group at
C-2 of the propionic residue (Figure 2 and Figure S9).
2
KOH in H O at 508C to form the corresponding potassium salt
2
8
. MS analysis, as reported in the Supporting Information, con-
firmed the conversion of the amine into the corresponding di-
thiocarbamate potassium salt in a yield of around 60%. The
salt 8 was treated immediately, after freeze-drying and without
any further purification, with the methyl ester of racemic 2-[4-
(bromomethyl)phenyl]propionic acid (9). The esterification of
We further investigated the molecular structure of 10
13
the propionic acid derivative, performed by using thionyl chlo-
ride in MeOH, was necessary to avoid an acid/base reaction be-
tween the carboxylic group and the dithiocarbamate potassi-
um salt 8. Compounds 8 and 9 were mixed together in DMF at
through C and HSQC NMR experiments (see Figures S10 and
S11 in the Supporting Information) and found at d=
199.52 ppm the characteristic peak of a quaternary carbon of
a dithiocarbamate unit, whereas the singlet at d=176.92 ppm
matches the carbonyl of the methyl ester group. In the aro-
matic region, peaks at d=143.07 and 142.39 ppm were found
for the two quaternary carbon atoms of the triazole rings (C-4
of triazole), the peaks at d=140.72 and 135.53 ppm arise from
the quaternary carbon atoms of the benzene ring and the two
intense peaks at d=130.69 and 128.63 ppm correspond to the
four tertiary carbon atoms of the benzene ring. The peaks of
the two tertiary triazole carbon atoms (C-5 of triazole) appear
at d=125.47 and 125.06 ppm, as expected. The two anomeric
carbon atoms appear at d=88.54 ppm and the peaks at d=
408C to give the desired iniferter 10 in a yield of 46%. The
new water-soluble iniferter 10 was completely characterised by
MS, NMR and UV spectroscopy (Figure 2 and Figures S9–S13).
Compound 10 was found to be soluble in water, methanol
and DMSO.
NMR characterisation of 10 was performed in CD OD and
3
not in D O due to a better resolution of the peaks. As expect-
2
ed, the introduction of the dithiocarbamate substituent at the
nitrogen atom broke the symmetry of the molecule. In fact,
49.82 and 47.81 ppm have been assigned to the carbon atoms
of the methylene groups at the a position with respect to the
nitrogen atom. The peak at d=45.67 ppm is related to the ter-
tiary carbon (CH) of the propionic acid chain and the peak at
d=42.97 ppm has been assigned to the benzylic carbon atom.
The heteronuclear multiple bond correlation (HMBC) analysis
showed that the signal at d=199.52 ppm, from the quaternary
carbon of the dithiocarbamate, exhibits cross peaks (see Fig-
ure S11), of different intensities, with only the methylene pro-
tons in the molecule (but not those of C-6 of the glucose units
because they are too far away), which led to the conclusion
that the C=S group is undoubtedly bonded to the central ni-
trogen atom.
Mass spectrometry (ESI-MS, see Figure S12 in the Supporting
Information) validated the synthesis showing the presence of
the expected signal at m/z=754.2128. A UV absorption spec-
trum of compound 10 was recorded to compare with that of
1
Figure 2. H NMR spectrum of iniferter 10.
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the well-known benzyl N,N-diethyldithiocarbamate (BDC) in-
iferter. A maximum absorbance peak was found at l=340 nm
unlabelled 2,4-D efficiently competes with the binding of
14
[ C]2,4-D. This competition is stronger than that of the struc-
turally related compound phenoxyacetic acid, thus confirming
the specificity of the binding.
(see Figure S13). This value corresponds to the n–p* transition
of the dithiocarbamate moiety and is close to the absorption
maximum of BDC (l=335 nm; see the Experimental Section).
The sizes, morphologies and compositions of the MIPs and
NIPs were evaluated by scanning electron microscopy (SEM)
and elemental analysis by means of energy dispersive X-ray
spectroscopy (EDS). As shown in Figure 4, the NIP particles are
spherical with a rough surface and sizes ranging from 200 to
300 nm, whereas the MIPs (right) are spherical and smooth
Synthesis of MIP nanogels using water-soluble iniferter
We then investigated the behaviour of the hydrophilic iniferter
10 in the synthesis of molecularly imprinted polymer nanopar-
ticles. Molecularly imprinted polymers are tailor-made antibody
mimics obtained by a templating process at the molecular
[
20]
level. They are prepared by co-polymerising functional and
cross-linking monomers around a template molecule. This
leads to a 3D polymer network containing cavities that are
complementary to the template in terms of size, shape and
positions of functional groups. Thus a “molecular memory” is
introduced into the polymer, thereby allowing the molecular
recognition and binding of target analytes with a specificity on
a par with biological antibodies. MIPs can therefore be seen as
synthetic antibody mimics and have been widely used, in re-
sponse to growing demands, in environmental analysis, clinical
Figure 4. Representative SEM images of NIP (left) and MIP (right) nanoparti-
cles prepared in water using the water-soluble iniferter (10).
[21]
diagnostics, production monitoring, biosensors and biochips.
In this work we chose the herbicide 2,4-dichlorophenoxyacetic
acid (2,4-D) as a model template. An MIP for this target has al-
with sizes ranging from 180 to 200 nm. The observed differ-
ence in size between the MIPs and NIPs is in accord with the
trend described in the literature for this type of polymerisation
[
22]
ready been described in the literature. Here, the reagents
were adapted to allow polymer synthesis in water by substitut-
ing the water-soluble cross-linker bis(acryloyl)piperazine for the
previously used ethylene glycol dimethacrylate and the new
iniferter 10 for the azo initiator 2,2’-azobis(2,4-dimethylvalero-
[24]
in organic solvents. Elemental analyses of the MIPs and NIPs
were performed after washing them three times in water and
methanol to remove potentially unreacted dithiocarbamate.
The analyses revealed the presence of sulfur atoms in both
nanoparticles (see Figures S15 and S16 in the Supporting Infor-
mation), which suggests that the initiator function is still at-
[23]
nitrile). MIPs and NIPs were prepared at high dilution.
A
non-imprinted control polymer (NIP) was synthesised in the
same way but by omitting the template.
[25]
The ability of the polymers to bind their target 2,4-D was
tached and that a second polymerisation using the living
character of iniferter polymerisation should be feasible.
1
4
evaluated by radioligand binding experiments with [ C]2,4-D.
The resulting binding curves are shown in Figure 3. As can be
seen, the MIP binds more of the radioligand than the NIP,
thereby confirming the imprinting effect. To confirm specific
binding, a competitive radioligand binding experiment was
Living character of water-soluble iniferter 10
An important feature of CLRP techniques is the ability to re-
start a new polymerisation upon triggering the initiation stimu-
lus without adding new initiator. This feature is crucial for per-
forming post-modifications on a pre-formed matrix to mimic
the natural bottom-up synthetic approach and to modulate
14
performed by incubating constant amounts of [ C]2,4-D and
MIP with varying concentrations of unlabelled 2,4-D or of the
structurally related molecule phenoxyacetic acid (see Fig-
ure S14 in the Supporting Information). As can be seen, the
[26]
the physical and chemical properties of materials. We there-
fore attempted a second polymerisation with the NIP nanopar-
ticles, which are used as macroinitiator. Ethylene glycol metha-
crylate phosphate (EGMP) was chosen as the new monomer
because its phosphate group can be easily detected by EDS.
The NIP particles were suspended in buffer containing the mo-
nomer. The initiation was triggered by irradiation with a UV
lamp having a maximum emission peak at 365 nm and the re-
action was allowed to continue at room temperature for 20 h.
After washing with water and methanol to remove unreacted
phosphate monomer, the nanoparticles were dried and ele-
mental analysis was carried out to determine their composi-
tion. The presence of the phosphorus peak in the EDS spec-
trum (see Figure S17 in the Supporting Information) and the
Figure 3. Binding curves for radiolabelled 2,4-D (0.4 pmol) on MIP and NIP in
20 mm sodium phosphate buffer (pH 7).
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Acknowledgements
This work was supported by the Region of Picardy, France (co-
funding of equipment under CPER 2007–2013 and the Nano-
toxiscreen project). We thank Franck Merlier for mass spec-
trometry, Frꢁdꢁric Nadaud for SEM and Elise Prost for NMR
analyses.
Keywords: click chemistry
nanoparticles · polymerisation
·
imprinting
·
iniferters
·
Figure 5. Size distributions of pristine (a) and p(EGMP)-modified (b) NIPs in
water as measured by dynamic light scattering.
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[
We have developed a strategy for the synthesis of a new
water-soluble dithiocarbamate photoiniferter platform that
allows the incorporation of different hydrophilic end groups by
copper(I)-catalysed azide–alkyne cycloaddition (“click chemis-
try”). In the example described here, unprotected glucose units
were used as hydrophilic groups on the dithiocarbamate in-
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molecularly imprinted nanoparticles in water and successive
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range of water-soluble monomers makes our iniferter a useful
tool for the preparation of biocompatible polymer systems.
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different mono- and more complex saccharides with the possi-
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Experimental Section
[
Experimental details, compound characterisation data and copies
of NMR spectra of new compounds can be found in the Support-
ing Information
Received: February 17, 2016
Published online on && &&, 0000
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FULL PAPER
Molecular imprinting: The synthesis of
a new water-soluble dithiocarbamate in-
iferter platform (see figure) for the prep-
aration of molecularly imprinted poly-
mer nanogels in aqueous solvents by
photoinduced living-radical polymeri-
sation is described. Water solubility was
achieved through the attachment, by
click chemistry, of two hydrophilic moi-
eties, namely unprotected glucose units.
&
Living Radical Polymerisation
P. Bonomi,* M. D. Attieh, C. Gonzato,
K. Haupt*
&
& – &&
A New Versatile Water-Soluble
Iniferter Platform for the Preparation
of Molecularly Imprinted
Nanoparticles by Photopolymerisation
in Aqueous Media
&
&
Chem. Eur. J. 2016, 22, 1 – 6
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