Single-chain polymeric nanoparticles by stepwise folding

Article abstract of DOI:10.1002/anie.201100104

Light-induced self-assembly leads to the folding of synthetic random-coil polymers into highly stable single-chain polymeric chiral nanoparticles (see picture; green: side chains, blue: phenyl rings, red: nitrophenyl leaving groups). The folding of the po

Full text of DOI:10.1002/anie.201100104

DOI: 10.1002/anie.201100104
Folding Processes
Single-Chain Polymeric Nanoparticles by Stepwise Folding**
Tristan Mes, Rob van der Weegen, Anja R. A. Palmans,* and E. W. Meijer*
In an effort to mimic the folding of natural polymers,[1–3]
foldamers, which are oligomers that adopt well-defined
secondary structures, have been studied in great detail.[4,5]
Dendrimers have also been developed that adopt folded
conformations in solution.[6–9] In all of these systems, the
conformational synchronization that occurs over extended
distances amplifies small energy differences, leading to highly
stable, folded macromolecules.[10] The benefits of introducing
synchronized conformational motions into macromolecules
have been clearly demonstrated by Parquette and co-workers.
They showed high enantioselectivity in a catalytic hydro-
genation reaction, which resulted from chiral information at
the periphery of dendrimers relayed to an achiral catalyst
complex in the core.[11]
We are intrigued by the many possibilities of well-defined
nanosized objects formed by the folding of a single-chain
polymer. These polymers are functionalized in the side chains
with recognition units and can, after folding into a well-
defined object, express specific functions, such as sensing or
catalysis. In that sense, they partially mimic the properties of
biomacromolecules, but can be made using the immense
number of monomers and polymerization techniques avail-
able. Initially, these single-chain polymeric nanoparticles have
been obtained by covalent intramolecular cross-linking.[12–20]
Using this approach, a variety of nanosized macromolecules
in the range of 5–20 nm became available, which showed great
potential in drug-delivery systems,[21] (multistep) catalytic
conversions,[22–25] and nanotechnology.[14–19] Noncovalent
interactions, such as hydrogen bonds, p–p interactions, and
hydrophobic interactions, also generate these particles, but
now with the ability to respond to external stimuli. This
approach has been successfully introduced by our[26,27] and
other[28,29] groups using hydrogen-bonding motifs, with the
ureidopyrimidinone group[30–33] being a well-known example.
The characterization of the nanoparticles has been restricted
to size-exclusion chromatography (SEC) and atomic force
microscopy (AFM). Both techniques showed a significant
collapse of the polymer chains, but no evidence for true
folding has been observed to date.
Herein we show that single-chain polymeric nanoparticles
(SCPNs) comprising an internal helical architecture can be
obtained by noncovalent interactions and that the folding
process can be followed by circular dichroism (CD) spectros-
copy. Our recognition unit of choice is the chiral benzene-
1,3,5-tricarboxamide (BTA) moiety, which we have studied in
great detail using a combination of ultraviolet (UV) and CD
spectroscopy and which self-assembles into helical stacks
stabilized by threefold intermolecular hydrogen bonding.[34–38]
The BTAs self-assemble in a cooperative fashion and follow a
nucleation–elongation growth mechanism. The transition
from the molecularly dissolved state to the aggregated state,
indicated by the temperature of elongation Te , is abrupt and
highly concentration-dependent.[36] We anticipated that the
cooperative self-assembly of dangling BTAs as side chains
would supply us with detailed information on the folding
behavior and that the inner structure of the polymeric
nanoparticles would be revealed by CD spectroscopy. To
follow the folding process, we introduced a photochemical
switch to turn on the secondary interactions. The photolabile
o-nitrobenzyl protecting group is used to avoid solubility
issues and allows controlled BTA self-assembly.[39,40] The
design of the system and the polymers we studied in this
investigation are given in Scheme 1.
For the synthesis of 1, we used atom-transfer radical
polymerization (ATRP) with activators regenerated by elec-
tron transfer (ARGET) as the polymerization technique,[41]
followed by post-modification using alkyne–azide coupling.
Silyl-protected propargyl methacrylate and isobornyl meth-
acrylate were polymerized in a ratio of 80:20, employing
benzyl bromoisobutyrate as the initiator and CuBr/TPMA/
Sn(EH)2 as the catalyst (see the Supporting Information for
details).[41,42] Isobornyl methacrylate was selected to enhance
the solubility of the final polymer in apolar solvents.[43] Silyl
protection was necessary to prevent interaction of the alkyne
function with copper.[44] After precipitation, the number-
average molecular weight (Mn) of the polymer was
[*] T. Mes, R. van der Weegen, Dr. A. R. A. Palmans,
Prof. Dr. E. W. Meijer
1
32 kgmolÀ1, as determined by H NMR spectroscopy, corre-
sponding to an average degree of polymerization of 180. SEC
analysis in THF showed a Mn of 22 kgmolÀ1 and a polydis-
persity index (PDI) of 1.63 (polystyrene standards). The
incorporation of propargyl groups was 25%, which was close
to the feed ratio of 20%. The deprotection of the silyl group
was achieved quantitatively. The enantiomerically pure,
azide-functionalized “caged” BTA unit was synthesized in
five steps and was fully characterized (see the Supporting
Information). The protected BTA azide was coupled to the
alkyne-functionalized polymer using CuI-catalyzed cycload-
dition to afford polymer 1 (Scheme 1, see the Supporting
Information for details).[45,46] We functionalized half of the
Laboratory of Macromolecular and Organic Chemistry
Institute for Complex Molecular Systems
Eindhoven University of Technology
P.O. Box 513, 5600 MB Eindhoven (The Netherlands)
Fax: (+31)40-245-1036
E-mail: a.palmans@tue.nl
e.w.meijer@tue.nl
[**] This work was supported by the Council of Chemical Sciences of the
Netherlands Organization for Scientific Research (NWO-CW).
Prof. Dr. Jim Feast, Dr. Matthew Carnes, and Nabil Tahiri are
acknowledged for stimulating discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100104.
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Next, the feasibility to fully
deprotect polymer 1 to polymer 2
(Scheme 1) was evaluated. Irradia-
tion of polymer 1 (c = 3 mgmLÀ1 in
[D2]tetrachloroethane) with UV
light (l = 354 nm) resulted in full
photolytic cleavage of the o-nitro-
benzyl group within 20 min, as seen
by the disappearance of the ben-
zylic signal in 1H NMR spectrum
(Supporting
Information,
Fig-
ure S2).[48] The infrared spectrum
of polymer 2 in the solid state after
workup (Supporting Information,
Figure S3) showed vibrations at
positions typical for threefold heli-
cal intermolecular hydrogen bond-
ing in BTAs.[49]
In dilute solutions, the nature of
the solvent is of high importance to
induce self-assembly of the BTA
moieties in polymer 2. While the
helical self-assembly of model BTA
4 was demonstrated in MCH, poly-
mer 1 and 2 were found to be
insoluble in this solvent. To recon-
cile the solvent preferences of the
polymethacrylate backbone and
BTA self-assembly, we decided to
Scheme 1. a) Representation of a random-coil polymer that folds into an ordered chiral single-chain
polymeric nanoparticle. b) Chemical structures of the polymers that can be triggered to fold. Upon
irradiation of 1, the o-nitrobenzyl group is cleaved to afford 2, allowing self-assembly under selected
conditions.
available alkyne groups with the BTA moiety, yielding a
polymer containing around 20 BTA molecules per chain.
According to the 1H NMR spectrum, Mn was estimated to be
47 kgmolÀ1, while SEC analysis in chloroform revealed a Mn
of 26 kgmolÀ1 and a PDI of 1.7 (polystyrene standards).
To confirm the feasibility of our approach to “cage” the
BTA moieties by one UV labile o-nitrobenzyl group, we first
investigated the self-assembly of model compounds 3 and 4
(Scheme 2). Irradiation of 3 in [D4]MeOH with UV light (l =
354 nm, T= 208C, c = 5 mgmLÀ1) in a photoreactor resulted
in full conversion of 3 into 4 within two hours of irradiation, as
determined by 1H NMR (Supporting Information, Figure S1).
Irradiation did not result in degradation of the BTA motif.
Both 3 and 4 are molecularly dissolved in [D4]MeOH,
preventing the formation of helical supramolecular poly-
mers.[47] Next, we deprotected 3 in methylcyclohexane
(MCH), a solvent in which 3 should be molecularly dissolved
and 4 self-assembles into supramolecular polymers with
preferred M helicity.[35,36] Indeed, CD spectroscopy of 3 in
MCH (c = 1.2 ꢀ 10À5 m) showed no Cotton effect. A Cotton
effect arose upon irradiating the solution, which showed
saturation after about 60 min of irradiation (Figure 1). The
magnitude (À16 mdeg at l = 223 nm), sign, and shape of the
CD spectrum is similar to those found in other chiral BTAs
dissolved in MCH at a similar concentration and temper-
ature.[47] This result indicates that o-nitrosobenzaldehyde,
which is released during the reaction,[39] does not interfere
with the self-assembly process and that supramolecular
polymers with a preferred helicity are formed upon depro-
tection.
apply solvent mixtures, more specifically a mixture of 1,2-
dichloroethane (DCE) and MCH for the deprotection
Scheme 2. Design of a “caged” BTA. Upon irradiation of 3, the
o-nitrobenzyl group is cleaved to afford 4, allowing self-assembly under
selected conditions.
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MCH 70:30 vol%) was followed as a function of time using
UV spectroscopy (Supporting Information, Figure S5).
Already after 10 min of irradiation, the deprotection reaction
was complete, as evidenced by saturation of the UV
absorption signal. CD analysis of the sample that was
deprotected at room temperature for 20 min showed a very
small Cotton effect of À2 mdeg at l = 225 nm (Figure 3a,
Figure 1. Development of the Cotton effect in the conversion of
compound 3 into 4 as measured at 223 nm as a function of irradiation
time (T=208C, c=1.2ꢀ10À5 m in MCH).
Figure 3. a) Fully deprotected polymer 2 before (black curve) and after
heating to 808C and cooling to 208C (gray curve). cBTA =7.5ꢀ10À5 m,
DCE/MCH 70:30 vol%, T=208C, 20 min UV irradiation. b) Evolution
of the Cotton effect of 1 as a function of photoirradiation time tUV with
intermittent heating to 808C and cooling to 208C. Heating and cooling
step: vertical lines, deprotection step: horizontal lines;
reaction of 1. Importantly, the CD spectra were measured
after heating the sample to 808C and slow cooling to room
temperature. A pronounced negative Cotton effect in depro-
tected polymer 2 was observed with a maximum at l = 225 nm
(Supporting Information, Figure S4), typical of helical hydro-
gen bonded BTA aggregates, when measured in a mixture of
g g heated sample, deprotected sample. cBTA =7.5ꢀ10À5 m,
DCE/MCH 70:30 vol%, l=225 nm, T=208C.
~
&
DCE/MCH 65:35 vol% (BTA content
cBTA = 7.5 ꢀ
10À5 molLÀ1, T= 208C).[51] A systematic investigation of the
effect of solvent composition on the absolute CD intensity
resulted in the data summarized in Figure 2. We used the
concentration-independent anisotropy value (gvalue) of the
Cotton effect at l = 225 nm. Interestingly, in pure DCE,
polymer 2 already showed a negative Cotton effect, which
increased upon increasing the MCH concentration. A max-
imum value of the Cotton effect was found in a 70:30 DCE/
MCH mixture. Increasing the amount of MCH results in a
decrease of the CD intensity. Therefore, the solvent (combi-
nation) has to balance the backbone solubility of both the
protected and deprotected polymer and the self-assembly
capability of the chiral BTA unit.[49,51]
black line). This value is significantly lower than the
maximum value of À40 mdeg (gvalue = À9.8 ꢀ 10À4) found for
polymer 2 in the same solvent mixture (Figure 2). The latter
result was obtained after heating and cooling the sample.
Gratifyingly, heating the solution to 808C followed by cooling
to 208C at a rate of 5 KminÀ1 resulted in a pronounced Cotton
effect of À37 mdeg at l = 225 nm (Figure 3a, gray line). This
interesting behavior was evaluated in further detail by
performing CD measurements on a solution of 1 (cBTA
=
7.5 ꢀ 10À5 molLÀ1, DCE/MCH 70:30 vol%) after irradiating
the solution for short time intervals. CD spectra were
measured immediately after UV irradiation and also after
heating to 808C and cooling to 208C (Figure 3b). For each
individual deprotection step, it was observed that the Cotton
effects before and after irradiation were of similar size.
Heating to 808C resulted in complete disappearance of the
Cotton effect. However, upon cooling, the Cotton effect
increased proportionally to the amount of deprotected
BTAs.[43] Interestingly, the CD cooling curves of 1 after 2
and 5 min of irradiation corresponding to 60 and 95% of
deprotected BTAs, respectively, showed an onset of aggrega-
tion that shifted from approximately 558C to 758C (Fig-
ure 4a).
Having established an optimal solvent mixture, the
deprotection reaction of 1 (cBTA = 7.5 ꢀ 10À5 molLÀ1, DCE/
To experimentally test our concept of the single-chain
polymer nanoparticles by stepwise folding, it is important to
exclude intermolecular self-assembly. Therefore, we com-
pared the self-assembly and the ability to transfer chiral
information by the “sergeants and soldiers” principle of BTAs
present in polymer 2, with the “free” C3-symmetrical BTAs
that have been studied before. Where the latter showed a
strong concentration dependent temperature of elongation
(Supporting Information, Figure S6), polymer 2 showed a
Figure 2. Dependence of the gvalue of 2 on the solvent composition
(cBTA =7.5ꢀ10À5 m, l=225 nm, T=208C).
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5087

Communications
recovered after the addition of > 1000 equivalents of quinu-
clidine (Supporting Information, Figure S11).
The results presented herein introduce single-chain poly-
meric nanoparticles by stepwise folding, which is controlled
by side-chain aggregation. By careful selection of the solvent
(a mixture of DCE and MCH), we are able to balance the
solubility of the main chain with the hydrogen bonding
required for folding of polymer 2. Folding is achieved by
controlled cooling of the solution of polymer 2 to arrive at the
thermodynamically stable state. When polymer 2 is formed
from 1 by irradiation at room temperature, the system resides
in a kinetically trapped or collapsed state; that is, a
unimolecular glass or “molten globule” state. The more
thermodynamically favorable folded state is achieved by an
additional heating/cooling step. Temperature plays a decisive
role: At high temperatures, BTAs are not aggregated, the
polymer is unfolded, and at the same time the polymer
backbone is flexible. Slowly reducing the temperature induces
BTA aggregation because there is sufficient mobility within
the polymer to adopt an optimal conformation for self-
assembly to occur.
We anticipate that the self-assembly occurs within a single
chain, as the onset of self-assembly is determined by the local
concentration of dangling BTAs on the chain and is inde-
pendent of the overall concentration of the polymer. More-
over, unfolding experiments with the hydrogen-bond break-
ing solvent HFIP shows a significant increase in stability of
the BTA-helix in the single-chain polymer nanoparticle
compared to the same helix of unbound or “free” BTAs.
The observed aggregation behavior in the SCPNs described
herein partly mimics the folding of proteins, and has also been
described in synthetic systems, such as foldamers and DNA
origami structures.[4,52,53] The latter also require small temper-
ature jumps to arrive at full self-assembly.
Figure 4. a) CD spectra of 2 versus temperature after 2 (gray curve)
and 5 min of irradiation (black curve) cBTA =3.25ꢀ10À5 m, DCE/MCH
70:30 vol%, l=225 nm. b) CD spectra of 2 versus temperature at
different concentrations. From top to bottom: 1.5, 3.0, 4.5, 6.0,
7.5ꢀ10À5 m. DCE/MCH 70:30 vol%, l=225 nm.
concentration-independent onset of aggregation (Figure 4b),
and the increase of the CD intensity was a more gradual
process. Normalizing the curves in Figure 4b for concentra-
tion by plotting the gvalue as a function of temperature
(Supporting Information, Figure S7) reveals that all cooling
curves can be superimposed. The onset of aggregation was
studied by changing the BTA incorporation (Figure 4a and
Supporting Information, Figure S8). As the onset strongly
depends on the local BTA concentration and not on the
overall concentration, the aggregation process is predom-
inantly a single-chain folding process. More evidence that
single-chain folding is operative was shown by the absence of
chirality transfer from chiral to achiral BTA polymers,
indicating the absence of intermolecular self-assembly (Sup-
porting Information, Figure S9).
Finally, we investigated the influence of additives on the
stability of the folded structures. We prepared a solution of 2
(cBTA = 8.5 ꢀ 10À5 molLÀ1, DCE/MCH 70:30 vol%) and
added various amounts of hexafluoroisopropanol (HFIP)
(Figure 5). The Cotton effect gradually disappeared upon the
addition of HFIP. After the addition of 1000 equivalents, the
Cotton effect was completely absent. In contrast, the addition
of 15 equivalents of HFIP is sufficient to fully disrupt
aggregation of the “free” C3-symmetrical BTAs (Supporting
Information, Figure S10). The folding of polymer 2 was
reversible as the Cotton effect was almost completely
In conclusion, we have been able to follow and control the
folding of polymers into an ordered chiral single-chain
polymer nanoparticle. The high stability and chiral confor-
mation of the folded particles make them excellent candidates
for compartmentalized catalytic systems.[54] Our current work
is focused on the folding kinetics and on the development of
water-based systems with catalytically active groups embed-
ded in the hydrophobic compartment.
Received: January 6, 2011
Revised: February 1, 2011
Published online: April 18, 2011
Keywords: circular dichroism · folding · nanoparticles ·
.
photodeprotection · supramolecular chemistry
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