Noncovalently connected micelles, nanoparticles, and metal-functionalized nanocages using supramolecular self-assembly

Article abstract of DOI:10.1021/ja800230k

An SCS pincer -based nitroxide-mediated polymerization (NMP) initiator has been synthesized and utilized to polymerize tert-butyl acrylate (^tBuA), affording polymers with control over molecular weight and polydispersity. ¹H NMR spectroscopy indicates that the sulfur end group remains intact after deprotection of the P^tBuA segment to yield a poly(acrylic acid) segment. The hydrophilic polymer-tethered SCS ligand has been demonstrated to bind to palladium(II), as characterized by a distinctive Pd-C shift in the ¹³C NMR spectrum and a diagnostic metal-to-ligand charge-transfer band in the UV-vis spectrum. A pyridine-functionalized NMP initiator has also been synthesized and used to initiate the NMP of styrene with good control and end group fidelity. The binding of these two chain end ligand-functionalized polymers to form an amphiphilic metallosupramolecular diblock copolymer is facile, as indicated through extended ¹H and ¹³C NMR studies. The self-assembly of this diblock into well-defined, monodisperse, noncovalently connected micelles (NCCMs) is reported and has been characterized by dynamic light scattering, transmission electron microscopy, and atomic force microscopy. The NCCMs were selectively stabilized throughout the shell layer to produce stable noncovalently connected nanoparticles, resulting in a distinctive reduction in the solution hydrodynamic radius and zeta potential compared to those of the precursor micelle. The hydrophobic core domain was then readily removed via dialysis at low pH to afford a hollow polymeric nanocage with well-defined interior functionality. A significant increase in the solution hydrodynamic radius and shape by AFM analysis was observed upon removal of the core, and the hydrophilic nanocages were shown to be ineffective in the sequestration of hydrophobic dye molecules relative to the parent nanoparticle.

Full text of DOI:10.1021/ja800230k

Published on Web 06/13/2008
Noncovalently Connected Micelles, Nanoparticles, and
Metal-Functionalized Nanocages Using Supramolecular
Self-Assembly
Adam O. Moughton and Rachel K. O’Reilly*
MelVille Laboratory for Polymer Synthesis, Department of Chemistry, UniVersity of Cambridge,
Lensfield Road, Cambridge CB2 1EW, United Kingdom
Received January 10, 2008; E-mail: rko20@cam.ac.uk
Abstract: An SCS “pincer”-based nitroxide-mediated polymerization (NMP) initiator has been synthesized
and utilized to polymerize tert-butyl acrylate (tBuA), affording polymers with control over molecular weight
and polydispersity. 1H NMR spectroscopy indicates that the sulfur end group remains intact after deprotection
of the PtBuA segment to yield a poly(acrylic acid) segment. The hydrophilic polymer-tethered SCS ligand
has been demonstrated to bind to palladium(II), as characterized by a distinctive Pd-C shift in the 13C
NMR spectrum and a diagnostic metal-to-ligand charge-transfer band in the UV-vis spectrum. A pyridine-
functionalized NMP initiator has also been synthesized and used to initiate the NMP of styrene with good
control and end group fidelity. The binding of these two chain end ligand-functionalized polymers to form
an amphiphilic metallosupramolecular diblock copolymer is facile, as indicated through extended 1H and
13C NMR studies. The self-assembly of this diblock into well-defined, monodisperse, noncovalently connected
micelles (NCCMs) is reported and has been characterized by dynamic light scattering, transmission electron
microscopy, and atomic force microscopy. The NCCMs were selectively stabilized throughout the shell
layer to produce stable noncovalently connected nanoparticles, resulting in a distinctive reduction in the
solution hydrodynamic radius and zeta potential compared to those of the precursor micelle. The hydrophobic
core domain was then readily removed via dialysis at low pH to afford a hollow polymeric nanocage with
well-defined interior functionality. A significant increase in the solution hydrodynamic radius and shape by
AFM analysis was observed upon removal of the core, and the hydrophilic nanocages were shown to be
ineffective in the sequestration of hydrophobic dye molecules relative to the parent nanoparticle.
1. Introduction
nanoscaled assemblies for utilization as new materials with
desirable functions and properties.4–12
The term “supramolecular” encompasses many chemical and
biological systems; by definition, these systems exhibit the
association of several molecules, which are held together by
intermolecular forces. Supramolecular structures are constructed
through a delicate balance between strong covalent bonds that
hold the molecular building blocks together and the reversible
intermolecular forces that assemble them. These reversible,
cohesive forces are comparatively weak, noncovalent interac-
tions1 and include van der Waals forces, hydrogen and metal-
to-ligand bonding, electrostatic forces, hydrophobic-hydrophilic
interactions, and π-π stacking. Noncovalent interactions be-
tween molecules impart an extra form of hierarchal assembly
and organization upon the system to afford various well-defined
supramolecular structures, on a larger scale than that of their
component parts.2,3 This organization or energy minimization
of the system is termed “self-assembly”.1 Nature uses the unique
power of this self-assembly process to construct the elegant
supramolecular architectures seen in biological systems. In
recent years, researchers have tried to mimic the kind of
structural complexity found in Nature in their design of synthetic
To this end, the designed manipulation of noncovalent inter-
actions between specifically chosen organic molecules, or in
particular polymers, is a powerful assembly tool.13 This strategy
has been exploited for polymeric systems in recent years via
the incorporation of H-bonding motifs and metal-ligand binding
sites by many research groups, but in particular those of
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Assembly of Noncovalently Connected Nanostructures
A R T I C L E S
Rowan.41–43 To date, the most promising and facile route toward
nanosized and utilizable assemblies involves the self-assembly
of polymers into vesicle or micelle-type structures.44–50 To
enable phase-separated self-assembly, amphiphilic diblock
copolymers must be used, i.e., those which contain hydrophobic
and hydrophilic segment(s), which can mimic natural phospho-
lipids and form supramolecular structures with predictable
morphologies.51,52
different polymer chains are covalently connected at their
junction, is the most common way to produce such assemblies.7,53
It has also been shown in recent years by a number of research
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copolymers can be covalently stabilized throughout their core
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amidationchemistrytoaffordrobustcross-linkednanoparticles.54–61
From these nanoparticle scaffolds, it has been demonstrated that
permeable, water-filled, cage-like nanostructures can be formed
upon core removal, using either ozonolytic or hydrolytic
degradation chemistry.4,56,62 The utilization of a nanoparticle
template for the construction of nanocages has advantages, such
as the well-defined and robust nature of the resultant cage-like
structures, although the harsh excavation chemistries employed
can lead to nanocage degradation or loss of reactive functionality
within the interior.63–66
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A R T I C L E S
Moughton and O’Reilly
systems.31–33,74 Their elegant work has utilized the catalytic
potential of metal complexes on a polymer support, notably for
an SCS “pincer”-Pd(II) complex system for use in Heck
catalysis.34–36 The complexation of this Pd(II)-SCS complex
motif is also well known with pyridine, nitrile, and phosphine
functionalities.29–34,75–78 Schubert and co-workers have recently
pioneered the application of synthetic strategies toward metal-
lopolymer NCCMs using metal-ligand interactions.21,22 In
recent years, Schubert and co-workers have demonstrated that
the incorporation of terpyridine ligands onto polymer chain ends
enables access to an interesting block copolymer architecture,
a metallosupramolecular diblock copolymer, via bis-complex-
ation to ruthenium, among many other metals.25–28 Moreover,
through tailored selection of the polymer utilized to form the
amphiphilic metallodiblock copolymer, supramolecular archi-
tectures such as metal-linked NCCMs can be achieved upon
self-assembly.21,22
Recently, the preparation of tailor-made functionalized poly-
mers for self-assembly has been markedly advanced by the
developments in controlled radical polymerization (CRP) tech-
niques. CRP allows for the synthesis of well-defined block
copolymers with tunable molecular weights (Mn) and narrow
polydispersities (Mw/Mn) for applications in self-assembly.6
Moreover, CRP techniques such as reversible addition frag-
mentation chain transfer (RAFT)79–82 and nitroxide-mediated
polymerization (NMP)83–86 allow for the preparation of chain-
end-functionalized polymers via the prefunctionalization of the
chain-transfer agent or initiator species, respectively. This
concept has been used to synthesize a wide range of polymers
bearing specifically targeted functional groups at their chain
termini. For example, Hawker and co-workers showed that
pendant end groups such as pyrene could be incorporated onto
a range of different polymers prepared by NMP and the end
groups were still present post-polymerization, thus demonstrat-
ing excellent polymerization end-group fidelity.87 Schubert and
co-workers have also made a significant contribution to this field
by utilizing a terpyridine-functionalized NMP initiator capable
of binding to a range of metal centers.23,27 This functional
initiator effectively mediates the controlled NMP of styrene,
vinylpyridines, N′,N′-dimethylacrylamide, isoprene, and acry-
lates to obtain polymers with predictable Mn and low Mw/Mn
that are valuable building blocks for utilization in the synthesis
of metallosupramolecular polymer architectures.27
In this work, we describe the design and preparation of
NCCMs which are self-assembled from an unsymmetrical
supramolecular metallodiblock copolymer. An unsymmetrical
binding unit was specifically chosen to join the two homopoly-
mer blocks, to form the diblock, to allow for facile removal of
one of the ligands to facilitate core removal. This strategy utlizes
two ligand chain-end-functionalized homopolymers (of which
one is hydrophobic and other is hydrophilic) which both undergo
monocomplexation to a Pd(II) metal center to self-assemble to
form an amphiphilic diblock copolymer. This metal complex
at the interface between the two polymers utilizes the relatively
weak coordination of a pyridine moiety to a Pd(II) metal center
and a strongly bound SCS pincer ligand and represents the first
report of an unsymmetrical metal-ligand interaction for the
formation of a supramolecular block copolymer for self-
assembly into micellar morphologies. This strategy relies upon
the incorporation of the two complexing ligands onto the chain
ends of two different polymer blocks. To achieve this goal and
produce well-defined polymers with predictable molecular
weights, NMP was used since we could readily synthesize two
functional alkoxyamine NMP initiator species using well-
established functionalization chemistries. The resultant end-
functionalized, monodisperse polymers, with easily tunable
molecular weights, were utilized to form well-defined supramo-
lecular structures which could be readily tuned by tailoring the
monomer to initiator ratios during polymer synthesis. These
metallopolymers were then self-assembled to form well-defined
micellar structures (NCCMs) which were stabilized throughout
their shell domain to form robust and stable, noncovalently
connected nanoparticles (NCCNs). Core removal of these
NCCNs, by exhaustive dialysis at low pH, has been demon-
strated to form hydrophilic, well-defined, cage-like nanostruc-
tures or nanocages via selective cleavage of the metal-
hydrophobic chain bond while ensuring retention of the metal
functionality within the interior of the nanostructure. Core
removal exposes a nanostructure whose interior domain is
functionalized with SCS pincer-Pd(II) complexes.
2. Experimental Section
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Materials. Tetrahydrofuran (THF, 99%), methanol (99%), and
all other chemicals were used as received from Aldrich, Fluka, and
Acros unless otherwise stated. tert-Butyl acrylate and styrene
monomers were distilled over CaH2 prior to use and stored at -5
°C. 2,2,5-Trimethyl-4-phenyl-3-azahexane-3-oxy and N-tert-butyl-
O-(1-(4-(chloromethyl)phenyl)ethyl)-N-(2-methyl-1-phenylpropyl)-
hydroxylamine were synthesized as previously reported in the
literature.86 The pendant alcohol-functionalized SCS pincer ligand
was synthesized as reported in the literature.88 The palladium(II)
precursor complex, [Pd(PhCN)2Cl2], was synthesized according to
a previously reported literature preparation.89
Instrumentation. Nuclear magnetic resonance (NMR) experi-
ments (1H and 13C) were performed on a Bruker AVANCE 400
FT-NMR spectrometer using deuterated solvents. Coupling con-
stants are in hertz, and chemical shifts are reported in parts per
million relative to CHCl3 (7.26 ppm for 1H and 77.2 ppm for 13C)
or DMSO-d6 (2.50 ppm for 1H and 39.52 ppm for 13C). Extended
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A R T I C L E S
1H and 13C NMR spectra were recorded on an AVANCE 500 Cryo
FT-NMR spectrometer, all at 25 °C.
4.02 (s, 4H, CH2SPh), 3.51 (d, 1H, NCH, diastereoisomer A), 3.34
(d, 1H, NCH, diastereoisomer B), 2.44-2.39 (m, 1H, CH(CH3)3),
1.63 (d, 3H, diastereoisomer A), 1.58 (d, 3H, diastereoisomer B),
1.29 (d, 3H, diastereoisomer A), 1.09 (s, 9H, C(CH3)3, diastereo-
isomer A), 0.97 (d, 3H, diastereoisomer B), 0.85 (s, 9H, C(CH3),
diastereoisomer B), 0.59 (d, 3H, diastereoisomer A), 0.25 (d, 3H,
diastereoisomer B). 13C NMR (CDCl3, 400 MHz): δ 145.3, 142.5,
142.2, 138.9, 138.8 (ArC), 137.9, 136.4, 136.1, 131.0, 128.8, 128.6,
127.7, 127.4, 127.2, 126.4, 126.3, 126.2, 126.2, 83.3, 82.5, 77.2,
72.2, (CH2OCH2) 72.1, (CH2OCH2) 71.4, 60.5, 38.9, 32.0, 31.7,
28.4, 24.7, 23.2, 22.7, 22.2, 22.0, 21.2, 15.2, 14.1. IR (νmax/cm-1):
3058-2866 (C-H), 1583 (aromatic), 1480 (aromatic), 1360
(N-O), 1088 (C-O-C), 821 (1,3,5-trisubst. Ph ring). LC-MS: m/z
690.35 (M+, 100%). C,H,N found: C, 76.63; H, 7.61; N, 2.05%.
C44H51NO2S2 requires C, 76.59; H, 7.45; N, 2.03%.
Synthesis of Pyridyl NMP Initiator 2. A stream of air was
bubbled through a mixture of toluene (125 mL) and ethanol (125
mL) for 1 h. 4-Vinylpyridine (3.58 g, 34.0 mmol), 2,2,5-trimethyl-
4-phenyl-3-azahexane-3-oxy86 (4.99 g, 22.7 mmol), (R,R)-(-)-N,N′-
bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane-diamine-mana-
ganese(III) chloride (2.06 g, 3.24 mmol), and sodium borohydride
(1.72 g, 45.4 mmol) were then added, one immediately following
the other. Air was bubbled through the mixture for 17 h. The
reaction mixture was then filtered through silica gel in a sintered
glass funnel and rinsed with dichloromethane followed by methanol.
The filtrate was concentrated under vacuum and purified by flash
chromatography, packed in dichloromethane, eluting with 20:1
dichloromethane/methanol (Rf ) 0.2) to yield the product as a light
brown oil which crystallizes at -5 °C into a light brown crystalline
solid, 2 (3.84 g, 52%). 1H NMR (CDCl3, 400 MHz): δ 8.50-8.70
(br m, 2H, py-R-H), 7.45-7.30 (br m, 2H py-ꢁ-H), 7.29-7.11 (m,
5H, ArH), 4.95-4.87 (m, 1H, CH3CH), 3.43-3.33 (dd, 1H, NCH,
diastereoisomer A), 2.34-2.25 (m, 1H, CH(CH3)3), 1.61 (d, 3H,
diastereoisomer A), 1.55 (d, 3H, diastereoisomer B), 1.27 (d, 3H,
diastereoisomer A), 1.05 (s, 9H, C(CH3)3, diastereoisomer A), 0.95
(d, 3H, diastereoisomer B), 0.80 (s, 9H, C(CH3), diastereoisomer
B), 0.54 (d, 3H, diastereoisomer A), 0.25 (d, 3H, diastereoisomer
B). 13C NMR (CDCl3, 400 MHz): δ 154.3, 153.5, 149.8 (Py-R-C),
142.1, 141.9, 130.5, 130.7, 127.5, 127.3, 126.5, 126.4, (ArC), 82.5,
81.3, 77.0, 72.2, 60.7, 32.0, 28.4, 24.4, 23.0, 21.8. IR (νmax/cm-1):
3038-2869 (C-H), 1598 (aromatic), 1482 (aromatic), 1362
(N-O), 1105 (C-N). LC-MS: m/z 326.5 (M+, 100%). C,H,N
found: C, 77.29; H, 9.36; N, 8.52%. C21H30N2O requires C, 77.26;
H, 9.26; N, 8.58%.
Size exclusion chromatography/gel permeation chromatography
(SEC/GPC) measurements were performed using a Viscotek
VE1122 solvent delivery system with a Viscotek VE3580 RI
detection system using THF as eluent at a flow rate of 1 mL/min,
unless otherwise stated. The molecular weights of polymers were
calculated relative to polystyrene or poly(methyl methacrylate)
standards. UV-vis spectra were recorded on a Varian Cary 4000
UV-vis spectrophotometer in THF unless otherwise stated. Infrared
spectroscopy was recorded on a Perkin-Elmer Precisely, Spectrum
100 FT-IR spectrometer.
Hydrodynamic diameters (Dh), size distributions, and zeta poten-
tials (ꢀ) for the micelles and nanoparticles in aqueous solutions
were determined by dynamic light scattering (DLS). The DLS
instrumentation consisted of a Malvern Zetasizer Nano ZS instru-
ment operating at 25 °C with a 635-nm laser module. Measurements
were made at a detection angle of 173° (back scattering), and
Malvern DTS 4.00 software was utilized to analyze the data. All
determinations were made in triplicate (with 12 runs recorded).
Static light scattering (SLS) measurements were recorded on a
Wyatt Dawn Helios II.
The height measurements and distributions for the nanoparticles
were determined by tapping-mode atomic force microscopy (AFM)
under ambient conditions in air. The sample solutions were prepared
for AFM analysis by dilution (typical concentrations ca. 0.002 mg/
mL) and deposition of a drop (2 µL) onto freshly cleaved mica
and allowed to dry freely in air. The number-average particle heights
(Hav) and diameter (Dav) values and standard deviations were
generated from the sectional analysis of 100 particles from at least
five different analysis regions.
TEM samples were diluted with a 1 wt % phosphotungstic acid
stain (1:1). Carbon grids were prepared by argon plasma treatment
to increase the surface hydrophilicity. Micrographs were collected
at 64000× magnification unless otherwise stated. Histograms of
number-average particle diameters (Dav) and standard deviations
were generated from the analysis of a minimum of 150 particles
from at least three different micrographs.
Mass spectra were acquired by matrix-assisted laser desorption/
ionization time-of-flight (MALDI-ToF) mass spectrometry using a
Bruker Daltonics Ultraflex II MALDI-ToF mass spectrometer,
equipped with a nitrogen laser delivering 3-ns laser pulses at 337
nm. In general, solutions of dithranol as matrix, NaTFA as cation-
ization agent, and polymer were prepared in THF at a concentration
of 0.2 g/L. Ten-microliter aliquots of matrix, polymer, and NaTFA
solutions were applied sequentially to the target, followed by solvent
evaporation, to prepare a thin matrix/analyte film. The samples were
measured in reflection ion mode in all cases.
Synthesis of SCS NMP Initiator 1. 3,5-Bis(phenylsulfido-
methyl)benzyl alcohol88 (1.00 g, 2.84 mmol) was dissolved in dry,
degassed THF (10 mL) under a nitrogen atmosphere. NaH as a
60% dispersion in mineral oil (0.60 g, 14.9 mmol) was added, and
the reaction mixture was stirred at room temperature for 30 min.
The chloro-functionalized alkoxyamine initiator, N-tert-butyl-O-
(1-(4-(chloromethyl)phenyl)ethyl)-N-(2-methyl-1-phenylpropyl)-
hydroxylamine86 (1.07 g, 2.84 mmol), was added as a solution in
THF via cannular transfer, and the reaction was refluxed for 16 h
under nitrogen. Upon the solution cooling to room temperature,
acetic acid (ca. 5 mL) was added dropwise under nitrogen flow to
decompose any excess sodium hydride. Dichloromethane (100 mL)
was then added. The organic layers were washed with water (100
mL), sodium hydroxide (100 mL), and then a saturated brine
solution (100 mL). The organic phase was dried over magnesium
sulfate, filtered, and concentrated under vacuum. The crude product
was purified by flash chromatography, eluting with 3:2 hexane/
dichloromethane solution to give the product, 1 (Rf ) 0.5 in 3:2
hexane/dichloromethane) as a light-yellow gum, (0.82 g, 42%). 1H
NMR (CDCl3, 400 MHz): δ 7.43-7.09 (m, 22H, ArH), 4.97 (br s,
1H, CH3CH), 4.45 (s, 2H, PhCH2OCH2), 4.44 (s, 2H, CH2OCH2Ph),
General Acrylate Polymerization Using 1. tert-Butyl acrylate
(1.5 g, 11.7 mmol), the SCS pincer alkoxyamine initiator 1 (0.162
g, 0.23 mmol), and 2,2,5-trimethyl-4-phenyl-3-azahexane-3-oxy
(0.0052 g, 0.0234 mmol) were placed in an oven-dried ampule with
a stirrer bar. The ampule was degassed three times and sealed under
nitrogen, and the polymerizations were heated at 125 °C for 115 h.
For lower conversions, shorter reaction times were used. The
polymer was then dissolved in a minimum amount of THF and
purified by precipitation into ice-cold methanol (repeated three
times) and dried in a vacuum oven at room temperature overnight.
SCS pincer chain-end-functionalized poly(tert-butyl acrylate) (Pt
-
NMR
BuA) 3 was isolated as a white solid (0.62 g, 60%). Mn
)
4500 g/mol, MnGPC ) 5200 g/mol, Mw/Mn ) 1.14. IR (νmax/cm-1):
2978, 2933, 1722, 1480, 1449, 1392, 1366, 1254, 1141, 1035, 909,
751. 1H NMR (CDCl3, 500 MHz): δ 1.20-1.50 (br, (CH3)3C),
1.24-1.68 (br, CH2 of the polymer backbone), 1.74-1.94 (br, CH2
of the polymer backbone), 2.15-2.35 (br, CH of the polymer
backbone), 4.05 (s, CH2SPh in end group), 4.41 (s, CH2OCH2 in
end group), 4.42 (s, CH2OCH2 in end group), 7.11-7.27 (m, ArH
in end groups). 13C NMR (CDCl3, 500 MHz): δ 21.2 (CH3CHCH3
on the chain end), 27.9-28.1 ((CH3)3C on the side chain),
35.7-37.2 (carbon on the polymer backbone), 41.7-42.2 (carbon
on the polymer backbone), 80.2 ((CH3)3C on the polymer side
chain), 125.5-135.8 (ArC on the chain ends), 173.6-173.8 (CdO
on the polymer side chain).
9
J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8717

A R T I C L E S
Moughton and O’Reilly
General Styrene Polymerization Using 2. Styrene (3.03 g, 29.1
mmol) and the pyridyl ligand alkoxyamine initiator 2 (0.19 g, 0.582
mmol) were placed in an ampule with a stirrer bar. The ampule
was degassed three times and sealed under nitrogen, and the
polymerizations were heated at 125 °C for 12 h. For lower
conversions, shorter reaction times were used. The polymer was
then dissolved in a minimum amount of THF and purified by
precipitation into a rapidly stirred solution of ice-cold methanol
(repeated three times) and dried in a vacuum oven at 40 °C
overnight. Pyridyl chain-end-functionalized polystyrene (PS) 4 was
Amphiphilic Block Copolymer Formation, 7. Complexed
NMR
poly(acrylic acid) (PAA) 6 (Mn
) 2900 g/mol, 0.050 g, 0.17
NMR
mmol), and pyridine end-functionalized PS 4 (Mn
) 3600
g/mol, MnGPC ) 2400 g/mol, Mw/Mn ) 1.18; 0.069 g, 0.17 mmol),
were dissolved in N,N-dimethylformamide (DMF, 10 mL). The
mixture was allowed to stir for 4 h under ambient conditions.
Removal of the solvent under vacuum afforded 7 as a brown solid
NMR
1
(0.119 g, 100%). Mn
) 6700 g/mol. H NMR (DMF-d7, 500
MHz): δ 1.22-1.70 (br, CH2 of the polymer backbone), 1.74-2.04
(br, CH2 of the polymer backbone), 2.15-2.41 (br, CH of the
polymer backbone), 4.20 (s, CH2OCH2 in end group), 4.26 (s,
CH2OCH2 in end group), 4.48 (Br s, CH2SPh in end group),
6.20-7.30 (m, ArH in side chain), 7.11-7.27 (m, ArH in end
groups), 8.16-8.26 (m, co-ord R pyr ArH). 13C NMR (DMF-d7,
500 MHz): δ 26.8-43.8 (polymer backbone C), 124.2-136.4 (C,
SPh on the chain ends), 175.9 (CdO on side chain). IR (νmax/cm-1):
3500, 2800, 1941, 1875, 1712, 1601, 1583, 1493, 1452, 1235, 1171,
1115, 1068, 1029, 908, 878, 810, 758, 698, 539. UV/vis (DMF):
λmax ) 350 nm.
isolated as a white solid (1.59 g, 81% yield). MnNMR ) 3600 g/mol,
GPC
Mn
) 2400 g/mol, Mw/Mn ) 1.18. IR (νmax/cm-1): 1598 (py),
1569 (py), 1584, 1515, 1443, 1394, 1362 (N-O), 1296, 1263, 1172,
1147, 1102, 1067, 1058, 1108, 939, 838, 823, 797, 763, 724, 704,
689, 655. H NMR (CDCl3, 500 MHz): δ 1.22-1.70 (br, CH2 of
1
the polymer backbone), 1.74-2.04 (br, CH2 of the polymer
backbone), 2.15-2.41 (br, CH of the polymer backbone), 6.20-7.30
(m, ArH in side chain), 7.11-7.27 (m, ArH in end groups), 8.58
(m, R pyr. ArH). 13C NMR (CDCl3, 500 MHz): δ 149.5 (R pyr.
ArC), 131.0-122.5 (ArC on side chain), 46.4-36.4 (carbons on
the polymer backbone), 31.6, 30.9, 28.2, 21.2.
Micellization of Amphiphile 7 To Afford 8. A round-bottom
flask equipped with a stir bar was charged with 7 (0.120 g, 0.018
mmol), and DMF (120 mL) was added. The solution was allowed
to stir at room temperature for 1 h to ensure the mixture was
homogeneous and that all of the polymer was dissolved. Deionized
nanopure water (130 mL) was added via a metering pump at the
rate of 10 mL/ h. After all of the water had been added, the opaque
micelle solution was transferred to dialysis tubing (MWCO ≈ 3.5
kDa) and dialyzed against deionized nanopure water exhaustively
to remove all of the DMF. The final volume of 8 was 390 mL,
affording a polymer concentration of ca. 0.31 mg/mL. Dh(DLS) )
79 ( 1 nm; ꢀ ) -52 ( 1 mV; Dav(TEM) ) 54 ( 5 nm; Dav(AFM)
Complexation of 3 with Pd(II) To Give Metal-Complexed
PtBuA 5. Polymer 3 (0.050 g, 0.0097 mmol) was dissolved in
acetonitrile (5 mL), and the solution was placed under nitrogen.
The palladium precursor complex, [Pd(MeCN)4(BF4)2] (0.00517
g, 0.012 mmol), was added, and the mixture was stirred at room
temperature for 24 h. After evaporation of the solvent under
vacuum, 3 was redissolved in THF (1 mL) and purified by
precipitation into methanol/water (4:1). The solvent was decanted
off, and the polymer was redissolved in THF (ca. 100 mL), dried
over magnesium sulfate, and filtered, and the solvent was removed
under vacuum to give a light yellow polymer, 5 (0.047 g, 94%).
NMR
GPC
Mn
) 5200 g/mol, Mn
) 4400 g/mol, Mw/Mn ) 1.34. IR
) 78 ( 12 nm; Hav(AFM) ) 2.6 ( 0.6 nm. UV/vis (H2O): λmax
)
(νmax/cm-1): 2976, 2911, 1724, 1478, 1446, 1392, 1367, 1253, 1229,
1140, 1113, 1029, 928, 844, 766, 750. 1H NMR (CDCl3, 500 MHz):
δ 1.27-1.50 (br, (CH3)3C), 1.24-1.72 (br, CH2 of the polymer
backbone), 1.72-1.92 (br, CH2 of the polymer backbone), 2.15-2.42
(br, CH of the polymer backbone), 4.40 (br s, CH2SPh in end
group), 4.45 (s, CH2OCH2 in end group), 4.55 (s, CH2OCH2 in
end group), 6.74-7.18 (m, ArH in end groups). 13C NMR (CDCl3,
500 MHz): δ 21.2 (CH3CHCH3 on the chain end), 25.4-25.7
((CH3)3C on the side chain), 34.2-34.4 (carbon on the polymer
backbone), 41.7-42.1 (carbon on the polymer backbone), 80.3
((CH3)3C on the polymer side chain), 125.7 ((CH3)3C-O) on the
polymer side chain), 125.5-135.8 (ArC, SPh on the chain ends),
151.5 (Pd-C on chain end) 173.6-173.8, (CdO on the polymer
side chain). UV/vis (DMF): λmax ) 350 nm.
350 nm. Lyophilization of a portion of this solution gave 8 as a
light brown solid.
Shell Cross-Linking of Micelle 8 To Give Nanoparticle 9. To
a stirred solution of micelle 8 (100 mL, 0.31 mg/mL) in a round-
bottom flask was added, dropwise over 10 min, a solution of 2,2′-
(ethylenedioxy)bis(ethylamine) (0.000082 g, 0.00055 mmol) in
deionized water (2 mL). The solution was allowed to stir for 2 h at
room temperature. To this reaction mixture was added dropwise,
via a metering pump at the rate of 15 mL/h, a solution of 1-[3′-
(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (0.0003 g,
0.0011 mmol) dissolved in deionized water (1 mL). The reaction
mixture was allowed to stir overnight at room temperature,
transferred to presoaked dialysis membrane tubes (MWCO ≈ 3.5
kDa), and dialyzed against deionized water for 4 d to remove small-
molecule contaminants. The final volume of 9 was 160 mL,
affording a polymer concentration of ca. 0.30 mg/mL. Dh(DLS) )
71 ( 1 nm; Dg(SLS) ) 54 nm, ꢀ ) -25 ( 1 mV; Dav(TEM) ) 48
( 4 nm; Dav(AFM) ) 66 ( 6 nm; Hav(AFM) ) 4.4 ( 1.0 nm.
UV/vis (H2O): λmax ) 350 nm. Lyophilization gave 9 as a light
brown solid.
Hollowing-Out of Nanoparticle 9 To Give Nanocage 10. Nano-
particle 9 (30 mL) was dialyzed against THF/water (1:4) to swell
the hydrophobic core for 1 d. This solution was then dialyzed
against a 10 mM phosphate buffer solution, pH ) 5.0, for 4 d to
cleave the metal-hydrophobic chain bond. The resultant solution
was then exhaustively dialyzed against a THF/water (1:4) solution
for 4 d to remove the core and then dialyzed into nanopure water
exhaustively for 4 d, to remove all of the THF (all dialysis tubing
was MWCO ≈ 12-14 kDa). The final volume of 10 was 30 mL,
affording a polymer concentration of ca. 0.30 mg/mL. Dh(DLS) )
94 ( 1 nm; Dg(SLS) ) 101 nm; ꢀ ) -33 ( 2 mV; Dav(TEM) )
74 ( 7 nm; Dav(AFM) ) 139 ( 11 nm; Hav(AFM) ) 1.5 ( 0.4
nm. UV/vis (H2O): λmax ) 350 nm. Lyophilization gave 10 as a
light brown solid.
Deprotection of Metal-Complexed PtBuA 5 To Give Metal-
Complexed PAA 6. To a 100 mL, round-bottom flask equipped
with a stir bar was added 5 (MnNMR ) 5200 g/mol, 0.100 g, 0.019
mmol), followed by dry dichloromethane (5 mL). The mixture was
allowed to stir for 30 min to dissolve the polymer and then cooled
to 0 °C. Trifluoroacetic acid (TFA, 0.918 g, 8.04 mmol) was then
added at 0 °C. After the mixture was allowed to stir overnight at
room temperature, the dichloromethane and excess TFA were
removed at room temperature by passing air through the flask
overnight. The polymers were purified by dissolving in THF (10
mL) and water (10 mL), transferred to presoaked dialysis membrane
tubes, and dialyzed against deionized water for 3 d. Lyophilization
of the water solution inside the dialysis tubes gave 6 as a light
NMR
brown solid (0.056 g, 97%). Mn
) 2900 g/mol. 1H NMR
(DMSO-d6, 500 MHz): δ 1.0-2.3 (br, CH and CH2 of polymer
backbone), 4.35 (br s, CH2SPh in end group), 4.19 (s, CH2OCH2
in end group), 4.28 (s, CH2OCH2 in end group), 6.68-7.16 (m,
ArH in end groups), 11.8-13.4 (br, COOH). 13C NMR (DMSO-
d6, 500 MHz): δ 124.2-136.3 (C, SPh on the chain ends), 152.5
(Pd-C on chain end). IR (νmax/cm-1): 3500, 2800, 1941, 1875,
1712, 1601, 1583, 1493, 1452, 1235, 1171, 1115, 1068, 1029, 908,
878, 810, 758, 698, 539. UV/vis (DMF): λmax ) 350 nm.
9
8718 J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008

Assembly of Noncovalently Connected Nanostructures
A R T I C L E S
t
Scheme 1. Synthesis of NMP Initiators (a) 1 and (b) 2
Scheme 2. Polymerization Conditions of BuA Using Initiator 1
Table 1. tBuA Polymerization Data Using Initiator 1 at 125 °C,
Bulk
[M]:[1]:[free nitroxide]
time (h)
Mn(NMR)
Mn(GPC)
Mw/Mn
[200]:[1]:[0.05]
[100]:[1]:[0.05]
[50]:[1]:[0.05]
116
95
46
25 600
7 800
4 500
24 600
9 800
5 200
1.20
1.22
1.14
3. Results and Discussion
We first incorporated an SCS pincer ligand onto a chloro-
functionalized NMP initiator to make a novel SCS pincer NMP
initiator, 1, which could potentially facilitate Heck catalysis
when complexed to a Pd(II) metal center and bound to a polymer
support. This has been reported previously by Weck and co-
workers for similar Pd-pincer complexes.29,34–36 The com-
plexation of this ligand is well known for pyridine func-
tionalities,32,37,75 and to utilize this unsymmetrical Pd(II) binding
system in block copolymer self-assembly, we synthesized a
novel pyridyl-functionalized NMP initiator, 2, which would
complex to the Pd metal center in the pincer complex.75
fragment can be observed in its new environment adjacent to
the nitroxide fragment and aromatic ring as a doublet at δ 1.27.
The 13C NMR spectrum of 2 shows a distinctive peak for the
carbons R to the pyridine nitrogen at δ 149.8. Further structural
confirmation of 2 was indicated by elemental analysis, and LC-
MS showed a 100% peak for the molecular ion at ca. 326.5
Da.
Polymerization of tert-Butyl Acrylate Using Initiator 1. The
t
initiator 1 was utilized in the NMP of BuA at 125 °C in the
presence of free nitroxide. This afforded polymers with con-
trolled molecular weight and polydispersity, as is expected for
the NMP of acrylates (Scheme 2). For the eventual formation
of the metallodiblock copolymer, theoretical degrees of polym-
erization (DPs) of 50, 100, and 200 were targeted, which can
be achieved by altering the monomer-to-initiator ratio and the
polymerization time to access various conversions (Table 1).
The SCS pincer ligand, bearing a pendant alcohol, and the
chloro-NMP universal initiator were reacted, forming the target
SCS pincer ligand-functionalized NMP initiator 1 using sodium
hydride as a strong base (Scheme 1a). Upon reaction completion,
any excess sodium hydride was quenched by adding acetic acid
dropwise to the reaction mixture. The product was then separated
from the starting materials by flash chromatography, yielding
1 as a light yellow gum in a 42% yield. The 1H NMR spectrum
of 1 shows all of the diastereomeric proton peaks associated
It has been reported that, for the controlled polymerization
of acrylates using NMP techniques, an excess of free nitroxide
is required;84 thus, 5 mol % of free nitroxide was added to push
the equilibrium in favor of dormant chains to increase the control
1
with the product SCS-functionalized NMP initiator.86 The H
t
NMR spectrum revealed that there were no peaks at δ ) 4.60
for the CH2Cl or CH2OH methylene protons of the two starting
materials. The new ether linkage protons of 1 (CH2OCH2) were
observable as two inequivalent proton environments as singlets
at δ 4.44 and 4.45, which both integrate to two protons. The
over the polymerization. The kinetics for the NMP of BuA
initiated by 1 (kp ) 4.0 × 10-4 min-1) in the presence of free
nitroxide were slower than those reported by Hawker and co-
workers86 for the NMP of tBuA using a nonfunctional
alkoxyamine initiator in the presence of free nitroxide. In
addition, an apparent induction period of ca. 8 h was observed,
but after this time a linear relationship between ln([M]0/[M])
versus time was observed (Figure 1a), indicating no detectable
termination occurring in this system.
structure of 1 was confirmed by elemental analysis, and the 13
C
NMR spectrum of 1 shows distinctive peaks such as two ether
linkage carbon shifts at δ 72.2 and 72.1 and the central aromatic
ring carbon ortho to the CH2SPh groups at δ 138.8.
A second ligand-NMP initiator was synthesized with a
pendant pyridine moiety, 2, using a method similar to that
reported in the literature (Scheme 1b).86 The novel initiator 2
was synthesized in a 52% yield, and the structure was confirmed
Good agreement between the molecular weights of the
resultant polymers as determined by NMR and GPC analysis
was observed, indicating no unfavorable interaction on the GPC
column of the thio-phenyl moieties and excellent end group
fidelity (Figure 1b).
by H and 13C NMR analysis. In the H NMR spectrum of 2,
nearly identical shifts are observed for the diastereomeric peaks
on the nitroxide fragment which are found for end-group signals
attributable to 1. However, structurally indicative peaks for 2
are observable as a broad multiplet at δ 8.60, accounting for
two pyridine ring protons R to the para ring nitrogen atom.
The proton added as a hydride from NaBH4 across the olefinic
1
1
Figure 1b also shows a good linear dependence of molecular
weight with respect to percentage conversion, which is a key
feature of a controlled radical polymerization. Importantly, the
SCS ligand end group remained intact after the polymerization,
1
as proven by extended H NMR spectroscopy; peaks corre-
sponding to end-group ligand proton environments, such as the
9
J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8719

A R T I C L E S
Moughton and O’Reilly
Table 2. Bulk NMP of Styrene Using Initiator 2, Using 200 equiv of
Monomer Relative to 2 at 125 °C
time/ h
conv (%)
Mn,theor(NMR)
Mn(GPC)
Mw/Mn
1
2
3
4
6
11
19
32
41
49
63
95
4 000
6 700
8 500
10 200
13 100
19 800
2 800
5 100
7 000
8 600
10 800
17 700
1.28
1.21
1.17
1.15
1.13
1.19
induction period observed, indicating a controlled polymeriza-
tion process with minimal termination occurring (Figure 2a).
A plot of theoretical Mn(NMR) versus conversion (Figure 2b)
shows that the molecular weights determined by GPC measure-
ments showed good agreement with theoretical molecular
weights. However, the molecular weights determined by GPC
measurements for pyridine end-functionalized PS show a
consistent shift below theoretical values obtained from the NMR
spectrum, indicating an unfavorable interaction of the pyridine
moiety at the end of these polymers on the GPC column, as
reported previously for terpyridine end-functionalized poly-
mers.26
A low-molecular-weight pyridine chain-end-functionalized PS
block was analyzed using MALDI-ToF mass spectrometry.
Figure 3 shows the MALDI-ToF mass spectrum of PS, in which
separate oligomers are clearly resolved and separated by m/z
104, corresponding to the mass of styrene. This family of peaks
corresponds to the expected product, where one end is pyridyl-
functionalized and the other end is functionalized with the free
nitroxide fragment from the initiator. MALDI-ToF mass spec-
trometry thus further supports the end-group fidelity of the
pyridyl functionality of the PS blocks.
t
Figure 1. (a) Kinetic plot for the NMP of BuA at 125 °C in bulk with
initiator 1, [M]:[1]:[free nitroxide] ) [200]:[1]:[0.05]. (b) Plot of molecular
weight [Mn(GPC)] against conversion; the trendline is Mn,theor(NMR), with
polydispersity in parentheses.
Scheme 3. Polymerization of Styrene Using Pyridyl-Functionalized
NMP Initiator 2
CH2OCH2 methylene signals at δ 4.45 and 4.44 and CH2SPh
at δ 4.01, were found for all PtBuA polymers and were
integrated with respect to broadened polymer backbone signals
and side-chain tert-butyl signals in the region δ 1.00-2.50. From
this, a theoretical DP could be calculated by comparing end
group to polymer chain integrals, and hence Mn(NMR) could
be calculated and showed good agreement with values calculated
by GPC analysis, which indicated that excellent end-group
fidelity is achieved during the polymerization. Extended 13C
NMR spectroscopy shows the presence of SPh phenyl ring
carbons in the region δ 125.5-135.7, showing further evidence
for the functional end group.
Polymerization of Styrene Using Initiator 2. The NMP
initiator 2 (Scheme 3) provided similar control, initiating the
NMP of styrene at 125 °C, affording polymers with predictable
molecular weights and low polydispersities, as is expected for
the NMP of styrene derivatives.86 The results of the polymer-
ization at various conversions are summarized in Table 2.
A linear kinetic relationship of ln([M]0/[M]) versus time (kp
) 2.8 × 10-3 min-1) was observed for this system, with no
Figure 2. (a) Kinetic plot for the NMP of styrene at 125 °C in bulk with
initiator 2, [M]:[2] ) [200]:[1]. (b) Plot of molecular weight [Mn(GPC)]
against conversion; the trendline is Mn,theor(NMR), with polydispersity in
parentheses.
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Assembly of Noncovalently Connected Nanostructures
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substitution, which facilitated its displacement by the pyridine
moiety on initiator 2. A similar ligand-exchange experiment with
2 using the SCS pincer complex starting material bearing a
chloro ligand proceeded in such a facile manner only when the
chloro species was pretreated with silver triflate. This produced
the visible precipitation of silver chloride as a consequence of
the abstraction of the chloride ligand from the complex, after
which the naked palladium(II) metal ion formed readily
underwent complexation with 2.
1
Both complexation routes were followed by H NMR spec-
troscopy, and nearly identical shifts were observed for both
reactions. A 1H NMR spectrum of the reaction mixture showed
an upfield shift of the R proton peaks on the pyridine ring from
δ 8.60 (uncoordinated) to δ 8.15 (coordinated), observable after
only 5 min of stirring at room temperature in CDCl3.75 This
shift of the R proton peaks is due to the ring current shielding
effect of the phenyl rings (on the sulfur atoms of the pincer
ligand) when the pyridine ligand is complexed to the Pd metal
center. The R proton peaks are also broadened, suggesting
hindered rotation of the pyridine ligand with respect to the plane
of coordination,75 consistent with literature reports. Small peaks
at δ 8.60 were still observable in the 1H NMR spectrum,
suggesting that uncomplexed pyridine ligand was still present
in solution. However, this observation may be explained by a
slow exchange of pyridine and a coordinating solvent (such as
CDCl3) on the NMR time scale, consistent with literature
reports75 for similar complexation experiments for SCS-Pd(II)-
pyridine systems.
Metal Complexation of Poly(tBuA) Block 3 To Give 5. The
complexation of the SCS pincer ligand-functionalized PtBuA 3
proceeded in nearly quantitative yields to give 5 after stirring
with a [Pd(MeCN)4(BF4)2] precursor complex overnight at room
temperature in acetonitrile (Scheme 4). The complexation of 3
was similar to that for 1, although longer reaction times were
required to enable complete complexation of the polymer blocks.
Complexation appeared to have gone to completion from
extended 1H and 13C NMR spectroscopy studies, showing only
complexed proton signals and no uncomplexed peaks by
comparison with model complexation experiments with the
initiator 1.75 The observable shifts were consistent with the
Pd(II) complex of 1, and the complexed polymer 3 also showed
the distinctive MLCT band at λ ≈ 350 nm in the UV-vis
spectrum in THF.
Deprotection of 5 To Give Pd-Complexed PAA 6. Cleavage
of the tert-butyl ester groups in the complexed PtBuA 5 to form
metal-complexed PAA 6 was achieved by treating 5 with anhy-
drous TFA in dichloromethane at room temperature overnight
(Scheme 4). Infrared spectroscopy was used to monitor the progress
of the reaction and also to confirm that the deprotection of all the
ester groups had gone to completion. The IR spectra of 6 displayed
a shift in the carbonyl stretch from ν ≈ 1720 cm-1 in 5 to 1705
cm-1 with a distinctive broadening of the peak, indicative of
carboxylic acid carbonyl stretching. Also evident from the IR
spectra of 6 was the stretching associated with broad H-bonded
carboxylic acid OH stretches at ν ≈ 3175 cm-1, providing further
evidence for ester deprotection. The integrity of the SCS pincer
end-group complex in 6 after deprotection was crucial to the
eventual formation of the diblock copolymer 7 from the constituent
end-functionalized homopolymers 5 and 6. Thus, an extended 1H
NMR spectrum of 6 in DMSO-d6 was used to show that the SCS
complex was still intact after deprotection conditions. Indicative
end complex peaks for coordinated CH2SPh proton environments
were still identifiable as a broad singlet at δ 4.65 and CH2OCH2
Figure 3. MALDI-ToF MS of pyridyl-functionalized polystyrene block
4, run in a dithranol matrix with silver trifluoroacetate cationizing agent.
Preliminary Metal Complexation Experiments of SCS NMP
Initiator 1. To establish a straightforward route toward the
palladium(II) complexation of chain-end-functionalized PtBuA/
PAA polymers, first the palladium(II) complex of the SCS pincer
NMP initiator 1 was synthesized. This proceeded by refluxing
1 in acetonitrile with a presynthesized palladium precursor
complex, trans-[Pd(PhCN)2Cl2], as reported previously in the
literature.76 The chloro-Pd(II) complex of 1 showed a distinctive
Pd-C shift at δ 149.5 in the 13C NMR spectrum, indicating
successful palladation at the carbon ortho to the pincer “arms”,
which is consistent with the literature for similar SCS-based
Pd(II) complexes.77 No evidence of the original ortho carbon
signal at δ 138.2 indicated complete metal insertion. In addition,
the Pd(II) complex gave a distinctive metal-to-ligand charge-
transfer (MLCT) band at λ ≈ 350 nm in the UV-vis spectrum.
However, a route toward palladium(II) complexation was
required which would allow for the more facile displacement
of the pendant ligand by a pyridine functionality. To obtain such
a complex, 1 was reacted with a more labile precursor Pd
complex, commercially available [Pd(MeCN)4(BF4)2], at room
temperature in acetonitrile.75 This complex also showed a
distinctive Pd-C shift in the 13C NMR spectrum at δ 151.2.77
Evidence for the complete complexation of 1 was provided by
1H NMR spectroscopy due to complexed diastereotopic CH2SPh
proton signals appearing downfield-shifted by δ 0.5 from the
signals for the uncomplexed ligand, to δ 4.60. Their was no
evidence for the presence of the original singlet for uncomplexed
CH2SPh proton signals at δ 4.1, indicating complete metal
complexation. The shifted complexed signal is also significantly
broadened due to the slow conformational interconversion of
the Pd(II)-containing five-membered ring. These observations
are consistent with those reported in the literature.75 There is
also an upfield shift for the ether linkage protons of 1,
CH2OCH2, from ca. δ 4.45 to ca. δ 4.34, and no evidence of
the original signal.
Preliminary Investigations To Complex NMP Initiators 1
and 2. The facile complexation route with [Pd(MeCN)4(BF4)2]
produced the charged Pd(II) complex of 1, bearing an aceto-
nitrile (MeCN) ligand, which was found to undergo ligand
displacement with the pyridine-functionalized initiator 2 to form
the desired complex after stirring in chloroform at room
temperature for only 5 min. This proved to be straightforward,
since the pendant MeCN ligand is particularly labile toward
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A R T I C L E S
Moughton and O’Reilly
Scheme 4. Complexation of PtBuA 3 To Afford 5 and Deprotection To Give Complexed PAA 6
Scheme 5. Synthesis of Palladium(II)-Complexed NCC Amphiphilic Diblock Copolymer 7
protons at δ 4.55, and when integrated with respect to side-chain
measurements (80 ( 1 nm). The size and shape of NCCMs 8 were
measured in the solid state by AFM and TEM (Figures 4 and 6).
The results are summarized in Table 3.
acid proton integrals, these peaks gave a block length (DP) of ca.
1
40, as was found by extended H NMR spectroscopic measure-
ments for 3. The 13C NMR spectrum of 6 in DMSO-d6 also showed
distinctive Pd-C shifts associated with the end-group SCS complex
at δ 150.3, and the complexed PAA polymer 6 also showed a
distinctive MLCT band in the UV-vis spectrum in DMF.
Amphiphilic Block Copolymer Formation from 4 and 6
To Give 7. Equal molar equivalents of the metal-complexed
PAA block 6 and pyridine end-functionalized PS block 4 were
dissolved in DMF and stirred at room temperature (Scheme 5).
Cross-Linking of 8 To Afford NCCNs 9. The hydrophilic shell
of NCCMs 8 was selectively cross-linked to form NCCNs 9
(Scheme 6) using amidation coupling chemistry. This was achieved
by activating a fraction of the carboxylic acid groups in the PAA
shell with 1-[3′-(dimethylamino)propyl]-3-ethylcarbodiimide me-
thiodide (0.25 equiv based upon the remaining acid functionalities),
followed by reaction with a linker molecule, 2,2′-(ethylene-
dioxy)bis(ethylamine) (0.125 equiv based upon the remaining acid
functionalities) overnight at room temperature. It has been sug-
gested that 25% cross-linking was sufficient to ensure that robust
and stable nanoparticles were formed that still maintain a high
degree of permeability and hence enable removal of the core after
shell stabilization to form nanocage 10. Cross-linking was suc-
cessful, as evidenced by a marked reduction in the hydrodynamic
diameter Dh of the nanoparticle (71 ( 1 nm) compared to that of
the micelles (80 ( 1 nm), as measured by DLS analysis. This is
consistent with literature reports for covalently bonded PAA-b-PS
micelle/nanoparticle systems. Zeta potential measurements, as
determined by electrophoretic light scattering, were all negative
and indicate, as expected, a negative charge on the surfaces of the
micelles and nanoparticles. The micelle ꢀ values were more highly
negative than were those values measured for their nanoparticle
1
The formation of the diblock copolymer was evident from H
NMR spectroscopy, with the amphiphilic diblock copolymer 7
showing an upfield shift of the pyridine ring R proton peaks
from δ 8.60 (uncoordinated) to δ 8.15 (coordinated) in the
1
extended H NMR spectrum in DMF-d7, indicating complex-
ation of the two chain-end ligand functionalities and hence
diblock copolymer formation.
Micellization of 7 To Afford 8. Micelles of narrow size dis-
tribution, 8, composed of the block copolymer PAA41-[Pd]-PS35,
7 (0.120 g, 0.018 mmol), were formed by slow addition (10 mL/
min) of an equal volume of nanopure water to a stirred solution of
the diblock copolymer in DMF, followed by exhaustive dialysis
against deionized water to remove the organic phase (Scheme 6).
The well-defined structure of 8 in solution was evident from DLS
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Assembly of Noncovalently Connected Nanostructures
A R T I C L E S
Scheme 6. (i) Micellization of Amphiphilic Diblock Copolymer 7 To Afford NCCMs 8; (ii) Covalent Cross-Linking in the Outer Shell To Afford
NCCNs 9; and (iii) Core Removal To Give Nanocages 10
Table 3. Characterization Data for NCCMs 8 and the
Corresponding NCCNs 9 and Nanocages 10
However, initial dialysis of 9 in a 1:4 THF/H2O solvent mixture
was necessary to swell and solubilize the hydrophobic core to aid
DLS
AFM
TEM
zeta
removal. The THF/H2O solution of 9 was then dialyzed exhaus-
tively in a 10 mM HCl buffer solution (pH 5.0) to protonate the
pyridine end group. The solution was then dialyzed extensively in
1:4 THF/H2O to remove all of the free PS chains (care was taken
to ensure that high-molecular-weight dialysis tubing was utilized
to facilitate transport of the polymer chains through the membrane).
This polymer solution was then dialyzed exhaustively in deionized
water for 4 days, incorporating 20 water changes. The loss of the
PS core was inferred by the DLS analysis of the newly formed
nanocages 10 due to a significant increase in the hydrodynamic
diameter in solution (94 ( 1 nm) from the micelle and the
nanoparticle. This increase is indicative of the PAA chains being
more spatially extended in solution, since there is now no
hydrophobic interior (no hydrophobic effect) constricting their
extension in aqueous solution. The size and shape of the core-
hollowed nanoparticles or nanocages 10 were measured in the solid
state by AFM and TEM; the results are summarized in Table 3. A
representative TEM image of 10 is shown in Figure 5, and
representative AFM images of 9 and 10 are in Figure 6. It is clear
from Figure 5 that relatively well-defined nanostructures are still
present in solution, although their size has increased markedly and
they appear to be less spherical than the parent micelles and
nanoparticles. Figure 6 highlights the decrease in height upon
removal of the glassy PS core upon nanocage formation. A clearly
flattened polymer ring can be observed which is proposed to
b
Dav (nm)
b
Hav (nm)
c
Dav (nm)
particle
Dha (nm)
ꢀd (mV)
8
9
10
80 ( 1
71 ( 1
94 ( 1
78 ( 12
66 ( 6
139 ( 11
2.6 ( 0.6
4.4 ( 1.0
1.5 ( 0.4
54 ( 5
48 ( 4
74 ( 7e
-52 ( 1
-25 ( 1
-33 ( 2
a Number-averaged hydrodynamic diameters of particles in aqueous
solution by DLS. b Average heights and diameters of particles were
measured by tapping-mode AFM, calculated from the values for ca. 100
particles. c Average diameters of particles were measured by TEM,
calculated from the values for ca. 150 particles. d Zeta potential, from 16
determinations of 10 data sets. e Note that particles no longer appear to
be spherical by TEM analysis.
counterparts, thus supporting the synthetic transformation occurring
in the shell layer of the micelle upon consumption of carboxylate
groups during cross-linking to the nanoparticle (Table 3). The size
and shape of the NCCNs 9 were measured in the solid state by
AFM and TEM. As previously observed for related nanostructures,
the NCCNs in this study deform to a lesser extent on the carbon-
coated TEM grid than they do on the mica substrate which was
utilized for AFM.90
Hollowing-Out PS Core of 9 To Afford 10. NCCNs 9 were
hollowed out by removal of the PS core domain via cleavage of
the pyridine-palladium noncovalent bond at the core-shell
interface (Scheme 6). This was achieved through protonation of
the pyridine moiety on the chain end of the PS blocks at low pH.
Figure 4. Histogram showing the size distribution of the NCCMs 8 by TEM and a representative TEM image of 8 obtained by drop-depositing solutions
on carbon grids and staining with phosphotungstanic acid. TEM scale bar ) 100 nm.
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A R T I C L E S
Moughton and O’Reilly
Figure 5. Histogram showing the size distribution of the nanocages 10 by TEM and a representative TEM image of 10 obtained by drop-depositing
solutions on carbon grids and staining with phosphotungstanic acid. TEM scale bar ) 100 nm.
Figure 6. Representative tapping-mode AFM images of (a) NCCNs 9, (b) nanocages 10, and (c) nanocages 10 after further dialysis. The solutions were
drop-deposited onto freshly cleaved mica and allowed to dry under ambient conditions.
and redissolved in 1.5 mL of 70:30 D2O/THF-d8. An extended 1H
NMR spectrum was run on both samples in the presence of
deuterated THF to swell any PS in the core domain of either 9 or
1
10. The H NMR spectrum of 9 clearly showed the presence of
aryl signals corresponding to PS (from δ 6.20 to 7.30) and signals
attributable to cross-linked PAA, whereas the 1H NMR spectrum
of 10 did not show any signals in the aromatic region corresponding
to PS (δ 6.2-7.3) but did show the presence of cross-linked PAA
domain.
To further confirm the hollow nature of the particles 10, SLS
measurements were performed to determine the average radius
of gyration, Rg. The ratio Rg/Rh is useful for analyzing the
structure of a particle, as ratios equal or greater than 1 indicate
that a hollow particle has been formed.91 The Rg/Rh ratio for
the parent nanoparticle was ca. 0.8, which is consistent with a
spherical micelles structure, and after core excavation the
nanocage 10 had an Rg/Rh ratio of ca. 1.1. This clearly supports
the formation of a hollow cage-like structure.
Figure 7. UV-vis spectrum demonstrating the different sequestration
abilities of the nanocage 10 and nanoparticle solution 9 with Nile red.
represent the PAA cage, yet a small central nodule within this ring
was also visible which may be a result of incomplete removal of
the PS core domain. Despite this, the AFM images obtained for
nanocage 10 suggest that these two domains are no longer
covalently connected. This was confirmed by further dialysis of
the nanocage solution for 4 days, which allowed for the complete
removal of the PS core domain (Figure 6c). Further work is
currently underway to explore in more detail the excavation of the
core domain and improve its efficiency. UV-vis analysis of the
resultant solution demonstrated the characteristic signal (at ca. 350
nm, as was observed in the parent micelles and nanoparticles)
attributable to the Pd, thus indicating that the metal center is still
complexed within the nanocage after core removal. A 10-mL
portion of the NCCNs 9 and the nanocages 10 was lyophilized
One expected difference between the parent NCCN and its
derived nanocage is the ability of the NCCN to uptake
hydrophobic guest molecules as a result of its amphiphilic
character and hydrophobic core domain. Thus, the removal of
the core domain in NCCN 9 to afford a hollow hydrophilic
nanocage was expected to have a significant effect on the
sequestration ability of nanostructure 10. Nile red (9-diethyl-
amino-5H-benzo[R]phenoxazine-5-one) was chosen, given its
absorbance in a region (ca. 550 nm) of the spectrum which is
far removed from the absorbances due to the polymer or
nanostructure (around and below 300 nm). This was achieved
experimentally using previously reported techniques.66 Equiva-
lent molar amounts of 9 and 10 were incubated overnight with
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Assembly of Noncovalently Connected Nanostructures
A R T I C L E S
a large excess of Nile red, residual dye was removed by filtration
through a 0.45-µm Teflon membrane, and the UV-vis spectrum
was recorded for each solution (Figure 7). A control experiment
using only water showed no significant absorbance after
filtration, and this resultant absorbance reading was used as a
background for subsequent measurements of 9 and 10. The
nanocage 10 showed little uptake of the hydrophobic guest
compared to the parent nanoparticle, confirming that core
excavation had been moderately successful.
the metal center is still present within the nanostructure. These novel
metal-functionalized nanocages were found to be highly hydrophilic
and demonstrated significantly reduced uptake of hydrophobic guest
molecules. Studies are underway to explore the availability of these
metal centers within the nanostructures and their potential in
pseudo-homogeneous supported Heck coupling reactions. Further
work is also investigating the re-incorporation of hydrophobicity
into the central core domain to allow for re-establishment of the
amphiphilic character of the nanostructure and thus allow for the
preparation of an internal cavity and confined hydrophobic
environment within catalytically functionalized nanostructures.
Conclusions
Acknowledgment. The authors acknowledge the assistance of Mr.
Matthew Stanford (University of Warwick) for MALDI-ToF MS
analysis, Mr. Jared Skey and Dr. Jeremy Skepper (University of
Cambridge) for TEM analysis, and Dr. Kevin Jackson (Wyatt
Technologies) for SLS assistance. The authors thank Professor Sir
Richard Friend (University of Cambridge) for valuable discussions
and also thank the elemental analysis and mass spectrometry service
(University of Cambridge) for their invaluable help. The authors thank
the IRC in Nanotechnology, the Royal Society, and Downing College
for funding.
Synthetic strategies for the preparation of novel NCCM, NCCN,
and functional core-hollowed nanostructures (nanocages) have been
developed. To obtain these structures, a novel synthetic strategy
has been developed using the chain-end functionalization of
homopolymer blocks which have been assembled to afford
unsymmetrical amphiphilic metallodiblock copolymers which can
be further self-assembled to form well-defined micelles and
nanoparticles. Utilizing a range of techniques such as SLS, DLS,
AFM, and TEM analysis, we have shown that architectures
produced utilizing this noncovalently connected diblock strategy
are directly analogous to covalently connected micelles/nanopar-
ticles and that the synthetic methodology toward them is just as
facile. From the noncovalently connected nanoparticles, hollow
cage-like structures could be prepared using extremely mild
techniques to partially excavate the core domain while ensuring
JA800230K
(90) Huang, H.; Kowalswski, T.; Wooley, K. L. J. Polym. Sci. Part A:
Polym. Chem. 2003, 41, 1659–1668.
(91) Burchard, W. AdV. Polym. Sci. 1983, 48, 1–124.
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