Efficient fabrication of polymer nanoparticles via sonogashira cross-linking of linear polymers in dilute solution

Article abstract of DOI:10.1002/pola.27942

The synthesis of single-chain nanoparticles by palladium-catalyzed Sonogashira coupling between a terminal alkyne and a di-halo aryl cross-linker is reported. Statistical copolymers with trimethylsilyl protected alkyne groups pendent to the linear methacr

Full text of DOI:10.1002/pola.27942

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Efficient Fabrication of Polymer Nanoparticles via Sonogashira
Cross-Linking of Linear Polymers in Dilute Solution
1
1
2
1
3
Alka Prasher, Conor M. Loynd, Bryan T. Tuten, Peter G. Frank, Danming Chao,
4
Erik B. Berda
1
Department of Chemistry, University of New Hampshire, Durham, New Hampshire, 03824-3598
2
Material Science Program, University of New Hampshire, Durham, New Hampshire, 03824-3598
3
College of Chemistry, Jilin University, Changchun, People’s Republic of China
4
Department of Chemistry and Material Science Program, University of New Hampshire, Durham, New Hampshire, 03824-3598
Correspondence to: E. B. Berda (E-mail: Erik.berda@unh.edu)
Received 24 July 2015; accepted 10 September 2015; published online 20 October 2015
DOI: 10.1002/pola.27942
ABSTRACT: The synthesis of single-chain nanoparticles by
palladium-catalyzed Sonogashira coupling between a terminal
alkyne and a di-halo aryl cross-linker is reported. Statistical
copolymers with trimethylsilyl protected alkyne groups pend-
ent to the linear methacrylate back bones were synthesized
using reversible addition-fragmentation chain transfer polymer-
ization post polymerization de-protection providing terminal
alkyne functionalized linear polymer chains. These linear poly-
mer chains were intramolecularly cross-linked via bifunctional
cross-linkers. The resulting well-defined covalently bonded
nanoparticles were characterized via triple-detection size exclu-
sion chromatography where MALS detector provided molecu-
lar weight information and viscometric detection characterizes
particle size and conformations. The particle size could be
readily tuned through polymer molecular weight and by
degree of cross-linking. C
V
2015 Wiley Periodicals, Inc. J. Polym.
Sci., Part A: Polym. Chem. 2016, 54, 209–217
KEYWORDS: nanoparticles; sonogashira coupling; size exclusion
chromatography; transmission electron microscopy
2
2
23,24
INTRODUCTION Advances in polymer science have recently
led to novel synthetic methodologies to complex macromo-
lecular structures. The synthesis of structurally well-defined
polymeric functional nanoparticles in particular has attracted
attention over the past several years. These functionalized
nanomaterials have myriad potential applications in the fields
and Coumarin, Bergman cyclization,
sulfonyl nitrene
2
5
26
27
insertion, Menschutkin reaction, and olefin metathesis
represents a few examples of covalent cross-linking chemistry.
Recent development in fields of various controlled polymer-
ization techniques have enabled the synthesis of polymers
with well-defined architecture and reduced heterogeneity
across a particular sample. The intrachain covalent link-
ages result in structures more robust than proteins due to
thermal and chemical stability. Albeit rudimentary in struc-
ture, an organic chemist’s toolbox is enriched with efficient
synthetic transformations capable of incorporating reactive
handles to the polymer chains that could facilitate intrachain
folding.
1
,2
3,4
5
of drug delivery, biomemtic system, chemosensors, and
2
8
6
molecular imaging. One route for the synthesis of structurally
well-defined polymer nanoparticles is via self assembly and
7
cross-linking of amphiphilic block copolymers. This method,
while ubiquitous has a lower size limit of about 20–30 nm. An
alternate approach to particles in the 5–20 nm size range
involves intramolecular cross-linking of linear polymer chains
into single-chain nanoparticles (SCNP); nano-sized cross-
linked gels with dimensions smaller than the original solvated
Requirements for an effective intrachain collapse of single
polymer chain include: facile and controllable incorporation
of an appropriate reactive precursor to the polymer chain, a
highly selective and quantitative post polymerization modifi-
cation reaction with negligible side products, and mild reac-
tion conditions to favor intrachain cross-linking as compared
with interchain cross-linking. One example of such effective
synthetic reactions is the Sonogashira coupling. The
8
–10
polymer coil.
A range of different cross-linking chemistries
comprising intramolecular covalent bonds, noncovalent inter-
actions and dynamic covalent bonds have been investigated in
9
11–13
dilute conditions for the synthesis of SCNP. ,
High-
temperature intramolecular dimerization of the benzocylobu-
1
4,15
16–19
tene group,
click reactions,
photochemically triggered
2
0
21
Diels–Alder reaction,
photodimerization of anthracene,
Additional Supporting Information may be found in the online version of this article.
2015 Wiley Periodicals, Inc.
V
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Sonogashira coupling, a palladium catalyzed cross-coupling
reaction to form carbon–carbon bonds, was first reported by
Kenkichi Sonogashira, Yosuo Tohda, and Nobue Hagihara.
TSKgel SuperMultipore HZ-M columns (4.6 3 150 mm), one
Tosoh TSKgel SuperH3000 column (6 3 150 mm) and one
Tosoh TSKgel SuperH4000 column (6 3 150 mm). Increment
refractive index values (dn/dc) were calculated online
assuming 100% mass recovery (RI as the concentration
detector) using the Astra 6 software package (Wyatt Tech-
nologies) by selecting the entire trace from analyte peak
onset to the onset of the solvent peak or flow marker. This
method gave the expected values for polystyrene (dn/
2
9
The coupling has received considerable attention in the field
of organic synthesis because of its great potential to carry
out various organic transformations with a high degree of
regio-selectivity. The high efficacy, selectivity, high yield, neg-
ligible byproducts, and mild reaction conditions make the
Sonogashira coupling an efficient candidate for a macromo-
lecular reaction. The Sonogashira coupling polymerization
has been used to synthesize various conjugated polymers
dc 5 0.185, M 5 30k) when applied to a narrow PDI PS
n
standard supplied by Wyatt. Absolute molecular weights and
molecular weight distributions were calculated using the
Astra 6 software package. Intrinsic viscosity (g) and visco-
metric radii (R ) were calculated from the differential vis-
g
cometer detector trace and processed using the Astra 6
software.
3
0–33
and supramolecular polymers.
In the present work, we
introduce the Sonogashira coupling as a method for the syn-
thesis of SCNPs. We present here the synthesis of polymeric
nanoparticles via addition of an external cross-linker. This
route involves: (1) Synthesis of random copolymers contain-
ing trimethylsilyl protected alkyne groups distributed along
the polymer chain. (2) Removal of the trimethylsilyl group to
yield the corresponding terminal alkyne functionalized ran-
dom copolymers. (3) Use of an appropriate bifuctional diha-
lide cross-linker and application of Sonogashira coupling
Synthesis of Monomer Trimethylsilyl Propargyl
Methacrylate
To a suspension of silver chloride (0.30 g, 2.1 mmol) in
3
4–36
50 mL of dry dichloromethane was added propargylmetha-
reaction conditions
coupling.
for an efficient intrachain cross-
crylate (2.8 g, 0.02 mol) and 1,8-diazabicyclo[5.4.0] undec-7-
3
7
ene (DBU), (0.44 g, 2.94 mmol). An appearance of dark
color was observed. After stirring at room temperature for
about 15 minutes, chloromethylsilane (3.15 g, 0.03 mol) was
added dropwise and stirred for 24 hours at 45 8C. The reac-
tion mixture was then diluted with 100 mL of n-hexane and
the organic phase was washed with saturated aqueous
sodium bicarbonate, 1% hydrochloric acid and water, respec-
tively. The extract was dried over magnesium sulfate, filtered,
and concentrated under reduced pressure to give a yellow
liquid. The crude product was further purified by column
chromatography eluting with a solvent mixture of 25:1 n-
EXPERIMENTAL
Chlorotrimethylsilane, silver chloride, 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU), propargyl methacrylate, tetrabutylammo-
niumfloride (TBAF), 4-Cyano-4-[(dodecylsulfanylthiocarbo-
nyl)sulfanyl] pentanoic acid, triethylamine, Copper(I) iodide
(
CuI), tetrakis(triphenylphosphine)palladium (0) were pur-
chased from Sigma Aldrich and were used as received.
Methyl methacrylate (Sigma Aldrich) was passed over a col-
umn of basic alumina (Sigma Aldrich) prior to usage. Chloro-
form-d (Cambridge Isotope Laboratories, Inc.) Hydrochloric
1
Hexane and diethyl ether to obtain a colorless liquid (75%
acid (EMD), Glacial acetic acid (EMD), anhydrous magnesium
sulfate (EMD), Sodium Bicarbonate (Fischer Science Educa-
tion) were used as received. n-Hexane, diethyl ether
dichloromethane (DCM), tetrahydrofuran (THF), N,N-dime-
thylformamide (DMF) were purchased as analytical grade
1
yield). H NMR (400 MHz, CDCl , d): 6.18 (s, 1H, CH), 5.62
3
(
3
s, 1H, CH), 4.76 (s, 2H, CH2), 1.97 (s, 3H, CH ), 0.19 (s, 9H,
1
3
Si(CH ) ) (Fig. S1, Supporting Information). C NMR (400
3
3
MHz, CDCl , d): 166.96, 136.14, 126.97, 99.55, 92.34, 53.38,
3
1
18.10, 20.12 (Fig. S2, Supporting Information).
solvents (Sigma Aldrich) and were used as received. H NMR
(
400 MHz) spectra were recorded on a Varian Associates
Mercury 400 spectrometer. Solvents (CDCl3) contained
.03% v/v TMS as an internal reference, chemical shifts (d)
Control Experiments
0
Test Reaction between Propargyl Methacrylate and
Bromobenzene
are reported in ppm relative to TMS. Following abbreviations
are used for peaks: s 5 singlet, d 5 doublet, t 5 triplet,
m 5 multiplet, br 5 broad. Transmission Electron Microscopy
Bromobenzene (1 g, 6.3 mmol), Pd(PPh
mmol) and copper iodide (11 mg, 0.06 mmol) were dissolved
in 10 mL (6:4, THF/Et N) in a schlenk flask and were
3 4
) (69 mg, 0.06
(
TEM) images were recorded using a Zeiss LEO 922 X oper-
3
3
8
ating at 120 kV with a Gatan Multi-scan bottom mount digi-
tal camera. Samples were prepared by drop casting 2 lL of a
nano particle solution (0.002 mg/mL) on to Formvar carbon
film coated 400 square mesh copper grids and dried over-
night in air while protected from dust. Size exclusion chro-
matography (SEC) was performed on a Tosoh EcoSEC dual
detection (RI and UV) SEC system coupled to an external
Wyatt Technologies miniDAWN Treos multiangle light scat-
tering (MALS) detector and a Wyatt Technologies ViscoStarII
differential viscometer. The column set was two Tosoh
degassed with argon for 30 minutes. The reaction mixture
was magnetically stirred at 70 8C for a period of 30 minutes.
Propargyl methacrylate (0.78 g, 6.3 mmol) was added to the
mixture via a syringe. The reaction mixture after addition was
heated at a temperature of 70 8C over night. Excess of solvent
was evaporated in vaccum. The crude product was dissolved
in 50 mL of hexanes and passed through a plug of silica to
remove any unreacted palladium and copper catalyst. The
1
crude mixture was further analyzed via H NMR without fur-
ther purification (Fig. S5, Supporting Information).
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Test Reaction between Polymer Poly(propargyl
methacrylate-co-methyl methacrylate) (PgMA-co-MMA)
and Bromobenzene
precipitated in to cold water. The precipitate was then fil-
tered and dried under vacuum to give a P1 as a white pow-
1
der. H NMR (400 MHz, CDCl , d): 4.50–4.70 (s, CH AC,
3
2
The procedure for this test reaction was adapted from the test
reaction done on the model monomer. Poly(propargyl
methacrylate-co-methyl methacrylate) (PgMA-co-MMA) 100 mg,
PgMA), 3.54–3.67 (s, CH AOA (O)C), MMA,), 2.47 (S, (CH,
3
PgMA), 1.60–1.41(br, (CH AC(CH ), MMA, PgMA), 0.84–1.02
2
3
(br, (CH (C), MMA, PgMA) (Fig. S8, Supporting Information)
3
M 5 16 kg/mol, 0.006 mmol), containing 35% of alkyne
w
(M 5 17.5 kg/mol, M 5 21.1 kg/mol, PDI 5 1.2).
n
w
(
0.0021 mmol) Pd(PPh ) (0.5 mg, 0.0004 mmol) and copper
3 4
General Procedure for Synthesis of Nanoparticle NP1
About 100 mg of polymer P1 (0.005 mmol) containing 45%
of the alkyne functionality (0.002 mmol), and copper iodide
iodide (0.076 mg, 0.0004 mmol) were dissolved in a 10 mL solu-
tion of (6:4, THF/Et N) in a schlenk and was degassed with
3
argon for 30 minutes. Bromobenzene (0.32 mg, 0.0021 mmol)
was added to the mixture via a syringe. The reaction mixture
after addition was heated over-night at a temperature of 70 8C.
The resulting brown solution was passed through a silica column
flushed with THF to remove any unreacted palladium and cop-
per catalyst. The solution was evaporated under reduced pres-
sure to a volume of approximately 2 mL and was precipitated in
(
CuI) (0.002 mmol, 0.49 mg) were dissolved in a solution of
dry and already degassed 10 mL solution of (5:5, THF/Et N)
3
under argon in an oven dried three neck round bottom flask.
The solution was heated at 40 8C for approximately 30
minutes. To the resulting solution 1,4-diiodobenzene
(
0.32 mg, 0.001 mmol) and tetrakis(triphenylphosphine)pal-
ladium (0) (Pd(PPh ) ) (2.3 mg, 0.002 mmol) with respect
a minimum amount of cold water to obtain a yellowish powder
3 4
1
to the alkyne functionality in a 10 mL solution of (5:5, THF/
Et N) was added drop wise over a period of 1 hour. The
3
(
H NMR, Fig. S6, Supporting Information).
General Procedure for Synthesis of Trimethylsilyl
Protected Copolymer
Synthesis of Poly(trimethylsilyl propargyl methacrylate-
co-methyl methacrylate) (PTMSPMA-co-MMA) P1-TMS
An oven dried 10 mL schlenk flask was charged with a mix-
ture of MMA (0.33 g, 3.3 mmol) and TMSPgMA (0.65 g,
reaction mixture was heated at 40 8C overnight and turned
brown in color. The resulting brown solution was passed
through a silica column flushed with THF to remove any
unreacted palladium and copper catalyst. The solution was
evaporated under reduced pressure to a volume of approxi-
mately 2 mL and was precipitated in a minimum amount of
1
3
.3 mmol). 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]
pentanoic acid (12 mg, 0.04 mmol) and AIBN (0.65 mg,
.004 mmol) were then added, in stock solutions in dime-
cold water to obtain a yellowish powder. H NMR (400
MHz, CDCl , d): 7.8–7.9 (Ar), 4.50–4.70 (s, CH AC, PgMA),
3
2
0
3
.54–3.67 (s, CH AOA (O)C), MMA,), 1.60–1.41(br,
3
thylformamide with a final volume of 2 mL. The polymeriza-
tion mixture was degassed by three freeze-pump-thaw
cycles. The schlenk flask was then heated in an oil bath at
(
2 3 3
CH AC(CH ), MMA, PgMA), 0.84–1.02 (br, (CH (C), MMA,
PgMA) (M 5 19.4 kg/mol, M 5 27.2 kg/mol, PDI 5 1.4).
n
w
80 8C for 24 hours. After the polymerization was complete
RESULTS AND DISCUSSION
the schlenk flask was opened to air. The resulting viscous
polymer was diluted with 3 mL of THF and precipitated in
The alkyne functional group is a versatile functional group,
which has been used extensively in organic chemistry for a
variety of reactions. In polymer chemistry, alkyne functional-
ity has been exploited as a coupling technique via the
copper-catalyzed azide click cycloaddition. Ruiz de Luzuriaga
and coworkers used the copper catalyzed CAN click reaction
1
4
0 mL of ice-cold water. 1H NMR (400 MHz, CDCl3, d):
.50–4.70 (s, CH2AC, TMSPgMA), 3.54–3.67 (s, CH3AOA
(
O)C), MMA,), 1.60–1.41(br, (CH AC(CH ), MMA, TMSPgMA),
2 3
0
.84–1.02 (br, (CH (C), MMA, TMSPgMA), 0.16 (s, (CH ) SiA)
3 3 3
TMSPgMA) (Fig. S7, Supporting Information).
1
7
to synthesize SCNPs for the first time. SCNPs of various
General Procedure for Deprotection
Synthesis of Poly(propargyl methacrylate-co-methyl
methacryate) (PgPMA-co-MMA) P1
chemical nature were synthesized using an intrachain cross-
coupling click cycloaddition with a di-alkyne cross-linker.
3
9
In any macromolecular synthesis, protection of the alkyne
bond has been mandated to avoid any chain transfer reac-
tions and branching events during radical polymeriza-
The copolymer P1 (865 mg, 0.049 mmol) containing 45%
0.022 mmol) of the trimethylsilyl protected alkyne was dis-
solved in argon purged 100 mL THF. Acetic acid (0.002 mL,
.033 mmol) was added to the solution. Argon was bubbled
to the solution (ꢀ30 min) and the solution was cooled to
5 8C in an ice-salt–water bath. A 1 M solution of tetrabuty-
(
4
0,41
tion.
However, in an interesting example SCNPs has been
0
synthesized by using Glaser–Hay coupling using an unpro-
4
2
tected alkyne functionality. In a recent work photoactivated
thio-yne coupling have been explored as an efficient syn-
2
4
3
lammoniumfloride (TBAF) (0.033 mL, 0.033 mmol) was
added slowly via a syringe (ꢀ5 min). The resulting mixture
was stirred at this temperature for 30 minutes and then
warmed to ambient temperature followed by stirring for 24
hours. The solution was passed through a short silica column
to remove the excess of TBAF, followed by washing with
additional THF. The resulting solution was then concentrated
under a reduced pressure to a small volume, which was then
thetic approach to synthesize SCNPs. To our knowledge
synthesis of SCNP via the palladium catalyzed Sonogashira
coupling has not been demonstrated yet. The monomer tri-
methylsily propargylmethacrylate (TMSPgMA) was synthe-
3
7
sized according to a literature procedure. Copolymers of
methylmethacrylate (MMA) and TMSPgMA with different
chain lengths and varying amount of TMSPgMA were synthe-
sized using reversible addition-fragmentation chain transfer
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SCHEME 1 Schematic illustration of the synthesis of SCNPs. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
(
RAFT) polymerization (Scheme 1). RAFT polymerization
counterpart. The coupling reaction was applied to a model
linear copolymer PgMA-co-MMA with bromobenzene as a
model mono functionalized aryl halide. H NMR again
was selected due to its excellent control over molecular
weight and a narrow molecular weight distribution.
4
4
1
1
H
NMR spectroscopy was used to determine the composition
of various linear copolymers. The mole fraction of TMSPgMA
and MMA were calculated from the ratio of the peak area
around 0.19 ppm, corresponding to nine methyl protons in
trimethylsilyl propargyl group, to the total area of peak at
showed a quantitative conversion with disappearance of the
alkyne peak and appearance of additional peaks in the aro-
matic region (Fig. S6, Supporting Information). Having shown
that the model mono-functionalized aryl halide readily
undergoes a quantitative macromolecular reaction, copoly-
mers were submitted to Sonogashira coupling conditions to
induce collapse by using a difunctionalized cross-linker
(Scheme 1) In order to adapt Sonogashira coupling condi-
tions that are successful for small molecules, any SCNP syn-
thesis reaction requires consideration of some important
issues. Since Sonogashira coupling is sensitive to reaction
conditions and substrates, changes in reaction components
often necessitates changes in other reaction conditions (i.e.,
solvent, reaction temperature, catalyst, base, copper salt). We
have investigated various reaction conditions for an efficient
nanoparticle synthesis, and the ideal conditions are given in
the “Experimental” section. 1,4-Diiodobenzene is an efficient
and appropriate choice for the external cross-linker due to
its high reactivity as well as its commercial availability.
3.6 ppm, which is attributed to methyl protons of MMA (Fig.
S3, Supporting Information). Deprotection of these linear
copolymers using TBAF/CH COOH yielded the corresponding
3
4
0
alkyne functionalized copolymers. The mole fraction of
PgMA and MMA were calculated from the ratio of the peak
area at 2.5 ppm, corresponding to alkyne protons of propar-
gyl methacrylate, to the area of peak methyl protons of MMA
at 3.6 ppm (Fig. S4, Supporting Information).
In order to better understand Sonogashira coupling as an
effective candidate for this macromolecular conjugation reac-
tion, the standard coupling was performed on monomeric
propargyl methacrylate and bromobenzene as a model aryl
3
8 1
halide counterpart.
H NMR spectroscopy was used to
monitor the reaction and showed appearance of peaks in the
aromatic region as well as decrease in the intensity of the
alkyne peak in the crude mixture after 24 hours reflux (Fig.
S5, Supporting Information). Having shown that the reaction
gave a quantitative conversion on a model monomer, a test
reaction was carried on a model linear alkyne functionalized
random copolymer with a mono functionalized halogen
The nomenclature used in this work is as follows: Each lin-
ear random copolymer is given a prefix (P) and is assigned
with a number. The corresponding nanoparticles obtained by
the cross-coupling reaction is given a prefix NP with a corre-
sponding number. Initial attempts of the cross-coupling reac-
tion were performed on a parent polymer scaffold P1,
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FIGURE 1 (A) Normalized SEC traces (MALS, THF) before cross-linking of linear polymer precursors and after cross-linking of the
1
corresponding nanoparticles (P1, NP1). (B) TEM image of the nanoparticle (NP1). (C) H NMR overlay spectrum of polymer P1 and
nanoparticle NP1. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
(
(
M
n
5 17.5 kg/mol) containing 45% of alkyne functionality
lar weight confirms the addition of an external cross-linker
in to the parent polymer. The viscometer data, molecular
weight data, and peak retention time for the polymer as well
as for the nanoparticles are given in Table 1. The observed
phenomenon could be explained due to a relative high poly-
mer concentration in the reaction mixture as well as of high
cross-linking density. The visual evidence for nanoparticle
formation was provided by transmission electron microscopy
(TEM) [Fig. 1(B)], which agrees with the size provided by
the viscometric detector. The cross-linked nanoparticles were
Fig. S8, Supporting Information) with a total polymer con-
centration of approximately 5 mg/mL. The resulting nano-
particles were characterized by triple detection SEC. A
decrease in retention time was observed in all SEC detector
traces [MALS, Fig. 1(A)] (RI, Fig. S10, Supporting Informa-
tion) indicating that the nanoparticles obtained are bigger in
size than the parent polymer. Formation of nanoparticle is
confirmed by a decrease in the intrinsic viscosity (g), indicat-
ing a more compact globule. An increase in viscometric
1
radius (R ), provided by SEC detection with a differential vis-
further characterized by H NMR spectroscopy, for the trans-
g
cometer, with a concomitant increase in the value of molecu-
formation of P1 in to NP1 [Fig. 1(C)]. The decrease in
TABLE 1 SEC Data for Polymers P1, P2, P3, P4, and Corresponding Nanoparticles NP1, NP2, NP3, NP4
Retention
M
n
M
w
g
R
g
a
b
c
d
e
Sample
(kg/mol )
(kg/mol )
PDI
% Alkyne
Time (min )
(mL/g )
(nm )
P1
17.5
19.4
11.3
21.1
34.5
39.4
16.4
29.4
21.1
27.2
13.4
24.1
55.4
43.4
28.1
32.1
1.2
1.4
1.2
1.2
1.6
1.1
1.7
1.2
45
13
50
na
35
na
23
na
23.8
23.0
24.9
25.6
22.0
23.9
22.7
24.3
51.3
47.9
30.0
11.3
57.2
21.3
36.2
21.9
5.6
6.3
4.2
3.5
7.1
5.0
4.6
4.1
NP1
P2
NP2
P3
NP3
P4
NP4
c
All SEC data collected at 40 8C in THF.
Calculated from MALS detector trace.
Calculated from viscometric trace.
Calculated from viscometric trace.
a
d
e
Calculated from RI data.
b
w
Absolute M calculated from MALS data.
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FIGURE 2 Normalized SEC trace (THF, MALS) of linear copoly-
mer P2 and corresponding nanoparticle NP2. [Color figure can
be viewed in the online issue, which is available at wileyonline-
library.com.]
FIGURE 4 Normalized SEC trace (THF, MALS) of linear copoly-
mer P4 and corresponding nanoparticle NP4. [Color figure can
be viewed in the online issue, which is available at wileyonline-
library.com.]
intensity of the characteristic alkyne resonance at d 5 2.5
ppm confirmed incorporation of the external cross-linker in
to the parent polymer.
amount of reactive alkyne moiety in the parent polymer, an
increase in the retention time was observed in all the SEC
traces of the corresponding nanoparticles. This observation
correlates with the fact that increase in intrachain cross-
linking is driven by the amount of reactive alkyne functional-
ity present.
In most cases reported in literature, SCNP synthesis involves
a post-polymerization transformation in dilute solution of a
concentration typically 1 mg/mL. So we decided to perform
the cross-linking reaction with concentration of 1 mg/mL on
a polymer (P2) containing 50% alkyne (Fig. S12, Supporting
Information). A greater shift in retention time in all SEC
traces confirmed formation of SCNPs and interestingly the
MALS trace showed a shoulder indicating a small amount of
interchain aggregates (MALS, Fig. 2) (RI, Fig. S14, Supporting
Information). Another cross-linking reaction was performed
on a polymer scaffold with a relative high molecular weight
Further experiments were carried out to study the effect of
polymer concentration in the reaction mixture on the cross-
linking phenomenon. The cross-linking reaction was carried
out on another parent polymer P4 with 23% alkyne, (Fig.
S20, Supporting Information) with a final polymer concentra-
tion of 2 mg/mL. The SEC traces showed both interchain as
well as intrachain cross-linking (MALS, Fig. 4) (RI, Fig. S22,
(
Table 1) and 35% alkyne (Fig. S16, Supporting Information).
Supporting Information). The presence of a significant
As expected intrachain cross-linking was observed in all SEC
traces with a small interchain aggregate (MALS, Fig. 3) (RI,
Fig. S17, Supporting Information). With an increase in the
amount of interchain aggregates was evident by a big peak
in the MALS trace, while a small shoulder was also observed
in the RI detector. Decrease in the value of the intrinsic vis-
g
cosity (g) as well as the viscometric radius (R ) corroborates
the formation of nanoparticle (Table 1). The observed phe-
nomenon confirms that changing the concentration of the
reaction mixture can modulate the cross-linking. In summary,
this study demonstrated that interchain cross-linking
occurred at a higher concentration (5 mg/mL). At intermedi-
ate concentration (2 mg/mL) both inter and intrachain
cross-linked particles were observed. At a low concentration
(
1 mg/mL), intrachain cross-linked nanoparticles were
obtained with a shift to greater retention time in the SEC
traces.
Alternatively, the cross-linking phenomenon was investigated
for polymers (P5–P6) with the same amount of alkyne func-
tionality and different molecular weight (Table 2). The cross-
linking coupling reaction was performed on a relatively high
molecular weight P5 with 30% alkyne (Fig. S24, Supporting
Information). All SEC traces showed an increase in retention
time with the MALS trace showing some amount of inter-
chain aggregates (MALS, Fig. 5) (RI, Fig. S2, Supporting
FIGURE 3 Normalized SEC trace (THF, MALS) of linear copoly-
mer P3 and corresponding nanoparticle NP3. [Color figure can
be viewed in the online issue, which is available at wileyonline-
library.com.]
214
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TABLE 2 SEC Data for Polymer P5, P6 and Corresponding Nanoparticles NP5 and NP6
M
n
M
w
Retention
g
R
g
a
b
c
d
e
Sample
(kg/mol )
(kg/mol )
PDI
% Alkyne
Time (min )
(mL/g )
(nm )
P5
78.2
61.3
30.1
21.1
23.3
25.4
91.8
72.3
34.8
24.1
28.8
30.5
1.2
1.1
1.1
1.1
1.2
1.2
30
na
30
na
50
na
21.12
23.11
24.24
25.74
29.23
29.29
38.00
30.80
15.12
6.84
8.1
6.9
4.3
3.9
5.8
5.3
NP5
P6
NP6
P7
50.88
53.72
NP7
c
All SEC data collected at 40 8C in THF.
Calculated from MALS detector trace.
Calculated from viscometric trace.
Calculated from viscometric trace.
a
d
e
Calculated from RI data.
b
w
Absolute M calculated from MALS data.
Information). Similarly, a cross-linking reaction was carried
out on a low molecular weight polymer P6 with the same
amount of alkyne present (Fig. S28, Supporting Information).
Intrachain cross-linking was observed leading to an increase
in the retention time in all the three SEC traces (MALS, Fig.
The alkyne functional moiety is capable of undergoing a self
click homocoupling reaction via the Glaser–Hay reaction
mechanism. The homocoupling of acetylenic functionality is
often concomitant to the metal catalyzed cross-coupling reac-
tions. In order to ascertain that the cross-linking reaction is
taking place via the palladium catalyzed Sonogashira cou-
pling between and alkyne and an aryl halide, rather than by
an alkyne homocoupling, a control experiment was per-
formed. Polymer (P7) was subjected to Sonogashira coupling
conditions without addition of an external dihalo cross-
linker. There was not any significant change in the retention
time before and after the cross-linking, suggesting that an
aryl halide is required under these reaction conditions (Table
6) (RI, Fig. S30, Supporting Information). As expected, there
is a greater shift in the retention time of the high molecular
weight polymer nanoparticle as compared with the low
molecular weight polymer nanoparticle.
A decrease in intrinsic viscosity (g), along with the reduction
in viscometric radius R confirms the formation of the corre-
g
sponding nanoparticles (Table 2). The retention time of the
nanoparticle formed from the high molecular weight polymer
was shorter as compared with the retention time of the
nanoparticle formed from a low molecular weight polymer.
The above phenomenon can be explained by the fact that the
higher molecular weight polymer (P5) formed a bigger nano-
particle (NP5) with a longer retention time as compared
with the lower molecular weight (P6) forming a smaller
nanoparticle (NP6) with a shorter retention time.
2, Fig. S32, Supporting Information). We believe that the
selectivity of the Sonogashira coupling over the alkyne
homocoupling under the given conditions is dependent on
the choice of base as well as the solvent. A detailed study of
reaction optimization with different catalysts, bases, as well
as external cross-linkers is undergoing in our lab.
FIGURE 5 Normalized SEC trace (THF, MALS) of linear copoly-
mer P5 and corresponding nanoparticle NP5. [Color figure can
be viewed in the online issue, which is available at wileyonline-
library.com.]
FIGURE 6 Normalized SEC trace (THF, MALS) of linear copoly-
mer P6 and corresponding nanoparticle NP6. [Color figure can
be viewed in the online issue, which is available at wileyonline-
library.com.]
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CONCLUSIONS
11 C. K. Lyon, A. Prasher, A. M. Hanlon, B. T. Tuten, C. A.
Tooley, P. G. Frank, E. B. Berda, Polym. Chem. 2015, 6, 181–
Random copolymers containing terminal alkyne moieties
have been prepared by RAFT polymerization. We have
shown that both inter and intrachain cross-linked polymer
nanoparticles can be synthesized via palladium catalyzed
Sonogashira coupling. At a high polymer concentration in the
reaction mixture, interchain cross-linking predominated,
while by decreasing the concentration intrachain cross-
linking was favored. We also demonstrated that by changing
the molar percent of alkyne functionality in the parent poly-
mer, the size of resulting nanoparticle could be controlled.
Although current SCNP literature has many examples of
nanoparticle synthesis, it still lacks a thorough study on how
the nanoparticle formation is affected by the manner in
which intrachain cross-linking is performed. In this perspec-
tive, we have presented the synthesis of polymer nanopar-
ticles from single polymer chains by the Sonogashira
coupling reaction conditions and further, we envision to
study the effect of polymer architecture on the single-chain
folding behavior. The Sonogashira coupling reaction can be
applied in inducing intrachain covalent bond formation
either with in-built reactive precursors, or via an external
cross-linker. Currently, research efforts are going on in our
lab to synthesize single-chain nanoparticles under Sonoga-
shira coupling reaction conditions from in-built reactive pre-
cursor functionalized polymers. We are testing similar
synthetic conditions with the same reactive partners placed
in a variety of positions.
1
97.
1
2 A. Sanchez-Sanchez, S. Akbari, A. Etxeberria, A. Arbe, U.
Gasser, A. J. Moreno, J. Colmenero, J. A. Pomposo, ACS
Macro Lett. 2013, 2, 491–495.
13 M. Seo, B. J. Beck, J. M. J. Paulusse, C. J. Hawker, S. Y.
Kim, Macromolecules (Washington, DC) 2008, 41, 6413–6418.
14 E. Harth, B. V. Horn, V. Y. Lee, D. S. Germack, C. P.
Gonzales, R. D. Miller, C. J. Hawker, J. Am. Chem. Soc. 2002,
1
24, 8653–8660.
1
5 T. A. Croce, S. K. Hamilton, M. L. Chen, H. Muchalski, E.
Harth, Macromolecules 2007, 40, 6028–6031.
6 L. Oria, R. Aguado, J. A. Pomposo, J. Colmenero, Adv.
Mater. (Weinheim, Ger.) 2010, 22, 3038–3041.
7 A. Ruiz de Luzuriaga, N. Ormategui, H. J. Grande, I.
1
1
Odriozola, J. A. Pomposo, I. Loinaz, Macromol. Rapid Com-
mun. 2008, 29, 1156–1160.
1
8 A. Sanchez-Sanchez, I. Perez-Baena, J. A. Pomposo, Mole-
cules 2013, 18, 3339–3355.
9 D. Chao, X. Jia, B. Tuten, C. Wang, E. B. Berda, Chem. Com-
mun. (Cambridge, UK) 2013, 49, 4178–4180.
0 O. Altintas, J. Willenbacher, K. N. R. Wuest, K. K.
1
2
Oehlenschlaeger, P. Krolla-Sidenstein, H. Gliemann, C. Barner-
Kowollik, Macromolecules (Washington, DC) 2013, 46, 8092–8101.
21 P. G. Frank, B. T. Tuten, A. Prasher, D. Chao, E. B. Berda,
Macromol. Rapid Commun. 2014, 35, 249–253.
22 J. He, L. Tremblay, S. Lacelle, Y. Zhao, Soft Matter 2011, 7,
2
380–2386.
2
3 B. Zhu, G. Qian, Y. Xiao, S. Deng, M. Wang, A. Hu, J.
Polym. Sci. Part A: Polym. Chem. 2011, 49, 5330–5338.
2
2
4 P. Wang, H. Pu, M. Jin, J. Polym. Sci. Part A: Polym. Chem.
011, 49, 5133–5141.
ACKNOWLEDGMENTS
25 P. T. Dirlam, H. J. Kim, K. J. Arrington, W. J. Chung, R.
Sahoo, L. J. Hill, P. J. Costanzo, P. Theato, K. Char, J. Pyun,
Polym. Chem. 2013, 4, 3765–3773.
The authors thank the Army Research office for financial sup-
port through award number W911NF-14-1-0177 and NSF for
support through award NSF EEC 0832785. We also acknowl-
edge the University of New Hampshire for financial support.
2
6 I. Perez-Baena, F. Barroso-Bujans, U. Gasser, A. Arbe, A. J.
Moreno, J. Colmenero, J. A. Pomposo, ACS Macro Lett. 2013,
2, 775–779.
2
7 A. E. Cherian, F. C. Sun, S. S. Sheiko, G. W. Coates, J. Am.
Chem. Soc. 2007, 129, 11350–11351.
8 J. F. Lutz, M. Ouchi, D. R. Liu, M. Sawamoto, Science 2013, 341,
29 K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
975, 16, 4467–4470.
30 T. Kaneko, Y. Togashi, M. Teraguchi, T. Aoki, Chem. Lett.
014, 43, 1219–1221.
REFERENCES AND NOTES
2
1
2
S. K. Hamilton, E. Harth, ACS Nano 2009, 3, 402–410.
1
S. Jiwpanich, J. H. Ryu, S. Bickerton, S. Thayumanavan, J.
Am. Chem. Soc. 2010, 132, 10683–10685.
2
3
H. Takahashi, S. Sawada, K. Akiyoshi, ACS Nano 2010, 5,
3
37–345.
31 H. Sogawa, Y. Miyagi, M. Shiotsuki, F. Sanda, Macromole-
cules 2013, 46, 8896–8904.
4
4
G. Wulff, B. O. Chong, U. Kolb, Angew. Chem. Int. Ed. 2006,
5, 2955–2958.
32 S. Shanmugaraju, H. Jadhav, R. Karthik, P. S. Mukherjee,
RSC Adv. 2013, 3, 4940.
5
M. A. J. Gillissen, I. K. Voets, E. W. Meijer, A. R. A. Palmans,
Polym. Chem. 2012, 3, 3166–3174.
33 R. Grisorio, G. P. Suranna, P. Mastrorilli, G. Allegretta, A.
Loiudice, A. Rizzo, G. Gigli, K. Manoli, M. Magliulo, L. Torsi, J.
Polym. Sci. Part A: Polym. Chem. 2013, 51, 4860–4872.
6
C. T. Adkins, H. Muchalski, E. Harth, Macromolecules 2009,
42, 5786–5792.
3
4 R. Chinchilla, C. N aꢀ jera, Chem. Rev. 2007, 107, 874–922.
7
2
R. K. O’Reilly, C. J. Hawker, K. L. Wooley, Chem. Soc. Rev.
006, 35, 1068–1083.
35 H. Plenio, Angew. Chem. Int. Ed. 2008, 47, 6954–6956.
8
2
B. S. Murray, D. A. Fulton Macromolecules (Washington, DC)
011, 44, 7242–7252.
36 T. Hoshi, I. Saitoh, T. Nakazawa, T. Suzuki, J. Sakai, H.
Hagiwara, J. Org. Chem. 2009, 74, 4013–4016.
9
M. Aiertza, I. Odriozola, G. Caba n~ ero, H. J. Grande, I. Loinaz,
Cell. Mol. Life Sci. 2012, 69, 337–346.
37 F. Yhaya, S. Binauld, Y. Kim, M. H. Stenzel, Macromol.
Rapid Commun. 2012, 33, 1868–1874.
1
2
0 O. Altintas, C. Barner-Kowollik, Macromol. Rapid Commun.
012, 33, 958–971.
38 X. Zhao, H. Jiang, K. S. Schanze, Macromolecules 2008, 41,
3422–3428.
216
JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2016, 54, 209–217

JOURNAL OF
POLYMER SCIENCE
WWW.POLYMERCHEMISTRY.ORG
ARTICLE
3
9 A. Ruiz de Luzuriaga, I. Perez-Baena, S. Montes, I. Loinaz, I.
42 A. Sanchez-Sanchez, I. Asenjo-Sanz, L. Buruaga, J. A.
Pomposo, Macromol. Rapid Commun. 2012, 33, 1262–1267.
Odriozola, I. Garcia, J. A. Pomposo, Macromol. Symp. 2010,
296, 303–310.
4
3 I. Perez-Baena, I. Asenjo-Sanz, A. Arbe, A. J. Moreno, F. Lo
40 A. Scarpaci, C. Cabanetos, E. Blart, V. Montembault, L.
Verso, J. Colmenero, J. A. Pomposo, Macromolecules 2014, 47,
Fontaine, V. Rodriguez, F. Odobel, J. Polym. Sci. Part A: Polym.
Chem. 2009, 47, 5652–5660.
8270–8280.
4
4 J. Chiefari, Y. K. Chong, F. Ercole, J. Krstina, J. Jeffery, T.
4
1 J. Geng, G. Mantovani, L. Tao, J. Nicolas, G. Chen, R.
P. T. Le, R. T. A. Mayadunne, G. F. Meijs, C. L. Moad, G.
Moad, E. Rizzardo, S. H. Thang, Macromolecules 1998, 31,
5559–5562.
Wallis, D. A. Mitchell, B. R. G. Johnson, S. D. Evans, D. M.
Haddleton, J. Am. Chem. Soc. 2007, 129, 15156–15163.
WWW.MATERIALSVIEWS.COM
JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2016, 54, 209–217
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