A facile approach to architecturally defined nanoparticles via intramolecular chain collapse

Article abstract of DOI:10.1021/ja026208x

A novel approach is presented for the controlled intramolecular collapse of linear polymer chains to give well-defined single-molecule nanoparticles whose structure is directly related to the original linear polymer. By employing a combination of living free radical polymerization and benzocyclobutene (BCB) chemistry, nanoparticles can be routinely prepared in multigram quantities with the size being accurately controlled by either the initial degree of polymerization of the linear chain or the level of incorporation of the BCB coupling groups. The latter also allows the cross-link density of the final nanoparticles to be manipulated. In analogy with dendritic macromolecules, a significant reduction of up to 75% in the hydrodynamic volume is observed on going from the starting random coil linear chains to the corresponding nanoparticles. The facile nature of the living free radical process also permits wide variation in monomer selection and functional group incorporation and allows novel macromolecular architectures to be prepared. Furthermore, the use of block copolymers functionalized with benzocyclobutene groups in only one of the blocks gives, after intramolecular collapse, a hybrid architecture in which a single linear polymer chain is attached to the globular nanoparticle.

Full text of DOI:10.1021/ja026208x

Published on Web 06/28/2002
A Facile Approach to Architecturally Defined Nanoparticles
via Intramolecular Chain Collapse
†
Eva Harth, Brooke Van Horn, Victor Y. Lee, David S. Germack, Chad P. Gonzales,
Robert D. Miller, and Craig J. Hawker*
Contribution from the Center for Polymeric Interfaces and Macromolecular Assemblies,
IBM Almaden Research Center, 650 Harry Road, San Jose, California, 95120-6099
Received March 15, 2002
Abstract: A novel approach is presented for the controlled intramolecular collapse of linear polymer chains
to give well-defined single-molecule nanoparticles whose structure is directly related to the original linear
polymer. By employing a combination of living free radical polymerization and benzocyclobutene (BCB)
chemistry, nanoparticles can be routinely prepared in multigram quantities with the size being accurately
controlled by either the initial degree of polymerization of the linear chain or the level of incorporation of
the BCB coupling groups. The latter also allows the cross-link density of the final nanoparticles to be
manipulated. In analogy with dendritic macromolecules, a significant reduction of up to 75% in the
hydrodynamic volume is observed on going from the starting random coil linear chains to the corresponding
nanoparticles. The facile nature of the living free radical process also permits wide variation in monomer
selection and functional group incorporation and allows novel macromolecular architectures to be prepared.
Furthermore, the use of block copolymers functionalized with benzocyclobutene groups in only one of the
blocks gives, after intramolecular collapse, a hybrid architecture in which a single linear polymer chain is
attached to the globular nanoparticle.
7
Introduction
spherical macromolecules such as dendrimers (1-10 nm) or
the self-assembly of linear block copolymers into polymeric
micelles followed by chemical cross-linking to give nanopar-
The synthesis and application of polymeric nanoparticles has
attracted significant attention in recent years with further
refinement of traditional methods as well as novel strategies
for their preparation being developed.1-3 One of the driving
forces for this interest has been the realization that functionalized
nanoparticles can be considered as building blocks for a variety
of nanotechnological applications, ranging from vectors for drug
8
ticles with typical dimensions ranging from 20 to 200 nm. As
a consequence, the ability to routinely prepare nanoparticles in
the 5-20 nm size range is limited.
To address this issue, a new strategy involving the collapse
and intramolecular coupling of single-polymer chains to give
9
,10
discrete nanoparticles has been proposed. While promising,
this strategy has drawbacks, primarily the competing and
statistically favored intermolecular cross-linking reaction which
4
and DNA delivery systems to templating agents for nanoporous
microelectronic materials. The strategies for preparing nano-
5
particles can be broadly classified into two main approaches, a
top-down approach where emulsion polymerization techniques
are further refined and optimized, leading to the development
of microemulsion procedures resulting in particles from 20 to
-
5
necessitated the use of ultra-dilute reaction conditions (ca. 10 -
-
6
1
0
M). This precludes the synthesis of these nanoparticles
on a useful (>multigram) scale. In addition, even at these ultra-
0 nm.6 More recently, bottom-up techniques have been
introduced which either rely on the synthesis of discrete
(6) (a) Candau, F. In Microemulsions: Fundamental and Applied Aspects;
Kumar, P., Mittal, K. L., Eds.; Marcel Dekker: New York, 1998. (b) Zhang,
G.; Niu, A.; Peng, S.; Jiang, M.; Tu, Y.; Li, M.; Wu, C. Acc. Chem. Res.
5
2
001, 34, 249. (c) Matyjaszewski, K.; Qiu, J.; Tsarevsky, N. V.; Charleux,
B. J. Polym. Sci., Part A: Polym. Chem. 2000, 38, 4724. (d) Landfester,
K. AdV. Mater. 2001, 13, 765. (e) Pilcher, S. P.; Ford, W. T. J. Polym.
Sci., Part A: Polym. Chem. 2001, 39, 519.
7) (a) Bosman, A. W.; Jansen, H. M.; Meijer, E. W. Chem. ReV. 1999, 99,
1665. (b) Hecht, S.; Fr e´ chet, J. M. J. Angew. Chem., Int. Ed. 2001, 40, 74.
(c) Percec, V.; Cho, W. D.; Ungar, G.; Yeardley, D. J. P. J. Am. Chem.
Soc. 2001, 123, 1302. (d) Moore, J. S. Acc. Chem. Res. 1997, 30, 402. (e)
Topp, A.; Bauer, B. J.; Klimash, J. W.; Spindler, R.; Tomalia, D. A.; Amis,
E. J. Macromolecules 1999, 32, 7226.
*
To whom correspondence should be addressed. E-mail: hawker@
almaden.ibm.com.
†
Present address: Xenoport Inc., 3410 Central Expressway, Santa Clara,
(
CA 95051.
(
(
1) Bergbreiter, D. E. Angew. Chem, Int. Ed. 1999, 38, 2870.
2) (a) Monteiro, M. J.; Bussels, R.; Wilkinson, T. S. J. Polym. Sci., Part A:
Polym. Chem. 2001, 39, 2813. (b) Park, M. K.; Xia, C.; Advincula, R. C.
Langmuir 2001, 17, 7670.
(
(
(
3) (a) Thurmond, K. B., II; Kowalewski, T.; Wooley, K. L. J. Am. Chem.
Soc. 1997, 119, 6656. (b) Demers, L. M.; Park, S. J.; Taton, T. A.; Li, Z.;
Mirkin, C. A. Angew. Chem, Int. Ed. 2001, 40, 3071.
(8) (a) Huang, H.; Remsen, E. E.; Kowalewski, T.; Wooley, K. L. J. Am. Chem.
Soc. 1999, 121, 3805. (b) Ma, Q.; Wooley, K. L. J. Polym. Sci., Part A:
Polym. Chem. 2000, 38, 4805. (c) Liu, S.; Armes, S. P. J. Am. Chem. Soc.
2001, 123, 9910.
(9) (a) Antonietti, M.; Bremser, W.; Pakula, T. Acta Polym. 1995, 46, 37. (b)
Davankov, V. A.; Ilyin, M. M.; Tsyurupa, M. P.; Timofeeva, G. I.;
Dubrovina, L. V. Macromolecules 1996, 29, 8398. (c) Martin, J. E.;
Eichinger, B. E. Macromolecules 1983, 16, 1345. (d) Martin, J. E.;
Eichinger, B. E. Macromolecules 1983, 16, 1350.
4) (a) Liu, M.; Fr e´ chet, J. M. J. Pharm. Sci. Technol. Today 1999, 2, 393. (b)
Liu, J.; Zhang, Q.; Remsen, E. E.; Wooley, K. L. Biomacromolecules 2001,
2
, 362. (c) Niemeyer, C. M. Angew. Chem., Int. Ed. 2001, 40, 4128.
5) (a) Hedrick, J. L.; Miller, R. D.; Hawker, C. J.; Carter, K. R.; Volksen,
W.; Yoon, D. Y.; Trollsas, M. AdV. Mater. 1998, 10, 1049. (b) Hawker, C.
J.; Hedrick, J. L.; Miller, R. D.; Volksen, W. MRS Bull. 2000, 25, 54. (c)
Yang, S.; Mirau, P. A.; Pai, C. S.; Nalamasu, O.; Reichmanis, E.; Lin, E.
K.; Lee, H. J.; Gidley, D. W.; Sun, J. N. Chem. Mater. 2001, 13, 2762.
(10) Mecerreyes, D.; Lee, V.; Hawker, C. J.; Hedrick, J. L.; Wursch, A.; Volksen,
W.; Magbitang, T.; Huang, E.; Miller, R. D. AdV. Mater. 2001, 13, 204.
10.1021/ja026208x CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 8653-8660
9
8653

A R T I C L E S
Harth et al.
dilute conditions intermolecular cross-linking was still evident
which results in poorly defined materials and in some cases
gelation. To overcome this difficulty a continuous addition
strategy for the successful synthesis of discrete nanoparticles
by intramolecular cross-linking has now been developed. This
permits the full potential of this strategy for the synthesis of
well-defined and functionalized nanoparticles to be achieved.
Furthermore the polymeric nanoparticles that are obtained from
this procedure are freely soluble in common solvents and do
not need surfactants, during either their synthesis or the
subsequent stabilization of the resulting nanoparticle solutions.
In many respects these new nanoparticle systems resemble
dendrimers, although larger molecular sizes may be more easily
prepared and they have the potential to be available in greater
quantity.
the aldehyde, 6 (7.16 g, 54.2 mmol), diluted in 34 mL of dry THF,
was added slowly. The mixture warmed to room temperature, and
stirring continued for 2 h. The reaction was treated sequentially with
4 3
saturated NH Cl and saturated NaHCO solution, and the crude product
was filtered over Celite, washed with diethyl ether/hexane (1:1), and
evaporated to dryness (no heat) to give the crude product. Further
purification by column chromatography using 5% diethyl ether/hexane
as an eluting solvent followed by Kugelrohr distillation (75 °C, 1.0
mm) gave the pure styrene derivative, 4, as a colorless liquid (5.50 g,
-1
1
7
8%); IR 2925, 1627, 1473, 989, 901, and 829 cm ; H NMR (400
MHz, CDCl ) δ 7.26 (d, 1H, J ) 7.4 Hz, ArH), 7.20 (s, 1H, ArH),
3
7.04 (d, 1H, J ) 7.4 Hz, ArH), 6.74 (dd, 1H, J ) 17.5 Hz, J′ ) 10.8
Hz, CH), 5.70 (d, 1H, J ) 17.5 Hz, CH
2
), 5.20 (d, 1H, J ) 10.8 Hz,
); C NMR (100 MHz, CDCl ) δ 146.09, 145.75,
37.94, 136.69, 125.71, 122.58, 119.90, 112.38, 29.52, and 29.35. Anal.
Calcd for C10 10; C, 92.2; H 7.80. Found: C, 92.0; H, 8.03.
13
CH
2
), 3.19 (s, 4H, CH
2
3
1
H
Random Copolymer of 4 and Styrene, 8. The alkoxyamine
initiator, 7 (32.5 mg, 0.1 mmol),12 dissolved in styrene (10.4 g, 100
mol) and 4-vinylbenzocyclobutene, 4 (3.25 g, 25.0 mmol), was added
to a glass ampule with a stir bar. After three freeze and thaw cycles
the ampule was sealed under argon and heated for 6 h at 120 °C. The
resulting polymer was dissolved in dichloromethane and purified by
precipitation into a 1:1 mixture of 2-propanol/acetone followed by
reprecipitation into methanol to give 8 as a colorless powder (12.1 g,
Experimental Section
General Methods. Commercial reagents were obtained from Aldrich
and used without further purification. Analytical TLC was performed
on commercial Merck plates coated with silica gel GF254 (0.24 mm
thick). Silica gel for flash chromatography was Merck Kieselgel 60
(230-400 mesh, ASTM). Nuclear magnetic resonance was performed
on a Bruker AVANCE 400 FT-NMR spectrometer using deuterated
solvents and the solvent peak as a reference. Gel permeation chroma-
tography was performed in tetrahydrofuran (THF) on a Waters
chromatograph equipped with four 5-µm Waters columns (300 mm ×
8
9
8%), M
09, and 699 cm ; H NMR (400 MHz, CDCl
), 1.83-1.26 (m, CH
, CH); 13C NMR (100 MHz,
) δ 145.0-146.4, 1127.9, 125.5, 121.8, 42.0-44.0, 40.4, and
w
) 111 000; PDI ) 1.11; IR 3100-2850, 1601, 1492, 1452,
-
1
1
3
) δ 7.24-6.57 (m,
ArH), 3.05 (br s, CH
CDCl
9.2.
Random Copolymer of 4 and n-Butylacylate, 10. The alkoxyamine
2
2
3
7
0
.7 mm) connected in series with increasing pore size (100, 1000, 100,-
00, 1,000,000 Å). A Waters 410 differential refractometer and a 996
2
photodiode array detector were employed. The polystyrene molecular
weights were calculated relative to linear polystyrene standards, whereas
the poly(n-butyl acrylate) molecular weights were calculated relative
to poly(n-butyl acrylate) standards.
initiator 7 (32.5 mg, 0.1 mmol) was dissolved in n-butyl acrylate (10.2
g, 72.0 mmol) and 4 (1.04 g, 8.0 mmol) and placed in a glass ampule
with a stir bar. After three freeze and thaw cycles the ampule was sealed
under argon and heated for 15 h at 125 °C. The resulting polymer was
3-Carboxaldehydebicyclo[4,2,0]octa-1,3,5-triene or 4-Carboxal-
dissolved in dichloromethane and precipitated in MeOH/H
give 10 as a colorless gum (10.2 g, 91%), M ) 77 500; PDI ) 1.12;
) δ 6.83-6.63 (m, ArH), 4.10-3.83 (m,
), 2.22-1.01 (m, CH , CH ).
2
O (3:1) to
dehydebenzocyclobutene, 6. To a 500-mL flask was added 50 mL
dry of THF, Mg turnings (2.88 g, 120 mmol), and 1,2-dibromoethane
w
1
H NMR (400 MHz, CDCl
CH ,CH), 3.05 (bs, CH
3
(4 drops). The reaction mixture was then heated under reflux for 15
1
1
2
2
2
3
min, 4-Bromobenzocyclobutene, 5, (20.0 g, 109 mmol) in 25 mL THF
was added via a dropping funnel to form the Grignard reagent. After
addition and rinsing the dropping funnel with 25 mL of dry THF, the
reaction mixture was heated for an additional 45 min under reflux to
give a green brown solution. The reaction mixture was then cooled to
Methyl(2,2,5-Trimethyl-3-(benzylethoxy)-4-phenyl-3-azahexane)-
poly(ethylene Glycol), 12. NaH (0.23 g, 6.3 mmol) was slowly added
to a mixture of monomethylpoly(ethylene glycol), 14 (7.85 g, 1.57
mmol), and 18-crown-6 (10 mg) dissolved in 10 mL of THF under a
constant argon flow. After 15 min, the chloromethyl-substituted
alkoxyamine, 13 (1.16 g, 3.14 mmol)12 was added to the reaction
mixture, which was subsequently heated at reflux for 16 h. After the
addition of a few drops of water to neutralize the excess NaH, the
reaction mixture was concentrated, dissolved in dichloromethane,
filtered, and evaporated to dryness. The crude product was obtained
after flash chromatography eluting with dichloromethane gradually
increasing to 10% methanol/dichloromethane to give the PEG-macro-
0
°C, DMF (15 mL, 210 mmol) was added dropwise to the solution,
and the reaction mixture was heated under reflux for 15 min. The
reaction mixture was poured onto 150 g of ice, acidified to pH ) 4,
and neutralized with saturated NaHCO solution. The crude product
3
was extracted with ethyl acetate, the organic phase was filtered over
Celite, and evaporation of the solvent gave the crude product. The
product was purified by column chromatography using 10% diethyl
ether/hexane as eluting solvents and was finally purified by Kugelrohr
distillation (145 °C, 0.5 mm) to give the aldehyde, 6, (11.7 g, 81.2%)
as a colorless liquid; IR 3000-2800, 1690, 1598, 1216, 1067 and 827
-
1
initiator, 12, as a colorless solid (8.03 g, 89%); IR (KBr) 3439 cm
-
1
1
(
NH), 1693 cm (amide). H NMR (400 MHz, CDCl
ArH), 5.10 (d, CH), 4.92 (d, CH OAr), 3.65 (s, OCH
.28 (d, CH), 2.43 (m, CH), 1.65 (d, CH ), 1.52 (d, CH
), 1.05 (s, t-Bu), 0.89 (d, CH ), 0.80 (s, t-Bu), 0.61
).
Poly(ethylene glycol)-b-(styrene-co-benzocyclobutene), 15. The
poly(ethylene glycol) terminated alkoxyamine, 12 (500 mg, 0.1 mmol)
) 5 000, PDI ) 1.06) was dissolved in styrene (10.4 g, 100 mol)
3
) δ 7.4-7.1 (m,
), 3.41 (d, CH),
), 1.40 (m,
-
1
1
2
2
cm ; H NMR (400 MHz, CDCl
3
) δ 9.9 (s, 1H, CHO), 7.65 (dd, 1H,
3
3
3
J ) 7.4 Hz, J′ ) 1.2 Hz, ArH), 7.50 (s, 1H, ArH), 7.14 (dd, 1H, J )
1
3
CH), 1.33 (d, CH
3
3
7
.4 Hz, J′ ) 1.2 Hz, ArH), 3.15 (s, 4H, CH
2
); C NMR (100 MHz,
3 3
(d, CH ), and 0.22 (d, CH
CDCl ) δ 192.28, 153.69, 146.57, 135.4, 130.26, 122.89, 122.81, 29.97,
3
and 29.23. Anal. Calcd for C
H, 5.94.
9 8
H O; C, 81.8; H 6.10. Found: C, 81.7;
(M
n
3
-Ethenylbicyclo[4,2,0]octa-1,3,5-triene or 4-Vinylbenzocyclobutene,
. To a 500-mL round-bottom neck flask was added (Ph) PCH Br (24.3
g, 68.1 mmol), 110 mL of dry THF, and the solution was cooled to
78 °C. n-BuLi (2.5 M in hexane, 26.4 mL, 66 mmol) was added
and 4-vinylbenzocyclobutene, 4 (3.25 g, 25.0 mmol) in a glass ampule
with a stir bar. After three freeze and thaw cycles the ampule was sealed
under argon and heated for 6 h at 125 °C. The resulting polymer was
4
3
3
-
dropwise, and the reaction mixture was allowed to warm to room
temperature The yellow-orange solution was cooled to -78 °C, and
(
12) (a) Benoit, D.; Chaplinski, V.; Braslau, R.; Hawker, C. J. J. Am. Chem.
Soc. 1999, 121, 3904. (b) Dao, J.; Benoit, D.; Hawker, C. J. J. Polym. Sci.,
Part A: Polym. Chem. 1998, 36, 2161. (c) Hawker, C. J.. J. Am Chem.
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8
654 J. AM. CHEM. SOC. VOL. 124, NO. 29, 2002
9

Nanoparticles via Intramolecular Chain Collapse
A R T I C L E S
dissolved in dichloromethane and purified by precipitation into a 1:1
mixture of isopropoanol/acetone followed by reprecipitation into
Scheme 1. Coupling Reaction of Benzocyclobutene Derivatives,
1.
methanol to give 15 as a colorless powder (10.7 g, 76.1%), M )
w
1
8
9 500; PDI ) 1.12; H NMR (400 MHz, CDCl
3
) δ 7.24-6.57 (m,
, CH).
ArH), 3.65 (s, OCH ), 3.05 (br s, CH ), 1.83-1.26 (m, CH
2
2
2
General Procedure for Nanoparticle Formation, 9. In a 500-mL
three-necked flask equipped with a internal thermometer, condenser,
and septum, 120 mL of benzyl ether was heated at 250 °C under argon.
A solution of the benzocyclobutene (BCB)-functionalized linear
polymer, 8 (4.00 g, M ) 108 000; PDI ) 1.15, 7.5 mol % BCB),
n
dissolved in benzyl ether (40 mL) was added dropwise via a peristaltic
pump at ca. 12.8 mL/h with vigorously stirring under argon. After
addition the reaction mixture was heated for an additional 1 h, the
solvent was distilled under reduced pressure, and the remaining crude
product was dissolved in dichloromethane and precipitated into
methanol. This gave the nanoparticles, 9, as a colorless solid (3.76 g,
1
9
4% yield), H NMR (400 MHz, CDCl
3
). The significant change is
Scheme 2. Synthesis of Benzocyclobutene Monomer, 4.
the disappearance of the aliphatic benzocylobutene protons at 3.05 on
formation of the cross-linked nanoparticles; all other aspects of the
spectrum are similar.
Results and Discussion
In developing a new strategy for nanoparticle formation, we
were drawn to the field of living free radical polymerizations
where the high degree of control is a result of an equilibrium
between dormant and reactive propagating radicals. As a result,
the reactive radical chain ends are present in extremely low
concentrations.13 This general concept, that is, only the reactive
species need to be at ultra-dilute concentrations, was then applied
to the formation of nanoparticles by intramolecular coupling.
In this case, the linear polymer, which contains numerous latent
coupling groups along the backbone, is added slowly to a heated
solvent in which the coupling groups are either thermally or
chemically activated. As a consequence, the traditional condi-
tions of ultrahigh dilution need only be met for the reactive
intermediates and not for the polymers themselves. Following
this coupling event, the nanoparticles should be unreactive,
which allows their concentration to increase to very high levels,
and in the formulation of thermosetting materials.15 Upon
heating, the benzocyclobutene group, 1, undergoes ring opening
to give the extremely reactive o-quinoid structure, 2, which
primarily reacts via an irreversible dimerization reaction to form
the dibenzocyclooctadiene derivative, 3, as well as a mixture
of unidentified oligomeric materials (Scheme 1). The direct
result of this chemistry is the selective formation of cross-links
from the coupling of two or more benzocyclobutene units.16
Having identified the benzocyclobutene functionality as the
critical coupling group for the preparation of nanoparticles, the
desired monomer, 4-vinylbenzocyclobutene, 4, was prepared
from 4-bromobenzocyclobutene, 5, by initial Grignard formation
followed by reaction with N,N-dimethylformamide to give the
aldehyde, 6. Wittig coupling of 6 with methyltriphenylphos-
phonium bromide afforded the desired styrene derivative, 4, in
high yield (Scheme 2). As anticipated, the incorporation of the
cyclobutene group into the monomer, 4, did not decrease its
stability when compared to styrene, and 4 proved to be stable
to a wide variety of reaction conditions.
(0.1-1.0 M) without intermolecular cross-linking reactions
leading to gelation or coupling of individual nanoparticles. The
ability to work at 0.1-1.0 M concentrations can be compared
to the impractical concentration levels (ca. 10-6 M) required
for traditional ultrahigh dilution techniques.
To satisfy these demands, the nature of the cross-linking
group is critical; it must be selectively activated and react
rapidly, leading to efficient intramolecular bond formation. It
is also important that this reaction is irreversible and leads to a
coupled structure that is subsequently unreactive under the
reaction conditions. To fulfill these goals, our attention was
directed to the benzocyclobutene group (BCB) which has found
The key to the success of this intramolecular chain collapse
strategy is the elimination of intermolecular cross-linking
between BCB groups on different chains. Since it was envisaged
that this critical balance between intramolecular coupling and
intermolecular cross-linking would be influenced by the number
and placement of BCB units along the polymeric backbone,
accurate control of the starting linear polymers structure was
also considered important. To achieve this and to permit a wide
variety of linear polymers to be conveniently prepared, the
polymerization of the desired monomer, 4-vinylbenzocy-
clobutene, 4, was examined under living free radical condi-
1
4
wide use as a latent Diels-Alder reagent in organic synthesis
(
13) (a) Matyjaszewski, K.; Qiu, J.; Tsarevsky, N. V.; Charleux, B. J. Polym.
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tions. Copolymerization of 4 with vinyl monomers such as
2
000, 38, 4776. (d) Bon, S. A. F.; Steward, A. G.; Haddleton, D. M. J.
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9
VOL. 124, NO. 29, 2002 8655

A R T I C L E S
Harth et al.
Scheme 3. Synthesis of Benzocyclobutene Functionalized Linear Polystyrene, 8.
apparent as evidenced by the increase in molecular weight of
the product from its base value of 65 000 for a discrete
nanoparticle due to chain-chain coupling. This ability to readily
identify chain-chain coupling has been previously observed for
dendrimer chemistry where even minor amounts of intermo-
lecular coupling can be easily detected by gel permeation
chromatography (GPC).
This ability is due to the molecular weight doubling on
chain-chain coupling, and the combination of this feature with
the low polydispersity of the initial chains results in a lower
limit of ca. 1-2% of intermolecular cross-linking being readily
detected as a higher molecular shoulder under standard GPC
18
-3
conditions. At higher concentrations of ca. 9.0 × 10 M cross-
linking to a swollen gel occurs very rapidly due to the large
number of BCB functional groups along the polymeric back-
bone. While these concentrations are comparable to results
obtained with other traditional ultra-high dilution techniques,9
the results are in stark contrast to the continuous addition
strategy. In this approach, a concentrated solution ([BCB] )
0.2 M) of the same starting linear polymer, 8, is continuously
added via a peristaltic pump to a high-boiling solvent, such as
,10
Figure 1. Variation in molecular weight of final macromolecule, Mw, with
total concentration of BCB groups in solution; (0) ultra-high dilution
strategy; (0) continuous addition strategy; (I) represents that an insoluble
gel was produced (starting linear polymer; Mw ) 95 000; PDI ) 1.11).
procedure, leading to random incorporation of the reactive BCB
units and low polydispersities for the resulting copolymers, 8
19
dibenzyl ether, heated at 250 °C to give a final BCB
concentration of 0.05 M. After addition, the solvent is removed,
and the nanoparticles, 9, are isolated using normal precipitation
techniques (Scheme 4). No gelation or intermolecular cross-
linking is observed under these conditions, and only after
increasing the final concentration of BCB groups to 0.12 M
were minor amounts of nanoparticle coupling observed. The
ability to successfully conduct these chain-collapse reactions
at final BCB concentrations of 0.01-0.1 M represents an
increase of 3-4 orders of magnitude when compared to the
traditional ultrahigh dilution strategy (Figure 1). This permits
multigram samples to be prepared on a routine basis with
standard laboratory equipment, a dramatic improvement com-
pared to previous approaches.
A significant feature of the above concentration studies is
the reduction in hydrodynamic volume of the random coil linear
polymer on intramolecular collapse to give the final nanoparticle.
In the above example, the original linear polymer has a
molecular weight, Mw of 95 000 amu; however, upon reaction
the macromolecule decreases in size to give a nanoparticle with
an apparent or polystyrene equivalent Mw of 65 000 amu.
Dynamic light scattering was also employed to follow this
decrease in size, and a reduction in the hydrodynamic radius,
Rh from 8.7 to 6.6 nm, was observed upon intramolecular
collapse. Since no byproducts are produced during this reaction
(
Scheme 3). At molecular weights less than 120 000 amu the
polydispersities for these random copolymers were 1.08-1.16,
which increased to 1.19-1.26 for molecular weights above
2
significantly reduced concentration of initiating groups at these
high molecular weights and has been observed previously for
both ATRP- and nitroxide-mediated procedures.17
The BCB-functionalized polystyrene derivatives, 8, could be
readily characterized by standard techniques and incorporation
of the BCB units monitored by 1H NMR which showed
characteristic aliphatic resonances for the cyclobutene ring at
00 000 amu. This increased polydispersity is due to the
3
.10 ppm. Intramolecular collapse was initially examined under
traditional ultrahigh dilution techniques. For this, a solution of
a 80:20 styrene/BCB random copolymer, 8 (Mw ) 95 000; PDI
)
1.11) in dibenzyl ether was heated at a variety of concentra-
18
tions under N2 for 30 min at 250 °C. As can be seen in Figure
-
5
1
, at very low concentrations of BCB groups, ca. 5.0 × 10
M (see inset, Figure 1), intermolecular cross-linking becomes
(17) (a) Hawker, C. J.; Bosman, A. W.; Harth, E. Chem. ReV. 2001, 101, 3661-
3688. (b) Kamigaito, M.; Ando, T.; Sawamoto, M. Chem. ReV. 2001, 101,
3689-3746. (c) Matyjaszewski, K.; Xia, J. Chem. ReV. 2001, 101, 2921-
2990.
(
18) The concentration of BCB groups is an overall concentration in solution
and is independent of the molecular weight of the linear polymer. For
example, a 80/20 styrene/BCB copolymer has a repeat unit consisting of 4
styrene monomers (4 × 104) and one BCB monomer (1 × 130), which
equals a repeat unit molecular weight of 546. Therefore 4.00 g of this 80/
(19) A reaction temperature of 250 °C corresponds to the exotermic maximum
of the DSC curve relating to ring opening of the cyclobutene ring, the
maximum was chosen to ensure efficient and rapid formation of the reactive
o-quinoid intermediate.
-
3
2
7
0 copolymer contains, 4.00/546 ) 7.32 × 10 mol of repeat units or
.32 millimole equivalents of BCB. Dissolution in 50 mL of dibenzyl ether
then leads to an overall concentration of 0.146 M.
8656 J. AM. CHEM. SOC.
9
VOL. 124, NO. 29, 2002

Nanoparticles via Intramolecular Chain Collapse
A R T I C L E S
Scheme 4. Schematic Representation of the Intramolecular
Collapse of the Linear Polymer, 8, To Give the Nanoparticle, 9.
Figure 2. Comparison of 1H NMR spectrum for (a) the starting linear
polymer, 8, 80/20 Sty/BCB, Mw ) 95 000, PDI ) 1.12; and the resulting
nanoparticle, 9, Mw ) 65 000, PDI ) 1.10.
and no molecular weight lost, this decrease can only be due to
a change in the architecture of the macromolecule from a
random coil to a nanoparticle. Again, this is consistent with
dendrimer chemistry where the compact, three-dimensional
dendritic structure leads to an apparent molecular weight which
2
0
is significantly smaller that the actual molecular weight.
Further confirmation of the structural change was obtained
from NMR studies; of particular note is the observed absence
of unreacted BCB units in the final nanoparticles, 9. As shown
1
in Figure 2, comparison of the H NMR spectra for the starting
Figure 3. Overlay of GPC traces for (a) the starting linear polymer, 8, Mw
) 105 000, PDI ) 1.12; and nanoparticles, 9, with (a) 0 mol % BCB
incorporation, (b) 5 mol % BCB incorporation, (c) 10 mol % BCB
incorporation, (d) 20 mol % BCB incorporation, and (e) 25 mol % BCB
incorporation.
linear polymer, 8, and the nanoparticle, 9, shows the prominent
resonance for the aliphatic protons of the cyclobutene group at
.10 ppm in the former, which completely disappear after
3
collapse, and a broad resonance at 2.0-3.0 ppm is observed.
This is consistent with ring opening of the benzocyclobutene
group and coupling to give cyclooctane derivatives and higher
aliphatic coupled oligomers. A direct consequence of this ring
opening is that the BCB groups undergo reaction to give dimers
and oligomers that do not undergo any further coupling
chemistry. This fulfils one of the requirements discussed above
for a successful intramolecular chain collapse reaction and
permits the substantial build-up of product in the final reaction
mixture. The lack of reactivity can also be demonstrated by
repeated thermal cycling of the isolated nanoparticles, which
results in no observable change in physical properties such as
molecular weight, NMR spectra, and so forth. Formation of the
nanoparticles also leads to an increase in the glass transition
temperature of the nanoparticles when compared to the starting
linear polymers. The BCB functionalized linear polystyrenes,
1
05 °C, while the glass transition temperature for the nanopar-
ticles, 9, increase by ca. 20 °C to 120-130 °C at 20% BCB
incorporation with an associated broadening of the transition.
All of the above data is consistent with the intramolecular
collapse of a random coil linear polymer to give a single, higher-
density nanoparticle.
This unique feature of being able to tailor the nanoparticle
via the starting linear polymer was then examined in detail using
three different series of polystyrene derivatives, ca. 44 000;
1
10 000; and 230 000 amu containing varying levels of BCB
incorporation from 1.25 to 30% (Table 1). Under the continuous
addition technique described above, conversion of the linear
polymers to nanoparticles was a facile process at all molecular
weights and percent BCB incorporations studied. At concentra-
tions of up to 0.01-0.1 M, no indication of intermolecular cross-
linking was observed, and in each case the GPC trace shifted
to lower hydrodynamic volumes. As can be seen in Figure 3,
for the same molecular weight of the starting linear polymer,
8
, show Tg’s similar to that observed for polystyrene, ca. 100-
(
20) (a) Fr e´ chet, J. M. J. Science 1994, 263, 1710. (b) Fischer, M.; V o¨ gtle, F.
Angew. Chem., Int. Ed. 1999, 38, 885. (c) Hawker, C. J.; Fr e´ chet, J. M. J..
J. Am. Chem. Soc. 1990; 112, 7638. (d) Tomalia, D. A.; Naylor, A. M.;
Goddard, W. A., III. Angew. Chem. Int. Ed. Engl. 1990, 29, 138.
8
, a systematic decrease in the hydrodynamic volume of the
nanoparticles is observed on increasing the percent of benzo-
J. AM. CHEM. SOC.
9
VOL. 124, NO. 29, 2002 8657

A R T I C L E S
Harth et al.
Table 1. Comparison of the Polystyrene Equivalent Molecular
Weights and PDI for the Starting Linear Polymers, 8, and the Final
Nanoparticles, 9
linear
nanoparticle
composition
M
w
PDI
M
w
PDI
%BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
Sty/BCB
44 000
44 500
1.09
1.08
1.09
1.10
1.07
1.15
1.12
1.14
1.15
1.10
1.16
1.11
1.12
1.23
1.25
1.22
1.19
1.26
1.24
1.23
1.21
1.24
1.23
41 700
38 200
29 100
20 700
18 500
103 000
94 500
79 300
59 800
56 000
44 200
42 800
40 500
189 800
174 000
109 000
98 000
91 500
81 000
80 300
66 000
62 000
63 500
1.09
1.12
1.11
1.12
1.12
1.17
1.19
1.18
1.18
1.19
1.16
1.15
1.09
1.26
1.22
1.26
1.18
1.16
1.17
1.19
1.17
1.25
1.16
2.50
5.00
45 500
10.00
15.00
20.00
1.25
43 500
44 000
110 500
113 000
109 000
108 000
112 000
110 000
111 000
112 000
231 000
235 000
228 000
230 000
233 000
231 000
235 000
230 000
229 000
234 000
2.50
5.00
7.50
10.00
15.00
20.00
25.00
1.25
2.50
5.00
Figure 4. Variation in the percent reduction in molecular weight21 for the
nanoparticles, 9, with the mol % of BCB units in the starting linear polymer,
7.50
10.00
12.50
15.00
20.00
25.00
30.00
8, for 44 K (b), 110 K (9), and 230 K (b) series.
Table 2. Comparison of Molecular Weight (Linear Standard
Equivalent) and PDI for the Starting Functionalized Linear
Polymers, 10, and the Final Nanoparticles, 11
linear
nanoparticle
composition
M
w
PDI
M
w
PDI
%BCB
cyclobutene groups, which is consistent with an increase in the
level of intramolecular coupling and a more globular, three-
dimensional structure. The other pertinent feature of Figure
MMA/BCB
MMA/BCB
MMA/BCB
n-BuA/BCB
n-BuA/BCB
n-BuA/BCB
n-BuA/BCB
52 500
54 500
56 000
74 500
77 500
75 000
73 000
101 000
92 000
85 000
92 000
95 000
89 500
1.17
1.12
1.13
1.10
1.12
1.09
1.09
1.18
1.14
1.14
1.13
1.11
1.12
36 500
28 000
26 900
58 100
45 700
33 500
27 800
73 500
48 500
34 000
70 500
52 000
36 500
1.14
1.11
1.13
1.12
1.14
1.09
1.10
1.20
1.13
1.17
1.10
1.09
1.14
10.00
15.00
20.00
5.00
10.00
15.00
20.00
5.00
10.00
20.00
5.0
10.0
20.0
3b-e is the symmetrical nature/low PDI of the GPC traces for
the nanoparticles and the associated lack of higher-molecular
weight shoulders. This demonstrates that even at high BCB
loadings, ca. 25 mol %, no detectable amount of intermolecular
cross-linking is occurring.
a
Sty/Cl-Sty/BCBa
Sty/Cl-Sty/BCB
a
Sty/Cl-Sty/BCB
PEG-Sty/BCBb
Analysis of the trends within each series showed that the
percent reduction in hydrodynamic volume increases with both
increasing molar percentage of BCB and the molecular weight
of the starting linear polymer. In each case, the actual molecular
weight of the cross-linked macromolecules is significantly
greater than the apparent molecular weight. For example, a 70/
b
PEG-Sty/BCB
PEG-Sty/BCBb
a
b
1
0 mol % incorporation of p-chloromethylstyrene
5000; PDI ) 1.06.
PEG block, Mn
)
30 styrene/BCB random copolymer with an initial molecular
weight, Mw ) 234 000 (PDI ) 1.23) gives a nanoparticle with
a polystyrene equivalent molecular weight, Mw ) 63 500 (PDI
)
1.16) which represents a reduction in hydrodynamic volume
of 73%. The actual molecular weight of the final nanoparticle
was also determined by light scattering and found to be 230 000
which is within experimental error of that of the starting linear
polymer which demonstrates that the actual molecular weights
of the starting linear polymer and the final nanoparticles are
approximately the same. This collapse and associated change
in hydrodynamic volume is therefore due to the formation of
up to 310 intramolecular links per nanoparticle, assuming that
each activated BCB group reacts with one other activated BCB
group. Interestingly, all plots are of a similar shape and seem
to reach a plateau of between 65 and 75% reduction in apparent
molecular weight (Figure 4). It should also be noted that in the
control experiments, heating polystyrene with 0% BCB incor-
Figure 5. GPC traces for (a) the starting poly(ethylene glycol)-b-poly-
(styrene-co-benzocyclobutene), 15, (Mw ) 95 000, PDI ) 1.11) and (b)
the final hybrid nanoparticle-linear block copolymer, 16, (Mw ) 52 000,
PDI ) 1.09).
2
2
poration resulted in no detectable change in the chromatographic
or spectral properties of the polymers.
(
21) Percent reduction in molecular weight is calculated from the difference
between the actual molecular weight and the apparent molecular weight as
Examination of the data in Table 1 also demonstrates the
inherent versatility of this approach in controlling the size of
the final nanoparticle. Not only can the size and cross-link
density of the nanoparticle be controlled by the level of BCB
incorporation, but the molecular weight of the starting linear
determined by GPC; (M
w
actual - M
w
apparent)/M
w
actual × 100%,
(
22) This is based on the assumption of one BCB unit reacting with a second
BCB unit forming an intramolecular dimer. While it is an efficient process,
there is the possibility of side reactions which will affect the absolute
numbers of cross-links; therefore, this number may represent an upper limit.
8658 J. AM. CHEM. SOC.
9
VOL. 124, NO. 29, 2002

Nanoparticles via Intramolecular Chain Collapse
A R T I C L E S
Scheme 6. Formation and Intramolecular Collapse of the
PEG-b-PSt/BCB Block Copolymer, 15, To Give a Hybrid
Linear-Nanoparticle Copolymer, 16.
Scheme 5. Schematic Representation of the Intramolecular
Collapse of a Random n-Butyl Acrylate-Based Linear Polymer, 10,
To Give the Nanoparticle, 11.
Table 2, starting linear polymers based on methyl methacrylate
(MMA) or n-butyl acrylate (n-BuA) can be employed as the
backbone polymer with no change in the efficiency of the
intramolecular collapse process. For example, copolymerization
of an 85:15 mixture of n-butyl acrylate and the vinyl BCB
derivative, 4, in the presence of the alkoxyamine initiator, 7,
proceeds smoothly to give the well-defined random copolymer,
10, with a molecular weight, Mw of 75 000 and a polydispersity
of 1.09. Addition of a concentrated solution of 10 (0.1 M) to
dibenzyl ether, heated at 250 °C gives a poly(n-butyl acrylate)
nanoparticle, 11, with an apparent molecular weight, Mw of
33 500 and a polydispersity of 1.09. (Scheme 5). The relative
selectivity of the thermal procedure used to activate the BCB
group also allows other functional groups such as chloromethyl
substituents to be introduced into the linear polymer, thereby
leading to functionalized nanoparticles.
It should however be realized that this intramolecular collapse
procedure is not limited to simple linear random copolymers.
Additional structural features can be built into the starting
materials, which are then translated into the nanoparticle
structure. For example, block copolymers can potentially be used
in such an approach, and if the reactive BCB groups are
contained in only one of the blocks, novel macromolecular
architectures can be prepared in which a controlled number of
linear chains, one or two for AB and ABA block copolymers
respectively, are attached to the nanoparticle. To test this
hypothesis, functionalized poly(styrene)-b-poly(ethylene glycol)
polymer also plays a key role in determining the hydrodynamic
volume of the final nanoparticle. For example, a polystyrene
derivative with a 10% incorporation of BCB and a molecular
weight, Mw, of 112 000 gives a nanoparticle with a Rh of 6.2
nm. Increasing the molecular weight, Mw, of the starting linear
polymer to 233 000 while still retaining the 10% incorporation
of BCB gives a larger nanoparticle with a Rh of 9.5 nm. In
turn, a polystyrene derivative with an analogously higher
molecular weight of 229 000 but with a 25% incorporation of
BCB gives a nanoparticle with a Rh of 6.4 nm, very similar to
the first example with a lower molecular weight (117 000) and
level of BCB incorporation (10%). A consequence of this is
that the size and physical characteristics of the final nanoparticle
can be directly dictated by the structure and functionality of
the starting linear polymer.
The versatile nature of this intramolecular chain collapse
approach to nanoparticles coupled with the ability to prepare a
wide variety of linear polymers by living free radical techniques
also opens up the possibility of preparing well-defined nano-
particles incorporating functional groups, nonstryrenic mono-
mers, or different macromolecular architectures. As shown in
J. AM. CHEM. SOC.
9
VOL. 124, NO. 29, 2002 8659

A R T I C L E S
Harth et al.
AB block copolymers were prepared by living free radical
procedures. The alkoxyamine substituted poly(ethylene glycol)
macroinitiator, 12, was obtained by reaction of the sodium salt
of monomethylpoly(ethylene glycol), 13 (Mn ) 5000, PDI )
polymer chains to give single-molecule nanoparticles. By using
a continuous addition strategy in conjunction with thermally
activated benzocyclobutene-coupling chemistry, intermolecular
cross-linking can be effectively eliminated even at high con-
centrations (0.1 M) which makes this a practical technique for
the large-scale synthesis of well-defined nanoparticles. The size
and cross-link density of the final nanoparticles can be accurately
controlled by the initial degree of polymerization of the linear
chain and the level of incorporation of the BCB coupling units.
Conversion of the starting random coil linear polymer to the
final nanoparticle results in a significant reduction in apparent
molecular weight, up to 65-75%, which is fully consistent with
the adoption of a dense, three-dimensional structure. The
versatility of this approach is further demonstrated by the use
of functionalized linear polymers and block copolymers to give
reactive and architecturally complex nanoparticles, such as
hybrid linear-nanoparticle copolymers. While the resulting
nanoparticles share many features in common with dendritic
macromolecules, it should be emphasized that a consequence
of starting from preformed linear polymers is the ability to
prepare larger molecular sizes more easily and the availability
of the nanoparticles is greatly increased when compared to
dendrimers.
1
.06), with the chloromethyl substituted alkoxyamine, 14. The
macroinitiator, 12, was then used to initiate the polymerization
of a mixture of styrene and 4 at 120 °C to give the desired AB
block copolymer, 15, which contains the cross-linking BCB units
in the second block only (Scheme 6).
Reaction of 15 under continuous addition conditions then
results in the selective intramolecular collapse of the second
block to give a novel hybrid linear-nanoparticle architecture,
16, in which a single water soluble PEG linear chain is attached
to a three-dimensional cross-linked polystyrene nanoparticle,
similar in structure to that of hybrid dendritic-linear block
copolymers.23 As can be seen in Figure 5, the effect of
intramolecular collapse is clearly evident in the shift of the GPC
trace for the starting poly(ethylene glycol)-b-poly(styrene-co-
benzocyclobutene), 15, (Mw ) 95 000, PDI ) 1.11) to that of
the final hybrid nanoparticle-linear block copolymer, 16, (Mw
)
52 000, PDI ) 1.09) and demonstrates the controlled nature
of this procedure. The solubility of these hybrid block copoly-
mers were similar to that for the parent polystyrene nanoparticles
which may be due to the relatively small size of the PEG block.
Future work will examine the effect of larger PEG blocks on
the solubility and phase behavior of hybrid PEG-PSt diblock
copolymers.
Acknowledgment. Financial support from the MRSEC
Program of the National Science Foundation under Award
Number DMR-9808677 for the Center for Polymeric Interfaces
and Macromolecular Assemblies, NIST/ATP Cooperative Agree-
ment No. 70NANB8H4013, and the IBM Corporation are
gratefully acknowledged. We also thank Ron Huang, Stanford
University for preliminary DLS measurements.
Conclusions
In conclusion, we have demonstrated a viable synthetic
strategy for the controlled intramolecular collapse of linear
(
23) (a) Malenfant, P. R. L.; Groenendaal, L.; Fr e´ chet, J. M. J. J. Am. Chem
Soc. 1998, 120, 10990. (b) Iyer, J.; Fleming, K.; Hammond, P. T.
Macromolecules 1998, 31, 8758-8765. (c) Rom a´ n, C.; Fischer, H. R.;
Meijer, E. W. Macromolecules 1999, 32, 5525-5531. (d) Gitsov, I.; Fr e´ chet,
J. M. J. Macromolecules 1993, 26, 6536-6537.
JA026208X
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