Photoinduced heterodisulfide metathesis for reagent-free synthesis of polymer nanoparticles

Article abstract of DOI:10.1039/c4cc08000a

Reagent-free synthetic methods are of great interest because of their simplicity and implications in green chemistry. We have taken advantage of photoinduced heterodisulfide metathesis to generate crosslinked polymer nanoparticles. The method of development and the mechanistic basis for the synthetic approach are outlined in this communication.

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ARTICLE TYPE
Photoinduced Heterodisulfide Metathesis for Reagent-free Synthesis of
Polymer Nanoparticles
a
Longyu Li, Cunfeng Song, Matthew Jennings and S. Thayumanavan*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Reagent-free synthetic methods are of great interest, because
Photochemical reactivity of disulfides has been known for
1
0
of their simplicity and implications in green chemistry. We 50 several decades. Disulfides are thought to undergo hemolytic
have taken advantage of photoinduced heterodisulfide
metathesis to generate crosslinked polymer nanoparticles.
The method development and the mechanistic basis for the
synthetic approach are outlined in this manuscript.
cleavage, giving thiol radicals, which can attack nearby disulfide
5
c,
bonds, resulting in disulfide exchange under photoirradiation.
1
0b, 10e
We were interested in exploring this photo-induced
1
0
metathesis of disulfide molecules containing pyridyl disulfide
(PDS) units. PDS units are well known for their unreactive
byproduct, pyridothione, during disulfide exchange reactions,
which provides the opportunity for reliably generating
55
Metathesis reactions have found utility in many synthetic and
supramolecular chemistry strategies. For example, diene
metathesis has found use in the syntheses of polymers and small
1
1
unsymmetrical disulfides. However, it is not clear whether such
a possibility exists in a photochemical disulfide metathesis
1
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3
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2
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3
4
4
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molecules, while strategies such as imine and hydrazone
metathesis reactions have found use in supramolecular chemistry 60 reaction. In fact, ultraviolet (uv) irradiation of 2,2’-
and dynamic combinatorial chemistry, among others. All these
reactions are reversible under the reaction conditions and this
provides the opportunity to obtain the thermodynamically
favorable structure, under a given set of conditions. For example,
dipyridyldisulfide (DPDS) results in the formation of pyridine-2-
1
2
sulfonic acid, presumably due to oxidation (scheme S1). This
suggests that hydrogen abstraction by the thiyl radical is much
slower than the oxidation reaction. Considering that pyridyl
the host identification process for a guest molecule in dynamic 65 groups are relatively electron poor compared to the alkyl thiols,
combinatorial chemistry reaction is driven by the templation by
the guest molecule to select for a specific host structure among
the myriad possibilities. Disulfide metathesis reactions have also
been used in this context both by Mother Nature for stabilizing
we were also concerned that the homolytic cleavage of the
disulfide bond between an alkyl group and a pyridyl group will
result in the formation of two sulfonic acids.
4
the desired protein secondary and tertiary structures and for
identifying optimal host geometries in supramolecular
5
chemistry. More recently, photolabile nature of disulfides have
Scheme 1. Hypothesized reaction scheme of photo-induced disulfide
been exploited to produce bulk hydrogels from oligomeric
5
c
metathesis of PDS-OH
disulfide molecules and polymeric disulfides. Although this has
provided very interesting materials in their own respect, this
observation also indicates a rather uncontrolled nature of photo-
induced disulfide metathesis reactions. We sought to develop a
photo-induced disulfide metathesis reaction that can provide
greater control such that we can achieve well-defined, crosslinked
polymeric nanostructures and we outline our findings in this
manuscript.
To investigate the possibility, we first used photochemical
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0
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reaction of 2-hydroxyethyl 2-pyridyl disulfide (PDS-OH, 1) as a
3
model system. A solution of 2.5 mg/mL of 1 in CD OD was
irradiated with a UV lamp (15 W) with a 350 nm light source. If
this reaction were to be a purely disulfide exchange reaction due
to thiyl radical formation and then recombination, molecule 1 will
be in equilibrium with bis(2-hydroxyethyl) disulfide (2) and
DPDS (3). Ideally, a statistical ratio of 2:1:1 of the products 1-3
would be obtained (Scheme 1). However, the starting material 1
was being continuously consumed with a concurrent increase in
Photo-chemically driven reactions are interesting, because
these are reagentless reactions. Photoreactions based on the
6
7
dimerization of thymine and coumarin or that of benzophenone
8
moieties have been used quite extensively. The dimerization
1
the concentration of 2. As shown in the H NMR spectra over
reactions are reverted by a higher energy photo-chemical
irradiation, while the reactive radicals generated from
benzophenone often provides irreversible products. The photo-
induced disulfide formation reaction has the potential of being
generated by a photochemical reaction, but being reverted by a
biologically relevant stimulus, the redox potential of the
irradiation time (Fig. 1), the integrated signal intensity of the
triplet at 2.94 ppm, arising from the CH
sulfur in 1, decreased with the corresponding increase in the
intensity of the triplet at 2.83 ppm (the same CH protons in 2).
Finally, the disappearance of peak at 2.94 ppm showed that no
2
protons attached to
2
9
85 starting material 1 remained in the reaction mixture. Also, there is
intracellular environment.
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are encouraging for the use of heterodisulfides containing PDS
units for controlled polymer nanoparticle synthesis.
Prior to utilizing this in nanoparticle synthesis however, we
were interested in investigating the reasons for the observed
oxidation of pyridine thiyl radical. Presumably, this oxidation is
caused by the oxygen in the reaction mixture. To check this
hypothesis, we excluded oxygen from the reaction by performing
three freeze-pump-thaw cycles. Analysis of the PDS-OH (1)
photochemical reaction under these conditions shows that the
product generation has become seemingly slower than the
reaction where the oxygen was not rigorously removed (Fig. 2).
Even after 4 hours of irradiation, there was still 50 % of starting
material 1 left in the reaction, consistent with a reaction in
equilibrium. Note that the starting material 1 was completely
consumed in about 2 hours without oxygen exclusion. In addition
to the expected DPDS (3) product, there are additional peaks in
the aromatic region in this reaction mixture, as shown in Fig. 2.
Analysis of this NMR indicates that the byproduct of this reaction
is indeed due to hydrogen abstraction by the thiopyridyl radical to
generate pyridothione (Scheme 3). In fact, we have shown that
direct irradiation of DPDS (3), after the freeze-pump-thaw cycle,
cleanly produces pyridothione rather than 4 (Fig. S6). Several
observations are noteworthy here: (i) the thiyl radical from
1
2
2
3
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Fig. 1 Time-dependent 1H NMR spectra of the photo-induced reaction of 2-
hydroxyethyl 2-pyridyl disulfide (PDS-OH, 1). Control spectra of bis(2-
hydroxyethyl) disulfide (DPDS, 2), 2, 2’-dipyridyl disulfide (3) and 2-
thiopyridone were also included. The concentration was 2.5 mg/mL. The
final product after photoirradiation was determined to be pyridine-2-sulfonic
acid (4).ꢀ
Scheme 2. Scheme of photo-induced chemistry reaction of PDS-OHꢀ
no evidence of the formation of DPDS (3) in the reaction mixture. 35 pyridine undergoes oxidation to pyridine-2-sulfonic acid (4)
However, we did find that the formation of 2 was accompanied
by the formation of pyridine-2-sulfonic acid (4) (Scheme 2).
Finally, we found that the percent conversion in this reaction was
lower at higher concentrations (Fig. S4). This is typical of
under ambient conditions; (ii) this reaction can be mitigated by
rigorously excluding oxygen from the reaction mixture; (iii) in
the absence of oxygen, the thiopyridyl radical undergoes both
radical recombination (evidenced by the formation of DPDS from
5
photochemical reactions as the fluence of light was kept the same 40 1) and hydrogen abstraction (evidenced by the formation of
in all these reactions. Two features are readily discerned from
these observations: (i) no equilibrium is observed in this photo-
induced disulfide metathesis; (ii) while the pyridothiyl radical is
readily oxidized, the alkylthiyl radical undergoes a radical
pyridothione from 1 and from DPDS irradiations).
Overall, photochemical irradiation of PDS-OH (1) results in
the homolytic cleavage of the disulfide bond to generate a pyridyl
and an aliphatic thiyl radical. The aliphatic radical undergoes
1
0
recombination reaction to produce 2. These initial observations 45 rapid recombination to generate the corresponding disulfide.
However, the stability provided by resonance in thiopyridyl
radical seems to be sufficient to slow down radical recombination
or hydrogen abstraction, but is not sufficient to inhibit oxidation
to the corresponding sulfonic acid 4. In the absence of oxidative
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0
pathway, this radical does ultimately undergo radical
recombination and hydrogen abstraction. These latter processes
also provide the opportunity for the photochemical reaction of 1
to be under equilibrium and thus slow down the conversion of
starting material to the product. In other words, the oxidized
byproduct serves to drive the equilibrium towards the right in the
reaction of 1. Therefore, in reactions where we need the
thiopyridyl byproduct to be continuously removed, the reaction
should be carried out without excluding oxygen (vide infra).
55
Fig. 2 Time-dependent 1H NMR spectra of the photo-induced disulfide
metathesis of 2-hydroxyethyl 2-pyridyl disulfide (PDS-OH, 1) under
anaerobic condition. Control spectra of bis(2-hydroxyethyl) disulfide (2), 2,
2
’-dipyridyl disulfide (DPDS, 3) and 2-thiopyridone were also included. The
concentration was 2.5 mg/mL.
Scheme 3. Photo-induced reaction of PDS-OH under unaerobic condition.
Scheme 4. Representation of photo-induced crosslinking reaction of random
copolymers containing PDS groups.ꢀ
2
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Encouraged by these observations, we then envisaged the
possibility of utilizing this methodology for preparing
a
crosslinked polymer nanoparticle. We wanted to test this for a
well-characterized polymer and polymer nanoparticle so that the
validation of this methodology will be robust. A 3:7 random
copolymer of the oligoethyleneglycol methacrylate monomer (5)
and the PDS-ethyl methacrylate monomer (6), shown as structure
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7
in Scheme 4, has been shown to form micelle-like assemblies in
9
c, 11b, 13
Fig. 4 a) Absorption spectra of pyridothione in UV-vis. Pyridothione, which
is a byproduct by the reaction between PDS with DTT and shows
characteristic absorption at 343 nm wavelength, is monitored in each
nanogel (2 mg/mL) prepared. b) Time dependent crosslinking density of the
nanogels with different concentrations of polymer solution, from 1 mg/mL
to 10 mg/mL.
water.
This assembly has been previously shown to be
1
1
2
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also crosslinked to form a polymer nanogel, triggered by the thiol
exchange reaction with dithiothreitol (DTT).
A solution of polymer 7 (1 mg/mL) in water was found to
aggregate to form an assembly of 9 nm in hydrodynamic diameter,
as discerned by dynamic light scattering (Fig. 3a). This solution
was subjected to irradiation in photochemical reaction chamber at
analysis using the small molecule model system above, the
thiopyridyl radical gets converted to pyridine-2-sulfonic acid 4.
The unreacted PDS in the polymer can be treated with a thiol to
reliably generate pyridothione, which can be readily monitored
3
50 nm for 2 hours. At this time, the size of the assembly
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assessed by DLS again and the size of the assembly was found to
be 13 nm, which is close to the size of the aggregate prior to
crosslinking (Fig. 3b). This observation suggests that the disulfide
metathesis occurs sufficiently fast such that the crosslinking
reaction is mostly intra-aggregate. The slight size increase could
be the result of a small amount of inter-aggregate crosslinking or
the swelling that is likely to occur in a crosslinked nanoparticle,
when the hydrophobic components are reduced. Alternately, this
size increase could also be attributed to the adventitious heating
that occurs during photochemical irradiation of the sample. This
latter possibility is consistent with the size increase in PEG-based
assembles at higher temperatures.
11a
spectroscopically due to its distinct absorption at 343 nm. The
concentration of pyridothione generated then gives us the amount
of unreacted PDS in the mixture. As shown in Fig. 4a, there was
very little difference between the absorption spectra before and
after the photoirradiation. However, the addition of excess DTT
into both samples results in significant difference between the
absorbance of the peak at 343 nm due to the difference in extent
of pyridothione generated. The crosslinking density was then
calculated using ratio of the intensities. If I
intensity at 343 nm of the irradiated sample by adding excess
DTT, while I is that of the unirradiated sample, then the
crosslinking density was calculated from I /I . Thus, the
N
is the increased
M
N
M
crosslinking density of the nanoparticle was found to be 33%
after 2 hours photoirradiation, when the concentration of the
polymer was 2 mg/mL. The crosslinking density could be
systematically varied using different irradiation times, as shown
in Fig. 4b. Interestingly, the crosslink density scales much slower
with irradiation time at higher concentrations (Fig. 4b). This
might seem counter-intuitive at first, because a reaction seems
slower at higher concentration. This is indeed consistent with
Fig. 3 DLS sizes in hydrodynamic diameter, a) micelle aggregates prepared
with polymer solutions with different concentrations, b) nanogels prepared
with polymer solutions with different concentrations, the photoirradiation time
was 2 h for all samples.
If it is indeed due to temperature variations and not due to
inter-aggregate reaction, we should be able to systematically tune
the size of the nanoparticle by varying the concentration of the
polymer. Indeed, when we varied the sample concentrations from
3
3
4
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0
5
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1
mg/mL to 10 mg/mL, the size of the micelle aggregates
increased from 9 nm to 20 nm with the increasing concentration
(Fig. 3a). Upon irradiation, the size of the nanogel only slightly
increased even at 10 mg/mL concentration from 20 nm to 38 nm
(
Fig. 3b). If the observed size increase at 1 mg/mL were due to
inter-aggregate crosslinking, when the concentration is increased
by an order of magnitude the size of the nanoparticle should have
substantially increased or even formed a bulk gel. Instead, the
size has only slightly increased. This suggests that the observed
size increase upon crosslinking is most likely due to temperature
increase in solution, and the photo-induced crosslinking is
predominantly intra-aggregate.
Fig. 5 Dye release from the nanogels prepared via photoirradiation for 2 h
in response to varied GSH concentrations, a) 0 mM, b) 10 mM. Sample
concentration was 0.1 mg/mL. FRET experiment based DiI/DiO exchange,
c) micelle aggregates, d) nanogels prepared via photoirradiation for 2 h.
Sample concentration was 0.1 mg/mL.ꢀ
Next, we were interested in estimating the crosslink density
in the nanoparticle. We utilized the residual PDS units present in
the polymer nanoparticle to estimate this. According to our
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photochemical reactions between small molecules (Fig. S4),
support of this work.
because we are measuring the percent conversion of starting
material and the reagent here is light, which is constant at all
different concentrations.
Notes and references
a
Department of Chemistry, University of Massachusetts, Amherst, MA
1003
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To test if the difference in the extent of PDS generation is
0
indeed due to crosslinking, we incorporated hydrophobic guest 60 E-mail: thai@chem.umass.edu
molecules inside these nanogels prior to the photoirradiation.
With the dye molecule, DiI, incorporated into the nanoparticle,
the guest molecule was found to be stably encapsulated in the
nanoparticle over a 24 hours time period, even after a 10-fold
dilution (Fig. 5a). However, when glutathione (GSH) was added
to this solution at 10 mM concentration, the guest molecule
seems to be releasing over time (Fig. 5b).
† Electronic Supplementary Information (ESI) available: See the
Supporting Information for the synthesis and characterization of PDS-OH,
random copolymer and nanoparticles. See DOI: 10.1039/b000000x/
1
1
2
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1 (a) G. C. Fu, S. T. Nguyen, R. H. Grubbs, J. Am. Chem. Soc. 1993, 115,
9
856-9857; (b) D. S. La, J. B. Alexander, D. R. Cefalo, D. D. Graf, A. H.
Hoveyda, R. R. Schrock, J. Am. Chem. Soc. 1998, 120, 9720-9721; (c) S. J.
Connon, S. Blechert, Angew. Chem. Int. Ed. 2003, 42, 1900-1923; (d) H. Mutlu,
L. M. de Espinosa, M. A. R. Meier, Chem. Soc. Rev. 2011, 40, 1404-1445; (e)
K. B. Wagener, J. M. Boncella, J. G. Nel, Macromolecules 1991, 24, 2649-
To further confirm that the encapsulation stability could be
easily tuned by simply varying the irradiation time, fluorescence
resonance energy transfer (FRET) based encapsulation stability
2
657; (f) Y.-X. Lu, Z. Guan, J. Am. Chem. Soc. 2012, 134, 14226-14231; (g) M.
J. Koh, R. K. M. Khan, S. Torker, A. H. Hoveyda, Angew. Chem. Int. Ed. 2014,
5
3, 1968-1972.
2
(a) K. Oh, K.-S. Jeong, J. S. Moore, Nature 2001, 414, 889-893; (b) T.
1
4
assay was carried out. In this experiment, a faster FRET
evolution suggests leaky nanoparticle, while an unchanged FRET
over time suggests stably encapsulated guests inside the
nanoparticle. Indeed, we observed that there was a rapid
evolution of FRET with time in the micelle aggregates without
any photoirradiation (Fig. 5c), compared to the nanoparticle
prepared using a 1 hour irradiation (Fig. S8). The evolution of
FRET was even slower after 2 hours of irradiation (Fig. 5d),
suggesting that the encapsulation stability can indeed be tuned by
varying the irradiation time.
Nishinaga, A. Tanatani, K. Oh, J. S. Moore, J. Am. Chem. Soc. 2002, 124,
5934-5935; (c) G. K. Cantrell, T. Y. Meyer, J. Am. Chem. Soc. 1998, 120,
8
3
035-8042; (d) C. D. Meyer, C. S. Joiner, J. F. Stoddart, Chem. Soc. Rev. 2007,
6, 1705-1723; (e) D. Janeliunas, P. van Rijn, J. Boekhoven, C. B. Minkenberg,
J. H. van Esch, R. Eelkema, Angew. Chem. Int. Ed. 2013, 52, 1998-2001; (f) P.
Taynton, K. Yu, R. K. Shoemaker, Y. Jin, H. J. Qi, W. Zhang, Adv. Mater.
2
014, 26, 3938–3942.
3 (a) A. K. H. Hirsch, E. Buhler, J.-M. Lehn, J. Am. Chem. Soc. 2012, 134,
4
1
177-4183. (b) J. F. Folmer-Andersen, J.-M. Lehn, J. Am. Chem. Soc. 2011,
33, 10966-10973. (c) M. J. Barrell, A. G. Campaña, M. von Delius, E. M.
Geertsema, D. A. Leigh, Angew. Chem. Int. Ed. 2011, 50, 285-290; (d) A.
Dirksen, S. Dirksen, T. M. Hackeng, P. E. Dawson, J. Am. Chem. Soc. 2006,
1
28, 15602-15603; (e) M.-K. Chung, C. M. Hebling, J. W. Jorgenson, K.
Severin, S. J. Lee, M. R. Gagné, J. Am. Chem. Soc. 2008, 130, 11819-11827.
(a) G. Markus, F. Karush, J. Am. Chem. Soc. 1957, 79, 134-139; (b) M.
4
Rueping, B. Jaun, D. Seebach, Chem. Commun. 2000, 22, 2267-2268; (c) W. J.
Wedemeyer, E. Welker, M. Narayan, H. A. Scheraga, Biochemistry 2000, 39,
Conclusions
4
5
1
207-4216.
In summary, we have demonstrated that: (i) PDS-containing
asymmetrically substituted disulfides can be homolytically
cleaved using photochemical irradiation; (ii) although the alkyl
substituted thiyl radical consistently undergoes radical
recombination, the reactivity of the thiopyridyl radical is
(a) S. Otto, R. L. E. Furlan, J. K. M. Sanders, J. Am. Chem. Soc. 2000, 122,
2063-12064; (b) S. Otto, R. L. E. Furlan, J. K. M. Sanders, Science 2002, 297,
590-593; (c) J. Li, J. M. A. Carnall, M. C. A. Stuart, S. Otto, Angew. Chem. Int.
Ed. 2011, 50, 8384-8386; (d) D. Basak, R. Kumar, S. Ghosh, Macromol. Rapid
Commun., 2014, 35, 1340–1344.
3
3
4
4
5
0
5
0
5
0
6
1
H. Kuang, H. He, J. Hou, Z. Xie, X. Jing, Y. Huang, Macromol. Biosci. 2013,
3, 1593-1600.
dependent on the presence of oxygen; (iii) in the presence of 100
oxygen, the thiopyridyl radical gets converted to pyridine-2-
sulfonic acid, while it undergoes hydrogen abstraction or radical
recombination in deoxygenated solutions; (iv) the oxidation
7 (a) J. W. Chung, K. Lee, C. Neikirk, C. M. Nelson, R. D. Priestley, small
2
4
7
8
012, 8, 1693-1700; (b) J. He, X. Tong, Y. Zhao, Macromolecules 2009, 42,
845-4852; (c) J. Jiang, B. Qi, M. Lepage, Y. Zhao, Macromolecules 2007, 40,
90-792.
J. S. Kim, J. H. Youk, Polymer 2009, 50, 2204-2208.
105
9 (a) S. Chakravarthi, C. E. Jessop, N. J. Bulleid, EMBO reports 2006, 7, 271-
75; (b) Z. Luo, K. Cai, Y. Hu, L. Zhao, P. Liu, L. Duan, W. Yang, Angew.
reaction also provides a pathway for driving the equilibrium
towards the desired product; (v) this feature was used for the
reagentless synthesis of crosslinked polymer nanoparticles; (vi)
2
Chem. Int. Ed. 2011, 50, 640-643; (c) J.-H. Ryu, S. Jiwpanich, R. Chacko, S.
Bickerton, S. Thayumanavan, J. Am. Chem. Soc. 2010, 132, 8246-8247; (d) L.
Li, K. Raghupathi, C. Yuan, S. Thayumanavan, Chem. Sci. 2013, 4, 3654-3660;
(e) A. V. Kabanov, S. V. Vinogradov, Angew. Chem. Int. Ed. 2009, 48, 5418-
the size of the nanoparticle can be conveniently varied by tuning 110
the size of the nanoaggregates, because the photo-induced
crosslinking was predominantly intra-aggregate; and (vii) the
crosslink density and encapsulation stability of this nanoparticle
5
1
1
429.
0 (a) B. Milligan, D. E. Rivett, W. E. Savige, Aust. J. Chem. 1963, 16, 1020-
029; (b) B. Nelander, S. Sunner, J. Am. Chem. Soc. 1972, 94, 3576-3577; (c)
Y. R. Lee, C. L. Chiu, S. M. Lin, J. Chem. Phys. 1994, 100, 7376-7384; (d) D.
Gupta, A. R. Knight, Can. J. Chem. 1980, 58, 1350-1354; (e) H. Otsuka, S.
Nagano, Y. Kobashi, T. Maeda, A. Takahara, Chem. Commun. 2010, 46, 1150-
1152; (f) E. Banchereau, S. Lacombe, J. Ollivier, Tetrahedron Lett. 1995, 36,
115
can be simply varied by altering the irradiation time. In addition
to the typical advantages of a reagentless reaction, the fact that
this reaction is carried out in water and that the byproduct of this
8
2
197-8200; (g) E. Banchereau, S. Lacombe, J. Ollivier, Tetrahedron 1997, 53,
087-2102.
reaction is highly water-soluble sulfonic acid that can be easily 120
removed by dialysis suggest that this methodology offers a
promising new approach for nanoparticle synthesis. Since the
crosslinks generated here are biologically relevant, this method
11 (a) Y. Kakizawa, A. Harada, K. Kataoka, J. Am. Chem. Soc. 1999, 121,
1247-11248; (b) J.-H. Ryu, R. T. Chacko, S. Jiwpanich, S. Bickerton, R. P.
Babu, S. Thayumanavan, J. Am. Chem. Soc. 2010, 132, 17227-17235.
2 (a) W. Adam, G. N. Grimm, S. Marquardt, C. R. Saha-Möller, J. Am. Chem.
Soc. 1999, 121, 1179-1185; (b) T. S. Lobana, I. Kinoshita, K. Kimura, T.
Nishioka, D. Shiomi, K. Isobe, Eur. J. Inorg. Chem. 2004, 2004, 356-367;
1
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also could have implications in generating new materials of
interest in biology and medicine.
1
3 L. Li, J.-H. Ryu, S. Thayumanavan, Langmuir 2013, 29, 50-55.
14 S. Jiwpanich, J.-H. Ryu, S. Bickerton, S. Thayumanavan, J. Am. Chem. Soc.
010, 132, 10683-10685.
2
Acknowledgements
We thank the NIGMS of the National Institute of Health (GM-
065255) and the Army Research Office (63889CH) for partial
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