Rigid hydrophilic structures for improved properties of conjugated polymers and nitrotyrosine sensing in water

Article abstract of DOI:10.1021/ol1001768

Chemical Equation Presented The efficient synthesis of a hydrophlic monomer bearing a three-dimensional noncompliant array of hydroxyl groups Is described that prevents water-driven excimer features of hydrophobic poly(p-phenylene ethynylene) backbones, Sensitivity of the polymer to 3-nltrotyrosine is also discussed.

Full text of DOI:10.1021/ol1001768

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1292-1295
Rigid Hydrophilic Structures for Improved
Properties of Conjugated Polymers and
Nitrotyrosine Sensing in Water
Brett VanVeller, Koji Miki, and Timothy M. Swager*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
tswager@mit.edu
Received January 24, 2010
ABSTRACT
The efficient synthesis of a hydrophilic monomer bearing a three-dimensional noncompliant array of hydroxyl groups is described that prevents
water-driven excimer features of hydrophobic poly(p-phenylene ethynylene) backbones. Sensitivity of the polymer to 3-nitrotyrosine is also
discussed.
Fluorescent conjugated polyelectrolytes (CPEs) are made
water-soluble by pendant ionic functionalities along the
polymer backbone. CPEs have seen application in a variety
of chemical and biological sensing schemes1 because the
intra- and interchain migration of excitons along the polymer
backbone results in the amplification of fluorescence signals
relative to small-molecule fluorophores.1a,2 However, the
rigid hydrophobic main chains of CPEs are prone to
interpolymer π-π interactions leading to broad, ill-defined
emission features and reduced luminescence.3 Supramolecu-
lar and macromolecular approaches to mitigate these effects
have been developed that effectively isolate polymer chains
from each other.4,5 However, these strategies can result in
large interpolymer separation that can reduce energy transfer
between chains, which is the basis of some transduction
schemes.1b
energy transfer necessary for amplification.6 We hypoth-
esized that monomer 1, with its three-dimensional hydrophilic
architecture, might impart the same properties to water-
soluble polymers as 2 does in nonpolar media.
Figure 1. Three-dimensional monomers.
The synthesis of 1 began with p-bromanil (3); double
addition of TIPS acetylide to 3 followed by SnCl2
reductive aromatization provided 4.7 We envisioned that
the three-dimensional carbon framework might be estab-
lished in one step via a double aryne-cycloaddition
The three-dimensional, noncompliant structure of iptycene-
type monomers (2, Figure 1) has been shown by our
laboratory to prevent strong quenching interactions between
polymer chains while still promoting productive interpolymer
10.1021/ol1001768  2010 American Chemical Society
Published on Web 03/01/2010

protocol.8 In the event, addition of n-BuLi to dienophile
precursor 4 at -45 °C produces a benzyne intermediate
after initial lithium-halogen exchange. This putative
dienophile underwent [4 + 2] cycloaddition with 59 to
provide a mixture of 6-anti and 6-syn cycloaddition
products in a ratio of 1.7:1. The reaction was evaluated
under a variety of solvent and temperature conditions (a
more detailed discussion can be found in Supporting
Information), but the ratio of isomers varied only slightly.
The isomers were not easily separated, so the mixture was
carried on to the next step; however, sufficient quantities
of 6-anti could be isolated to confirm the stereochemistry
by X-ray crystallography (Scheme 1). The structure of
2). Despite a modest yield, this procedure creates con-
siderable complexity in a single step. Further, this
transformation can be performed on multigram scales
(>5 g).
Modeling studies suggested that the double dihydroxy-
lation of 6 would occur on the less hindered face of the
alkene in 6-anti/syn to produce the corresponding isomers
8-anti and 8-syn (Scheme 2). Unfortuantely, all attempts
with a variety of NMO-mediated osmium tetroxide dihy-
droxylation conditions (Upjohn process)10,11 showed no
conversion of starting material. However, 1H NMR analyses
of the crude reaction mixtures revealed the amount of 6-syn
diminished relative to 6-anti with increasing OsO4 loadings.
To investigate this observation further, a reaction using a
stoichiometric amount of OsO4 was performed, and 7 was
obtained. While dioxo-diosmium type species are known,12
Scheme 1. Synthesis of the Carbon Framework
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Scheme 2. Dihydroxylation
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Org. Lett., Vol. 12, No. 6, 2010
1293

the cis-dioxo variant 7 demonstrates remarkable stability in
a variety of solvents and can be purified by silica gel
chromatography. The steric bulk surrounding the osmium
in this system likely prevents reoxidation by NMO, thus
trapping the osmium catalyst and halting the catalytic cycle.
These observations led us to examine the Sharpless
asymmetric dihydroxylation (SAD), where conditions
allow for hydrolysis of the osmate ester before reoxida-
tion.13 After some modification of the SAD conditions
(see Supporting Information), separable isomers of 8-anti
and 8-syn were isolated in excellent yield and the
geometry of dihydroxylation was confirmed by X-ray
crystallography (Scheme 2).
high molecular weight (Mn ) 14,500, PDI ) 1.7, DP ) 18)
and highly water-soluble (>8 mg/mL) polymers in good
yield.
The immediate effects of incorporating a monomer such
as 1-anti with its noncompliant three-dimensional architec-
ture can be seen in Figure 2. The emission characteristics of
Global deprotection of 8-anti (see Supporting Information
for 8-syn) with BCl3 to remove the acetonide groups followed
by TBAF to remove the TIPS groups provided 1-anti
(Scheme 3). Unfortunately, homopolymerization of 1-anti
Figure 2. UV-vis absorbance and fluorescence spectra of P1-anti
in water (black), P1-anti in 1X PBS (red), P-peg in water (blue),
and P-peg in 1X PBS (green).
Scheme 3. Deprotection and Polymerization
P1-anti in comparison to an analogous control polymer (P-
peg)5a lacking a deaggregating structure16 is evident by the
sharper, well-defined emission features. Further, sensing of
biological analytes will likely not take place in pure water
but in higher ionic strength solutions, such as phosphate-
buffered saline (PBS). Indeed, P1-anti shows the same sharp
emission features in 1X PBS with a quantum yield within
the error of measurement (Table 1). The control polymer,
Table 1. Peak Analysis for Figure 2
peak
ΦF (%) heighta fwhma,b ratioc
P1-anti, water
P1-anti, 1X PBS
P-peg, water
19
17
19
12
49
50
41.81
36.99
22.10
10.86
143.7
149.9
32.50
24.82
92.47
100.29
28.48
29.51
1.30
1.50
0.24
0.11
5.04
5.08
using palladium-mediated oxidative homocoupling of acety-
lenes14 was not possible, and only insoluble material could
be isolated.
Attempts to polymerize diol protected versions of 1-anti
and then deprotect after polymerization also failed to yield
water-soluble homopolymers. These observations suggest the
rigid structure of 1-anti may not provide enough favorable
entropic interactions with water to produce a soluble ho-
mopolymer. Copolymerization, however, with the sulfonated
diiodide 103a,15 by Sonogashira polymerization produced
P-peg, 1X PBS
P1-anti, water/glycerold
P1-anti, water/methanold
a Arbitrary units. b fwhm ) full width at half-maximum. c Ratio ) (peak
height):(fwhm). d At 1:1.
however, shows lower energy emission features, consistent
with the formation of low-energy emissive traps arising from
interpolymer π-π interactions. Peak analysis data in Table
1 shows numerically what is visually represented in Figure
2. The presence of 1-anti (P1-anti) produces distinctly
sharper fluorescence signals with visible vibrational features.
The blue-shifted absorbance and emission of P1-anti relative
to the control is due to a lower HOMO level resulting from
the absence of conjugated oxygen lone pairs in 1-anti.
Interestingly, despite the sharper emission peaks of P1-anti,
there is not an observed increase in quantum yield often seen
(12) (a) Phillips, F. L.; Skapski, A. C. J. Chem. Soc., Dalton Trans.
1975, 2586. (b) Casey, C. P. J. Chem. Soc., Chem. Commun. 1983, 126.
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1994, 94, 2483.
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2000, 38, 4669.
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(16) CPE copolymers with 2 are not readily soluble in water; see: Zheng,
J.; Swager, T. M. Chem. Commun. 2004, 2798.
Chem. B. 2003, 107, 6544
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1294
Org. Lett., Vol. 12, No. 6, 2010

when bulky side chains are used. This may indicate that P1-
anti is still in an aggregated form. Indeed, more solubilizing
water/alcohol solvent mixtures show higher quantum yields
relative to pure water (Table 1), indicating a decrease in
aggregation (see Supporting Information for spectra).
To further understand the nature of P1-anti in solution,
Stern-Volmer quenching experiments were performed with
3-nitrotyrosine, a modified tyrosine residue associated with
over 50 disease states (Figure 3).17 A greater quenching
indicating a decrease in aggreagation with better solvents.
Quenching experiments performed with P-peg as control
showed no response, presumably because the aggregated
emissive states of the polymer provide lower energy states
than the LUMO of 3-nitrotyrosine (see Suporting Information
for spectra).
In summary, we have developed an expedient synthesis
of monomer 1-anti (and 1-syn, see Supporting Information).
Further, the hydrophilic three-dimensional structure of 1-anti
was shown to promote spectral purity with decreased lower
energy excimer emission in both water and PBS despite an
aggregated state. Further interchain energy migration was
shown through Stern-Volmer analysis, and work toward
applying interpolymer energy transfer for further sensing
applications is underway.
Acknowledgment. Financial support for this work was
provided by the Natural Science and Engineering Council
of Canada (NSERC). The authors also thank Dr. Dahui Zhao
for the synthesis of compound 4. We are grateful for funding
from the U.S. Army through the Institute for Soldier
Nanotechnologies, under Contract W911NF-07-D-004 with
the U.S. Army Research Office.
Figure 3. Fluorescence spectra for the addition of micromolar
quanitites of 3-nitrotyrosine to P1-anti in 1X PBS. Stern-Volmer
plot (inset), KSV ) 27,737.
Supporting Information Available: Experimental pro-
cedures and characterization data, including CIF files. This
material is available free of charge via the Internet at
http://pubs.acs.org.
constant can be expected for more aggregated polymers
because of increased interchain exciton migration and transfer
to the electron-deficient nitroaromatic. Indeed, a KSV of
27,737 was found in PBS and the KSV decreased for better
solvents (4,774 in water and 1,232 in water/methanol),
OL1001768
(17) Neumann, H.; Hazen, J. L.; Weinstein, J.; Mehl, R. A.; Chin, J. W.
J. Am. Chem. Soc. 2008, 130, 4028, and references therein.
Org. Lett., Vol. 12, No. 6, 2010
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