Highly water-soluble neutral near-infrared emissive BODIPY polymeric dyes

Article abstract of DOI:10.1039/c2jm14920f

Three highly water-soluble near-infrared emissive polymeric BODIPY dyes (polymers A-C) were prepared by the palladium-catalyzed Suzuki polymerization of highly water-soluble 2,6-diiodo-3,5-distyryl-BODIPY dyes with 1,4-phenyldiboronic acid and 2,7-bis(4,4

Full text of DOI:10.1039/c2jm14920f

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PAPER
Highly water-soluble neutral near-infrared emissive BODIPY polymeric
dyes†
a
Shilei Zhu, Nethaniah Dorh, Jingtuo Zhang, Giri Vegesna, Haihua Li, Fen-Tair Luo, Ashutosh Tiwari
a
a
a
b
c
a
*
a
*
and Haiying Liu
Received 1st October 2011, Accepted 16th November 2011
DOI: 10.1039/c2jm14920f
Three highly water-soluble near-infrared emissive polymeric BODIPY dyes (polymers A–C) were
prepared by the palladium-catalyzed Suzuki polymerization of highly water-soluble 2,6-diiodo-3,5-
distyryl-BODIPY dyes with 1,4-phenyldiboronic acid and 2,7-bis(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-9,9-di[1-[2-(2-methoxyethoxy)ethoxy]ethyl]fluorene, respectively. Partial
replacement of fluorine subunits of BODIPY cores at 4,4-positions of polymer C with ethynyl subunits
resulted in a highly water-soluble BODIPY polymeric dye (polymer D). Polymers A–D show solubility
of at least 20 mg mLꢀ1 in aqueous solution. For comparison purposes, polymers E and F were prepared
by palladium-catalyzed Sonogashira polymerization of highly water-soluble 2,6-diiodo-3,5-distyryl-
BODIPY dye with highly water-soluble 1,4-diethynylbenzene and 2,6-diethynyl BODIPY dye bearing
branched oligo(ethylene glycol)methyl ether residues, respectively. Upon comparison, polymer E shows
low solubility in aqueous solution (0.1 mg mLꢀ1), whereas polymer F is almost insoluble in aqueous
solution (less than 0.05 mg mLꢀ1), but both are soluble in organic solvents such as chloroform, DMSO
and DMF (at least 10 mg mLꢀ1).
dyes and only a few reported near-infrared emissive small
molecular BODIPY dyes are soluble in aqueous solution.7
Recently, we and other groups reported some deep-red and near-
infrared emissive polymeric BODIPY dyes,9–15 but none of these
polymeric BODIPY dyes are soluble in aqueous solution.9–13
BODIPY-based polymers with significantly extended p-conju-
gation systems tend to aggregate in aqueous solution due to
strong p–p stacking interactions among highly hydrophobic
polymer backbones; this poses a serious challenge in preparing
highly water-soluble neutral near-infrared emissive polymeric
BODIPY dyes. In biological systems there is a growing need for
such highly water soluble, near-infrared emissive, fluorescent
dyes to study fixed cells and tissues with minimal influence from
auto-fluorescence.16,17
Introduction
4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes
have attracted renewed interest because of their unusual and
remarkable properties such as large molar extinction coefficients,
narrow absorption bands, sharp emissions, high fluorescence
quantum yields, and outstanding chemical, thermal, and pho-
tostabilities. They have found a wide variety of applications in
light-harvesting systems,1 biological probes,2 supramolecular
fluorescent gels,3 solar cells4 and ion sensing and signaling.5
BODIPY dyes typically exhibit visible absorption and fluores-
cent emission between 470 and 550 nm. Different tuning strate-
gies have been used to extend p-conjugation of BODIPY dyes for
the absorption and emission maxima in the deep-red and near-
infrared region by functionalizing BODIPY cores at the meso-,
2,6- and 3,5-positions, fusing some aromatic rings to the BOD-
IPY core, and replacing pyrrole by isoindole.6–8 However, most
reported studies have focused on small molecules of BODIPY
We hypothesized that near-infrared emissive neutral polymeric
BODIPY dyes would be solubilized in aqueous solution if we
could effectively prevent their strong p–p stacking interactions
among the polymer backbones. We further hypothesized that
adding highly hydrophilic branched oligo(ethylene glycol)methyl
ether residues as polymer side chains to BODIPY will enhance
their enthalpic interactions with water. In order to test our
hypothesis, we prepared five near-infrared emissive polymeric
BODIPY dyes bearing highly hydrophilic branched oligo
(ethylene glycol)methyl ether side chains (polymers A–F) via
palladium-catalyzed Suzuki and Sonogashira coupling poly-
merization (Scheme 1). Polymers A–D are highly soluble in
aqueous solution (at least 20 mg mLꢀ1) due to weak p–p stacking
aDepartment of Chemistry, Michigan Technological University, Houghton,
MI, 49931, USA. E-mail: hyliu@mtu.edu; tiwari@mtu.edu
bUniversity Libraries, University of Alabama, Tuscaloosa, AL, 35487-
0266, USA
cInstitute of Chemistry, Academia Sinica, Taipei, Taiwan, 11529, Republic
of China
† Electronic supplementary information (ESI) available: Additional
information on preparation, characterization and optical data of highly
water-soluble near-infrared emissive neutral polymeric BODIPY dyes is
available online. See DOI: 10.1039/c2jm14920f
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J. Mater. Chem., 2012, 22, 2781–2790 | 2781

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Scheme 1 Chemical structures of near-infrared emissive polymeric BODIPY dyes.
interactions among polymer backbones and strong hydrophilic
nature of branched oligo(ethylene glycol)methyl ether side
chains, that effectively enhances enthalpic interactions of the
copolymeric BODIPY dyes with water. The weak p–p stacking
interactions between the polymer backbones result from the
steric hindrance of protons from co-monomeric phenyl units
with protons of methyl groups at 1,7-positions and protons of
vinyl groups at 3,5-positions of BODIPY cores, ortho-substituent
groups of BODIPY units at the meso positions in polymer C, and
ethynyl subunits at 4,40-positions in polymer D. Upon compar-
ison, polymer E is slightly soluble in water (0.1 mg mLꢀ1) whereas
polymer F is almost insoluble in aqueous solution (less than 0.05
mg mLꢀ1). But polymers E and F are soluble in common organic
solvents such as chloroform, DMF and DMSO (at least 10 mg
mLꢀ1). Furthermore, polymer F has low solubility in ethanol
even though branched oligo(ethylene glycol)methyl ether resi-
dues were also introduced to 2,6-diethynyl-BODIPY dye co-
monomer.
detect the polymers. Molecular weights were determined relative
to polystyrene standards. The potential aggregation behavior of
polymeric BODIPY dye in aqueous solution was determined by
dynamic light scattering (Coulter NP4 Plus, Beckman Coulter,
Fullerton, CA). UV spectra were taken on a Perkin Elmer
Lambda 35 UV/VIS spectrometer. Fluorescence spectra were
recorded on a Jobin Yvon Fluoromax-4 spectrofluorometer.
Fluorescence quantum yields of BODIPY dyes and polymers
were measured in methylene chloride, ethanol, acetone and
water/ethanol where applicable. Emission spectra for fluorescent
dyes were collected at 1 nm intervals using the appropriate
optimized wavelength with excitation and emission band widths
of 2 nm and 5 nm, respectively. Absorption spectra were
collected from 300 nm to 800 nm by diluting the same amount of
each polymer or BODIPY dye in methylene chloride, ethanol,
acetone and mixed solution of water and ethanol. Ethanol–water
dilution experiments were conducted by making 0.01 mg mLꢀ1
solutions of each polymer or BODIPY dye in the appropriate
ethanol–water dilution from 0% to 100% water, and absorption
and emission spectra of polymers were collected under the same
polymer concentrations. Fluorescein dye (fn ¼ 85% in 0.1 N
NaOH aqueous solution) was used as a standard to determine
the fluorescence quantum yields of BODIPY dyes 2, 8, 9, 16, 17,
and 18.18–21 Sulforhodamine 101 dye (fn ¼ 95% with excitation
wavelength at 577 nm in ethanol) was used as the fluorescence
standard to determine fluorescence quantum yields of BODIPY
dyes 5, 10, A and all polymeric BODIPY dyes.22 The corre-
sponding fluorescence spectrum for each sample was obtained
using the appropriate excitation wavelength (please see Table S1
in the ESI†). Both samples and reference dyes were prepared
under identical conditions and the absorption and emission
spectra were acquired under the same experimental conditions.
Experimental section
Instrumentation
1H NMR and 13C NMR spectra were acquired on a 400 MHz
Varian Unity Inova spectrophotometer instrument. Molecular
weights of the polymers were determined by gel permeation
chromatography (GPC) by using a Waters Associates Model
6000A liquid chromatography. Mobile phase was HPLC grade
THF that was filtered and degassed by vacuum filtration through
a 0.5 mm fluoropore filter prior to use. A Waters Model 440
ultraviolet absorbance detector at a wavelength of 254 nm and
a Waters Model 2410 refractive index detector were used to
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The areas for all emission spectra were calculated by integration
of peak and the corresponding absorbance was used to plot
graphs of integrated area vs. absorbance in Origin 8.0. Each plot
of integrated area vs. absorbance contained the corresponding
reference data at that wavelength as well as the data for the test
sample. A linear fit was then used to determine the slope of the
line (gradient) for the reference and the test sample. The
quantum yields of each sample were calculated using the
following equation:22
water. It displays an emission maximum at 697 nm, 697 nm and
722 nm in CH2Cl2, ethanol and water solution, respectively.
Polymer A
2,6-Diiodo-3,5-distyryl BODIPY dye 5 (180 mg, 0.07 mmol),
benzene-1,4-diboronic acid (13.3 mg, 0.077 mmol), Pd(dppf)2Cl2
(3.0 mg) and Na2CO3 (74 mg, 0.7 mmol) were added to a 50 mL
flask under a nitrogen atmosphere. When toluene (12 mL), EtOH
(4 mL) and H2O (6 mL) were added to the flask, the mixture was
ꢁ
Fx ¼ Fst(Gradx/Gradst)(h2x/hs2t)
stirred at 80 C under a nitrogen atmosphere for 2 days. After
removal of the solvent, the residue was dissolved in ethyl acetate
and washed with water twice. The organic layer was collected,
dried over anhydrous Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure and purified using a TLC
plate (hexane/CH2Cl2/EtOAc/MeOH, 5/3/1/1, v/v) to attain
Where the subscripts ‘st’ and ‘x’ stand for standard and test,
respectively, F is the fluorescence quantum yield, Grad repre-
sents the gradient from the plot of integrated fluorescence
intensity versus absorbance, and h is the refractive index of the
solvent.
1
polymer A as green oil (108 mg). H NMR (400 MHz, CDCl3):
d 7.52 (d, J ¼ 14.4, 2H), 7.29 (br, 4H), 7.23 (br, 2H), 7.00 (br,
2H), 6.90 (br, 2H), 6.72 (br, 2H), 6.61 (s, 2H), 6.54 (d, J ¼ 14.4,
2H), 4.15–4.04 (m, 6H), 3.96 (br, 2H), 3.57–3.43 (m, 112H), 3.32–
3.27 (m, 24H), 2.53–2.46 (m, 2H), 2.44–2.38 (m, 4H), 2.12–2.10
(m, 2H), 1.34 (br, 6H), 1.25 (t, J ¼ 7.6 Hz, 3H). IR (cmꢀ1): 2868,
1732, 1594, 1508, 1446, 1416, 1363, 1268, 1247, 1182, 1095, 1023,
963, 847, 767, 710. GPC (THF, polystyrene standard), Mn:
33 800 g molꢀ1; polydispersity: 1.8.
Materials
Unless otherwise indicated, all reagents and solvents were
obtained from commercial suppliers (Aldrich, Fluka, Acros,
Lancaster), and were used without further purification. Air- and
moisture-sensitive reactions were conducted in oven-dried
glassware using standard Schlenk line or drybox techniques
under an inert atmosphere of dry nitrogen. Compounds 2–4, 6–7,
11–14, and 16–18 were prepared and characterized according to
the literature.12,23–25
Polymer B
Polymer B was prepared according to the method for polymer A
1
by using BODIPY dye 5 and fluorene derivative. H NMR (400
2,6-Diiodo-3,5-distyryl BODIPY dye (5)
MHz, CDCl3): d 7.68 (br, 2H), 7.62 (br, 2H), 7.51 (br, 2H), 7.22
(br, 4H), 7.00 (br, 2H), 6.90 (br, 2H), 6.72 (br, 2H), 6.61 (s, 2H),
6.54 (d, J ¼ 14.4, 2H), 4.15–4.04 (m, 8H), 3.96 (br, 4H), 3.57–3.41
(m, 120H), 3.32–3.27 (m, 34H), 3.18 (br, 2H), 3.05 (br, 2H), 2.85
(br, 2H), 2.72 (br, 2H), 2.53–2.46 (m, 2H), 2.44–2.24 (m, 8H),
2.12–2.10 (m, 2H), 1.32 (br, 6H), 1.25 (t, J ¼ 7.6 Hz, 3H). IR
(cmꢀ1): 2869, 1732, 1575, 1594, 1508, 1448, 1362, 1268, 1247,
1176, 1099, 1019, 963, 849, 769, 711. GPC (THF, polystyrene
standard), Mn: 38 200 g molꢀ1; polydispersity: 1.7.
2,6-Diiodo-BODIPY dye (3) (261 mg, 0.37 mmol), and
compound 4 (1.0 g, 1.11 mmol) were refluxed in a mixture of
benzene (50 mL), piperidine (0.78 mL) and AcOH (0.67 mL) for
three and half an hours. Any water formed during the reaction
was removed azeotropically by heating the mixture in a Dean–
Stark apparatus. The mixture was concentrated in vacuo, diluted
with EtOAc (100 mL) and i-PrOH (50 mL), and washed with
aqueous 1 M HCl, saturated aqueous NaHCO3, and brine,
respectively. The organic phase was dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by silica
gel column chromatography (hexane/EtOAc/CH2Cl2/EtOH, 5/1/
3/1, v/v to hexane/acetone/CH2Cl2/EtOH, 5/1/3/1, v/v) to obtain
2,6-diiodo-3,5-distyryl BODIPY 5 (470 mg, 51%) as green
compound. 1H NMR (400 MHz, CDCl3): d 8.01 (d, J ¼ 16.8 Hz,
2H), 7.46 (d, J ¼ 16.8 Hz, 2H), 7.24 (dd, J ¼ 8.4, 1.6 Hz, 2H),
7.11 (d, J ¼ 8.4 Hz, 2H), 6.99–6.96 (m, 4H), 6.89 (d, J ¼ 8.8 Hz,
2H), 4.11 (q, J ¼ 7.2 Hz, 2H), 4.06–4.03 (m, 10H), 3.58–3.53 (m,
96H), 3.47–3.43 (m, 16H), 3.30 (s, 12H), 3.28 (s, 12H), 2.51 (t, J ¼
7.2 Hz, 2H), 2.42–2.36 (m, 4H), 2.13–2.09(m, 2H), 1.45 (s, 6H),
1.24–1.19(m, 3H). 13C NMR (100 MHz, CDCl3): d 173.2, 160.0,
150.6, 150.5, 149.2, 145.8, 139.6, 138.7, 133.5, 130.0, 129.8, 127.5,
120.5, 117.0, 115.5, 113.9, 113.7, 83.3, 72.1, 70.8, 70.7, 70.7, 70.6,
70.6, 69.5, 69.4, 67.3, 67.1, 60.7, 59.2, 40.2, 40.2, 30.9, 29.8, 24.8,
17.9, 14.4. IR (cmꢀ1): 2867, 1732, 1687, 1594, 1509, 1464, 1409,
1351, 1265, 1177, 1097, 1013, 959, 850, 807, 769, 711. HRMS
BODIPY dye A
2,6-Diiodo-3,5-distyryl BODIPY dye 5 (81 mg, 0.033 mmol),
phenylboronic acid (13 mg, 0.1 mmol), Pd(dppf)2Cl2 (1.2 mg) and
Na2CO3 (35 mg, 0.33 mmol) were added to a 50 mL flask under
a nitrogen atmosphere. When toluene (8 mL), EtOH (3 mL) and
H2O (4 mL) were added to the flask, the mixture was stirred at 80
ꢁC under a nitrogen atmosphere overnight. After removal of the
solvent, the residue was dissolved in ethyl acetate and washed with
water twice. The organic layer was collected, dried over anhy-
drous Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure and purified using a TLC plate (hexane/CH2Cl2/
EtOAc/MeOH, 5/3/1/0.7, v/v) to attain BODIPY dye A as green
oil (63 mg, 81%). 1H NMR (400 MHz, CDCl3): d 7.52 (d, J ¼ 16.4
Hz, 2H), 7.42–7.32 (m, 8H), 7.25–7.22 (m, 4H), 7.05 (dd, J ¼ 8.4,
1.6 Hz, 2H), 6.97 (d, J ¼ 8.4 Hz, 2H), 6.81 (d, J ¼ 8.4 Hz, 2H), 6.48
(d, J ¼ 1.6Hz, 2H), 6.44 (d, J ¼ 16.4 Hz, 2H), 4.12 (q, J ¼ 7.2 Hz,
2H), 4.04–3.99 (m, 6H), 3.92 (d, J ¼ 5.2 Hz, 4H), 3.61–3.48 (m,
112H), 3.33–3.32 (s ꢂ 2, 24H), 2.50 (t, J ¼ 7.2 Hz, 2H), 2.41–2.34
(m, 4H), 2.14–2.10 (m, 2H), 1.26 (s, 6H), 1.23 (t, J ¼ 5.4 Hz,
(MALDI) calcd for
C111H179BF2I2N2O39Na [M +
Na]+,
2490.0129; found, 2490.0188. It shows an absorption maximum
at 667 nm, 668 nm and 672 nm in CH2Cl2, ethanol and water,
respectively. It also exhibits a weak absorption peak at 628 nm in
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3H).13C NMR (100 MHz, CDCl3): d 173.3, 159.6, 150.2, 149.0,
139.6, 138.5, 135.6, 133.8, 133.7, 131.4, 130.7, 130.5, 130.0, 128.9,
128.5, 128.4, 128.1, 127.6, 120.0, 117.3, 115.3, 114.0, 113.6, 72.1,
70.8, 70.7, 70.6, 69.5, 67.3, 67.1, 60.7, 59.2, 40.3, 31.0, 24.8, 14.4,
12.9. IR (cmꢀ1): 2867, 1732, 1594, 1575, 1509, 1448, 1398, 1364,
1348, 1269, 1244, 1184, 1088, 1028, 1008, 995, 963, 847, 806, 773,
705. HRMS (MALDI) calcd for C123H189BF2N2NaO39 [M +
Na]+, 2368.3005; found, 2368.3052.
was dried over anhydrous Na2SO4, concentrated under reduced
pressure, and purified using a TLC plate (hexane/CH2Cl2/
EtOAc/MeOH, 5/3/1/1, v/v) to attain polymer D as green oil (18
mg). 1H NMR (400 MHz, CDCl3): d 7.52 (br, 2H), 7.31 (br, 4H),
7.08 (br, 2H), 6.91–6.67 (m, 5H), 6.59 (br, 4H), 4.15 (br, 2H), 4.06
(br, 4H), 3.96 (br, 4H), 3.84 (br, 4H), 3.57–3.22 (m, 164H), 2.41–
2.38 (m, 4H), 1.24 (s, 6H), 0.16 (br, around 12H).
Polymer E
Distyryl BODIPY dye (10)
2,5-Diiodo-23,5-distyryl BODIPY dye 5 (160 mg, 0.065 mmol),
compound 14 (70 mg, 0.078 mmol), CuI (1.2 mg), PdCl2(PPh3)2
(4.5 mg) and PPh3 (3.5 mg) were added to a 25 mL flask under
a nitrogen atmosphere. When THF (10 mL) and DIPEA (6 mL)
BODIPY dye 9 (500 mg, 0.557 mmol) and compound 4 (1.5 g,
1.67 mmol) were refluxed in a mixture of benzene (100 mL),
piperidine (1.2 mL) and AcOH (1.0 mL). Any water formed
during the reaction was removed azeotropically by heating the
mixture in a Dean-Stark apparatus. After 4 h, the mixture was
concentrated in vacuo, diluted with EtOAc (100 mL) and i-PrOH
(50 mL), and washed with water and brine, respectively. The
organic phase was dried over Na2SO4 and concentrated in vacuo.
The crude product was purified by silica gel column chroma-
tography (hexane/EtOAc/CH2Cl2/EtOH, 5/1/3/1, v/v to hexane/
acetone/CH2Cl2/EtOH, 5/1/3/1, v/v) to obtain distyryl BODIPY
ꢁ
were added to the flask, the mixture was stirred at 72 C under
a nitrogen atmosphere for 2 days. After removal of the solvent,
the residue was dissolved in CH2Cl2 and washed with water
twice. The organic layer was collected, dried over anhydrous
Na2SO4, and filtered. Then the filtrate was concentrated under
reduced pressure and then washed two times using Et2O (40 mL)
under ultrasound condition. The crude residue was then dis-
solved in methylene chloride (3 mL) and Et2O (30 mL) was added
dropwise to the solution under stirring conditions. The mixture
was left unperturbed for half an hour and the polymer that
precipitated as solid was collected. The operation was repeated
three times and the precipitated solid was dried under vacuum to
1
10 (210 mg, 14%) as green oil. H NMR (400 MHz, CDCl3):
d 7.97 (d, J ¼ 16.8 Hz, 2H), 7.43 (d, J ¼ 16.8 Hz, 2H), 7.22 (d, J ¼
8.4 Hz, 2H), 6.96–6.85 (m, 5H), 6.55 (s, 2H), 4.12 (s, 2H), 4.03–
4.01 (m, 10H), 3.83 (d, J ¼ 3.6 Hz, 2H), 3.84–3.37 (m, 132H),
3.30–3.21 (m, 32H), 2.38–2.35 (m, 4H), 1.51 (s, 6H). 13C NMR
(100 MHz, CDCl3): d 161.6, 157.1, 150.6, 150.0, 149.2, 145.5,
139.4, 136.2, 133.8, 130.4, 130.1, 120.4, 117.1, 116.9, 113.9, 113.7,
106.6, 100.7, 82.8, 72.1, 71.9, 71.1, 71.0, 70.8, 70.8, 70.7, 70.6,
70.6, 70.4, 69.8, 69.5, 69.4, 69.1, 67.9, 67.3, 67.1, 59.2, 59.1, 59.0,
40.3, 40.2, 17.2. IR (cmꢀ1): 2868, 1595, 1578, 1510, 1464, 1409,
1350, 1304, 1259, 1180, 1093, 1011, 960, 848, 806, 711. HRMS
1
obtain polymer E as green solid (132 mg). H NMR (400 MHz,
CDCl3): d 8.35 (br, 2H), 7.52 (br, 2H), 7.24 (br, 2H), 7.19 (br,
2H), 6.91 (br, 2H), 6.87 (br, 2H), 4.42 (br, 2H), 4.15–4.13 (m,
2H), 4.05 (br, 10H), 3.60–3.50 (m, 168H), 3.32–3.30 (m, 36H),
2.54 (br, 2H), 2.40 (br, 4H), 2.15–2.12 (m, 2H), 1.61 (br, 6H), 1.25
(br, 3H). IR (cmꢀ1): 2868, 1732, 1594, 1509, 1481, 1412, 1350,
1269, 1247, 1189, 1097, 1027, 850, 760, 730, 710. GPC (THF,
polystyrene standard), Mn: 42 200 g molꢀ1; polydispersity: 2.0.
(MALDI) calcd for
C119H197BF2I2N2NaO44 [M +
Na]+,
2684.1284; found, 2684.1326. It exhibits an absorption maximum
at 670 nm, 669 nm and 669 nm in CH2Cl2, ethanol and water,
respectively. It also displays a weak absorption peak at 623 nm in
water. It shows an emission maximum at 698 nm, 698 nm and 698
nm in CH2Cl2, ethanol and water solution, respectively.
Polymer F
Polymer F was prepared according to the method employed to
prepare polymer E by using BODIPY dye 5 and compound 18.
1H NMR (400 MHz, CDCl3): d 8.16 (d, J ¼ 15.2 Hz, 2H), 7.55 (d,
J ¼ 15.2 Hz, 2H), 7.24 (br, 2H), 7.14 (br, 2H), 6.97 (br, 6H), 6.91
(br, 2H), 6.73 (br, 2H), 4.15–4.13 (m, 2H), 4.05 (br, 8H), 3.94 (br,
2H), 3.60–3.50 (m, 168H), 3.32–3.30 (m, 36H), 2.62 (br, 6H), 2.51
(br, 2H), 2.42 (br, 6H), 2.13 (br, 2H), 1.55 (s, 12H), 1.25 (t, J ¼
5.4 Hz, 3H). IR (cmꢀ1): 2870, 1732, 1511, 1468, 1363, 1311, 1240,
1183, 1093, 1007, 851, 761, 710. GPC (THF, polystyrene stan-
dard), Mn: 40 500 g molꢀ1; polydispersity: 2.0.
Polymer C
Polymer C was prepared according to the method for polymer A
by using BODIPY dye 10.1H NMR (400 MHz, CDCl3): d 7.52
(br, 2H), 7.31 (br, 4H), 7.08 (br, 2H), 6.91–6.67 (m, 5H), 6.59 (br,
4H), 4.15 (br, 2H), 4.06 (br, 4H), 3.96 (br, 4H), 3.84 (br, 4H),
3.57–3.22 (m, 164H), 2.41–2.38 (m, 4H), 1.23 (s, 6H). IR (cmꢀ1):
2870, 1610, 1509, 1449, 1270, 1186, 1102, 1023, 849, 710, 667.
GPC (THF, polystyrene standard), Mn: 34 200 g molꢀ1; poly-
dispersity: 1.8.
Results and discussion
Synthesis and characterization of the BODIPY monomeric and
polymeric dyes
Polymer D
To a solution of trimethylsilylacetylene (0.6 mL) in anhydrous
THF (2 mL) was added ethylmagnesium bromide (0.5 mL). The
mixture was heated at 60 ꢁC during 2 hours, cooled down to
room temperature, and was added a solution of polymer C (20
mg) in anhydrous THF (2 mL). The mixture was stirred at 60 ꢁC
overnight. Water was added (10 mL) to the mixture, and the
mixed solution was extracted with CH2Cl2. The organic layer
We hypothesized that the use of highly hydrophilic branched
oligo(ethylene glycol)methyl ether residues as the polymer side
chains and effective prevention of strong stacking p–p interac-
tions among the polymer backbones would facilitate water
solubility of neutral near-infrared emissive polymeric BODIPY
dyes. In order to test our hypothesis, we chose previously
reported BODIPY dye with an ethyl phenoxybutanoate side
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Scheme 2 Synthetic route to highly water-soluble near-infrared emissive BODIPY polymeric dyes (polymers A and B).
chain instead of phenoxy-n-alkyl one for its hydrophilic feature.
We anticipate future potential use of the ester-functionalized side
chains as cell-trappable biosensors, although a wide variety of
aryl groups could be introduced to monomeric BODIPY dye at
the meso-position. Scheme 2 outlines the synthetic approach to
prepare highly water-soluble near-infrared emissive polymeric
BODIPY dyes. We introduced hydrophilic branched oligo
(ethylene glycol)methyl ether residues to BODIPY dye 3 at 3,5-
positions via the Knoevenagel reaction to prepare highly water-
soluble neutral BODIPY monomeric dye. 1,3,5,7-Tetramethyl-
BODIPY dye 2 was obtained by the condensation of ethyl 4-(4-
formylphenoxy)butanoate (1) with 2,4-dimethylpyrrole in the
presence of a catalytic amount of TFA, followed by oxidation
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and
chelation with BF3-etherate in the presence of N,N-diisopropy-
lethylamine (DIPEA) (Scheme 2). 2,6-Diiodo-BODIPY mono-
mer 3 was obtained by iodization of BODIPY dye 2 in mixed
solution of ethanol, THF, and water in the presence of iodine and
iodic acid. 2,6-Diiodo-3,5-distyryl-BODIPY monomeric dye 5
was prepared by condensation of methyl groups of BODIPY dye
3 at 3,5-positions with aldehyde derivative 4.4 Polymeric BOD-
IPY dyes (polymers A and B) were prepared using palladium-
Scheme 3 Synthetic route to a highly water-soluble neutral BODIPY dye (A).
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Fig. 1 1H NMR spectra of monomeric BODIPY dyes 5 and A, and polymer A in CDCl3 solution.
catalyzed Suzuki coupling reaction of 2,6-diiodo-3,5-distyryl-
BODIPY monomeric dye 5 with 1,4-phenyldiboronic acid and
2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,9-di[1-[2-
(2-methoxyethoxy)ethoxy]ethyl]fluorene in a mixed solution of
toluene, ethanol, and water for two days, respectively. Polymers
A and B readily dissolve not only in common organic solvents
such as THF, CH2Cl2, CHCl3, ethanol, acetone, ethyl acetate,
DMF, and DMSO, but also in water. Excellent water solubility
(at least 20 mg mLꢀ1) of polymers A and B arises from weak p–p
stacking interactions among polymer backbones, and highly
hydrophilic character of branched oligo(ethylene glycol)methyl
ether side chains on BODIPY cores at 3,5-positions. The weak
p–p stacking interactions among polymer backbones arise from
steric hindrance of protons of co-monomeric phenylene and
fluorene units with methyl groups at 1,7-positions, and vinyl
protons at 3,5-positions of BODIPY monomeric cores, causing
co-monomeric phenylene, and fluorene units perpendicular to
BODIPY monomeric cores. Please see the ESI† for additional 1H
NMR spectra and fluorescence spectra of polymeric and BOD-
IPY dyes.
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1
In order to compare the optical property and H NMR spec-
6.97 ppm, respectively. Other proton peaks of BODIPY dye 5 do
not undergo significant changes in chemical shifts after the
palladium-catalyzed Suzuki reaction. Chemical shifts similar to
BODIPY dye A were also observed in polymer A.
trum of polymer A, we prepared BODIPY dye A by replacing
two iodo groups at 2,6-positions of BODIPY monomeric dye 5
with two phenyl groups via palladium-catalyzed Suzuki reaction
of 1-phenylboronic acid with 2,6-diiodo-3,5-distyryl-BODIPY
monomeric dye 5 (Scheme 3). BODIPY dye A has still good
solubility with at least 20 mg mLꢀ1 in aqueous solution even
though two hydrophobic phenyl groups were introduced to
BODIPY dye 5 at 2,6-positions. The steric interactions of
protons from phenyl groups with methyl groups at 1,7-positions
and protons from vinyl groups at 3,5-positions restrict rotation
between phenyl groups at 2,6-positions and the BODIPY core
that can help reduce some p–p interactions among hydrophobic
BODIPY cores in aqueous solution.
We hypothesized that use of an ortho-substituent group of
branched oligo(ethylene glycol)methyl ether residues to phenyl
rings of BODIPY cores at the meso positions, and replacement of
fluorine subunits of BODIPY cores at 4,40-positions by ethynyl
subunits would help reduce p–p stacking interactions among the
polymer backbones to enhance the water solubility of BODIPY
polymeric dyes. We prepared polymer C by the palladium-
catalyzed Suzuki polymerization of 1,4-phenyldiboronic acid
with highly water-soluble 2,6-diiodo-3,5-distyryl-BODIPY dye
bearing an ortho-substituent group of tri(ethylene glycol)methyl
ether to the phenyl ring of the BODIPY core at the meso position
(10), and partially replaced fluorine subunits of BODIPY cores at
4,40-positions of polymer C with ethynyl subunits, resulting in E-
BODIPY polymeric dye (polymer D) (Scheme 4). A 66% degree
of postpolymerization functionalization was estimated from the
1H NMR spectra by comparing methyl peak area from the
ethynyl subunits to methyl peak area of BODIPY cores at 1,7-
positions. Both polymers C and D are highly soluble with at least
20 mg mLꢀ1 in aqueous solution. 2,6-Diiodo-BODIPY mono-
meric dye 10 was prepared in a similar way to synthesize BOD-
IPY monomeric dye (5) in Schemes 2 and 4.
After palladium-catalyzed Suzuki reaction, 2,6-diiodo-3,5-
distyryl-BODIPY monomeric dye 5 with 1-phenylboronic acid
for BODIPY dye A, doublet peaks at 8.01 ppm corresponding to
vinyl protons at 16-positions in BODIPY dye 5 shift to 6.54 ppm
in BODIPY dye A (Fig. 1). This is because the vinyl protons in
BOIDPY dye A are in the shielding zone of the phenyl substit-
uents at 2,6-positions and experience a shielding by 1.47 ppm.
Peaks between 6.99 and 6.96 ppm corresponding to phenyl
protons at the 17-positions in BODIPY dye 5 also move down-
field to 6.61 ppm in BODIPY dye A because the phenyl protons
at the 10-positions in BODIPY dye A are in the shielding zone of
the phenyl substituents at 2,6-positions. The peaks around 4.06–
4.03 ppm corresponding to the methylene groups at the 20-
positions in BODIPY dye 5 shift to high field at 3.96 ppm in
BODIPY dye A. Methyl protons at 1,7-positions of BODIPY
dye 5 shift to high field by 0.2 ppm after polymerization. Proton
peaks at 6.89 ppm and 7.11 ppm corresponding to the meso
phenyl protons at 9,10-positions shift downfield to 6.81 ppm and
For comparison purposes, we prepared polymers E and F by
palladium-catalyzed Sonogashira polymerization of highly
water-soluble 2,6-diiodo-3,5-distyryl-BODIPY dye 5 with highly
water-soluble 1,4-diethynylbenzene 14 and 2,6-diethynyl BOD-
IPY dye 18 bearing branched oligo(ethylene glycol)methyl ether
residues, respectively (Schemes 5 and 6). Co-monomers 14 and 18
were prepared and characterized according to reported
Scheme 4 Synthetic route to highly water-soluble BODIPY polymeric dyes (polymers C and D).
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Scheme 5 Synthetic route to a near-infrared emissive polymeric BODIPY dye (polymer E).
procedures (Schemes 5 and 6). Strong p–p stacking interactions
among rigid hydrophobic polymer backbones in aqueous solu-
tion make polymer E poorly soluble (0.1 mg mLꢀ1 in aqueous
solution) and polymer F almost insoluble in aqueous solution
even though additional branched oligo(ethylene glycol)methyl
ether residues were introduced to 1,4-diethynylbenzene and 2,6-
diethynyl-BODIPY co-monomers. Polymers E and F are soluble
in common organic solvents such as acetone, ethyl acetate,
methylene chloride, chloroform, dimethyl sulfoxide, and
dimethylformamide.
due to partial dye aggregation in aqueous solution although both
show relatively weak p–p stacking interactions among polymer
backbones. Another possibility is radiationless deactivation from
excited states of the polymers having pronounced intramolecular
charge transfer (ICT) character between the strong electron
donor (distyryl push moieties) and the electron accepting abilities
of the BODIPY (pull moieties) in significantly enhanced polar
solvents (H2O) since all polymer backbones including BODIPY
cores are non-polar and hydrophobic.26 In order to test our
hypothesis, we measured absorption and emission spectra of
polymers A–D in ethanol with the presence of different amounts
of water. An increase of water ratio to ethanol causes slight red
shifts in absorption and emission of the polymers (Fig. 2, S28,
S32 and S36 in the ESI†) and results in quenching of the poly-
mers. However, light scattering experiments did not show any
testable polymer aggregated nanoparticles. This suggests that
ICT may be responsible for fluorescence quenching of the poly-
mers A–D in aqueous solution.
Optical properties of the BODIPY monomeric and polymeric
dyes
2,6-Diiodo-3,5-distyryl BODIPY dyes bearing branched oligo
(ethylene glycol)methyl ether residue 5 is highly water-soluble
with low fluorescence quantum yield of less than 0.1%. Its low
fluorescence quantum yield arises from an efficient intersystem
crossing induced by the heavy atom effect of iodine and potential
dye aggregation in aqueous solution as the BODIPY dye shows
red shifts by 5 nm in absorption and emission from methylene
chloride to aqueous solution. Near-infrared emissive polymers
A–D show relatively high fluorescence quantum yields from 9.7%
to 14.5% in ethanol solution. However, they display much lower
fluorescence quantum yields from 0.9% to 1.8% in aqueous
solution (Table 1). This may result from self-quenching possibly
Even though two hydrophobic phenyl groups were introduced
to BODIPY dye 5 at the 2,6-positions to synthesize BODIPY dye
A, it is still highly water-soluble. Although BODIPY dye A shows
a high fluorescence quantum yield of 31.0% in ethanol, it shows
the same low fluorescence quantum yield of 3.3% in aqueous
solution as polymer A. This may again arise from the intra-
molecular charge transfer (ICT) in aqueous solution as its
absorption and emission spectra show slightly red shifts when the
Scheme 6 Synthetic route to a near-infrared emissive polymeric BODIPY dye (polymer F).
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Table 1 Absorption and emission peaks, and fluorescence quantum
yields of BODIPY dyes and polymers in methylene chloride, ethanol, and
aqueous solution.
BODIPY cores through single bond connections. However, the
poor p-conjugation of polymers A and B facilitates strong water
solubility of the polymers because of the relatively weak p–p
stacking interactions among polymer backbones with the pres-
ence of highly hydrophilic branched oligo(ethylene glycol)methyl
ether side chains that effectively enhances enthalpic interactions
of the copolymeric BODIPY dyes with water and significantly
increases water solubility of the polymers.
BODIPY
dye
Absorption
peak/nm
Emission
peak/nm
Fluorescence
quantum yield
Solvent
CH2Cl2
BODIPY
dye 2
501 (ref. 12)
510 (ref. 12) 76% (ref. 12)
BODIPY
dye 5
667
668
628, 672
697
697
722
696
696
708
685
681
709
684
682
691
688
687
693
685
685
693
718
719
730
510
1.3%
1.2%
<0.1%
9.1%
9.7%
1.8%
13.9%
14.5%
1.8%
39.3%
31.0%
3.3%
11.3%
11.9%
0.9%
8.9%
11.7%
0.9%
5.1%
7.2%
0.5%
4.3%
CH2Cl2
Ethanol
Water
CH2Cl2
Ethanol
Water
CH2Cl2
Ethanol
Water
CH2Cl2
Ethanol
Water
CH2Cl2
Ethanol
Water
CH2Cl2
Ethanol
Water
CH2Cl2
Ethanol
Water
Use of the ortho-substituent groups of tri(ethylene glycol)
methyl ether to the phenyl rings of BODIPY cores at the meso
positions does not improve the fluorescence quantum yield of
BODIPY polymeric dye (polymer C) in aqueous solution,
although it facilitates water solubility of polymer C by preventing
strong p–p stacking interactions among the polymer backbones
in aqueous solution. Polymer C shows slightly red shifts by 7 nm
and 6 nm in absorption and emission from ethanol to aqueous
solution, respectively (Table 1, and Fig. S34 and S35 in the ESI†).
We partially replaced fluorine subunits of BODIPY cores at 4,40-
positions of polymer C with ethynyl subunits, resulting in highly
water-soluble E-BODIPY polymeric dye (polymer D) as the
bulky ethynyl subunits at 4,40-positions may help prevent strong
p–p stacking interactions among the polymer backbones.
However, this approach does not enhance the fluorescence
quantum yield of polymer D, which displays red shifts by 5 nm
and 8 nm in absorption and emission from ethanol to aqueous
solution, respectively (Table 1, and Fig. S36 in the ESI†).
Polymer E is slightly soluble with 0.1 mg mLꢀ1 in aqueous
solution while polymer F is nearly insoluble in aqueous solution
(less than 0.05 mg mLꢀ1) with low solubility in ethanol (less than
1 mg mLꢀ1). Poor solubility of polymers E and F in aqueous
solution arise from strong p–p stacking interactions among the
polymer backbones because of their significantly extended p-
conjugation backbones leading to their absorption and emissions
at significantly longer wavelengths than polymers A–D in
methylene chloride solution (Table 1). Polymer E shows a very
low fluorescence quantum yield of 0.5% in aqueous solution with
absorption peak at 711 nm and emission peak at 730 nm. In
addition, polymer F displays a low fluorescence quantum yield of
2.0%, even in methylene chloride solution, with absorption peaks
at 635 nm and 719 nm, and emission peak at 740 nm (please see
Fig. S47 in the ESI†). Polymer F shows significant red shifts by 31
nm and 41 nm in absorption and emission spectra from methy-
lene chloride to aqueous solution, respectively, which indicates
that polymer F may be aggregated in aqueous solution (Fig. 4).
Polymer A 683
684
688
Polymer B 666, 621
664
671
663, 613
661, 610
662, 619
BODIPY
dye A
Polymer C 674, 616
672, 618
679, 621
Polymer D 673, 617
672, 617
677, 621
Polymer E 700
704
711
BODIPY
dye 16
499
533
536
Water
BODIPY
dye 17
BODIPY
dye 18
550
555
1.2%
1.8%
Water
Water
Polymer F 719, 635
733, 687
750, 700
740
758
781
513
2.0%
1.5%
0.3%
92%
CH2Cl2
Acetone
Water
BODIPY
dye 8
504
CH2Cl2
BODIPY
dye 9
535
546
3.5%
CH2Cl2
BODIPY
dye 10
670
669
623, 669
698
698
698
1.8%
1.0%
0.1%
CH2Cl2
Ethanol
Water
water ratio is increased in comparison to ethanol (Fig. 3).26 When
compared with BODIPY dye A, polymers A and B display
a slightly red shift by only 17 nm and 18 nm in emission in
aqueous solution, respectively (Table 1, and Fig. S27 and S31 in
the ESI†). This indicates that the polymer conjugation must be
weak, and phenyl and fluorene units are not well conjugated with
Fig. 2 Absorption (a) and emission spectra (b) of polymer A in ethanol solution with different amounts of water.
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Fig. 3 Absorption (a) and emission spectra (b) of BODIPY dye A in ethanol solution with different amounts of water.
Fund of Michigan (contract number: 06-1-P1-0283), and
National Science Foundation (to H.Y. Liu) and the ALS
Therapy Alliance (to A. Tiwari). We would like to acknowledge
reviewers’ invaluable comments on the manuscript.
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Acknowledgements
This work was supported by grants from NIH SBIR grant
(contract number: 1R43CA134039-01), the 21st Century Jobs
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