Synthesis and optical properties of tetraphenylmethane-based tetrahedral fluorescent compounds and their water-soluble PEG-linked polymers

Article abstract of DOI:10.1016/j.tetlet.2004.01.004

The synthesis and optical properties of tetrahedral fluorescent compounds comprising of tetraphenylmethane as the core and oligothiophenes as the chromophoric arms, and their water-soluble poly(ethylene glycol)-linked polymers are reported.

Full text of DOI:10.1016/j.tetlet.2004.01.004

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1593–1597
Synthesis and optical properties of tetraphenylmethane-based
tetrahedral fluorescent compounds and their water-soluble
PEG-linked polymers
Xue-Ming Liu, Chaobin He* and Jian-Wei Xu
Institute of Materials Research and Engineering, National University of Singapore, 3 Research Link, Singapore 117602, Singapore
Received 8 October 2003; revised 22 November 2003; accepted 5 January 2004
Abstract—The synthesis and optical properties of tetrahedral fluorescent compounds comprising of tetraphenylmethane as the core
and oligothiophenes as the chromophoric arms, and their water-soluble poly(ethylene glycol)-linked polymers are reported.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Tetrahedral organic compounds have attracted much
attention in the areas of chemistry and material sciences.
They have been investigated as light-emitting materials,1
electronically active materials,2 and as a molecular cal-
trop in scanning probe microscopy, etc.3 To date, most
tetrahedral light-emitting organic compounds have been
made from a tetraphenylmethane core, and several
chromophores such as vinylstilbene,1c triphenylethene,1c
and oxadiazolyl4 have been conjugated with the core. In
addition, water-soluble fluorescent tetrahedral and
dendritic materials derived from tetraphenylmethane
have drawn attention in the area of diagnostics and
sensoring.5 We herein report a novel class of tetrahedral
fluorescent organic compounds prepared from C(p-
C6H4Br)4 and oligothiophenes by Grignard and Suzuki
coupling reactions. We chose a-oligothiophenes as
fluorescent side arms in view of their well-established
optical and electronic properties,6 and their reactive
a-carbon sites that are useful handles for further structural
modification. The tetraphenylmethane–oligothiophene
fluorophores were conjugated with poly(ethylene glycol)
(PEG) to synthesize further water-soluble fluorescent
polymers. Such polymers with the tetrahedral hydro-
phobic fluorescent core being blocked by hydrophilic
PEG arms have shown good water solubility and mini-
mized aggregation in aqueous media.
The synthesis of compounds 1–9 is shown in Scheme 1.
All the newly synthesized compounds were fully char-
acterized.7 Firstly, the classic Grignard coupling method
was employed to synthesize the precursor compounds.
Compound 1 was obtained as a major product in 38%
yield. In addition, the di-substituted by-product 8 was
1
also isolated in 10% yield. The H NMR spectrum of 1
in CDCl3 exhibited one doublet–doublet (dd) signal at d
7.07 (3JHHa ¼ 3JHHb ¼ 3:6 Hz, b-H of thienyl), and a
doublet signal at d 7.54 (3JHH ¼ 8:4 Hz, phenyl-H). The
1H NMR spectrum of 8 in CDCl3 showed a well-
resolved dd signal (b-H of thienyl) and six doublet
signals (thienyl-H and Ph-H). The Grignard coupling
between C(p-C6H4Br)4 and 2,20-bithiophene-5-MgBr
gave 2 and a tri-substituted by-product 9 in 10% and 5%
yields, respectively. When a higher excess of the
Grignard reagent was used, 9 was still obtained and the
yields of both products were not changed significantly.
1
The H NMR spectrum of 2 in CDCl3 exhibited a dd
A general procedure for the Grignard coupling reactions. The
a-bromo-oligothiophene (12 mmol) dissolved in 50 mL of dry THF
was added dropwise into a magnesium (0.35 g, 14.4 mmol) suspen-
sion in dry THF (10 mL). After the addition, the reaction mixture
was heated at 65 ꢁC for 1 h. The Grignard solution was then added to
a mixture of C(p-C6H4Br)4 (1.0 g, 1.6 mmol) and [NiCl2(dppp)]
(50 mg) in 20 mL of THF. After being heated at 85 ꢁC for 3 days, the
solvent was removed and the residue was re-dissolved in dichloro-
methane. The dichloromethane solution was washed with a saturated
aqueous NH4Cl solution and dried (MgSO4). The crude product was
purified by silica gel column chromatography (first with hexanes,
then with hexanes/ethyl acetate 8:1) to give compounds 1, 2, 8, and 9
as light yellow solids in 5–38% yields.
Keywords: Tetrahedral material; Tetraphenylmethane; Oligothio-
phenes; Fluorescence.
* Corresponding author. Tel.: +65-68748145; fax: +65-68727528;
e-mail: cb-he@imre.a-star.edu.sg
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.004

1594
X.-M. Liu et al. / Tetrahedron Letters 45 (2004) 1593–1597
H
S
Br
C
H
MgBr
n
S
H
C
[NiCl2(dppp)]/THF
n
S
Br
or
H
B(OH)
2
S
n
Br
S
n
H
S
[Pd(PPh3)4]/
Br
toluene:K2CO3(2M aq.) 3 : 2
H
1 n = 1
2 n = 2
3 n = 3
1 n-BuLi/THF
2 CO2
3 H3O+
CO2H
S
CO2PEG
S
CO2H
C
CO2PEG
C
S
n
PEG/DCC
S
n
THF, refluxing
S
S
n
HO2C
n
PEGO2C
S
S
CO2H
CO2PEG
4 n = 2
5 n = 3
6 n = 2
7 n = 3
Br
C
Br
C
H
H
2
S
S
S
S
H
Br
2
H
S
H
8
9
Scheme 1.
3
3
signal at d 7.03 (3JHHa ¼ 3:6 Hz, JHHb ¼ 5:2 Hz, Hb of
bithienyl), and two doublet signals from the two sets of
Ph-H. The 1H NMR spectrum of 9 in acetone-d6 showed
3:6 Hz, JHHb ¼ 5:2 Hz, Hb of terthienyl), and two dou-
blet signals at d 7.39 (3JHH ¼ 7:6 Hz) and 7.60 (3JHH
¼
7:6 Hz), which were unambiguously assigned to the two
sets of Ph-H from the tetraphenylmethane unit.
two doublets at d 7.34 (3JHH ¼ 8:4 Hz) and 7.44 (3JHH
¼
8:8 Hz) in a ratio of 3:1, which are assigned to the two
kinds of phenyl groups of the core. Attempts to syn-
thesize 3 by the Grignard coupling method were not
successful even when a higher temperature and a longer
reaction time were used, and may be due to the difficulty
in forming the Grignard reagent of terthiophene.8
Alternatively, the Suzuki coupling method was
employed to prepare the precursor compounds 1–3 in
improved yields.à The 1H NMR spectrum of 3 in CDCl3
Compounds 2 and 3 showed maximum emission wave-
lengths in the visible spectral area, and so they were
converted to the corresponding carboxylic acids 4 and 5
by deprotonation of the a-protons of the thiophene
moieties and subsequent reactions with carbon diox-
ide.9; The IR spectra of 4 and 5 exhibited the charac-
teristic absorptions of –COOH at m (cmꢀ1): 3417, 1665,
§
exhibited characteristic dd signal at d 7.03 (3JHHa
¼
§
A general procedure for the synthesis of 4 and 5. Compound 2 or 3
(0.4 mmol) was dissolved in 30 mL of THF and was cooled to )70 ꢁC.
The n-BuLi/n-hexane solution (1.6 M, 0.5 mmol) was added to the
above solution dropwise through a syringe. The reaction mixture was
stirred for 2 h, during this period precipitates appeared. The mixture
was then bubbled with dry CO2 for 10 min, and a precipitate formed
immediately. The mixture was then allowed warm to r.t. and was
stirred for 1 h. The resultant suspension was acidified with 1 M HCl
to give a clear yellow solution. The organic layer was separated. The
aqueous layer was extracted with dichloromethane three times. The
combined organic layer was washed with water and dried (Mg2SO4).
Removal of the solvent gave the desired products as yellow solids.
The products were used directly without further purification.
à
A general procedure for the Suzuki coupling reactions. The C(p-
C6H4Br)4 (0.4 g, 0.6 mmol), oligothiophene-a-B(OH)2 (3.0 mmol)
and [Pd(PPh3)4] (72 mg, 0.06 mmol) were dissolved in 20 mL of
toluene and 32 mL of 2 M K2CO3 (aqueous). The mixture was
degassed by bubbling with nitrogen for 15 min and then refluxed for
three days under nitrogen. Upon completion, the reaction mixture
was diluted with 100 mL dichloromethane, the organic layer was
isolated and was washed with water, then dried (Mg2SO4). The crude
products 1–3 were purified by silica gel column chromatography as
described in the Grignard coupling method and were obtained as
light yellow solids in 40%, 25% and 20% yield, respectively.

X.-M. Liu et al. / Tetrahedron Letters 45 (2004) 1593–1597
1595
and 3432, 1661, respectively. Unlike similar tetrahedral
compounds derived from tetraphenylmethane,1d;4 com-
pounds 1–5, 8, and 9 did not show any glass transitions
as revealed by differential scanning calorimetry studies.
Interestingly, 2 exhibited a much higher melting point
than 1 and 3. Finally, reaction of 4 and 5 with excess
PEG using dicyclohexylcarbodiimide (DCC) as a dehy-
drating agent and 4-(dimethylamino)pyridinium p-tolu-
enesulfonate (DAPT) as a catalyst, yielded polymers 6
–
and 7 in good yields, following a literature method.10;
The products were purified efficiently by ultra-filtration
and were obtained as yellow semi-solids. The polymers
were very soluble in both common organic solvents and
Figure 1. Electronic absorption spectra of tetrahedral organic prod-
ucts in THF.
1
water. The H NMR spectra of 6 and 7 in acetone-d6
exhibited singlet signals due to PEG-H at d 3.60 and
3.70, respectively. The aromatic signals of the polymers
exhibited similar patterns to the starting compounds 4
and 5, indicating successful reactions of all the four
carboxylic groups with PEG and the near symmetrical
structures of both polymers. The complete esterification
of all the carboxylic groups by PEG was proved further
by the integration ratio of PEG-H to aromatic-H. The
IR spectra of 6 and 7 exhibited characteristic strong
absorptions at 1097 and 1099 cmꢀ1 ðmCAOACÞ, respec-
tively.
The UV–vis and fluorescence spectra of 1–5, 8, and 9 in
THF are shown in Figures 1 and 2, respectively. A
summary of their optical properties is given in Table 1.
All the compounds exhibit two absorption bands, which
are assigned in terms of the strong absorption band at
longer wavelength being associated with the p ! pꢁ
electron transfer of the entire chromophore, and the less
intense band with the p ! pꢁ local excitation of the
hetero-nucleus.11 The UV absorptions of the present
tetrahedral compounds show a significant red shift rel-
ative to their parent oligothiophene chromophores,11
due to conjugation involving the phenyl groups and a
possible weak hyperconjugation within the tetrahedral
molecules. As expected, the long wavelength p ! pꢁ
absorptions show a red shift with the increase of the
conjugation length of oligothiophene arms. Except for
the two derivatives of thiophene (1 and 8), compounds
2–5 and 9 emit bright indigo-blue light. A red shift of the
maximum emission wavelength is also observed with the
increase of the conjugation length of the oligothiophene
arms.
Figure 2. Fluorescence spectra of tetrahedral organic products in
THF.
Table 1. Optical properties of the tetrahedral organic compoundsa
kmax (nm)
kmax (nm)
Emission
Quantum
yield (%)
Absorption
e (Mꢀ1 cmꢀ1) · 104
1
2
3
4
5
8
9
298, 239
356, 248
383, 244
375, 235
395, 250
297, 239
364, 236
5.1, 2.8
11.2, 4.2
12.5, 5.7
6.2, 3.2
11.0, 5.1
3.1, 2.2
4.2, 3.5
360
426
0.6
1.4
2.7
2.5
4.5
1.5
5.5
467 (447)
447
478
358
450 (475)
a Data were determined in THF with concentrations of 1 · 10ꢀ5 M. The
emission spectra were taken by excitation at their longest wavelength
absorption maximum.
Figure 3 shows the UV–vis and fluorescence spectra of
polymer 6 in different organic solvents and water. A
summary of the optical properties of 6 and 7 in different
solvents is given in Table 2. The polymers 6 and 7
–
A general procedure for the synthesis of 6 and 7. Compound 4 or 5
(0.1 g), PEG (Mn 1000, 1.0 g), DAPT (15 mg) and DCC (0.2 g) were
dissolved in freshly dried THF (30 mL). The reaction mixture was
refluxed under nitrogen for 16 h. Upon completion, the reaction
mixture was filtered and the clear filtrate was concentrated to
dryness. The crude product was dissolved in 10 mL DMF and
dialyzed against water for 72 h using a dialysis bag with a molecular
weight cut-off of 2000 (Sigma D-7884). The obtained yellow aqueous
solution was again filtered with a 0.2 lm sized syringe filter. Removal
of water afforded the product as yellow semi-solids.
Figure 3. Electronic and fluorescence emission spectra of polymer 6 in
organic solvents and water.

1596
X.-M. Liu et al. / Tetrahedron Letters 45 (2004) 1593–1597
Table 2. Optical properties of polymers 6 and 7a
Solvent
6
7
kmax (nm) absorption kmax (nm) emission Quantum yield (%) kmax (nm) absorption kmax (nm) emission Quantum yield (%)
THF
378, 234
380, 238
378
455
471
466
514
15.4
15.9
14.1
3.2
392, 287, 235
396, 289, 238
393, 285
472
477
479
531
34.1
31.0
30.7
3.5
CHCl3
EtOH
H2O
375
392, 284
Size (nm)b
13.1 5.1 (polydispersity 0.49)
13.3 5.0 (polydispersity 0.45)
a Data were determined with concentrations of 1 · 10ꢀ4 M. The emission spectra were taken by excitation at their longest wavelength absorption
maximum.
b The average sizes of aggregates were determined in aqueous media.
exhibit similar maximum absorption wavelengths and
maximum emission wavelengths in all the organic sol-
vents tried. Unlike other PEG-linked fluorescent com-
pounds,12 the present PEG-linked tetrahedral
luminescent polymers did not show significant solvent
effects. In organic solutions, the quantum yields of
polymers 6 and 7 were around 15% and 32%, respec-
tively, which are significantly higher than those of their
parent carboxylic acids 4 and 5 in the same solvent. Such
significant increases in the quantum yields of the poly-
mers may be attributed to the PEG side arms, which
sterically reduce the intermolecular interaction of the
chromophoric cores in organic solutions thus decreasing
the non-emissive energy loss. In aqueous solutions, the
long wavelength absorption maxima of both polymers 6
and 7 are similar to those determined in organic solu-
tions, however, significant red shifts of maximum
emission wavelengths and decreases in fluorescence
intensities are observed. Such red shift of water-soluble
fluorescent compounds in aqueous media has been
observed previously and has been attributed to self-
aggregation due to the amphiphilic nature of the com-
pounds.9 This intermolecular aggregation is driven by
the hydrophobic–hydrophobic interactions of the chro-
mophores. We examined the self-aggregation of the
present tetrahedral polymers by dynamic light scattering
(DLS) studies. The DLS studies showed that both
polymers existed as nano-aggregates with an average
size of 13 nm and with relatively narrow size distribu-
tions (Table 2). The results showed that the branched
structures with hydrophobic chromophores are located
inside and effectively minimized the aggregation of the
amphiphilic polymers in aqueous media. It is important
to note that good water solubility and non-aggregating
properties are important for a fluorescent agent to be
used in bio-sensoring.5 Our preliminary studies showed
that the fluorescence intensities of 6 and 7 in pH buffers
were significantly enhanced in the presence of bovine
serum albumin, indicating they are potential protein-
labeling agents.
Acknowledgements
We are grateful to the Agency for Science, Technology
and Research, Singapore for their financial support.
References and notes
1. (a) Chan, L.-H.; Lee, R.-H.; Hsieh, C.-F.; Yeh, H.-C.;
Chen, C.-T. J. Am. Chem. Soc. 2002, 124, 6469–6479; (b)
Chan, L.-H.; Yeh, H.-C.; Chen, C.-T. Adv. Mater. 2001,
13, 1637; (c) Wang, S.; Oldham, W. J., Jr.; Hudack, R. A.,
Jr.; Bazan, G. C. J. Am. Chem. Soc. 2000, 122, 5695–5709;
(d) Wilson, L. M.; Griffin, A. C. J. Mater. Chem. 1993, 3,
991–994.
2. (a) Rathore, R.; Burns, C. L.; Deselnicu, M. I. Org. Lett.
2001, 3, 2887–2890; (b) Zimmermann, T. J.; Freundel, O.;
€
Gompper, R.; Muller, T. J. J. Eur. J. Org. Chem. 2000,
3305–3312.
3. (a) Li, Q.; Rukavishnikov, A. V.; Petukhov, P. A.;
Zaikova, T. O.; Keana, J. F. W. Org. Lett. 2002, 4,
3631–3634; (b) Mongin, O.; Gossauer, A. Tetrahedron
Lett. 1996, 37, 3825–3828.
4. Yeh, H.-C.; Lee, R.-H.; Chan, L.-H.; Lin, T.-Y. J.; Chen,
C.-T.; Balasubramaniam, E.; Tao, Y.-T. Chem. Mater.
2001, 13, 2788–2796.
5. (a) Toutchkine, A.; Kraynov, V.; Hahn, K. J. Am. Chem.
Soc. 2003, 125, 4132–4145; (b) Minard-Basquin, C.; Weil,
€
T.; Hohner, A.; Radler, J. O.; Mullen, K. J. Am. Chem.
Soc. 2003, 125, 5832–5838.
€
6. Roncali, J. Chem. Rev. 1992, 92, 711–738.
7. Physical data for compounds 1–9. 1. M.p. 236.2 ꢁC. Anal.
calcd for C41H28S4: C, 75.9; H, 4.3; Found: C, 76.2; H, 3.9.
1H NMR (CDCl3):
d
7.07 (dd, 4H, 3JHHa
¼
3JHHb ¼ 3:6 Hz, Hb of thienyl), 7.22–7.31 (m, 16H, aro-
matics), 7.54 (d, 3JHH ¼ 8:4 Hz, 8H, Ph-H). MS (EI): 648.2
(Mþ). 2. M.p. 346.7 ꢁC. Anal. calcd for C57H36S8: C, 70.0;
1
H, 3.7; Found: C, 69.5; H, 3.5. H NMR (CDCl3): d 7.03
3
3
(dd, 4H, JHHa ¼ 3:6 Hz, JHHb ¼ 5:2 Hz, Hb of bithienyl),
3
7.14 (d, 4H, JHH ¼ 3:6 Hz, bithienyl-H); 7.18–7.25 (m,
3
12H, aromatics), 7.32 (d, 8H, JHH ¼ 7:6 Hz, Ph-H), 7.60
(d, 8H, JHH ¼ 7:6 Hz, Ph-H). MS (EI): 977.4 (Mþ). 3.
3
M.p. 202.9 ꢁC. Anal. calcd for C73H44S12: C, 67.1; H, 3.4;
Found: C, 66.5; H, 3.7. 1H NMR (CDCl3): d 7.03 (dd, 4H,
3JHHa ¼ 3:6 Hz, 3JHHb ¼ 5:2 Hz, Hb of terthienyl), 7.10 (m,
In summary, we have synthesized a novel class of tet-
rahedral fluorescent compounds from tetrakis(4-bromo-
phenyl)methane and oligothiophenes, and synthesized
water-soluble fluorescent PEG polymers. Such water-
soluble fluorescent materials showed minimal self-
aggregation in aqueous media and are potential
bio-sensoring agents.
3
8H, terthienyl-H), 7.15 (d, 4H, JHH ¼ 4:0 Hz, terthienyl-
3
H), 7.19 (d, 4H, JHH ¼ 3:6 Hz, terthienyl-H), 7.22–7.38
3
(m, 8H, terthienyl-H), 7.39 (d, 8H, JHH ¼ 7:6 Hz, Ph-H),
3
7.60 (d, 8H, JHH ¼ 7:6 Hz, Ph-H). MS (FAB): 1306.0
(Mþ). 4. M.p. > 350 ꢁC (dec.). 1H NMR (DMF-d7): d 7.2–
3
7.6 (m, 24H, aromatics), 7.67 (d, 8H, JHH ¼ 8:8 Hz,
Ph-H). IR (KBr, cmꢀ1): 3417.0 (s), 1664.5 (s), 1458.1 (s),

X.-M. Liu et al. / Tetrahedron Letters 45 (2004) 1593–1597
1435.9 (m), 632.3 (s). MS (FAB): 1153.5 (Mþ). 5. M.p.
1597
3
thienyl-H), 7.31 (d, 2H, JHH ¼ 3:6 Hz, thienyl-H), 7.40
3
3
244.5 ꢁC. 1H NMR (acetone-d6):
d
7.35 (d, 4H,
3
(d, 4H, JHH ¼ 8:4 Hz, Ph-H), 7.52 (d, 4H, JHH ¼ 8:4 Hz,
Ph-H). MS (EI): 642.5 (Mþ). 9. M.p. 180.0 ꢁC. Anal. calcd
for C49H31BrS6: C, 66.0; H, 3.5; Found: C, 67.0; H, 4.0.
1H NMR (acetone-d6): d 6.70 (m, 4H, Hb of bithienyl),
3JHH ¼ 3:6 Hz, terthienyl-H), 7.38 (d, 4H, JHH ¼ 3:6 Hz,
terthienyl-H), 7.40–7.50 (m, 24H, aromatics), 7.70 (d, 8H,
3JHH ¼ 8:0 Hz, Ph-H), 7.74 (d, 4H, JHH ¼ 3:2 Hz, terthi-
3
enyl-H). IR (KBr, cmꢀ1): 3431.7 (s), 1660.8 (s), 1447.0 (m),
1259.0 (m), 794.5 (s). MS (FAB): 1482.2 (Mþ). 6. Mw,
7.02 (d, 8H, JHH ¼ 8:8 Hz, Ph-H), 7.08–7.17 (m, 11H,
3
3
bithienyl-H), 7.34 (d, 6H, JHH ¼ 8:8 Hz, Ph-H), 7.44 (d,
1
3
5800; Mn, 5160. H NMR (acetone-d6): 3.60 (s, PEG-H),
2H, JHH ¼ 8:4 Hz, Ph-H). MS (EI): 892.0 (Mþ).
3
7.2–7.6 (m, aromatics), 7.70 (d, JHH ¼ 7:8 Hz, Ph-H). IR
8. Field, J. S.; Haines, R. J.; Lakoba, E. I.; Sosabowski, M.
H. J. Chem. Soc., Perkin Trans. 1 2001, 3352–3360.
9. Kilbinger, A. F. M.; Schenning, A. P. H. J.; Goldoni, F.;
Feast, W. J.; Meijer, E. W. J. Am. Chem. Soc. 2000, 122,
1820–1821.
(KBr, cmꢀ1): 3431.7, 1642.4, 1458.1, 1351.2, 1247.9,
1096.8. 7. Mw, 5880; Mn, 5260. 1H NMR (acetone-d6):
3.7 (s, PEG-H), 7.3–7.6 (m, aromatics), 7.71 (d,
3JHH ¼ 8:0 Hz, Ph-H), 7.75 (d, JHH ¼ 3:6 Hz, terthienyl-
3
H). IR (KBr, cmꢀ1): 3432.8, 1648.4, 1460.0, 1351.0,
1249.9, 1098.8. 8. M.p. 215.0 ꢁC. Anal. calcd for
C33H22Br2S2: C, 61.7; H, 3.5; Found: C, 60.9; H, 3.5. H
10. Hawker, C. J.; Frechet, J. M. J. J. Am. Chem. Soc. 1992,
114, 8405–8413.
11. Chaloner, P. A.; Gunatunga, S. R.; Hitchcock, P. B. J.
Chem. Soc., Perkin Trans. 2 1997, 1597–1604.
12. Che, C.-M.; Zhang, J.-L.; Lin, L.-R. Chem. Commun.
2002, 2556–2557.
ꢀ
1
3
NMR (CDCl3): d 7.05 (dd, 2H, JHHa ¼ 3JHHb ¼ 3:6 Hz,
3
Hb of thienyl), 7.10 (d, 4H, JHH ¼ 8:8 Hz, Ph-H), 7.19 (d,
3
3
4H, JHH ¼ 8:8 Hz, Ph-H), 7.28 (d, 2H, JHH ¼ 3:6 Hz,