Synthesis and characterization of 9-(cycloheptatrienylidene)fluorene derivatives: Acid-triggered "switch on" of fluorophores

Article abstract of DOI:10.1021/ol047847a

(Chemical Equation Presented) A series of 9-(cycloheptatrienylidene) fluorene derivatives were synthesized in good yields through the Suzuki or Sonogashira cross-coupling reactions. Fluorescence "off-on" behaviors of these compounds were investigated on t

Full text of DOI:10.1021/ol047847a

ORGANIC
LETTERS
2005
Vol. 7, No. 1
87-90
Synthesis and Characterization of
9-(Cycloheptatrienylidene)fluorene
Derivatives: Acid-Triggered “Switch on”
of Fluorophores
Zixing Wang,† Yajun Xing,† Hongxia Shao,† Ping Lu,*,† and William P. Weber*,‡
Chemistry Department, Zhejiang UniVersity, Hangzhou, 310027, P. R. China, and
Loker Hydrocarbon Research Institute, Chemistry Department, UniVersity of
Southern California, Los Angeles, California 90089-1661
pinglu@zju.edu.cn; wpweber@usc.edu
Received October 19, 2004
ABSTRACT
A series of 9-(cycloheptatrienylidene)fluorene derivatives were synthesized in good yields through the Suzuki or Sonogashira cross-coupling
reactions. Fluorescence “off-on” behaviors of these compounds were investigated on the basis of variable acid concentrations. These compounds
were shown to be acid-sensing fluorophores with utility as indicators in acidic environments.
Optical pH sensors, based on the measurement of fluores-
cence intensity,1-2 fluorescence intensity ratios at two emis-
sion wavelengths,3 and fluorescence lifetime4 in response to
environmental acidity, have been investigated and used to
analyze biomolecules in living systems.5 Many efforts have
focused on designation and synthesis of pH-sensing fluoro-
phores for this purpose.6-8 Herein, we report new acid-
sensing fluorophores based on a 9-(cycloheptatrienylidene)-
fluorene core.
CT complexes. Compared to azulene, 9-(cycloheptatrienyli-
dene)fluorene (9-CHF) has seven- and five-member rings
but different connectivity. Little recent work on 9-CHFs has
been reported.11-13 Optical and electrochemical properties
(5) Haugland, R. P. Molecular Probes. Handbook of Fluorescent Probes
and Research Chemical, 7th ed.; Molecular Probes, Inc.: Eugene, Oregon,
1999.
(6) de Sliva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley, A.
J. M.; McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem. ReV. 1997, 97,
1515-1566.
(7) Elhabiri, M.; Siri, O.; Sornosa-Tent, A.; Albrecht-Gary, A.-M.;
Braunstein, P. Chem. Eur. J. 2004, 10, 134-141.
Azulene and its derivatives,9,10 nonbenzenoid aromatic
systems, have improved electron affinity for formation of
(8) (a) Niu, C.-G.; Zeng, G.-M.; Chen, L.-X.; Shen, G.-L.; Yu, R.-Q.
Analyst 2004, 129, 20-24. (b) Young, V. G.; Qiuring, H. L.; Sykes, A. G.
J. Am. Chem. Soc. 1997, 119, 12477-12480. (c) Gunnlaugsson, T.
Tetrahedron Lett. 2001, 42, 8901-8905.
† Zhejiang University.
‡ University of Southern California.
(1) Cajlakovic, M.; Lobnik, A.; Werner, T. Anal. Chim. Acta 2002, 455,
207-213.
(2) Lobnik, A.; Oehme, I.; Murkovic, I.; Wolfbeis, O. S. Anal. Chim.
Acta 1998, 367, 159-165.
(3) Ferguson, J. A.; Healey, B. G.; Bronk, K. S.; Barnard, S. M.; Walt,
D. R. Anal. Chim. Acta 1997, 340, 123-131.
(4) Lin, H.-J.; Szmacinski, H.; Lakowicz, J. R. Anal. Biochem. 1999,
269, 162-167.
(9) Schmitt, S.; Baumgarten, M.; Simon, J.; Hafner, K. Angew. Chem.,
Int. Ed. 1998, 37, 1077-1081.
(10) Ito, S.; Inabe, H.; Morita, N.; Ohta, K.; Kitamura, T.; Imafuku, K.
J. Am. Chem. Soc. 2003, 125, 1669-1680.
(11) Prinzbach, H.; Seip, D.; Knothe, L.; Faisst, W. Justus Liebigs Ann.
Chem. 1966, 698, 34-56.
(12) Ostrowski, S.; Makosza, M. Liebigs Ann. Chem. 1989, 95-97.
10.1021/ol047847a CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/10/2004

Scheme 1. Synthetic Routes to Various π-Conjugated Compounds with a 9-(Cycloheptatrienylidene)fluorene Core
of 9-CHF have not been studied systematically except for
its reversible UV-vis absorption based on acidity, which
was recently reported by our group.14 To investigate the
optoelectronic properties of 2,7-diaryl-substituted 9-(cyclo-
heptatrienylidene)fluorenes (DA-9-CHFs), a series of DA-
9-CHFs have been synthesized by palladium-catalyzed cross-
coupling reactions. These reactions show unique advantage
in the formation of sp2-sp2- and sp-sp2-hybridized carbon-
carbon single bonds. Among these are the Heck, Suzuki, and
Sonagoshira reactions. The Suzuki cross-coupling reaction15
shows specific advantages due to facile preparation of aryl-
boronic acids, its nontoxicity, compatibility, and stability to
air and moisture. Alternatively, the Sonagoshira reaction16,17
provides an effective way to build π-systems with triple
bonds. While aryl halides are typical substrates in both the
Suzuki and Sonagoshira reactions, only a few examples of
related nonbenzenoid aromatic halides have been reported.
On the basis of previous reports,12,13 almost all 2,7-di-
substituted-9-CHFs were constructed by two steps. The first
step was the reaction between tropylium tetrafluoroborate
and corresponding 2,7-disubstituted fluorenes in THF; the
second step was oxidation. The drawback was the relatively
low yields due to the acid- or base-sensitive 9-CHF core. In
this paper, various DA-9-CHFs were prepared through the
Suzuki or Sonogashira cross-coupling reactions starting from
2,7-dibromo-9-(cycloheptatrienylidene)fluorene (DB-9-CHF).
DB-9-CHF was selected as starting material due to its easier
preparation from 2,7-dibromo-9-lithiofluorene and tropylium
tetrafluoroborate in THF and followed by oxidation with
DDQ in benzene.13 The 9-CHF core survived after both the
Suzuki and Sonagoshira cross-coupling reactions because
these were carried out under mild conditions. In this way,
DA-9-CHFs could be prepared in 60-80% yields.
Pd-catalyzed cross-coupling reaction of DB-9-CHF with
3 equiv of phenylboronic acid or 1-naphthaleneboronic acid
under Suzuki conditions afforded 2,7-diphenyl-9-(cyclohep-
tatrienylidene)fluorene (1a) and 2,7-di(1-naphthyl)-9-(cyclo-
heptatrienylidene)fluorene (1b) in 66 and 60% yields, re-
spectively (Scheme 1). Under identical conditions, coupling
of DB-9-CHF with 1.1 equiv of phenylboronic or 1-naph-
thaleneboronic acid produced monosubstituted compounds
2a and 2b in 59 and 57% yields, respectively. 2a and 2b could
be used as intermediates for generating unsymmetrical DA-
9-CHFs, for example, 1c. The reaction of DB-9-CHF with 3
equiv of trimethylsilylacetylene (TMSA) or 2-methyl-3-
butyn-2-ol leads to the formation of 3a and 3b, in 64 and
75% yields, respectively, via the Sonogashira cross-coupling
reaction. Subsequent treatment of 3a and 3b with appropriate
base, followed by chromatography on silica gel using
n-hexane/dichloromethane as an eluent, gave 4 in 90 and
41% yields, respectively. Both 3a and 4 could be used as
substrates for the Hay coupling reaction18,19 to get desired
products. By analogy, DB-9-CHF could also be reacted with
1.1 or 3 equiv of arylethyne to produce 2-arylethynyl-7-
bromo-9-CHFs (5a and 5b) and diarylethynyl-9-CHFs (6a and
6b) in moderate yields. When 5a or 5b was used as the
substrate, unsymmetrical DA-9-CHFs (such as 6c) could be
obtained. Unsymmetrical compounds (7a and 7b) could also
be prepared from intermediate 2 by the Sonogashira cross-
coupling reaction.
Relatively lower yields are obtained from 3a compared to
3b because the trimethylsilyl group was a better leaving
group. Moreover, 20% yield of 4 was obtained as a byproduct
during the preparation of 3a. Compounds 6 could also be
synthesized from 4 in excellent yields. However, unsym-
metrical DA-9-CHFs (1c, 6c, 7a and 7b) were obtained in
(13) Minabe, M.; Tomiyama, T.; Nozawa, T.; Noguchi, M.; Nakao, A.;
Oba, T.; Kimura, T. Bull. Chem. Soc. Jpn. 2001, 74, 1093-1100.
(14) Wang, Z.; Li, W.; Lu, P. Sensor. Actuat. B 2004, 99 (2-3), 264-
266.
(15) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(16) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470.
(17) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627-630.
(18) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2632-2657.
(19) Hay, A. S. J. Org. Chem. 1962, 27, 3320-3321.
(20) Allen, M. T.; Miola, L.; Whitten, D. G. J. Am. Chem. Soc. 1988,
110, 3198-3206.
88
Org. Lett., Vol. 7, No. 1, 2005

Table 1. Absorption and Emission Properties of DA-9-CHFs
UV-visa λmax
(nm)/log ꢀ
excitationb λ max
emissionb λmax
quantum yieldc
relative fluorescence
enhancementd (Φa)
DA-9-CHFs
(nm)
(nm)
(Φ0)
1a
1b
1c
6a
6b
6c
7a
7b
389/4.57
387/4.51
388/4.18
398/4.41
400/4.59
390/4.41
380/4.50
390/4.45
323
326
321
340
366
355
340
348
359, 375
382
383
373, 392
394, 418
387, 409
379, 399
384
0.008
0.010
0.030
0.013
0.025
0.054
0.014
0.010
1.2
1.2
1.1
2.1
2.8
2.6
1.9
2.1
a UV-vis spectra were recorded in THF on a Shimadzu UV-2450 spectrophotometer. b Fluorescence spectra were recorded in THF on Shimadzu
RF-5301PC spectrofluorophotometer. c Quantum yields were calculated in THF based on trans,trans-1,4-diphenylbuta-1,3-diene as the standard (Φ ) 0.44).20
d Relative fluorescence enhancement (Φa) with respect to Φ0 of the corresponding free dye was recorded in THF with 0.5 M H2SO4.
Figure 2. UV-vis spectra of 1b in THF with H2SO4 concentrations.
Figure 1. Normalized absorption and emission of 1a and 6b with
0.5 M H2SO4 in THF.
the acid solution was neutralized, the solution color changed
back to yellow and fluorescence intensities decreased
simultaneously.
low yields. When 5a or 5b reacted with aryl boronic acid by
Suzuki conditions, almost none of the corresponding coupling
products were isolated.
On the basis of previous reports,13,14 9-CHFs showed
reversible acid-dependent absorption spectra, but without
emission. However, with DA-9-CHFs, weak purple-blue
emissions were observed in THF. After acidification with
sulfuric acid, the emission intensity increased dramatically.
Table 1 lists maximum absorption and emission wavelengths
for DA-9-CHFs in THF/H2SO4. Compound 6b exhibited
indigo fluorescence with an emission at 394 and 418 nm,
which was bathochromically shifted by 35 nm compared to
the emission of 1a (Figure 1).
1b illustrates the reversible acid-dependent absorption of
DA-9-CHFs. Thus, when a THF solution of 1b was acidified
by H2SO4, the solution color changed from yellow to
colorless as the acid concentration increased. Increasing
absorption at 325 nm was matched with decreasing absorp-
tion at 387 and 250 nm as H2SO4 concentration reached 0.75
mol L-1 (Figure 2). Moreover, the fluorescence intensity
increased dramatically. Emission at 384 nm increased as the
H2SO4 concentration reached 1.2 mol L-1 (Figure 3). When
Figure 3. Fluorescence spectra of 1b in THF with relative H2SO4
concentrations, excited at 326 nm.
Org. Lett., Vol. 7, No. 1, 2005
89

Figure 4. Absorption at 384 nm of 1b versus H2SO4 concentration.
Figure 5. Emission at 381 nm of 1b versus H2SO4 concentration.
Figure 4 shows the linear correlation between absorption
at 384 nm of 1b and H2SO4 concentration. Suitable H2SO4
concentration for reversible change was between 0 and 0.75
mol L-1. However, when the fluorescence technique was
used instead of ultraviolet absorption, the suitable H2SO4
concentration for reversible change was between 0 and 1.2
mol L-1 (Figure 5). Obviously, 1b is an ideally acid-sensing
fluorophore.
In conclusion, a series of DA-9-CHFs were synthesized
by the Suzuki or Sonogashira cross-coupling reactions in
moderate yields. Reversible changes were detected by both
UV-vis absorption and emission on changing acidities. The
acid-triggered “switch on” of emission intensity suggests that
2,7-diaryl-9-(cycloheptatrienylidene)fluorenes might be use-
ful as acid-sensing fluorophores. Although this system is far
from being an ideally broad pH sensor, it greatly comple-
ments normal pH sensors and supplies new indicators in ex-
treme regions. Further work in this area would be beneficial
to designing more excellent fluorophores for nonaqueous and
aqueous systems.
Acknowledgment. Ping Lu thanks National Science
Foundation of China (20074032, 20374045) and Ministry
of Education of China for financial support.
Supporting Information Available: Experimental details
and characterization for new compounds reported. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL047847A
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Org. Lett., Vol. 7, No. 1, 2005