Fluorescence "turn-on" sensing of carboxylate anions with oligothiophene-based o-(carboxamido)trifluoroacetophenones

Article abstract of DOI:10.1021/jo801178y

(Chemical Equation Presented) o-(Carboxamido)trifluoroacetophenones containing ter- or pentathiophene moiety as a fluorophore exhibit fluorescence enhancement upon binding carboxylate anions. Particularly, the terthiophene derivative shows a large fluorescence enhancement factor (FEF = 120). The enhancement is explained by intramolecular H-bonding stabilization of an anion-ionophore adduct, through which a possible quenching process, the n-π* transition from the trifluoroacetophenone moiety, is eliminated.

Full text of DOI:10.1021/jo801178y

Fluorescence “Turn-On” Sensing of Carboxylate
Anions with Oligothiophene-Based
o-(Carboxamido)trifluoroacetophenones
Dae-Sik Kim and Kyo Han Ahn*
Department of Chemistry and Center for Integrated
Molecular Systems, POSTECH, San 31 Hyoja-dong,
Pohang 790-784, Republic of Korea
ahn@postech.ac.kr
ReceiVed April 21, 2008
FIGURE 1. Structures of trifluoroacetophenone derivatives 1 and 2,
their anionic adducts, and dansyl analogue 3.
the trifluoroacetyl carbonyl carbon to form the corresponding
anion-ionophore adducts.5 Recently, we introduced the second
generation of trifluoroacetophenone ionophores, o-(carboxami-
do)trifluoroacetophenones 2,6a in which the carboxamide group
stabilizes the alkoxide adducts through enhanced intramolecular
H-bonding. The new ionophores 2 show significantly enhanced
binding affinity toward anions such as cyanide and
carboxylates.6b This approach of intramolecular H-bond stabi-
lization of anion-ionophore adducts also enabled us to introduce
a novel fluorescence sensor such as the dansyl derivative 3, in
which the sulfonamide NH acts as the H-bond donor.6c The
dansyl derivative 3 shows fluorescence enhancement rather than
quenching, upon addition of anions such as cyanide. We were
particularly interested in the fluorescence sensing of carboxy-
o-(Carboxamido)trifluoroacetophenones containing ter- or
pentathiophene moiety as a fluorophore exhibit fluorescence
enhancement upon binding carboxylate anions. Particularly,
the terthiophene derivative shows a large fluorescence
enhancement factor (FEF ) 120). The enhancement is
explained by intramolecular H-bonding stabilization of an
anion-ionophore adduct, through which a possible quench-
ing process, the n-π* transition from the trifluoroacetophe-
none moiety, is eliminated.
(2) (a) De Santis, G.; Fabbrizzi, L.; Licchelli, M.; Poggi, A.; Taglietti, A.
Angew. Chem., Int. Ed. Engl. 1996, 35, 202. (b) Gunnlaugsson, T.; Davis, A. P.;
O’Brien, J. E.; Glynn, M. Org. Lett. 2002, 4, 2449. (c) Bruseghini, I.; Fabbrizzi,
L.; Licchelli, M.; Taglietti, A. Chem. Commun. 2002, 1348. (d) Kondo, S.-i.;
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Ma´n˜ez, R.; Marcos, M. D.; Amoro´s, P.; Hoffmann, K.; Soto, J. J. Am. Chem.
Soc. 2005, 184.
Molecular sensing of anions has attracted growing attention
given that anions play important roles in chemical and biological
processes. Chemosensors based on anion-induced fluorescence
changes are particularly attractive because of the simplicity and
high detection limit of fluorescence detection methods.1 The
development of fluorescence “turn-on”-type sensors for anions
of biological importance remains a challenging object, because
anions may act as fluorescence quenchers and thus fluorescence
quenching rather than enhancement is observed in many cases.2
In some cases the fluorescence enhancement results from anion
sensing;3 however, only marginal enhancement in the fluores-
cence emission results with rare exceptions.4 Therefore, there
is need to develop fluorescence turn-on sensors for anions based
on new disciplines.
(4) Zyryanov, G. V.; Palacios, M. A.; Anzenbacher, P. Angew. Chem., Int.
Ed. 2007, 119, 7995.
Trifluoroacetophenone derivatives 1 (Figure 1) have been
utilized as unique ionophores for anions that reversibly add to
(5) (a) Meyerhoff, M. E.; Pretsch, E.; Welti, D. H.; Simon, W. Anal. Chem.
1987, 59, 144. (b) Mohr, G. J.; Lehmann, F.; Grummt, U. W.; Spichiger-Keller,
W. E. Anal. Chim. Acta 1997, 344, 215. (c) Mohr, G. J.; Spichiger, U. E.; Jona,
W.; Langhals, H. Anal. Chem. 2000, 72, 1084. (d) Lee, H.-J.; Yoo, I. J.; Yoo,
C. L.; Pyun, H.-J.; Cha, G. S.; Nam, H. Anal. Chem. 2000, 72, 4694.
(6) (a) Kim, Y. K.; Lee, Y.-H.; Lee, H.-Y.; Kim, M.-K.; Cha, G. S.; Ahn,
K. H. Org. Lett. 2003, 5, 4003. (b) Kim, D.-S.; Miyaji, H.; Chang, B.-Y.; Park,
S.-M.; Ahn, K. H. Chem. Commun. 2006, 3314. (c) Chung, Y. M.; Raman, B.;
Kim, D.-S.; Ahn, K. H. Chem. Commun. 2006, 186.
(1) Selected reviews on anion sensing: (a) Schmidtchen, F. P.; Berger, M.
Chem. ReV. 1997, 97, 1609. (b) Beer, P. D.; Gale, P. A. Angew. Chem., Int. Ed.
2001, 40, 486. (c) Martinez-Manez, R.; Sancenon, F. Chem. ReV. 2003, 103,
4419. (d) Gale, P. A. Coord. Chem. ReV. 2003, 240, 191. (e) Mart´ınez-Ma´n˜ez,
R.; Sanceno´n, F. J. Fluoresc. 2005, 15, 267.
10.1021/jo801178y CCC: $40.75
Published on Web 08/02/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6831–6834 6831

lates,5 an important class of organic compounds together with
amines. Although chemosensor 3detected an acetate ion in the
fluorescence enhancement mode, the fluorescence enhancement
factor was small (FEF ) 2.5), and also the binding mode did not
follow a 1:1 stoichiometry. We have suspected that, in addition to
the carbonyl carbon adduct, a deprotonated species forms owing
to the presence of acidic sulfonamide proton, and this deprotonated
species seems to influence the binding mode as well as the
fluorescence enhancement. To alleviate the deprotonated species,
we have designed new fluorescence sensors in which the recogni-
tion motif is connected to the fluorophore through a carboxamide
functionality, of which the proton is less acidic than that of the
sulfonamide group. As the fluorophore, we have selected oligoth-
iophenes for future elaboration of the chemosensors into polymeric
materials. Such polymeric materials may be also used for seques-
tering anions by using the reversibility of binding.
SCHEME 1. Synthesis of Chemosensors 4 and 5
Oligothiophenes have attracted considerable research interest
owing to their use as organic semiconductors for the realization
of devices such as field effect transistors, light-emitting diodes,
or photovoltaic cells.7 Also, oligothiophenes together with
monothiophenes readily undergo oxidative or electro-polymer-
ization to the corresponding polythiophenes.8 Despite their
intrinsic fluorescence and facile polymerization properties, little
effort has been made in the development of fluorescent sensors
based on oligothiophenes.9 Herein, we report new fluorescence
sensors based on terthiophene (4) and pentathiophene (5)
moieties (Scheme 1), which sense carboxylates with large
fluorescence enhancement (FEF ) up to 120) and in a 1:1
binding mode.
Compounds 4 and 5 were synthesized following the routes
described in Scheme 1. Coupling of aniline 6, prepared from
2-nitrobenzaldehyde, with acid chloride 7, prepared from
3-thienoic acid, afforded amide 8 in 62% yield, which was then
subjected to the Suzuki-Miyaura coupling with thiophenebo-
ronic acids 9 and 10 to give oligothiophenes 11 and 12 in
80-85% isolated yields, respectively. Finally, the Dess-Martin
oxidation of 11 and 12 afforded desired 4 and 5 in 55-59%
isolated yields, respectively (Supporting Information).
titration of 4 at 8.0 µM concentration toward AcO- and
collective emission data for all the anions are shown in Figure
2.
In line with our expectation, both 4 and 5 gave notable
enhancement in the fluorescent intensity for anions such as CN-,
AcO-, F-, and H2PO4-, whereas little or very small enhance-
ment for other anions. Of particular note is that the relative
fluorescence intensity among the three anions is much different,
showing the largest value in the cases of CN- and AcO-,
followed by F- and then H2PO4-. The enhancement was
dramatic and sensor 4 gave a 120-fold enhancement toward
AcO- at the saturation point (Figure 2a). Interestingly, sensor
4 shows a little difference between CN- and AcO-, while 5
shows a large difference. The fluorescence enhancement was
accompanied with a slight bathochromic shift (2.0 nm) in the
case of 4, whereas there was no shift in the case of 5 (Figure
2b,c). If we compare the fluorescence titration results, particu-
larly those obtained by 4, with those reported by the dansyl
derivative 3, two notable differences are observable: (i) 4
discriminates AcO- over F- and H2PO4-, whereas 3 does not;
(ii) 4 shows a dramatic increase in the fluorescence intensity
particularly toward carboxylate ions such as AcO-, but 3 does
not. These differences are promising properties for further
elaboration of 4 and its derivatives into polymeric sensing
materials for carboxylate functions in biomolecules such as
oligopeptides and proteins.
Photophysical properties of compounds 4 and 5 were evalu-
ated in CH3CN. Compound 4 displayed strong absorption
maxima at 241, 256, and 347 nm (ꢀ ) 17,550 M-1 cm-1), and
5 displayed strong absorption maxima at 242 and 403 nm (ꢀ )
36,080 M-1 cm-1). Compound 4 showed very weak fluores-
cence emission at 410 nm when excited at 347 nm, whereas
5 showed moderate fluorescence emission at 508 nm when
excited at 403 nm. The sensing ability of compounds 4 and
5 was evaluated by fluorescence titrations against increasing
concentrations of anions such as AcO-, F-, Cl-, Br-, NCS-,
H2PO4-, and HSO4 (as Bu4N+ salts) in acetonitrile. Al-
-
though we focused on carboxylate sensing, CN- was also
examined as a reference anion because our previous data
show that o-(carboxamido)trifluoroacetophenone ionophores
recognize it most strongly. The results of fluorescence
Since the binding interactions between the sensors and
carboxylate ions should be the same, other carboxylate anions
such as propanoate and pentanoate showed fluorescence en-
hancement similar to that of acetate (Supporting Information).
It is worth mentioning that none of the anions examined
(7) (a) Tour, J. M. Chem. ReV. 1996, 96, 537. (b) Roncali, J. Chem. ReV.
1997, 97, 173. (c) Schwab, P. F. H.; Smith, J. R.; Michl, J. Chem. ReV. 2005,
105, 1197. (d) Murphy, A. R.; Liu, J.; Luscombe, C.; Kavulak, D.; Frechet,
J. M. J.; Kline, R. J.; McGehee, M. D. Chem. Mater. 2005, 17, 4892.
(8) (a) Yamazaki, T.; Murata, Y.; Komatsu, K.; Furukawa, K.; Morita, M.;
Maruyama, N.; Yamao, T.; Fujita, S. Org. Lett. 2004, 6, 4865. (b) Segura, J. L.;
Gomez, R.; Reinold, E.; Bauerle, P. Org. Lett. 2005, 7, 2345.
-
showed fluorescence quenching, except for H2SO4 in which
(9) For poly(thiophene)-based sensors, see: (a) Ho, H. A.; Leclerc, M. J. Am.
Chem. Soc. 2003, 125, 4412. (b) Dore´, K.; Dubus, S.; Ho, H.-A.; Le´vesque, I.;
Brunette, M.; Corbeil, G.; Boissinot, M.; Boivin, G.; Bergeron, M. G.; Boudreau,
D.; Leclerc, M. J. Am. Chem. Soc. 2004, 126, 4240.
(10) (a) Valeur, B. Molecular FluorescencesPrinciples and Applications;
Wiley-VCH: New York, 2002. (b) Krasovitskii, B. M.; Bolotin, B. M. Organic
Luminescent Materials; VCH: Weinheim, 1988.
6832 J. Org. Chem. Vol. 73, No. 17, 2008

FIGURE 3. 19F NMR spectra of (a) 4 and its acetate mixtures: (b)
1.0, (c) 2.0, and (d) 4.0 equiv of AcO- (as Bu4N+ salt); taken in CDCl3
at 25 °C.
the carbonyl adducts should be responsible for the fluorescence
enhancement observed. Although the fluorescence quantum yield
increases as the carbonyl adduct forms, still the quantum yield
at the saturation point (ΦF ) 0.0081 in the case of 4; ΦF )
0.0796 in the case of 5) is smaller compared to that of the ter-
or pentathiophene itself (terthiophene, ΦF ) 0.07; pen-
tathiophene, ΦF ) 0.28, in dioxane).11 This comparison suggests
that the carboxamide substitution to the oligothiophenes may
lead to less efficient fluorophores.12
The molecular sensing of anions such as acetate reported so
far shows fluorescence quenching rather than enhancement in
most cases,2d-j as mentioned above. However, our oligoth-
iophene-based sensor 4 shows a large fluorescence enhancement
upon anion binding. It is clear that the intramolecular H-bonding
plays a key role for the fluorescence enhancement, because a
similar system that lacks an ortho-H-bonding acceptor shows
fluorescence quenching, as demonstrated previously with a para-
analogue of 3.6c The stabilization of anionic adducts through
intramolecular H-bonding seems to suppress possible quenching
processes by anionic guest, its adduct species, or both, otherwise
effective in the absence of such H-bonding. In addition, the
intramolecular H-bonding increases the conformational rigidity
of the adduct, partially contributing to the fluorescence enhance-
ment. The large fluorescence enhancement observed with 4 and
5 are likely owing to the elimination of the n-π* transition
from the trifluoroacetyl carbonyl conjugated to the benzene ring
upon binding carboxylate ions, which seems to intervene the
π-π* transition levels and thus quench the emission from the
oligothiophene fluorophores through a donor-excited photoin-
duced electron transfer mechanism.12a
The formation of anionic adducts is evident from 1H and 19
F
NMR analyses. Peaks for both 4 and its acetate adduct appeared
separately, indicating that the equilibration for the adduct
formation is slow compared to the NMR time scale. The amide
NH proton of 4, appearing at δ 11.0 ppm, shifted upfield (∆δ
) 0.2) upon addition of acetate. Also, the CF3 group of 4,
appearing at δ 6.5 ppm, shifted upfield (-8.4 ppm; ∆δ ) 14.9)
upon addition of the acetate anion (Figure 3). Similar upfield
shifts were observed in the case of 5 upon acetate binding
(Supporting Information).
FIGURE 2. (a) Fluorescence spectra of 4 (8.0 µM) with increasing
amounts of acetate ion (λex ) 347 nm). Inset: dependence of
fluorescence intensity (I/Io) with respect to [AcO-]0/[4]0. (b) Collected
fluorescence spectra obtained for an equimolar mixture of 4 (8.0 µM)
and each of the anion guests. (c) Collected fluorescence spectra obtained
for an equimolar mixture of 5 (4.0 µM) and each of the anion guests
(from the top: CN-, AcO-, F-, H2PO4-, SCN-, Cl-, Br-, and HSO4
;
-
To obtain thermodynamic data for the binding process
between 4 and acetate, we carried out isothermal titration
λex ) 403 nm).
case a little quenching was observed with 5. Both compounds
4 and 5 themselves gave low fluorescence quantum yields,
plausibly owing to the presence of trifluoroacetophenone moiety
of which n-π* transition seems to cause fluorescence quench-
ing.10
(11) Chosrovian, H.; Rentsch, S.; Grebner, D.; Dahm, D. U.; Birckner, E.;
Naarmann, H. Synth. Met. 1993, 23.
(12) We are currently investigating the change of fluorescence quantum yields
of oligothiophenes depending on the substitution pattern: (a) Ueno, T.; Urano,
Y.; Setsukinai, K.-i.; Takakusa, H.; Kojima, H.; Kikuchi, K.; Ohkubo, K.;
Fukuzumi, S.; Nagano, T. J. Am. Chem. Soc. 2004, 126, 14079. (b) Ryu, D.;
Park, E.; Kim, D.-S.; Yan, S.; Lee, J. Y.; Chang, B.-Y.; and Ahn, K. H. J. Am.
Chem. Soc. 2008, 130, 2394.
The fluorescence quantum yield increases as the amount of
acetate adduct increases (Supporting Information). Therefore,
J. Org. Chem. Vol. 73, No. 17, 2008 6833

toward the trifluoroacetyl group, which is in the order: CN- >
OAc- > F- > H2PO4 > other anions.
-
In summary, we have synthesized ter- and pentathiophene
derivatives of o-(carboxamido)trifluoroacetophenones as fluo-
rescence turn-on sensors for carboxylate anions. Both oligoth-
iophene derivatives detect carboxylate anions with fluorescence
enhancement. Particularly, the terthiophene-based sensor 4
shows a large fluorescence enhancement factor of 120 as well
as improved selectivity toward carboxylate anions over compet-
ing anions, compared to the previous dansyl derivative 3. Thus,
highly efficient fluorescence turn-on sensing of carboxylate
anions has been achieved, which will find further applications
in the development of chemosensors for biological molecules
containing carboxylate groups.
FIGURE 4. ITC titrations of 4 (b) and 5 (1) with acetate ion (as Bu4N+
salt) at 303 K in acetonitrile.
Experimental Section
For experimental details for the synthesis all the compounds and
titrations (NMR, fluorescence, and ITC), see Supporting Informa-
tion.
N-[2-(2,2,2-Trifluoroacetyl)phenyl]-2,5-di(thiophen-2-yl)thio-
phene-3-carboxamide (4). Rf ) 0.5 (hexane/EtOAc ) 4/1); mp
111 °C; 1H NMR (300 MHz, CDCl3) δ 11.19 (s, 1H), 8.95 (d, J )
6.0 Hz, 1H), 7.94-7.91 (m, 1H), 7.71 (td, J ) 15.9, 1.2 Hz, 1H),
7.48 (s, 1H), 7.36-7.35 (m, 2H), 7.29-7.17 (m, 3H), 7.06-7.00
(m, 2H); HRMS (FAB) calcd for C21H12F3NO2S3 (M + H)
464.0061, found 464.0063.
calorimetry (ITC). The thermodynamic data (∆H° ) -12.5 kcal/
mol and -∆TS° ) 6.3 kcal/mol, Kass ) 3.1 × 104 M-1, T )
303 K) obtained for the molecular interaction between 4 and
acetate ion indicate that the complex formation is driven by a
major favorable enthalpy change and a minor unfavorable
entropy change, which also supports the covalent adduct
formation. Also, the ITC binding isotherms were best fit by a
one-site binding model with a 1:1 binding stoichiometry (Figure
4).13 The association constant obtained for the complexation
process between 4 and the acetate ion was similar to that
obtained in the case of 2 but smaller than that obtained in the
case of 3. A similar level of thermodynamic parameters was
obtained for the binding process between 5 and the acetate ion
(∆H° ) -10.7 kcal/mol, -T∆S° ) 4.7 kcal/mol, Kass ) 2.2 ×
104 M-1).
N-[2-(2,2,2-Trifluoroacetyl)phenyl]-2,5-di(thiophen-2-yl)thio-
phene-3-carboxamide (5). Rf ) 0.4-0.6 (hexane/EtOAc ) 4/1);
1
mp 171 °C (dec); H NMR (300 MHz, CDCl3) δ 11.34 (s, 1H),
8.96 (d, J ) 9.0 Hz, 1H), 7.97 (d, J ) 9.0 Hz, 1H), 7.75 (t, J ) 6
Hz, 1H), 7.48 (s, 1H), 6.91-7.40 (m, 11H); HRMS (FAB) calcd
for C29H16F3NO2S5 (M + H) 627.9815, found 627.9812.
Acknowledgment. This work was supported by grants from
the Korea Health Industry Development Institute (A05-0426-
B20616-05N1-00010A) and Korea Research Foundation Grant
(KRF-2005-070-C00078).
Furthermore, we have already demonstrated that a carboxa-
mide proton ortho to the trifluoroacetyl group enhances its
binding ability toward anions such as carboxylates.6a Therefore,
the fluorescence behavior of 4 and 5 depending on the anions
can be explained by comparing the relative affinity of the anions
Supporting Information Available: Details for the synthesis
of compounds 4 and 5 and anion titration data (1H/19F NMR,
fluorescence, and ITC). This material is available free of charge
via the Internet at http://pubs.acs.org.
(13) F- shows a complex binding mode toward 4, whereas H2PO4- shows a
major 1:1 binding mode with other minor modes; The former anion can bind to
the carboxamide protons of the sensor itself and its adduct, whereas the latter
seems to bind similarly but to a lesser degree.
JO801178Y
6834 J. Org. Chem. Vol. 73, No. 17, 2008