ORGANIC

LETTERS

Efficient and Simple Colorimetric 2004

Vol. 6, No. 20
Fluoride Ion Sensor Based on 3445-3448
Receptors Having Urea and Thiourea
Binding Sites†
D. Amilan Jose, D. Krishna Kumar, Bishwajit Ganguly,* and Amitava Das*
Central Salt and Marine Chemicals Research Institute,
BhaVnagar: 364002, Gujarat, India
[email protected]; [email protected]
Received June 21, 2004

ABSTRACT

Novel colorimetric receptors for selective fluoride ion sensing containing anthraquinone as chromogenic signaling subunit and urea (N,N′′-
(9,10-dihydro-9,10-dioxo-1,2-anthracenediyl)bis[N′-phenyl])/thiourea (N,N′′-(9,10-dihydro-9,10-dihydro-9,10-dioxo-1,2-antrhacenediyl)bis[N-phenyl])
binding sites have been reported. These receptors have shown no affinity for other halide ions (Cl-, Br-, and I- ions). Well-defined color
change in the visible region of the spectrum was observed upon addition of fluoride ion in DMSO/CH3CN solution of the receptors 1 and 2.

The search of a chemosensor for recognition and sensing of transfer (PET) receptor molecules for fluoride ion.3,5 There
specific anionic analytes is emerging as a research area of is paucity of reports that describe the change in color in the
considerable importance.1 In particular, the development of visible region of the spectrum and thereby allow the naked
colorimetric anion sensing is even more important and eye detection for fluoride ion.6 Reports in this regard are
increasingly appreciated since naked eye detection can offer mostly restricted to the use of calix[4]pyrrole or its derivative,
qualitative and quantitative information.1,2 However, ex- dipyrrolylquinoxalines and 1,2-diaminoanthraquinone.6,7
amples in general, for the sensitive and simple-to-use The binding constant reported for the fluoride ion with di-
colorimetric anion sensors are rather limited compared to pyrrolylquinoxalines is relatively larger; however, for other
the fluorescence-based ones.2,3
(2) (a) Suksai, C.; Tuntulani, T. Chem. Soc. ReV. 2003, 32, 192-202.
Among various important anionic analytes, biologically (b) Sancenon, F.; Descalzo, A. B.; Manez, R. M.; Miranda, M. A.; Soto, J.
important fluoride ion is one of the most significant due to Angew. Chem., Int. Ed. 2001, 40, 2640-2643. (c) Lee, D. H.; Lee, H. Y.;
its role in dental care and treatment of osteoporosis.4 Many Hong, J.-Ju. Tetrahedron Lett. 2002, 43, 7273-7276. (d) Miyaji, H.; Sato,
W.; Sessler, J. L. Angew. Chem., Int. Ed. 2000, 39, 1777-1780. (e) Starnes,
examples are available on selective fluorescent photoelectron S. D.; Arungundram, S.; Saunders: C. H. Tetrahedron Lett, 2002, 43, 7785-
7788. (f) Zhou, L. L.; Sun, H.; Li, H.-P.; Wang, H.; Zhang, X.-H.; Wu,
† Authors would like to dedicate this paper to the memory of Prof. S.-K.; Lee, S.-T. Org. Lett. 2004, 6, 1071-1074. (g) D. H. Lee, K. H. Lee,
Bhaskar. G. Maiya. J-I. Hong. Org. Lett. 2001, 3, 5-8.
(1) (a) Gale, P. A. Coord. Chem. ReV. 2001, 213, 79-128. (b) Sessler, (3) (a) Xu., G.; Tarr, M. Chem. Commun. 2004, 9, 1050-1051 and
J. L.; Davis, J. M. Acc. Chem. Res. 2001, 34, 989-997. (c) Beer, P. D.; references therein. (b) Sole, S.; Gabbai, F. P. Chem. Commun. 2004, 11,
Gale, P. A. Angew. Chem., Int. Ed. 2001, 40, 486-516. (d) Schmidtchen, 1284-1285 and references therein.
F. P.; Bergeer, M. Chem. ReV. 1997, 97, 1609-1646. (e) de Silva, A. P., (4) (a) Krik, K. L. Biochemistry of Halogens and Inorganic Halides;
Gunaratne, H. Q. N.; Gunnlaugsson, T.; Hauxley, A. J. M.; McCoy, C. P., Plenum Press: New York, 1991; p 59l. (b) Kleerekoper, M.; Endocrinol
Rademacher, J. T.; Rice, T. E. Chem. ReV. 1997, 97, 1515-1566. Metab. Clin. North Am. 1998, 27, 441.

10.1021/ol048829w CCC: $27.50 © 2004 American Chemical Society

Published on Web 09/04/2004
receptors it is generally moderate and is of the order of 103. ion with receptor 1 did not show any color change even when
Despite considerable efforts, attempts to increase the recep- allowed to stand at room temperature for more than 24 h.
tor’s inherent affinity along with its specificity for fluoride However, the color of the DMSO/CH3CN (1:9, v/v) solution
ion has generally led to complexity of design and synthesis. changes, in the presence of fluoride ion, to pale red when
Thus, a challenge remains for chemists to make a colori- the temperature of the mixture was systematically raised from
metric sensor that is specific and sensitive and has a high rt to 60 °C; λmax at 422 nm for 1 disappears, while a new
association constant for fluoride ion, crucial factors for the λmax at 530 nm ( ) 8500 M-1 cm-1) with two isosbestic
design of a simple-to-use detection tool. points at 369 and 460 nm appears. Similar experiments with
One of the reports on the bis-urea functionality based corresponding Cl-, Br-, and I- salts were repeated, and no
fluorosensor (1,8-bis(N-phenylureido)naphthalene) for fluo- significant change in spectra was observed, suggesting no
ride ion describes a shift in λmax (from 315 to 370 nm) in binding or very weak binding of those ions to the receptor
the UV region of the electronic spectra on fluoride ion molecules.
binding.5a,b The association constant value (Kf) for this anion, To examine this behavior of receptor 1, ab initio quantum
is found to be ∼105, and more importantly the selectivity chemical calculations were performed. The structure of 1
for F- has been found to be 340 times greater than that for and 1F-, 1Cl-, and 1Br- were optimized at the Hartree-
Cl-. Similar studies with an analogous derivative derived Fock RHF/6-31G* level of theory.8 For computational
from 1,8-anthracenedimethylamine reveal that Kf for fluoride simplicity, the anthraquinone moiety was modeled with
ion binding is 7.12 × 105, while the selectivity compared to naphthaquinone. The conformation predicted for the receptor
Cl- is only 120.5h Closer examination into the structural 1 has been found to be intramolecularly hydrogen bonded
aspect of these two derivatives led us to presume that the (Figure 1a). The urea functional groups are not properly
larger separation distance between the two urea functionality aligned for binding the guest anions. The intramolecular
accounts for the observed decrease in selectivity in the latter N-H‚‚‚O hydrogen bonded distances calculated at HF/6-
case. One earlier report describes the use of 1,5-diaminoan- 31G* are 1.893 and 1.918Å, respectively. C-H‚‚‚O type
thraquinone for synthesis of corresponding urea and thiourea interactions have also been observed between the benzene
derivatives for use as a colorimetric sensor for various anions, hydrogen and the amide carbonyl group (Figure 1a). There-
including fluoride ion.7c However, no details such as as- fore, it appears that such a preferred conformation of receptor
sociation constant and comparison with the existing sensors 1 does not allow the fluoride ion to complex with the N-H
are provided. With this information available in the literature, donor atoms; hence, energy is required to properly orient
we decided to design a new sensor having an anthraquinone the amido functionality for complexation with the former
moiety as the colorimetric reporter group and with an anion. For further examination, we decided to model a
appropriate distance between the two urea functionalities to thiourea functionality instead of a urea group and optimized
achieve a higher association constant. the structure of receptor 2 at the HF/6-31G* level. It is known
Chromogenic sensor 1 (urea, N,N′′-(9,10-dihydro-9,10- that sulfur atom forms weaker hydrogen bonds, and hence 2
dioxo-1,2-anthracenediyl)bis[N′-phenyl]) was synthesized should act as a better receptor for F- at room temperature.9
following the methodology shown in (Scheme 1) and isolated The HF/6-31G*-calculated results suggest that the NH‚‚‚S
hydrogen bond (ca. 2.473 Å) is much longer than that of
NH‚‚‚O bonds in 1 and the thiourea groups are significantly
Scheme 1 deviated from the phenyl and naphthaquinone ring planes

(5) (a) Lee, J. Y.; Cho, E. J.; Mukamel, S.; Nam, K. C. J. Org. Chem.
2004, 69, 943-950. (b) Cho, E. J.; Moon, J. W.; Ko, S. W.; Lee, J. Y.;
Kim, S. K.; Yoon, J., Nam, K. C. J. Am. Chem. Soc. 2003, 125, 12376-
12377. (c) Miyaji, H.; Anzenbacher, P., Jr.; Sessler, J. L.; Bleasdale, E. R.;
Gale, P. Chem. Commun. 1999, 17, 1723-1725. (d) Anzenbacher, P., Jr.;
Jursikova, K.; Sessler, J. L. J. Am. Chem. Soc. 2000, 122, 9350-9352. (e)
J. Am. Chem. Soc. 2002, 124, 8644-8652. (f) Anzenbacher, P., Jr.; Try,
A. C.; Miyaji, H. J. Am. Chem. Soc. 2000, 122, 10268-10272. (g) Miyaji,
H.; Sato, W.; Sessler, J. L Angew. Chem., Int. Ed. 2000, 39, 1777-1780.
(h) Kim, S. K.; Yoon, J. Chem. Commun. 2002, 770-771.
(6) (a) Ghosh, T.; Maiya, B. J. Proc. India Acad. Sci. (Chem. Sci.) 2004,
116, 1-4. (b) Black, C. B.; Andrioletti, B.; Try, A. C.; Ruiperez, C.; Sessler,
as a pure compound in a reasonably good yield (60%). J. L. J. Am. Chem. Soc. 1999, 121, 10438-10439. (c) Lavigne, J. J.; Anslyn,
Receptor 2 (thiourea, N,N′′-(9,10-dihydro-9,10-dioxo-1,2- E. V. Angew. Chem., Int. Ed. 1999, 38, 3903. (d) Piatek, P.; Jurezak, J.
Chem. Commun. 2002, 20, 2450-2452.
anthracenediyl)bis[N′-phenyl]) was synthesized using phen- (7) (a) Black, C. B.; Andrioletti, B.; Try, A. C.; Ruiperez, C.; Sessler, J.
ylisothiocyanate instead of phenylisocyanate (Scheme 1). L. J. Am. Chem. Soc. 1999, 121, 10438-10439. (b) Angew. Chem., Int.
Ed. 2001, 40, 154-157. (c) Jimenez, D.; Manez, R. M.; Sancenon F, Soto,
Other synthetic methodologies are identical; however, the J. Tetrahedron Lett, 2002, 43, 2823-2825. (d) Desai, R. D.; Dalal, S. K.;
yield for receptor 2 was higher (82%). 1H NMR spectroscopy Parikh, A. R. J. Inst. Chem. (India) 1988, 60, 133-136.
and elemental analysis data for receptors (1 and 2) match (8) (a) TITAN; Wavefunction, Inc.: Irvine CA. (b) The interaction energy
is simply obtained by the energy of the complex subtracted by the sum of
with their proposed formulation. UV-vis spectra of 1 and 2 energies of constituents. The interaction is very strong due to charged
in DMSO/CH3CN (1:9, v/v) showed λmax at 422 nm ( ) hydrogen bonds; thus, the basis set superposition error (BSSE) is expected
to be negligible compared with the magnitude of the total interaction
8160 M-1 cm-1) and 459 nm ( ) 18680 M-1 cm-1), energies.
respectively. Preliminary titration experiments for fluoride (9) Zuika I. V.; Bankovski, A. Yu. Russ. Chem. ReV. 1973, 42, 22-36.

3446 Org. Lett., Vol. 6, No. 20, 2004

Figure 1. RHF/6-31G*-optimized geometries for the free receptor 1 (a) and its complexes with halides F- (c), Cl- (d), and Br- (e) and
for receptor 2 (b) and its complexes with halides F- (f), Cl- (g), and Br- (h) (color key: red ) oxygen; blue ) nitrogen; yellow ) sulfur;
greenish-yellow ) fluoride; green ) chloride; brown ) bromide).

(Figure 1b). Consequently, the intramolecular N-H‚‚‚O 2 at rt with F- as a guest in a DMSO/CH3CN (1:9, v/v)
hydrogen bond between the naphthaquinone carbonyl group solution show maxima at a mole fraction of 0.5 in each case,
and the donor N-H group becomes longer (2.112 Å) in this which signifies that the host binds the anionic guest in a 1:1
case. Therefore, it will be much easier for the receptor 2 to ratio. This also indicates that two urea/thiourea groups act
align the thiourea functionality for complex formation with as cooperative binding sites.
fluoride ion in comparison to receptor 1. This prompted us
to synthesize receptor 2. To our delight, preliminary titration
experiment in a DMSO/CH3CN (1:9, v/v) solution of receptor
2 with externally added fluoride ion shows an immediate
change in color at rt: the color changes from yellow to
purple, and the change could be detected by the naked eye.
Change in UV-vis spectra for the precise titration of receptor
1 at 60 °C and 2 at rt are shown in Figure 2. Similar
experiments performed with receptor 2 and corresponding
Cl-, Br-, and I- salts were repeated. For externally added
Cl- and I- salts, spectra almost remain unchanged, though
a little variation was observed with the Br- salt. These Figure 2. Change in UV-vis spectra for receptor 2 at rt (2.5 ×
suggest no binding and very little binding of Cl-/I- and Br- 10-5 M) (a) and receptor 1 at 60 °C (5 × 10-5 M) (b) in DMSO-
CH3CN (1:9, v/v) upon the addition of 7.5 × 10-6 to 5 × 10-4 M
ions, respectively, to the receptor molecule 2. of fluoride ion. No further change was observed on addition of
As seen in Figure 2, a bathochromic shift of 108 and 102 even higher concentration of fluoride ion.
nm was observed on complexation with F- for receptors 1
and 2, respectively. λmax of 422 nm for receptor 1 and 459
nm for receptor 2 bleaches on complexation with fluoride The association constant values for receptors 1 and 2
ion, and new absorption maxima develop at 530 nm and 561 calculated from the UV-vis titration data are summarized
nm, respectively. Simultaneous growth in absorbance at 310 in Table 1. Experimental results suggest that receptors 1 and
and 380 nm occurred, while two isobestic points 380 and 2 can be termed selective colorimetric sensors for F-.
500 nm were observed, respectively, for receptors 1 and 2 The relative preference in binding ability of 1 and 2 for
(Figure 2). Significant bathochromic shift for absorption F- is also evident in 1HNMR titration experiments in DMSO-
maxima in the visible region on fluoride ion complexation d6. A partial 1H NMR spectrum of receptor 2 is shown in
is presumably due to the charge-transfer interaction between (Figure 3), which shows the complete disappearance of the
the electron-rich urea/thiourea-bound fluoride ion and the signals for the amide -NH protons upon addition of 5 mol
electron-deficient anthraquinone moieties. This also suggests equiv of fluoride ion. A similar observation was reported
that the excited state would be more stabilized by fluoride earlier and is presumably due to strong hydrogen bonding
ion binding.1d,2a Job plots for receptor 1 at 60 °C and receptor with the fluoride ion.5a Signals for -NH protons at 9.719
Org. Lett., Vol. 6, No. 20, 2004 3447
 during complexation, one of the thioamide unit moves toward
Table 1. planarity, however, the other one remains perpendicular to
the phenyl ring plane. Being smaller in size, fluoride ion
aniona K1b (M-1) K2b (M-1)
approaches much closer to the cavity and interacts much
F- (4.4 ( 0.2)105 (8.2 ( 0.5)105 more strongly with the amide/thioamide protons. It is
Cl- interesting to note that the interatomic distances between the
Br- 3.4 ( 1.0
I-
complexed chloride ion and the four amide/thioamide protons
a Tertiary butyl salt of the respective anions were used for the studies.
are smaller than those of the corresponding bromide ions;
b K value reported (K1 for receptor 1 and K2 for receptor 2) is the average however, the binding energy has been found to be marginally
of the 11 independent data evaluated from each individual UV-vis titration preferred for Br- over Cl- in receptors 1 and 2 (Figure
data for the respective receptor and anion. Confidence limits for the
respective K values are also shown. 1d,e,g,h). The association constant obtained for the com-
plexation of Br- with receptor 2 supports our calculated
results (Table 1). The overall energetic preference for the
(1H,S) and 9.795 (1H,S) for 1 at 60 °C and 12.721 (2H,S) complexation of Br- over Cl- arises presumably due to the
and 13.30 (2H,S) for 2 at rt, respectively, disappear on lesser electrostatic repulsion between the amido/thioamido
association with the fluoride ion. Such shifts were not group and the naphthaquinone carbonyl group. The calculated
observed for Cl- and I-, and a small shift was observed when torsions at RHF/6-31G* suggest that in the case of Br-, one
of the thioamido groups is oriented more perpendicular with
respect to phenyl ring (52.0°) than that of Cl- (55.0°) and
hence experiences less electrostatic repulsion in the former
case. However, the other thioamido groups are positioned
in a similar manner in both cases. Furthermore, the calculated
binding energy for the receptor 2 with halides is relatively
larger than that of receptor 1. This result is qualitatively in
agreement with the observed association constant for recep-
tors 1 and 2 with fluoride ion (Table 1). It is known that the
degree of charge transfer from nitrogen to sulfur in thioamide
is significantly greater than that of nitrogen to oxygen in
amides, and hence the N-H bonds are better acceptors in
Figure 3. Partial 1H NMR (200 MHz) spectra of receptor 2 in the former case.10 Thus, the anthraquinone moiety acts not
DMSO-d6 at rt in (a) the absence and (b) the presence of 5.0 equiv only as a spectroscopy receptor group but also as an effective
of [(But)4N]F. template with an appropriate distance of separation between
the urea/thiourea groups for selective binding of the fluoride
ion.
receptor 2 was titrated with Br- salt solution. The small In conclusion, we have succeeded in preparing anion
change in UV-vis spectra for receptor 2 when titrated with sensors that not only allow for the facile colorimetric
different [Br-] allowed us to evaluate the association constant detection of F- ion but also are amenable to “color tuning”.
for Br- and is summarized in Table 1. It has been shown that urea and thiourea binding sites
The observed selectivity of receptors 1 and 2 for F- can anchored to anthraquinone signaling subunits are suitable
be explained on the basis of the RHF/6-31G*-optimized colorimetric reagents for F- sensing. The effect of subtle
structures for the complexes of receptors 1 and 2 with halides changes in the structure of the receptor (from urea to
(F-, Cl-, Br-) represented in Figure 1. Single-point interac- thiourea) has been observed. Receptors 1 and 2 have shown
tion energies calculated at the B3LYP/6-31G* level using little or no affinity for Cl-, Br-, and I- ions. Accordingly,
RHF/6-31G*-optimized geometries without basis set super- it is possible to conceive the use of these systems in various
position error correction are -120.2, -49.0, and -52.9 kcal/ sensing applications as well as in other situations such as
mol for F-, Cl-, and Br-, respectively, with receptor 1 and anion transport and purification, where the availability of
-127.8, -53.1, and -58.1 kcal/mol with receptor 2.8b The cheap and easy-to-make anion receptors would be advanta-
large binding energy difference between F- and Cl-/Br- may geous.
result in preferential binding for F- over Cl-/Br- in both
Acknowledgment. A.D. thanks DST (New Delhi) for
cases as observed in the titration experiment. The halide ions
financial support.
sit asymmetrically in receptor 1 and 2, and all four amide/
thioamide protons participate in hydrogen bonding with Supporting Information Available: Synthesis, UV-vis
anions (Figure 1c-h). The amido groups prefer to be in the spectra of receptors 1 and 2 with different anions, UV-vis
plane of the phenyl rings in receptor 1; however, the titration curves, color change, discussion on results of
thioamide groups in receptor 2 orient almost perpendicular electrochemical studies, and Cartesian coordinates of the
to the phenyl rings. Upon complexation of halides with calculated structures. This material is available free of charge
receptor 1, one of the amide units lies in the plane of the via the Internet at http://pubs.acs.org.
OL048829W
phenyl ring, but the other amide group deviates from
planarity by ∼18.0°. Interestingly, in the case of receptor 2, (10) Wiberg, K. B.; Rush, D. J. J. Am. Chem. Soc. 2001, 123, 2038-2046.

3448 Org. Lett., Vol. 6, No. 20, 2004