Colorimetric fluoride sensor based on a bisthiourea functionalized molecular clip

Article abstract of DOI:10.1055/s-0030-1258578

A new class of bisthiourea-functionalized molecular clips were designed and synthesized for anion recognition. Clip 1 showed excellent affinity to the biologically relevant fluoride ion in a 1:1 ratio as shown by UV-vis, H and ⁹F NMR studies. Moreover, the binding was accompanied with visually noticeable color changes, enabling the compound to act as a colorimetric fluoride sensor. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258578

LETTER
2553
Colorimetric Fluoride Sensor Based on a Bisthiourea Functionalized
Molecular Clip
Colorimetric
FliuoridepSensor ing Cao, Jiaoyang Ding, Jungang Wang, Yan Chen, Meng Gao, Weijian Xue, Anxin Wu*
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Central China Normal University,
Wuhan 430079, P. R. of China
E-mail: chwuax@mail.ccnu.edu.cn
Received 10 June 2010
molecular clips 1–5 were designed and synthesized by the
reaction of the corresponding diamino molecular clip with
isothiocyanate or isocyanate (Scheme 1). Because of the
special precaved structure of glycoluril molecular clip as
Abstract: A new class of bisthiourea-functionalized molecular
clips were designed and synthesized for anion recognition. Clip 1
showed excellent affinity to the biologically relevant fluoride ion in
a 1:1 ratio as shown by UV-vis, 1H and 19F NMR studies. Moreover,
the binding was accompanied with visually noticeable color chang- a space linker, as well as two cis-thiourea groups as poten-
es, enabling the compound to act as a colorimetric fluoride sensor.
tial H-bonded binding sites to anions, we envisioned that
these molecular clips might present suitable binding clefts
and sites to capture corresponding anions.
Key words: glycoluril, molecular clip, fluoride, sensor, thiourea
O
Recognizing and sensing of biologically important anion
ions via artificial receptors has recently grown into an area
of great interest in supramolecular and biological chemis-
try.1 Due to large variation in size, shape, charge distribu-
tion, and strong solvation, highly selective recognition for
anions is a challenging task. Among various important an-
ionic analytes, the recognition of fluoride ions as biologi-
cally and environmentally important anions is attracting a
great deal of interest because of its medical applications
such as dental heath and possible toxicity.2 Recently, con-
siderable efforts have been devoted to fluoride ion sensing
via UV-vis, fluorescence, or other methods.3–8 For exam-
ple, Sessler and co-workers had succeed in developing a
series of functionalized calix[4]pyrrole derivatives, and
dipyrrolyquinoxalines as new fluorescent chemosensors
for fluoride anions.4 Moreover, bis(thio)urea derivatives,5
organoboron compounds,6 amide macrocycles,7 and other
compounds8 were also applied to the field of recognizing
and sensing fluoride ions.
As the essential component of Nolte’s molecular clips,9
Rebek’s capsules,10 and the cucurbit[n]uril family of
macrocycles11, glycoluril has become a popular building
block for the preparation of new host system.12 Previous-
ly, we have developed a series of fluorescent molecular
clips based on glycoluril skeleton for sensing metal ions13
and phenols.14 As a part of our contribution to molecular
recognition, we have decided to investigate the use of gly-
coluril molecular clips for sensing anions. It is well known
that hydrogen bonding is widely used as the anion–recep-
tor interactions. Typically, molecules employing different
combination of amide, thiourea, and pyrrole units can of-
fer one or more H-bonded donor sites for effective bind-
ing and sensing of some anions.15 As a result, five
O
OH
O
O
CO2Et
CO2Et
HN
R1
HN
NH
R1
NH
(i)
(iii)
HO
HO
OH
(ii)
7
O
6
O
8 R1 = CO2Et
(vi)
Me
O
O
Me
O
O
N
N
Me
O
Me
R1
R1
O
O
N
N
N
R1
N
N
(v)
R1
NH
HN
HN
(vi)
X
X
N
NH
R2
NO2
NO2
R2
O
9 R1 = CO2Et
1 X = S; R2 = 4-nitrophenyl
2 X = S; R2 = phenyl
3 X = S; R2 = pentafluorophenyl
4 X = S; R2 = 3,5-bis(trifluoromethyl)phenyl
5 X = O; R2 = 4-nitrophenyl
Scheme 1 Reagents and conditions: (i) AcOH, Br2, H2O; (ii) EtOH,
HCl (g), 0 °C; (iii) PhH, H2NCONH2, TFA, reflux; (iv) 1,2-bis(bro-
momethyl)-3,6-dibromobenzene, KOt-Bu, DMSO; (v) H2, Pd/C,
DMF, r.t.; (vi) isothiocyanate or isocyanate, CH2Cl2, r.t.
Initially, UV-vis experiments were carried out in MeCN–
DMSO (9:1, v/v) solution.16 The absorbance spectrum of
compounds 1 and 5 showed peaks at 345 nm and 346 nm,
respectively. However, compounds 2–4 with anions did
not exhibit any significant absorbance peak.17 A solution
of receptor 1 was treated with the representative anions
such as tetrabutylammonium (TBA) fluoride, chloride,
bromide, iodide, hydrogen sulfate, perchlorate, hexafluo-
rophosphate, acetate, and dihydrogen phosphate. Figure 1
shows the absorption spectra of receptor 1 in the presence
of the various anions. The absorption peak at 345 nm was
shifted to 398 nm (Dlmax = 53 nm) when fluoride was add-
SYNLETT 2010, No. 17, pp 2553–2556
x
x
.x
x
.2
0
1
0
Advanced online publication: 23.09.2010
DOI: 10.1055/s-0030-1258578; Art ID: W09210ST
© Georg Thieme Verlag Stuttgart · New York

2554
L. Cao et al.
LETTER
ed. Significant bathochromic shift of the absorption max- tio.18 This also suggested that two cis-thiourea groups act
imum in the presence of fluoride ion was presumably due as cooperative binding sites.
to the charge-transfer interaction between the electron-
As shown in Figure 3, color changes could be observed
rich thiourea-bound fluoride ion and the electron-defi-
easily by mixing the receptor 1 and anions, respectively.
cient p-nitrophenyl moiety. For the externally added Cl–,
–
–
–
Various anions (F–, Cl–, Br–, I–, HSO4 , ClO4 , PF6 , AcO–,
–
–
–
Br–, I–, HSO4 , ClO4 , and PF6 salts, the UV spectra re-
–
and H2PO4 ) were added into 1 in DMSO. Specifically, it
mained almost unchanged, though a little variation was
was noticeable that a pale yellow receptor solution be-
came dark red when fluoride ions were added to receptor
1. The reason of the color change in the receptor solvent
could be ascribed to the charge-transfer interactions be-
tween the electron-rich fluoride ions and the electron-
deficient p-nitrophenyl moiety, which caused the elongat-
ed conjugation of the p-nitrophenyl moieties, resulting in
a visible color change.5d,i
–
observed with the AcO– and H2PO4 salts. These suggest-
–
ed no binding or very weak binding of Cl–/Br–/I–/HSO4 /
–
–
–
ClO4 /PF6 and AcO–/H2PO4 ions to the receptor 1, re-
spectively. For receptor 2, only F–, AcO–, and H2PO4 ions
–
produced a little change of the absorbance spectra.17
Figure 3 Color changes of receptors 1 (1.0·10–3 M) in DMSO with
the addition of TBA anions (4.0·10–3 M); A = free receptor, B = F–,
C = Cl–, D = Br–, E = I–, F = HSO4 , G = ClO4 , H = PF6 , I = AcO–,
J = H2PO4
–
–
–
–
To support the result obtained from UV-vis studies for re-
1
ceptor 1, we performed H NMR titration with TBAF.
Due to insufficient solubility of 1, NMR studies were per-
formed in DMSO-d6. However, we could not conduct the
1H NMR titration of 1 with fluoride ion due to the com-
plete disappearance of the signals of the thiourea–NH
upon addition of fluoride ion. As shown in Figure 4, the
signals of N–H protons that resonate at d = 10.71 and 9.58
ppm broadened gradually, and completely disappeared af-
ter adding 1.0 equivalent of fluoride ion. Similar observa-
tions were reported before and were attributed to the
strong hydrogen bonding with the fluoride ion.5d,h The dis-
appearance of all N–H proton signals also led us to spec-
ulate that the proton donor sites make a convergent array
of hydrogen bonding for binding fluoride ion by means of
a model of (N–H)4···F–. Meanwhile, the overlap of two C–
H proton signals (Ha and Hb) of aromatic ring suggested
the elongated conjugation of the p-nitrophenyl moieties.
Figure 1 Absorption spectra of receptor 1 (9.1 mM) upon addition
of a particular TBA salt (30 equiv) in MeCN–DMSO (9:1, v/v)
To investigate the binding abilities of receptor 1 to fluo-
ride ion, titration studies were performed (Figure 2). The
binding constant of 1 with fluoride was determined from
the titration data to be approximately 5.48 ( 0.40)×104
M–1.17 The Job plot for receptor 1 at 293 K with fluoride
ions as a guest in a MeCN–DMSO (9:1, v/v) solution
showed a maximum at a mole fraction of 0.5, which indi-
cated that the host binds to the anionic guest in a 1:1 ra-
Due to the application of 19F NMR as a very effective
probe for examining the interaction of the highly elec-
tronegative F– with hosts in solution,4e–4j,7c the ion-binding
properties of receptor 1 were probed by 19F NMR spec-
troscopy by addition of 1.0–10.0 equivalents of TBAF in
DMSO-d6 (Figure 5). When one equivalent of fluoride ion
was added to 1, the fluoride signal shifted from d = –107.7
to –152.4 ppm indicating that the fluoride ion was encap-
sulated by four N–H hydrogen bonds, which would shield
the fluoride and cause an upfield shift of the signal. Fur-
ther addition of fluoride in excess (5.0 equiv) shifted the
fluoride signal to d = –144.3 ppm which could be assigned
to the formation of hydrogen-bonded fluoride (HF)
species8g and the signal of free fluoride appeared firstly.
We speculated that four H atoms of thiourea groups bound
Figure 2 Spectral changes in a UV-vis titration experiment for re-
ceptor 1 (10 mM) in MECN–DMSO (9:1, v/v) in the presence of 0.1
to 50.0 equiv of TBAF predissolved in MeCN
Synlett 2010, No. 17, 2553–2556 © Thieme Stuttgart · New York

LETTER
Colorimetric Fluoride Sensor
2555
with fluoride ions after adding four equivalents of TBAF,
without more H atoms for bonding with more fluoride
ions. In addition, the septet of double peak (JHF = 106.0
Hz) would be the result of bonding between H and F. We
also noted that the signal was at the highest upfield region
when only 1.0 equivalent of TBAF was added, which pro-
vide further confirmation that F– is the best bonding as 1:1
inclusion complex in solution.
1
Based on the above-described UV-vis, H and 19F NMR
studies, we proposed that the process of recognition as fol-
low: when the receptor binds to 1.0 equivalent of fluoride
ions, four hydrogen bonds are constructed with F– to form
stable complexes. The RHF/6-31G*-optimized geometry
of 1·F– complex showed the possibility.17 Then, addition
of fluoride ions beyond one equivalent causes the depro-
tonation of four NH of thiourea and forms hydrogen-
bonded fluoride (HF) species (Figure 6). The deprotonat-
ed clip 1 could be stablilized by the delocalization of neg-
ative charge on the nitrogen atoms of the thiourea over the
nitrophenyl moieties. Interestingly, addition of a few
drops of water triggered the disappearance of the dark red
color of the 1–fluoride complex, which suggested the
whole procession of recognition and deprotonation was
reversible in nature.8g,17
1
Figure 4 Partial H NMR (600 MHz) spectra of 1 (40 mM in
DMSO-d6 at 293 K) upon successive addition of 0–1.0 equiv of [(n-
Bu)4N]F
In conclusion, we have synthesized five new molecular
clips 1–5 with two thiourea groups, of which 1 exhibits an
excellent affinity to fluoride ions. When 1 was treated
with fluoride ion, a distinct color change was observed by
extending the conjugated system, which is caused by the
formation of a fluoride–receptor complex. The skeleton of
glycoluril molecular clip acts as an effective template with
an appropriate distance of separation between the thiourea
groups for selective binding of fluoride ion. Studies aimed
at investigating the mechanism, scope of the recognition,
the synthesis, and application of the chemosensor based
on glycoluril molecular clips are under way and will be re-
ported in due course.
Figure 5 19F NMR (376 MHz) spectrum of 1 (20 mM in DMSO-d6
at 293 K) upon successive addition of 1.0–10.0 equiv of (n-Bu)4N+F–
in DMSO-d6
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
R
R
Me
O
Me
Me
O
O
Me
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
R
R
R
R
O
F–
O
additional 3 equiv
F–
1 equiv
S
N
N
N
N
S
NH
NH
HN
HN
O
N
N
S
S
H
S
H
O
F–
N
4 equiv
H+
S
H
H
N
O
Ha
Hb
F–
N
Ha'
O
N
O
Hb'
N
NO2
N
NO2
O
O
O
O
Figure 6 A proposed binding mode and deprotonation of 1 with fluoride ions
Synlett 2010, No. 17, 2553–2556 © Thieme Stuttgart · New York

2556
L. Cao et al.
LETTER
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Acknowledgment
We thank the National Natural Science Foundation of China (Grant
No. 20872042 and 21032001) for funding and the research was sup-
ported in part by the PCSIRT (No. IRT0953). We also gratefully
thank Prof. L. Isaacs for helpful discussions and Prof. Y. J. Pan for
HRMS.
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