Tunability of anion binding strength based on acyl-thiourea receptors containing isatin group

Article abstract of DOI:10.1016/j.saa.2008.12.042

Some acyl-thiourea derivatives containing isatin group were synthesized and their interactions with anions were investigated using UV-vis spectroscopy and ¹H NMR titrations in DMSO and DMSO-d₆, respectively. These compounds have a same molecular framework, functionalising with different groups lead to different anion binding strength of these receptors. Receptor 1 showed a higher binding affinity for AcO^- than for F^-, due to the cooperative multiple hydrogen bond interactions of AcO^- with the acyl-thiourea group and N-H group in the indole unit of receptor 1. Displacing the N-H proton in the indole unit with -CH₃ group, receptor 2 showed no obviously discriminative responses for F^-, AcO^- and H₂PO₄^- due to lack of such additional binding. In the case of receptor 3, which was functionalised with strong electron-withdrawing group, it showed selectively chromogenic response for F^- based on double deprotonation of the receptor in DMSO, whereas AcO^- and H₂PO₄^- induced single deprotonation only.

Full text of DOI:10.1016/j.saa.2008.12.042

Spectrochimica Acta Part A 72 (2009) 1043–1046
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
Tunability of anion binding strength based on acyl-thiourea
receptors containing isatin group
Shuzhen Hua,b, Yong Guoa, Jian Xua, Shijun Shaoa,∗
a Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
b Graduate School of the Chinese Academy of Sciences, Beijing 100039, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2008
Received in revised form 6 October 2008
Accepted 27 December 2008
Some acyl-thiourea derivatives containing isatin group were synthesized and their interactions with
anions were investigated using UV–vis spectroscopy and 1H NMR titrations in DMSO and DMSO-d6,
respectively. These compounds have a same molecular framework, functionalising with different groups
lead to different anion binding strength of these receptors. Receptor 1 showed a higher binding affin-
ity for AcO− than for F−, due to the cooperative multiple hydrogen bond interactions of AcO− with the
acyl-thiourea group and N–H group in the indole unit of receptor 1. Displacing the N–H proton in the
indole unit with –CH3 group, receptor 2 showed no obviously discriminative responses for F−, AcO− and
Keywords:
Anion recognition
Acyl-thiourea
Anion receptor
Isatin
−
H2PO4 due to lack of such additional binding. In the case of receptor 3, which was functionalised with
strong electron-withdrawing group, it showed selectively chromogenic response for F− based on double
deprotonation of the receptor in DMSO, whereas AcO− and H2PO4 induced single deprotonation only.
−
© 2008 Elsevier B.V. All rights reserved.
1. Introduction
2. Experimental
Anion recognition is an area of growing interest in supramolec-
ular chemistry due to its potential environmental, clinical and
biological applications [1–4]. Neutral anion receptors that bind
anions via hydrogen bonds are of considerable interest [5]. Recep-
tor systems that employ thiourea (urea) group to complex anionic
guests had been investigated extensively [6]. To obtain enhanced
binding ability and selectivity, many examples of N,N-substituents
modified thiourea based receptors such as amido-thiourea have
been reported [7–9], and the selective response towards acetate
anion has been demonstrated [7,8]. Acyl-thiourea based anion
receptors [10,11] and the selectivity for acetate anion in a mixed
DMSO–water medium have also been described [10]. On the other
hand, the indole group as a scaffold for anion recognition has been
reported recently [12–17]. However, it is still a significant challenge
to develop receptors that show controllable anion selectivities. We
envisioned that coupling the acyl-thiourea group with indole group
to form a multiple hydrogen bond binding sites would possibly pro-
vide better affinity and selectivity towards certain anions. Here, the
The receptors 1 and 3 were prepared by reaction of isatin with
excess of hydrazine hydrate followed by condensation with cor-
responding isothiocyanate, receptor 2 was prepared by the same
method using the N-methylisatin as starting material (Scheme 1).
2.1. Compounds 4 and 5
N-methylisatin was prepared according to the literature [18].
0.02 mol isatin (for 4) or N-methylisatin (for 5) was suspended
in ethanol, excess hydrazine hydrate (80%, 4 mL) was added, the
mixture was stirred for 16 h at room temperature, then the solvent
was removed under reduced pressure. Recrystallization in ethanol
afforded 4 and 5 as orange needles. TLC indicated that they are
single compound and used directly in next step.
2.2. Compound 1
0.22 g (1.5 mmol) Benzoyl chloride and 0.136 g (1.6 mmol)
sodium thiocyanate in 15 mL acetonitrile were stirred at room tem-
perature for 0.5 h, then 0.242 g (1.5 mmol) 4 in 10 mL DMF was
added dropwise, the mixture was stirred at room temperature for
24 h, then concentrated to ∼10 mL, poured into the ice-water, the
precipitate was collected and dried. Recrystallization in DMF-water
afforded 1 as yellow solid. Yield 74%.
evaluation of such receptors 1–3 (Scheme 1) using UV–vis and 1
H
NMR titrations is presented.
∗
Mp: 204–206 ◦C. MS (ESI): m/z 323.6 (M−H)+. 1H NMR
(400 MHz, DMSO-d6), ı (ppm): 15.74 (s, 1H, N–H), 11.94 (s, 1H, N–H),
Corresponding author. Fax: +86 931 8277088.
E-mail address: shaoguo@lzb.ac.cn (S. Shao).
1386-1425/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2008.12.042

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S. Hu et al. / Spectrochimica Acta Part A 72 (2009) 1043–1046
Scheme 1. Synthesis of 1–3.
11.19 (s, 1H, N–H), 7.98–7.96 (d, 2H), 7.67–7.63 (t, 1H), 7.58–7.51 (m,
3H), 7.41–7.37 (t, 1H), 7.10–7.06 (t, 1H), 6.93–6.91 (d, 1H). 13C NMR
(100 MHz, DMSO-d6), ı (ppm): 179.63, 166.76, 161.11, 143.17, 143.01,
140.66, 133.21, 132.35, 131.82, 128.84, 128.47, 122.57, 121.52, 119.94,
111.08.
in intensity gradually (Fig. S1). No obvious color changes of the
solution were observed. A well-defined isosbestic point observed
at 330 nm suggests the 1:1 host/guest binding stoichiometry and
simple equilibrium, this was further confirmed by the Job’s plot
experiments (Fig. S2). The association constants were calculated
to be 2.48 × 106 M−1 for AcO− through nonlinear least squares fit-
ting [19] by Origin software. F− and H2PO4 can induce similar
−
2.3. Compound 2
absorption spectra changes (Fig. S1), and the equilibrium constants
were calculated to be 1.96 × 105 M−1 and 1.46 × 105 M−1 for F−
and H2PO4−, respectively. The order of the affinities of receptor 1
towards anions in DMSO solution is: AcO− > F− > H2PO4− ꢀ Cl−, Br−,
0.22 g (1.5 mmol) Benzoyl chloride and 0.136 g (1.6 mmol)
sodium thiocyanate in 15 mL acetonitrile were stirred at room tem-
perature for 0.5 h, then 0.26 g (1.5 mmol) 5 in 10 mL DMF was added
dropwise, the mixture was stirred at room temperature for 24 h,
then concentrated to ∼10 mL, poured into the ice-water, the precip-
itate was collected and dried. Recrystallization in ethanol afforded
2 as orange solid. Yield 72%.
I−, HSO4 and ClO4−. The results clearly indicated that receptor 1
−
showed selectivity towards AcO− in DMSO, the nature of recog-
nition events was based on hydrogen bonding and the complexes
[LH2···X]− were formed. This process can be described by the fol-
lowing equilibrium developed by Fabbrizzi’s group [20–22].
MS (ESI): m/z 337.4 (M−H)+. 1H NMR (400 MHz, DMSO-d6), ı
(ppm): 14.24 (s, 1H, N–H), 12.18 (s, 1H, N–H), 8.02–8.00 (d, 2H),
7.70–7.66 (t, 1H), 7.57–7.50 (m, 4H), 7.14–7.06 (m, 2H), 3.22 (s, 3H).
IR (KBr): 3417, 3228, 3061, 1722, 1674, 1611, 1534, 1467, 1375, 1335,
LH2 + X− ↔ [LH2· · ·X]−
(1)
The selectivity of receptor 1 towards AcO− was probably due to
that the configuration of the anion was matching with the recep-
tor (Fig. 2). The acetate anion is planar and triangular, the distance
of two oxygen atoms might be fit in with the hydrogen atoms on
binding sites of receptor 1, it interacted with receptor 1 through the
thiourea group as well as the N–H of the indole unit, whereas the F−
is global and interacted with receptor 1 only through the thiourea
group, but its large negativity ensured that it had a slightly larger
1275, 1232 cm−1
.
2.4. Compound 3
0.728 g (3 mmol) 3,5-dinitrobenzoyl chloride and 0.273 g
(3.3 mmol) sodium thiocyanate in 30 mL acetonitrile were stirred
at room temperature for 0.5 h, then 0.484 g (3 mmol) 4 in 20 mL
DMF was added dropwise, the mixture was stirred at room tem-
perature for 24 h, then concentrated to ∼20 mL, poured into the
ice-water, the precipitate was collected and dried. Recrystallization
in DMF-water affords 3 as orange solid. Yield 54%.
−
association constant than H2PO4 (a tetrahedral shape anion and
Mp: 223–225.5 ◦C. MS (ESI): m/z 413.6 (M−H)+. 1H NMR
(400 MHz, DMSO-d6), ı (ppm): 9.13 (s, 2H), 9.04 (s, 1H, N–H), 7.95 (s,
1H), 7.61–7.59 (d, 1H), 7.45–7.41 (t, 1H), 7.14–7.10 (t, 1H), 6.96–6.94
(d, 1H). IR (KBr): 3213, 3037, 2926, 2874, 1703, 1666, 1548, 1462,
1342, 1122, 1095 cm−1
.
3. Results and discussion
3.1. UV–vis studies in DMSO
The UV–vis spectroscopy investigation of 1–3 was carried
out in DMSO. Receptor
1 showed two absorption bands at
382 nm (ε = 14200 M−1 cm−1) and 313 nm (ε = 12250 M−1 cm−1).
Upon addition of−anions such as F−, Cl−, Br−, I−, HSO4−, ClO4
,
−
AcO− and H2PO4 (all as their tetrabutylammonium salts), basic
anions such as F−, AcO− and H2PO4 remarkably changed the
−
absorption spectrum of 1, whereas the other anions tested induced
negligible responses (Fig. 1). During the titration of AcO− to the
solution of receptor 1, the band at 382 nm was increased in inten-
sity and blue-shift to 371 nm, the band at 313 nm was decreased
Fig. 1. UV–vis spectra of receptor 1 (5 × 10−5 M) recorded in DMSO after addition of
10 equiv. of anions.

S. Hu et al. / Spectrochimica Acta Part A 72 (2009) 1043–1046
1045
Fig. 2. Proposed binding mode of receptor 1 with F− and AcO−
.
two absorption bands at 378 nm (ε = 13660 M−1 cm−1) and 317 nm
(ε = 10850 M−1 cm−1). Upon addition of AcO− and H2PO4−, the band
at 378 nm was increased in intensity and blue-shift to 373 nm, the
band at 317 nm was disappeared, the changes of these two bands
were similar to that observed in the receptor 1, this process can be
described by the equilibrium (1). Along with increasing amounts of
anions, a new band at 486 nm and a broad band at about 600 nm
appeared and increased in intensity (Fig. S4). The color of the solu-
tion changed from yellow to orange. Obviously, the deprotonation
was occurred and the deprotonated form [LH]− was formed as
described by the following equilibrium (2):
has less basicity). These results are in agreement with the literature
reported recently [23].
To evaluate the contribution of N–H group in the indole unit
to the selectivity of receptor 1 for AcO−, receptor 2 was synthe-
sized, where the N–H proton in the indole unit was replaced by a
–CH3 group. Free receptor 2 showed one absorption band at 321 nm
(ε = 11660 M−1 cm−1). Upon addition of AcO−, the band at 321 nm
decreased in intensity and a new band at 366 nm appeared with
increased intensity (Fig. S3). No obvious color changes of the solu-
tion can be observed. Two clear isosbestic points appeared at 308
and 358 nm during the titrations. The association constants were
calculated to be 1.91 × 105 M−1 for AcO− according to a 1:1 sto-
ichiometry. Similar absorp−tion spectra changes were observed in
the case of F− and H2PO4 (Fig. S3), the equilibrium constant −is
[LH2· · ·X]− + X− ↔ [LH]− + HX−2
(2)
F− caused unique results (Fig. S4), addition of 0–10 equiv. of F−
induced similar spectrum and color changes to that of AcO− and
H2PO4−, the deprotonated form [LH]− was formed. Further addition
of F− caused more complex changes, when 10–15 equiv. of F− was
added, a band at 300 nm appeared, the band at 486 nm decreased
in intensity and band at 378 nm blue-shift to 360 nm, the broad
band at about 600 nm decreased in intensity. Along with increasing
amounts of F− was added (>15 equiv.), two new bands at about 440
and 670 nm appeared, the band at 300 nm increased in intensity
slightly, the color of solution turned from orange to dark-green. This
was due to the formation of doubly deprotonated receptor [L]2−, as
described by the following equilibrium (3):
calculated to be 1.23 × 105 and 1.09 × 105 M−1 for F− and H2PO4
,
respectively. It can be seen that the association constant of receptor
2 for AcO− was decreased, comparing with that of receptor 1, the
association constants for F− and H2PO4− were kept on a same level
with that of 1. This result indicated that the N–H group of the indole
unit played an important role in the recognition of AcO−.
To obtain better binding affinity towards anions, electron-
withdrawing group such as nitro was often introduced into
receptor to enhance the acidity of the anion binding subunit. How-
ever, in most cases, it was recognized that the hydrogen bond
donor was deprotonated and H+ transferred to the basic anion
[3,9,20–22,24–26]. Deprotonation processes can be used to colori-
metrically sense anions [27,28]. In the case of receptor 3, it showed
[LH]− + 2X− ↔ [L]2− + HX2−
(3)
Fig. 3. Titration of receptor 1 (5 × 10−2 M) in DMSO-d6 solution with AcO− (0, 0.5, 1.0, 1.5, 2.0 equiv.).

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S. Hu et al. / Spectrochimica Acta Part A 72 (2009) 1043–1046
Fig. 4. Titration of receptor 1 (5 × 10−2 M) in DMSO-d6 solution with F− (0, 0.5, 1.0, 1.5, 2.0 equiv.).
AcO− and H2PO4 cannot cause such double deprotonation,
which occurred only in DMSO solution. These results are in com-
plete agreement with the work described by Fabbrizzi’s group [3].
Thus, as expected, introducing strong electron-withdrawing group
into the receptor 1 to form the receptor 3, the selectivity response
for F− over AcO− was observed.
Acknowledgement
−
The authors thank the financial support of National Nature Sci-
ence Foundation of China (Grant Nos. 20372067 and 20672121).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.saa.2008.12.042.
3.2. 1H NMR studies in DMSO-d6
To further confirm the binding mode of receptor 1 with anions,
1H NMR titrations were carried out in DMSO-d6 solution. The pro-
tons of thiourea group in receptor 1 appeared at different chemical
shifts of 15.74 and 11.94 ppm due to the formation of intramolec-
ular hydrogen bonding [29], the N–H proton of indole unit was
appeared at 11.19 ppm. Upon addition of AcO−, the protons of
thiourea group were disappeared rapidly, the proton of indole
unit was broadened and disappeared after addition of 1 equiv.
of AcO− (Fig. 3), this clearly indicated that the three protons
were all participated in the formation of hydrogen bond between
receptor 1 and AcO−. In the case of F− (Fig. 4), the protons of
thiourea group were disappeared rapidly while the proton of indole
unit had no shift and not disappeared during the titration, this
result confirmed that F− interacted with receptor 1 through two
thiourea protons, the proton of indole unit was not included.
1H NMR titration of receptor 2 with anion was also carried out
(Fig. S5), these two protons of thiourea group appeared at 14.24
and 12.18 ppm, upon addition of AcO−, they all disappeared rapidly,
confirmed the formation of hydrogen bond between receptor 2 and
anions.
References
[1] P.A. Gale, S.E. García-Garrido, J. Garric, Chem. Soc. Rev. 37 (2008) 151.
[2] J.L. Sessler, P.A. Gale, W.S. Cho, in: J.F. Stoddart (Ed.), Anion Receptor Chem-
istry (Monographs in Supramolecular Chemistry), Royal Society of Chemistry,
Cambridge, UK, 2006.
[3] V. Amendola, D. Esteban-Gòmez, L. Fabbrizzi, M. Licchelli, Acc. Chem. Res. 39
(2006) 343.
[4] F.P. Schmidtchen, M. Berger, Chem. Rev. 97 (1997) 1609.
[5] M.M.G. Antonisse, D.N. Reinhoudt, Chem. Commun. (1998) 443.
[6] P.A. Gale, in: J.L. Atwood, J.W. Steed (Eds.), The Encyclopedia of Supramolecular
Chemistry, Dekker, New York, 2004, p. 31.
[7] T. Gunnlaugsson, P.E. Kruger, P. Jensen, J. Tierney, H.D. Ali, G.M. Hussey, J. Org.
Chem. 70 (2005) 10875.
[8] F.-Y. Wu, Z. Li, Z.-C. Wen, N. Zhou, Y.-F. Zhao, Y.-B. Jiang, Org. Lett. 4 (2002) 3203.
[9] L.S. Evans, P.A. Gale, M.E. Light, R. Quesada, Chem. Commun. (2006) 965.
[10] Y.-M. Zhang, J.-D. Qin, Q. Lin, T.-B. Wei, J. Fluorine Chem. 127 (2006) 1222.
[11] Y.-M. Zhang, C. Cao, W. Wei, T.-B. Wei, Chin. J. Chem. 25 (2007) 709.
[12] D. Curiel, A. Cowley, P.D. Beer, Chem. Commun. (2005) 236.
[13] K.-J. Chang, D. Moon, M.S. Lah, K.-S. Jeong, Angew. Chem., Int. Ed. 44 (2005)
7926.
[14] J.L. Sessler, D.-G. Cho, V. Lynch, J. Am. Chem. Soc. 128 (2006) 16518.
[15] X.-M. He, S.-Z. Hu, K. Liu, Y. Guo, J. Xu, S.-J. Shao, Org. Lett. 8 (2006) 333.
[16] F.M. Pfeffer, K.F. Lim, K.J. Sedgwick, Org. Biomol. Chem. 5 (2007) 1795.
[17] C. Caltagirone, P.A. Gale, J.R. Hiscock, S.J. Brooks, M.B. Hursthouse, M.E. Light,
Chem. Commun (2008) 3007.
[18] E.J. Moriconi, J.J. Murray, J. Org. Chem. 29 (1964) 3577.
[19] B. Valeur, J. Pouget, J. Bourson, J. Phys. Chem. 96 (1992) 6545.
[20] M. Boiocchi, L.D. Boca, D. Esteban-Gòmez, L. Fabbrizzi, M. Licchelli, E. Monzani,
J. Am. Chem. Soc. 126 (2004) 16507.
[21] D. Esteban-Gòmez, L. Fabbrizzi, M. Licchelli, J. Org. Chem. 70 (2005) 5717.
[22] D. Esteban-Gòmez, L. Fabbrizzi, M. Licchelli, E. Monzani, Org. Biomol. Chem. 3
(2005) 1495.
[23] Y.-H. Wang, H. Lin, J. Shao, Z.-S. Cai, H.-K. Lin, Talanta 74 (2008) 1122.
[24] S. Camiolo, P.A. Gale, M.B. Hursthouse, M.E. Light, A.J. Shi, Chem. Commun.
(2002) 758.
[25] P.A. Gale, K. Navakhun, S. Camiolo, M.E. Light, M.B. Hursthouse, J. Am. Chem.
Soc. 124 (2002) 11228.
[26] T. Gunnlaugsson, P.E. Kruger, P. Jensen, F.M. Pfeffer, G.M. Hussey, Tetrahedron
Lett. 44 (2003) 8909.
[27] T. Gunnlaugsson, M. Glynn, G.M. Tocci (née Hussey), P.E. Kruger, F.M. Pfeffer,
Coord. Chem. Rev. 250 (2006) 3094.
[28] R. Martínez-Mán˜ez, F. Sancenón, Chem. Rev. 103 (2003) 4419.
[29] R.K. Klaus, Coord. Chem. Rev. 216–217 (2001) 473.
4. Conclusions
The controllable anion selectivities were described. Based on the
UV–vis spectroscopy technique, the receptor 1 was found to have
a larger binding constant for AcO− than that of F−, due to an addi-
tional hydrogen bonding interaction, which was further confirmed
by the 1H NMR titration experiments. Once such additional binding
site was replaced, receptor 2 showed no obviously discriminative
response towards F−, AcO− and H2PO4−. Functionalising receptor
1 with strong electron-withdrawing group to form receptor 3, it
showed selectivity for F− due to the occurrence of double depro-
tonation in DMSO. AcO− and H2PO4 caused single deprotonation
only.
−