Anion recognition by a novel Fipronil-based receptor: efficient deprotonation or stable intermolecular hydrogen bonding

Article abstract of DOI:10.1016/j.tetlet.2007.10.155

Strong electron-deficient heterocycles of acetyl Fipronil (F3) was designed and synthesized, its ability for anion recognition was investigated by UV and NMR analyses. This novel Fipronil-based receptor F3 shows strong binding affinity with acetate (≥10

Full text of DOI:10.1016/j.tetlet.2007.10.155

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Tetrahedron Letters 49 (2008) 1087–1090
Anion recognition by a novel Fipronil-based receptor:
efficient deprotonation or stable intermolecular hydrogen bonding
Chuanxiang Liu, Xuhong Qian *, Jiaobing Wang, Zhong Li *
State Key Laboratory of Bioreactor Engineering and Shanghai Key Lab of Chemical Biology, School of Pharmacy,
East China University of Science and Technology, PO Box 544 Shanghai 200237, PR China
Received 23 June 2007; revised 22 October 2007; accepted 26 October 2007
Available online 5 December 2007
Abstract
Strong electron-deficient heterocycles of acetyl Fipronil (F3) was designed and synthesized, its ability for anion recognition was inves-
tigated by UV and NMR analyses. This novel Fipronil-based receptor F3 shows strong binding affinity with acetate (P107 Mꢀ1), phos-
phate or fluoride ion through efficient deprotonation. In addition, its interaction with chloride anion or other weak base anions through
stable intermolecular H-bonding was also reported.
Ó 2007 Elsevier Ltd. All rights reserved.
Anions play vital roles in biological and chemical pro-
cesses.1 The development of novel synthetic receptors2
bearing biologically importance for anions is recently
emerged as a significant important research area. Gener-
ally, synthetic receptors for anions employ various combi-
nations of pyrroles, guanidiniums, Lewis acids, amides,
and urea/thiourea groups as binding sites to form N–
Hꢁ ꢁ ꢁX hydrogen bonds. According to a recent view,3 ‘all
hydrogen bonds can be considered as incipient proton
transfer reactions, and for strong hydrogen bonds, this
reaction can be in a very advanced state’. Thus, it may
be the potential occurrences of an acid–base process for
comprehend the intrinsic interaction between a given
–NH-containing receptor, speciously those biomolecules
possibly binding with anions.
a
(1)
A ]
[ HA2 ]
[ LH
+
+
+
+
LH
A ]
A
A
A
A
(2)
(3)
(4)
[ LH
L
+
+
+
LH
LH
HA
A
L
L'H
Fig. 1. The possible equilibria of LH and Aꢀ.
the deprotonated Lꢀ (Eq. 2), which can be ascribed to a
‘frozen’ proton release from the donor (the acid) to the
acceptor (the base) and the more advanced proton release
process. In Eq. 4, the proton releases in the neutral receptor
LH itself to further generate the new receptor L0H, which
can be ascribed to anion-catalyzed organic reaction.5 We
were interested to verify whether Eq. 3 can be found
through simple biologically important receptor interacting
with anions in solution. For a definitive proton release
from the receptor to anion (Eq. 3), which mainly related
to the intrinsic acidity of LH,4n its acidity should be stron-
ger than those of the general urea or thiourea derivatives.
And also, the stability of HA in solution would be benefi-
cial to the proton release process according to the rule of
Eq. 2. Thus, further polarizing the N–H bonds and increas-
ing its hydrogen-bond donor tendencies are indispensable
through introducing the stronger electron-withdrawing
In general, the following four possible equilibriums
(Fig. 1) may take place in solution, involving the neutral
receptor LH and anion Aꢀ. Several groups4 have discussed
Eqs. 1 and 2 in detail by interaction of amide, urea or thio-
urea, pyrrole-based receptors with anions. A genuine
H-bond complex was formed (Eq. 1) and further to leave
*
Corresponding authors. Tel.: +86 21 64253589; fax: +86 21 64252603.
E-mail addresses: xhqian@ecust.edu.cn (X. Qian), lizhong@ecust.
edu.cn (Z. Li).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.155

1088
C. Liu et al. / Tetrahedron Letters 49 (2008) 1087–1090
substituents (e.g., –NO2, CF3), which should be appended
to the NH framework.4a The potential occurrence of a
strong acid–base process should be investigated with effi-
cient proton release from receptor to anion.
N
Cl
N
N
O
S O
O
H
H
CF3
(i)
N
+
S
O
F3C
NH2
With these considerations in mind, we observed that a
derivative of Fipronil6 N-(3-cyano-1-(2,6-dichloro-4-(tri-
fluoromethyl)phenyl)-4-(trifluoromethylsulfinyl)-1H-pyrazol-
5-yl)acetamide (F3, Fig. 2), which provides with three
strongly electron-withdrawing groups (–CN, –CF3, 2,6-
Cl2-4-CF3-phenyl) appended to the NH framework.
Herein, we report an example of novel Fipronil-based
receptor F3, which can recognize anions through efficient
deprotonation or stable intermolecular hydrogen bonding.
Generally, most pesticides such as Fipronil, which has a
functional group (–NH2), show only slightly reactive or,
indeed, non-reactive.7 Not surprisingly, the NH2 of Fipro-
nil is considerable unreactive with acetyl chloride through
the conventional methods. Thus, it appeared necessary to
use a novel strategy for the preparation of receptor F3.
Interestingly, compound F28 was obtained by introducing
a strongly dimethylammonium 4-methylbenzene-sulfonate
(1) into the above unreactive system. Further, oxidation
of compound F2 with equimolar of mCPBA gave the final
receptor F39 in good yields (Scheme 1).
Cl
Fipronil
1
N
S
N
S
Cl
Cl
N
N
N
N
CF3
CF3
(ii)
F3C
F3C
O
NH
O
NH
Cl
Cl
O
F3
F2
Scheme 1. Reagents and conditions: (i) CH3COCl, CH2Cl2, reflux (35%);
(ii) mCPBA, rt, CH2Cl2 (70%).
0.7
0.20
0.6
0.16
CH3COO-
0.5
0.12
H2PO4-
F-
0.08
0.4
The anion sensing ability of F3 was evaluated by UV
and proton NMR analyses. Figure 3 shows the spectro-
scopic changes observed when F3 is treated with increasing
quantities of tetrabutylammonium acetate (TBAA) in
CH3CN. In this case, the new peaks at 285 nm increased
upon the addition of TBAA, with saturation being
observed after the addition of ca. 1 equiv. There is a clear
isosbestic point at 238 nm, which indicates a clean conver-
sion throughout the titration process. This new band
reflects electronic modification of receptor takes place,
induced by N–H deprotonation. Standard 1:1 curve-fitting
procedures were then used to derive binding constants,10
which is at least equal to 4 ꢂ 107 Mꢀ1 in CH3CN and
exceeds that reported urea or thiourea4n (106 Mꢀ1). We
propose that the high oxoanions affinity of F3 results from
its stronger acidity than that of urea or thiourea
derivatives.
0
2
4
6
8
10 12
-
[A] 10-5M
0.3
0.2
0.1
0.0
200
250
300
350
400
Wavelength (nm)
Fig. 3. UV–vis titration of 20 lM F3 with Bu4N+AcOꢀ in CH3CN.
Arrows show changes due to increasing concentration of Aꢀ. The inset
shows the absorbance at 285 nm as a function of [AcOꢀ], ½H2PO ꢀꢃ and
4
[Fꢀ].
F3 disappeared, which indicates that the proton fleetly
release from receptor F3. In addition of a further excess
of TBAA (9.30 equiv and more), we observed the NH pro-
ton appeared at much downfield (13.96 ppm, Fig. 4), which
coincides with the –OH proton signal of the acetate acid
and indicates the proton transfer is almost finished.
1
The H NMR titration experiments of F3 with TBAA
was investigated in CD3CN. Upon the addtion of 0.34 or
2.58 equiv of TBAA, the NH proton signal (8.93 ppm) of
N
S
N
S
N
Cl
Cl
Cl
N
N
N
N
N
N
O
A
CF3
CF3
A
S
O
HA
CF3
F3C
F3C
F3C
O
N
NH
N
Cl
Cl
Cl
H
A
O
O
O
A = AcO, F, H2PO4
A = Cl, Br, I, ClO4,
HSO4, NO3, CF3SO2
F3
Fig. 2. The binding motif of F3 with Aꢀ.

C. Liu et al. / Tetrahedron Letters 49 (2008) 1087–1090
1089
Table 1
Affinity constants for the binding of anionsa by receptor F3
Anion
Ka (Mꢀ1
)
Anion
Brꢀ
HSO4
Iꢀ
Ka (Mꢀ1
)
AcOꢀb
H2PO4
Fꢀb
4.16 ꢂ 107
2.27 ꢂ 105
1.76 ꢂ 105
1.50 ꢂ 103
1.40 ꢂ 103
1.32 ꢂ 103
4.50 ꢂ 102
2.70 ꢂ 102
2.06 ꢂ 102
1.34 ꢂ 102
b
ꢀ
ꢀ
Clꢀ
NO3
CF3SO2
ꢀ
ꢀ
ꢀ
ClO4
a
The anions studied were in the form of their tetrabutylammonium
salts.
b
Determined in acetonitrile solvent by UV–vis; error 615%. The other
anions were determined by 1H NMR analysis in CDCl3 at 298 K; error
Fig. 4. 1H NMR spectra of F3 with tetrabutylammonium acetate in
CD3CN at 298 K (only NH and aromatic protons are shown)
[F3] = 8.0 ꢂ 10ꢀ3 M, [AcOꢀ] = 0–2.0 ꢂ 10ꢀ2 M.
610%.
Similarly, the same detectable spectral changes were
observed in the interaction of F3 with tetrabutylammo-
nium fluoride (TBAF) and tetrabutylammonium phos-
phate (TBAP). Those absorbances at 285 nm as a
function of anions (TBAA, TBAP and TBAF) are shown
in Figure 3. The NH proton chemical shifts of F3 in the
presence of TBAF or TBAP were also recorded (Supple-
mentary data). These binding constants are collected in
Table 1, along with those for other anions. On the basis
of the established bindinꢀg trend shown in Table 1
exposed to increasing concentrations of chloride. The
downfield shift of amide protons occurred in the 1:1 com-
plex from 8.50 to 12.60 ppm (Dd = 4.10 ppm). The reso-
nances for the acetyl protons of F3 were also slight
shifted (Fig. 5).
1
The H NMR titꢀration of F3 for HSO4ꢀ; NO3ꢀ, Brꢀ,
Iꢀ, ClO4ꢀ; CF3SO
was also carried out, respectively
2
(Fig. 6). The association constants of that complexation
were calculated by a 1:1 nonlinear curve fitting (Table 1).
An inspection of this table, which reveals that the greaꢀtest
ðCH3COOꢀ > H2PO > F , the binding of the oxoanions
affinity is displayꢀed for AcOꢀ, followed by H2PO ꢀ
>
>
ꢀ
4
4
is enhanced significantly than Fꢀ, which is presumed to be
Fꢀ > Clꢀ > NO3 > Brꢀ > HSO4 > Iꢀ > CF3SO
ꢀ
2
dependent on the less stability of HF in solution.4n
To evaluate chloride ions and other weak base anions,
we further study the interaction of F3 with anions by
UV–vis or NMR analyses. No spectral modifications
ClO4
.
ꢀ
One of the most interesting phenomenon is that the
acetyl Fipronil F3 shows most high binding affinity with
acetate anion, which might be helpful to comprehend the
outstanding performance11 of Fipronil in biological sys-
tems. Although several results were reported on the field
of the photoproducts12 and metabolites13 of Fipronil pesti-
cides, this report might provide a new viewpoint, from
molecular recognition of anions, probably to explain the
performance of Fipronil insecticide. In summary, we have
demonstrated here that the acetyl Fipronil F3 is able to
associate with anions through efficient deprotonation or
stable intermolecular hydrogen bonding.
were observed for Clꢀ, HSO4ꢀ; NO3
,
Brꢀ, Iꢀ,
ꢀ
ClO4ꢀ; CF3SO2ꢀ even if added in large excess (Supplemen-
tary data). Thus, the selectivity of F3 is mainly related to
the basicity of the anions. Furthermore, the 1H NMR
experiment in CDCl3 reveals that receptor F3 forms a
strong 1:1 complex, which implied the formation of an
intermolecular hydrogen bond between receptor F3 and
chloride ions. It is evident from that concerted downfield
shifts were observed for amide proton as receptor F3 was
Fig. 5. 1H NMR titration of F3 with tetrabutylammonium chloride in CDCl3 at 298 K [F3] = 8.0 ꢂ 10ꢀ3 M, [Clꢀ] = 0–2.0 ꢂ 10ꢀ2 M.

1090
C. Liu et al. / Tetrahedron Letters 49 (2008) 1087–1090
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5167; (f) Gale, P. A. Chem. Commun. 2005, 3761; (g) Causey, C. P.;
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G. D.; Katayev, E.; Lynch, V. M. Org. Lett. 2003, 5, 4141; (i) Wu,
F.-Y.; Li, Z.; Wen, Z.-C.; Zhou, N.; Zhao, Y.-F.; Jiang, Y.-B. Org.
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Tian, M.; Zhao, J.; Sun, S. J. Org. Chem. 2007, 72, 62; (l) Wu, J. S.;
Zhou, J. H.; Wang, P. F.; Zhang, X. H.; Wu, S. K. Org. Lett. 2005, 7,
2133; (m) Kim, Y. K.; Lee, Y. -H.; Lee, H.-Y.; Kim, M.-K.; Cha, G.
13
12
11
10
9
Cl-
NO3-
Br-
HSO-
4
I-
CF SO-
3
2
ClO -
4
´
S.; Ahn, K. H. Org. Lett. 2003, 5, 4003; (n) Esteban Gomez, D.;
Fabbrizzi, L.; Licchelli, M.; Monzani, E. Org. Biomol. Chem. 2005, 3,
1495.
5. This case can see as chemdosimeter approach for anion detection, for
´
´
´
review see: (a) Martınez-Manez, R.; Sancenon, F. Chem. Rev. 2003,
˜
´
´
´
103, 4419; (b) Martınez-Manez, R.; Sancenon, F. .Coord. Chem. Rev.
2006, 250, 3081.
˜
8
0
1
2
3
4
5
6
6. Tomlin, C. D. S., Ed.; The Pesticide Manual, 12th ed.; British Crop
Protection Council: Farnham, UK, 2000; pp 413–415.
Anion/ Equiv
Fig. 6. Plot of the chemical shift of the NH protons of F3 (3.46 ꢂ 10ꢀ2 M)
7. Goller, R.; Vors, J. P.; Caminade, A. M.; Majoral, J. P. Tetrahedron
Lett. 2001, 42, 3587.
upon increasing the concentration of nBu4N+Xꢀ in CDCl3.
8. Preparation of compound F2: A flame-dried flask was charged with
Fipronil (436 mg, 1 mmol), dimethylammonium 4-methylbenzenesulf-
onate (434 mg, 2 mmol) and CH2Cl2 (5 mL). Then a solution of acetyl
chloride (93.6 mg, 1.2 mmol) in CH2Cl2 was added. The reaction
mixture was refluxed under nitrogen atmosphere for 4 h. Water
(10 mL) was added and extracted with CH2Cl2 (3 ꢂ 10 mL). The
combined organic phase was washed with brine and dried over
anhydrous Na2SO4. After the removal of solvent, the residue was
purified by flash chromatography on silica gel to give F2 (161 mg,
35%). Mp 212.7–213.7 °C. IR (KBr): m 3220, 2250, 1690, 1580, 1500,
1400, 1310, 1080, 720, 690 cmꢀ1. 1H NMR (400 MHz, CDCl3, ppm) d
2.12 (s, 3H, CH3), 7.20 (s, 1H, NH), 7.77 (s, 2H).13C NMR (100 MHz,
CDCl3) d 168.0, 143.5, 136.6, 135.0, 134.5, 134.2, 133.0, 129.8, 126.8,
126.2, 123.3, 120.5, 110.6, 22.9. EIMS, 1.58 eV, m/z: 462 [M]+ (84.86),
420 (28.02), 351 (20.70), 213 (5.56), 43 (100). HRMS calcd for
Acknowledgements
This work is supported by the National Basic Research
Program of China (2003CB114400), Shanghai Leading
Academic Discipline Project (B507) and the National Nat-
ural Science Foundation of China.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
10.155.
C
14H6N4O1F6SCl2: 461.9521. Found: 461.9544.
9. The preparation of compound F3: A flame-dried flask was charged with
F2 (462 mg, 1 mmol), mCPBA (190 mg, 1.10 mmol) and CH2Cl2
(10 mL). The reaction mixture was stirred at room temperature for
24 h. Water (10 mL) was added and extracted with CH2Cl2
(3 ꢂ 10 mL). The combined organic phase was washed with brine
and dried over anhydrous Na2SO4. After the removal of solvent, the
residue was purified by flash chromatography on silica gel to give F3
(334 mg, 70%): Mp 208.9–210.0 °C. IR (KBr): m 3220, 2250, 1690,
1580, 1310, 1080, 720, 690 cmꢀ1. 1H NMR (400 MHz, CDCl3, ppm) d
2.09 (s, 3H, CH3), 7.72 (s, 1H), 7.80 (s, 1H), 8.52 (s, 1H, NH). 13C
NMR (100 MHz, CDCl3) d 167.4, 142.9, 137.0, 135.6, 134.5, 134.0,
126.7, 126.5, 126.0, 125.7, 123.4, 120.5, 109.6, 23.1. EIMS, 1.21 eV, m/
z: 478 [M]+, 408 (11.74), 367 (48.67), 213 (7.26), 43 (100). HRMS
calcd for C14H6N4O2F6SCl2: 477.9488. Found: 477.9493.
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