Efficient synthesis of a fluorescent tripod detection system for pesticides by microwave-assisted click chemistry

Article abstract of DOI:10.1016/j.carres.2008.10.014

A new tripod molecule containing an aromatic core bearing three peracetylated cyclodextrins was synthesized via a microwave-assisted Huisgen 1,3-dipolar cycloaddition and was studied by fluorescence spectroscopy. The photoluminescent properties of complex

Full text of DOI:10.1016/j.carres.2008.10.014

Carbohydrate Research 344 (2009) 161–166
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Efficient synthesis of a fluorescent tripod detection system for pesticides
by microwave-assisted click chemistry
*
Isabelle Mallard-Favier, Philippe Blach, Francine Cazier, François Delattre
Laboratoire de Synthèse Organique et Environnement, E.A. 2599, Université du Littoral Côte d’Opale, 145 Av. M. Schumann, 59140 Dunkerque, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new tripod molecule containing an aromatic core bearing three peracetylated cyclodextrins was syn-
thesized via a microwave-assisted Huisgen 1,3-dipolar cycloaddition and was studied by fluorescence
spectroscopy. The photoluminescent properties of complexation phenomena with different pesticides
were evaluated in acetonitrile. Fluorescence titrations have been performed to calculate binding con-
stants, sensitivity factors, and limit of detection of the resulting complexes. 2D NMR experiments con-
firmed the inclusion of pesticide in the hydrophobic cavity of the macrocycle and validated the
supramolecular association responsible for the quenching of the fluorescence.
Received 8 September 2008
Received in revised form 8 October 2008
Accepted 14 October 2008
Available online 1 November 2008
Keywords:
Click chemistry
Microwave
Ó 2008 Elsevier Ltd. All rights reserved.
Cyclodextrin
Cyclomaltooligosaccharide
Fluorescence
Pesticide
1. Introduction
with pesticides, none, to the best of our knowledge, was dedicated
to the direct determination of a pesticide guest by a fluorescent
Among the rapid and efficient methods widely used in organic
chemistry, the elaboration of 1,2,3-triazole derivatives by Huisgen
1,3-dipolar cycloaddition has become a powerful design tool for or-
ganic synthetic materials, and with the introduction of the ‘click’
concept, by Sharpless and co-workers in 2001, it has emerged as
the most popular reaction to date.1,2 At the same time, the 1,2,3-
triazole-based derivatives have received attention due to their
properties that are widely compatible with molecules of biological
interest such as antibacterial, antimicrobial, or antiallergic agents.3
Curiously enough, they were only recently explored for their spec-
troscopic fluorescent properties.4
In a continuing program on the design and synthesis of chemo-
sensors for recognition of environmentally important molecular
species,5 we have investigated the synthesis and emission proper-
ties of a new tripod fluorescent system, which bears a triazine core
with cyclomaltooligosaccharide (cyclodextrin, CD) units as well-
known molecular receptors. While the design and synthesis of tar-
get-selective receptors with luminescent signaling systems have
attained a significant position in supramolecular b-cyclodextrin
chemistry for alcohol,6 volatile organic compound, or metal-ion
detection,7,8 these systems are less frequently employed in the case
of pesticides. While relatively few reports in the literature have
been devoted to the spectrofluorimetric study of CD complexes
macrocycle–b-CD complex.9 For this purpose, we decided to ex-
plore the variation of fluorescence emission intensity induced by
the inclusion of a pesticide. While the synthesis of CD trimers is
more difficult than the synthesis of the analogous CD dimers,10
the central-substituted benzene architecture provides a tuneable
luminescent and easy-to-modulate core to build a multiple cyclo-
dextrin recognition system that should provide a higher binding
affinity.11 For the host moiety, we chose 6I-azido-6I-deoxy-cyclom-
altoheptaose peracetate (1) (6-azido-6-deoxy-peracetylated-b-
cyclodextrin) for its high solubility in organic solvents, which al-
lowed us to carry out an investigation of pesticide complexation
in acetonitrile.
Herein, we report the new fluorophore triazine tripod system
obtained by the Cu(I)-catalyzed azide–alkyne cycloaddition reac-
tion (CuAAC) between an excess of 1 and 1,3,5-tris(2-propynyl-
oxy)benzene (2). Moreover, based on the fact that new organic
synthetic strategies have been nowadays deeply affected by a port-
folio of technical improvements such as microwave-assisted or-
ganic chemistry (MAOS), which are well known to achieve new
chemical entities at a faster rate,12 we obtained the target structure
faster than is usually described for the classical ‘click’ reaction. To
our knowledge, this is the first example of the combination of
cyclodextrin synthesis with microwave-assisted click chemistry.
The photoluminescent properties of the complexation phenome-
non of this new fluorescent third cavity were also studied with
* Corresponding author. Tel.: +33 328658246; fax: +33 328237605.
E-mail address: delattre@univ-littoral.fr (F. Delattre).
four pesticides,
a-cypermethrin (an insecticide), pendimethalin
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.10.014

162
I. Mallard-Favier et al. / Carbohydrate Research 344 (2009) 161–166
O
washed with water and brine, dried over Na2SO4, and concen-
trated. The crude product was then purified on silica gel (SiO2,
3:2 hexane–EtOAc, Rf: 0.81) to give a cream-colored solid: 3.23 g,
85%.
O
CN
Cl
NO2
NO2
Et
1H NMR (CDCl3, 250 MHz): d 6.29 (s, 3H, Ar); 4.68 (d, 6H, J
2.1 Hz, OCH2); 2.46 (d, 3H, J 3 Hz, CH). 13C NMR (63 MHz, CDCl3):
d 159.3, 95.4, 78.5, 75.8, 56.1. The NMR data were in agreement
with those reported.14
Cl
Et
N
H
O
2.3. 1,3,5-Tris{N1-tris[(6I-deoxycyclomaltoheptaos-6I-yl)-1,2,3-
triazol-4-ylmethanoxy]}benzene peracetate (3)
II
I
NO2
N
1,3,5-Tris(2-propynyloxy)benzene (92 mg, 1 equiv), 6I-azido-6I-
deoxy-cyclomaltoheptaose peracetate (1, 3.09 g, 4.5 equiv), CuI
(219 mg, 3 equiv), and N-ethyldiisopropylamine (0.6 mL, 9 equiv)
were dissolved in 10 mL of DMSO in an 80-mL glass vial equipped
for mechanical stirring. The mixture was then irradiated for 1 h at
80 °C using an irradiation power of 210 W. After cooling, the mix-
ture was dissolved in CH2Cl2, washed with 10% EDTA (to oxidize
the Cu(I) ion into Cu(II) ion until the color of the washing reaction
changed from blue to colorless), and then with water and brine.
The organic extract was dried (Na2SO4), concentrated, and then
purified by column chromatography (SiO2, CH2Cl2, Rf: 0.61). A
slightly brown compound (358 mg, 15%) was obtained upon
recrystallization in EtOAc/hexane.
S
S
N
N
S
S
N
N
HCl
IV
III
Chart 1. Structure of pesticides (A:
D: imidacloprid).
a-cypermethrin, B: pendimethalin, C: thiram,
(a herbicide), thiram (an antimicrobial), and imidacloprid (an
insecticide) (Chart 1). The inclusion of these latter guests was
investigated by 2D NMR experiments to validate the supramolecu-
lar association.
1H NMR (CD3CN, 250 MHz): d 7.95 (s, 3H, CHN); 6.38 (s, 3H,
Ar); 5.42–5.20 (m, 21H, H-1, H-5); 5.11–4.90 (m, 31H, CH2, H-1,
H-6); 4.76–4.60 (m, 18, H2, H-6); 4.58–4.15 (m, 46H, CH2, H-3,
H-5, H-6), 4.11–3.94 (m, 16H, H-2, H-5), 3.90–3.70 (m, 14H, H-
4), 3.54–3.42 (7H, t, H-4); 2.32–2.18 (m, 117H, CH3CO). 13C
NMR (63 MHz, CD3CN): d 170.1, 166.2, 144.4 (C4triaz.), 131.6,
126.3 (C5triaz.), 96.9 (C-1), 94.6 (Caro), 76.5 (C-4), 70.5–69.7 (C-2,
2. Experimental
2.1. Apparatus
C-3, C-5), 62.4 (C-6), 61.4 (C-60), 59.8, 19.9. IR (KBr pellets,
m
All chemicals were purchased from Acros and Sigma–Aldrich
(USA), in the highest purity available. All solvents were used as
supplied without further purification. The pesticides pendimetha-
cmꢀ1) 2958 (C–H), 1752 (C@O), 1618 (N@N). MALDI-TOFMS calcd
for C261H339N9O165Na, m/z 6265.44; found m/z 6264.70. Anal.
Calcd for C261H339N9O165: C, 50.22; H, 5.47; N, 2.02. Found: C,
49.13; H, 5.75; N, 1.99.
lin (97% purity), a-cypermethrin (97% purity), thiram (97% purity),
and imidacloprid (97% purity) were purchased from AccuStandard,
Inc. Native b-cyclodextrin was purchased from Waters (Millipore
Corp.).
1H, 13C, 2D ROESY were recorded with a Bruker DPX 250 spec-
trometer working at 250 MHz and 63 MHz for 1H and 13C, respec-
tively. CDCl3 (99.9%) and CD3CN (99.9%) were purchased from
Acros Chemicals. 1H NMR data are reported as chemical shift, mul-
tiplicity (s, singlet; d, doublet; m, t, triplet; m multiplet). Fourier-
transform infrared (FTIR) spectra were recorded on a Perkin–Elmer
Spectrometrer BX in transmission mode between 400 and
4000 cmꢀ1, using pellets made with dried KBr and sample. MAL-
DI-TOFMS spectra were recorded on a Voyager-DE STR Applied
Biosystems spectrometer with 2,5-DHB as the matrix. UV–vis spec-
tra and fluorescence spectra were measured in a conventional
quartz cell on a Perkin–Elmer Lambda 2S spectrometer and on a
LS50B spectrometer, respectively. The fluorescence measurements
required that the excitation and emission slits be set at 4 nm.
The host–guest binding constants Kb for the inclusion com-
plexes of pesticides with fluorescent b-cyclodextrin 3 were calcu-
lated by the nonlinear Benesi–Hildebrand equation assuming a
1:1 inclusion model.13
3. Results and discussion
3.1. Synthesis
The synthetic route to the tripod is depicted in Scheme 1.
The starting material mono 6I-azido-6I-deoxy-b-cyclodextrin
was prepared by total azidolysis under microwave conversion from
mono 6I-deoxy-6I-O-(p-tolylsulfonyl)-b-cyclodextrin synthesized
by the method of Defaye et al.15 or Cazier et al.16 Peracetylation
with acetic anhydride in pyridine gave mono 6I-azido-6I-deoxy-
cyclomaltoheptaose peracetate (1) in good yield.17 O-Alkylation
of phloroglucinol with propargyl bromide in the presence of potas-
sium carbonate in DMF gave the desired compound 2 in 80%
yield.14,18 The final step consisted of 1,2,3-triazole ring formation
between azide 1 and alkyne 2. Click chemistry, which has already
been used in the synthesis of cyclodextrin derivatives, can be per-
formed using a Cu(I) ion source like CuI, CuSO4, or copper turnings
to catalyze the reaction.4b,19,20 The click reaction was performed
under microwave activation using CuI/DIEAP (N-ethyldiisopropyl-
amine) as catalyst with a much shorter time compared to the
18 h of reaction time of the thermal method.21 To confirm the
product, 1H spectra depicted in Figure 1 showed clearly 1,2,3-tria-
zole ring formation as demonstrated new peaks at d 7.95 assigned
to the 1,2,3-triazole linker. In terms of geometry, examination of
the 13C NMR chemical shifts shows that carbons C-4 and C-5 of
the triazole ring at d 144.4 and 126.3, respectively, correspond to
the formation of the 1,4 regioisomer.22
2.2. Preparation of 1,3,5-tris(2-propynyloxy)benzene (2)
To a stirred solution of propargyl bromide (80% toluene in
weight, 8.50 g, 4.5 equiv) and K2CO3 (8.87 g, 4.05 equiv) in DMF
(20 mL) was added phloroglucinol (2 g, 1 equiv) in DMF (12 mL)
over a period of 20 min. The mixture was stirred at room temper-
ature for 4 days and filtered. The solvents were evaporated in va-
cuo. The resulting residue was dissolved in dichloromethane,

I. Mallard-Favier et al. / Carbohydrate Research 344 (2009) 161–166
163
OAc
OAc
O
O
O
OAc
AcO
OAc
OAc
O
O
OAc
OAc
OAc
O
AcO
O
OAc
OAc
O
O
OAc
OAc
O
OAc
N3
AcO
O
OAc
O
O
AcO
OAc
O
OAc
1
CuI, DIEAP
O
MW, 210 W, 80 °C
DMSO
OAc
OAc
O
O
O
O
O
OAc
AcO
OAc
O
2
AcO
O
OAc
OAc
OAc
O
AcO
O
OAc
OAc
OAc
O
OAc
O
OAc
O
O
OAc
O
OAc
AcO
O
OAc
OAc
O
OAc
N
AcO
OAc
O
O
O
OAc
AcO
N
OAc
OAc
OAc
N
O
O
OAc
O
O
OAc
O
O
OAc
N
N
OAc
N
O
O
OAc
O
OAc
N
O
AcO
O
OAc
N
N
OAc
O
O
AcO
O
OAc
O
O
OAc
OAc
O
AcO
OAc
OAc
OAc
O
OAc
OAc
O
OAc
O
O
OAc
O
AcO
OAc
OAc
O
OAc
OAc
AcO
O
O
OAc
OAc O
O
AcO
OAc
O
OAc
3
Scheme 1. Synthesis of 1,3,5-tris{N1-tris[(6I-deoxycyclomaltoheptaos-6I-yl)-1,2,3-triazol-4-ylmethanoxy]}benzene peracetate (3).
3.2. 2D NMR spectra
As expected, the ROESY experiment shows spatial interactions
between the acetyl protons of the peracetylated cyclodextrin and
external protons of the cavity. Moreover, various dipolar correla-
tions were observed between various protons of pendimethalin
(B) and the inner protons (H-3 and H-5) of the CD unit, indicating
the presence of a guest in the hydrophobic cavity of the macrocy-
cle. To elucidate the contribution of each pesticide proton, the
pendimethalin was investigated by 1H COSY NMR spectroscopy.
A 2D ROESY NMR experiment was carried out in deuterated
acetonitrile to obtain the spacial information on the potential
inclusion of the guest molecules in the hydrophobic moieties of
the tripod detection system. The complexation of pendimethalin
(B) with the macrocycle was chosen as an example of interactions
between the two partners (Fig. 2).

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I. Mallard-Favier et al. / Carbohydrate Research 344 (2009) 161–166
Figure 1. 1H NMR spectrum of 1,3,5-tris{N1-tris[(6I-deoxycyclomaltoheptaos-6I-yl)-1,2,3-triazol-4-ylmethanoxy]}benzene peracetate (3) in acetonitrile.
inner protons
CH3CO-
NO2
H
N
Et
CH3
CH3
Et
O2N
H
Figure 2. Partial NMR 2D ROESY spectra of 3 (mixing time: 700 ms) in acetonitrile.
This experiment shows that only the methyl aromatic groups (d
2.17–2.20 and d 2.31, respectively) were involved in the complex-
ation, and no dipolar correlation was noted between the aromatic
protons of pendimethalin and H-3, H-5 of b-cyclodextrin. These
results suggest a non-axial accommodation of the phenyl moiety
of the guest associated with a partial inclusion into the hydropho-
bic cavity through the secondary hydroxyl side of the
cyclodextrins.
Figure 3 shows the fluorescence spectra of 3, at constant con-
centration, in acetonitrile with or without pendimethalin (B) as
an example of pesticide recognition. The fluorescence intensity de-
creases with increasing pesticide concentration until the extinc-
tion, which confirms that the pollutant compound was included
in the hydrophobic cavity of the macrocycle chemosensor. The ab-
sence of wavelength shift suggests that the environment around
the fluorescent tripod has not undergone changes during the com-
plexation phenomena and is consistent with the absence of corre-
lations between the aromatic core of the trimer and the pesticide.
Consequently, we assume that the quenching of fluorescence is
only induced by the inclusion of the pesticide in the cyclodextrin
3.3. Excitation and emission spectra
The excitation spectrum of 3 exhibited two absorption maxima
at 227 nm and 326 nm. The fluorescence optimal emission was ob-
served for an excitation at 227 nm, and showed characteristic
emission peaks at 315 and 329 nm that would arise from an n–p*
transition of the heteroaromatic molecular structure. Therefore,
the presence of oxygen did not influence the fluorescence emission
of 1,3,5-tris{N1-tris[(6I-deoxycyclomaltoheptaos-6I-yl)-1,2,3-tria-
zol-4-ylmethanoxy]}benzene peracetate (3).
cavity and is not due to p–p stacking interactions. Similar phenom-
ena were observed for all guests used in this work with modula-
tions in variations of fluorescence emission according to the
nature of the guest. This guest-induced variation of fluorescence
emission is coherent with the 2D NMR experiment, which has
shown an inclusion of pendimethalin in the peracetylated cyclo-
dextrin moieties of the triazole derivative.

I. Mallard-Favier et al. / Carbohydrate Research 344 (2009) 161–166
165
0
700
600
500
400
300
200
800
700
600
500
400
300
200
100
0
100
19
0.000020.000040.000060.00008 0.0001 0.000120.00014
320
330
340
350
360
370
380
390
400
Wavelength [nm]
Figure 3. Fluorescence spectra of 1 [1.64 ꢁ 10ꢀ5 mol Lꢀ1, kexc = 227 nm] in acetonitrile upon addition of pendimethalin II ((1) 0, (2) 1.53 ꢁ 10ꢀ6, (3) 3.07 ꢁ 10ꢀ6, (4)
4.6 ꢁ 10ꢀ6, ..., (19) 1.43 ꢁ 10ꢀ4 M); inset: fluorescence emission at 329 nm (point) and calculated curves obtained from nonlinear Benesi–Hildebrand equation (line).
plished in shorter time by microwave-assisted Huisgen 1,3-dipolar
cycloaddition. A fluorescence study revealed that the fluorescent
tripod exhibits a very good variation of emission fluorescence
when introducing pesticide guests inside the cyclodextrin cavity,
allowing one to classify this host as a fluorescent chemosensor.
In further work, we will concentrate our efforts on the improve-
ment of new sensitive probes for studying the interaction of
nonfluorescent pesticide guests with derivatives of our structural
cyclodextrin design.
Table 1
Binding constants (Kb), limit of detection (LOD), and sensitivity factors of 3
I
II
III
IV
Kb (ꢁ103 Mꢀ1
)
202.9 43
0.72
0.8
143.4 25
0.95
1.5
117.0 16
0.63
2.1
19.7 1.2
0.15
4
D
I/I0
LODa (ꢁ10ꢀ6 mol Lꢀ1
)
a
LOD: Limit of detection.
To classify compound 3 as the sensory system for detecting pes-
ticide molecules, we have determined the binding constants, and
have investigated the molecule-sensing ability for guest molecules
as shown in Table 1.
The binding constants were estimated assuming a 1:1 host–
guest complex formation, at different temperatures, by a nonlinear
square fitting analysis from the plot of the guest-induced emission
variation at 329 nm as a function of the guest concentration. In-
deed, although the host–guest complexation seems to be 1:3, it
is obvious that each cavity can include one guest. The inset in Fig-
ure 3 shows a good correlation between fluorescence titration and
computer simulation for complex formation of 3 and pendimetha-
lin, assuming departure of 1:1 complex formation. To show the
Acknowledgments
We thank the ‘Centre Commun de Mesure de Spectrometry de
masse’ of the Université des Sciences et Technologies de Lille for
Maldi-Tof spectra. The mass spectrometry facility used in this
study was funded by the European Community (FEDER), the Re-
gion Nord-Pas de Calais (France), the CNRS, and the Université
des Sciences et Technologies de Lille.
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