5,5′-bis-vanillin derivatives as discriminating sensors for trivalent cations

Article abstract of DOI:10.1016/j.tetlet.2015.04.120

Abstract Several bis-vanillin derivatives containing semicarbazone moieties have been prepared and used in discriminating trivalent cations. The prepared probes are readily obtained and they are usually highly crystalline. Depending on the ligand and the studied cations, quenching, enhancement or no changes in the fluorescence spectrum were observed. Using a series of the prepared ligands allows distinguishing between Fe³⁺, Cr³⁺ and Al³⁺. Detection limits and selectivity in front of divalent cations have been evaluated.

Full text of DOI:10.1016/j.tetlet.2015.04.120

Tetrahedron Letters 56 (2015) 3988–3991
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
5,50-Bis-vanillin derivatives as discriminating sensors for trivalent
cations
c
Ana M. Costero a,b, , Salvador Gil a,b, Margarita Parra a,b, Pedro M. E. Mancini c, , María N. Kneeteman ,
⇑
⇑
Matías I. Quindt c
a Centro de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Unidad Mixta Universidad Politécnica de Valencia-Universitat de Valencia, Spain
b Departamento de Química Orgánica, Universitat de Valencia, Dr. Moliner, 50, 46100 Burjassot (Valencia), Spain
c Departamento de Química, Facultad de Ingeniería Química, Universidad Nacional del Litoral, Santa Fe, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Several bis-vanillin derivatives containing semicarbazone moieties have been prepared and used in dis-
criminating trivalent cations. The prepared probes are readily obtained and they are usually highly crys-
talline. Depending on the ligand and the studied cations, quenching, enhancement or no changes in the
fluorescence spectrum were observed. Using a series of the prepared ligands allows distinguishing
between Fe3+, Cr3+ and Al3+. Detection limits and selectivity in front of divalent cations have been
evaluated.
Received 19 February 2015
Revised 28 April 2015
Accepted 29 April 2015
Available online 19 May 2015
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Fluorescence
Chemosensor
Sensing
Trivalent cations
Bis-vanillin
Semicarbazone
Introduction
purification process and adds to the appeal of these systems.
Among the different applications of hydrazones, they have been
The design and synthesis of chemosensors for transition and
p-block metal cations is an important subject in the field of
supramolecular chemistry because of their impact in the environ-
ment and in human health.1 Due to these facts the interest for
developing chemical sensors, able to detect the presence of triva-
lent cation ions in environmental and biological systems, has
increased in the last years. Among the different chemosensors,
those based on ion-induced changes in fluorescence are especially
suitable as they are easy to use and usually give an instantaneous
response with high sensitivity.2 Even though lately a large number
of publications related to trivalent cations recognition have
appeared in the literature3 only few of them indicate some selec-
widely used in cation sensing through different approaches.5 On
the other hand, the semicarbazone group also has been used as a
complexing moiety.6 This group presents an additional carbonyl
group that can be involved in complexation giving rise to more
stable complexes. Among the different dialdehydes that could be
used in the synthesis of dihydrazones or disemicarbazones we
decided to explore the utility of 5,50-bis-vanillin. 5,50-Bis-vanillin
is a bisphenol that can be easily prepared from the monomeric
compound in good yields and that can be functionalized at the car-
bonyl groups giving rise to a large number of compounds.7 Even
though it has been reported that some of these compounds are able
to complex Fe3+ and Cu2+ 7,8
the applicability of these derivatives in
,
tive discrimination between Cr3+, Fe3+ and Al3+ 4
.
sensing experiments has not been yet evaluated. However, the
simplicity of the synthetic procedures in addition to the low cost
of its preparation8,9 makes these types of compounds appropriate
candidates to evaluate their behaviour as chemosensors for differ-
ent cations. So we here report the synthesis and evaluation of a
library of 5,50-bis-vanillin (1) derivatives (Chart 1) that are cheaply
and easily prepared in one step10 from commercially available
compounds and that are able to act as selective chemosensors for
The hydrazone functional group has been extensively studied
and used in the context of supramolecular chemistry These com-
pounds are readily obtained, they are usually highly crystalline
and crash out of the reaction mixture, which simplifies their
⇑
Corresponding authors. Tel.: +34 963544410; fax: +34 963543831 (A.M.C.).
E-mail addresses: ana.costero@uv.es (A.M. Costero), pmancini@fiq.unl.edu.ar
Cr3+, Fe3+ and Al3+
.
(P.M.E. Mancini).
http://dx.doi.org/10.1016/j.tetlet.2015.04.120
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

A. M. Costero et al. / Tetrahedron Letters 56 (2015) 3988–3991
RHN-N=C
3989
C=N-NHR
OHC
CHO
O
OH HO
O
O
OH HO
O
O
1
2
3
4
R=
R=
R=
S
N
5 R=
6 R=
O
NH
N
O
NH2
NH2
Chart 1. Structures of the synthesized sensors.
Results and discussion
Synthesis and characterization
800
700
600
500
Ligand 4
Fe(III)
Cr(III)
Compounds 3, 5 and 6 had been previously reported8 whereas 2
and 4 are firstly described here. 5,50-Bis-vanillin was synthesized
by oxidant coupling of vanillin in the presence of sodium persul-
fate and iron sulfate with 95% yield after precipitation.7 Reaction
of 5,50-bis-vanillin with the corresponding hydrazine or semicar-
bazide produces compounds 1–6 that were isolated by filtration
and purified by recrystallization.9 All the new compounds were
characterized by 1H NMR, 13C NMR and MS.11,12
Compounds 1 and 2 do not present any absorption band at
wavelengths higher than 200 nm, compounds 4 and 5 show absorp-
tion bands in the zone of 220–250 nm and, finally, compounds 3
and 6 in addition to the band at 220–250 nm show a shoulder at
350 and 330 nm respectively. On the other hand, whereas 4 is fluo-
Al(III)
400
300
200
100
0
300
350
400
450
500
wavelength (nm)
1400
1200
1000
800
600
400
200
0
Fe(III)
Al(III)
Cr(III)
rescent (U = 0.21 measured at kexc = 278 nm) the other compounds
are scarcely fluorescent (
U < 0.001, kexc = 278 nm).
Sensing experiments
Examination of the recognition capabilities of 1–6 were carried
out in a series of UV and fluorescence spectroscopy studies in
DMSO solutions. After addition of 1 equiv of the cation (AlCl3,
Cr(NO3)3 and FeCl3)13 only a small bathochromic shift of the band
was observed in the absorption band. However some compounds
showed clear changes in their fluorescent properties in the pres-
ence of the studied cations. Thus, the fluorescence spectrum of
compound 6 showed a strong enhancement in the presence of
Fe3+ whereas no changes were observed for Al3+ and Cr3+. In
addition, the emission corresponding to ligand 4 experiments an
appreciable enhancement in the presence of of Fe3+ and Cr3+
whereas it was quenched in the presence of Al3+. What is more,
the emission band of this ligand was 6 nm hypsochromically
shifted in the presence of Cr3+ (Fig. 1).
300
350
400
450
500
wavelength (nm)
Figure 1. (up) Fluorescence spectra of ligand 4 (10ꢀ5 M in DMSO) free and in the
presence of 1 equiv of Fe3+, Cr3+ and Al3+ (kexc = 279 nm). (bottom) Fluorescence
spectra of ligand 6 (10ꢀ5 M in DMSO) in the presence of 1 equiv of Fe3+, Cr3+ and Al3+
(kexc = 278 nm). Free ligand 6 has not been represented because it is not fluorescent
in this range.
These results indicated that the substitution of the carbonyl
group of compound 4 by the imino group in compound 6 gives rise
to an important change in the sensing properties in front of Cr3+
.
Thus, whereas in compound 6 only small changes in the fluores-
cence of the ligand was observed, in the case of 4 a strong enhance-
ment of the fluorescence was induced. By contrast the observed
response with both ligands for Fe3+ and Al3+ was similar (enhance-
ment of the fluorescence for Fe3+ and no emission for Al3+) (Fig. 3).
Taking into account not only the fluorescence enhancement but
also the wavelength shift observed, ligand 4 was able to discrimi-
nate the three trivalent cations Fe3+, Cr3+ and Al3+ as can be seen in
Figure 2.

3990
A. M. Costero et al. / Tetrahedron Letters 56 (2015) 3988–3991
300
200
100
0
3.4
3.35
Cr(III)
Fe(III)
3.3
3.25
3.2
3.15
0
0.5
1
1.5
2
2.5
3
-50
-40
-30
-20
-10
0
Δλem
Equiv. Fe3+
-100
Al(III)
0.5
0.4
0.3
0.2
0.1
0
Figure 2. 2D representation of significative changes in the fluorescent properties of
4 in the presence of Fe3+, Cr3+ and Al3+
.
3000
2500
2000
1500
1000
500
3
Cr (III)
Fe (III)
Al(III)
0
0.5
1
1.5
2
2.5
3
Equiv. Al3+
0.1
0.08
0.06
0.04
0.02
0
0
250
350
450
550
wavelength (nm)
Figure 3. Fluorescence spectra of ligand 3 (10ꢀ5 M in DMSO) free and in the
presence of 1 equiv of Fe3+, Cr3+ and Al3+ (kexc = 278 nm).
0
0.5
1
1.5
2
2.5
3
Equiv. of Cr3+
From a qualitative point of view, ligand 6 was able to distin-
guish Fe3+ from Cr3+ and Al3+ whereas ligand 4 could be used to dis-
criminate between the three studied cations. On the other hand,
complexation with ligand 3 gave rise to higher fluorescence
enhancement. Thus whereas the fluorescence of ligand 4 showed
an enhancement around 400–500 times on complexation, that of
ligand, ligand 3 showed an enhancement higher than 1500 for
Figure 4. Stoichiometry determination of the complexes formed between ligand 3
and the studied trivalent cations.
H
O
N
N
N
Cr3+ and 2500 and Fe3+
.
N
N
Due to the stronger effect observed with ligand 3 the complex-
ation characteristics of this ligand were studied. Thus, titration
experiments developed with this ligand showed that the stoi-
chiometry of the formed complexes was 1:1 being the correspond-
ing complexation constants logK = 4.5 0.4, 5.2 0.4 and 4.4 0.5
for Fe3+, Cr3+ and Al3+, respectively14 (Fig. 4). In order to know the
functional groups involved in the complexation process 1H NMR
experiments were undergone.
O
O
HO
HO
Al+3
O
N
H
The changes observed in the 1H NMR spectrum of ligand 3 in the
presence of Al3+ (important upfield shift of the NH signal and
downfield shift of the azomethine hydrogen) suggest that both
the carbonyl and the imine nitrogen atom are involved in complex-
ation (Fig. 5). In addition, the sharper signals in the 13C NMR
spectrum of the complex indicate a conformational restriction
when compared with the free ligand. On the other hand, the
observed downfield shifts of the azomethine and carbonyl carbon
signals are compatible with the suggested structure. Finally, a
conformational change in the ligand could explain the shifts of
the bis-vanillin aromatic signals.
The sensing response of different divalent cations (especially
Fe2+) was studied to have additional information about the probes
selectivity. These cations did not induce any change in the
fluorescent response of the studied ligands. Finally the limits of
detection with this ligand were evaluated from the equation:
Figure 5. Model of complex proposed for 3ꢂAl3+ in DMSO based on the 1H NMR
observations.
LOD = K ꢁ Sb1/S, where K = 3, Sb1 is the standard deviation of the
blank solution and S is the slope of the calibration curve.15 The
obtained value was around 10ꢀ5 M for the three studied cations.16
Conclusions
Five bis-vanillin derivatives containing hydrazine or semicar-
bazone moieties have been studied as sensors for trivalent cations
(Fe3+, Cr3+ and Al3+). Two of these compounds have been reported
in this Letter for the first time. All the studied compounds are
easily prepared in one step from cheap commercial compounds
and they are isolated by precipitation and purified by

A. M. Costero et al. / Tetrahedron Letters 56 (2015) 3988–3991
3991
Rogado, M. A.; Vinuelas-Zahinos, E. Polyhedron 2005, 24, 2972; Jagst, A.;
Sanchez, A.; Vázquez-López, E. M.; Abram, U. Inorg. Chem. 2005, 44, 5738.
7. Delomenède, M.; Bedos-Beval, F.; Duran, H.; Vindis, C.; Baltas, M.; Nègre-
Salvayre, A. J. Med. Chem. 2008, 51, 3171.
recrystallization. The structural differences between the prepared
compounds have strong influence of their response in front of
trivalent cations. Thus, whereas compound 4 shows an appreciable
enhancement of fluorescence in the presence of Cr3+, the fluores-
cence of compound 6 does not experiment any change in the pres-
ence of this cation. On the other hand, chemosensor 3 was the most
sensible among all the prepared compounds. In conclusion, either
compound 4 alone or, even better an array containing several of
8. Belkheiri, N. PhD. Thesis, University of Toulouse, 2010.
9. General procedure to carboxamides: 5,50-Bis-vanillin (1) (0.66 mmol) was
suspended in absolute ethanol (30 ml) and semicarbazide (1.32 mmol) was
added to the suspension. The reaction mixture was refluxed for 24 h. At the
beginning of the heating all product is dissolved and over time it begins to
appear a new precipitate. The solid was filtered and dried to give a pure solid.
10. Bouguerne, X. B.; Belkheiri, N.; Bedos-Beval, F.; Vindis, C.; Uchida, K.; Duran, H.;
Grazide, M.-H.; Baltas, M.; Salvayre, R.; Nègre-Salvayre, A. Antioxid. Redox
Signaling 2011, 14, 2093.
the prepared sensors can be used to discriminate between Fe3+
Cr3+ and Al3+
,
.
11. General methods: The different materials were purchased and used as received.
Silica gel 60 F254 (Merck) plates were used for TLC. 1H and 13C NMR spectra
were recorded using a Bruker DRX-500 spectrometer (500 MHz for 1H and
126 MHz for 13C) and a Bruker Avance 400 MHz (400 MHz for 1H and 100 MHz
for 13C) with the deuterated solvent as the lock and residual solvent as the
Acknowledgments
We thank the Spanish Government and the European FEDER
funds (project MAT2012-38429-C04-02 and 01). SCSIE
(Universidad de Valencia) is gratefully acknowledged for all the
equipment employed. Also we thank the Santa Fe Government,
Argentina (project N°2010-038-11) and the Facultad de
Ingeniería Química (Universidad Nacional del Litoral) for the
equipment employed.
internal reference. HRMS were recorded using
Absorption spectra were recorded with
a
Shimadzu QP5050A.
a
Shimadzu UV-2101PC
spectrophotometer. Fluorescence spectra were carried out in a Varian Cary
Eclipse fluorimeter. 5,50Bis-vanillin was prepared following the procedure
described in Ref. 7.
12. Spectral data: 2 1H NMR (DMSO-d6, 500 MHz): 8.88 (s, 2H, NH); 7.90 (s, 2H,
CH@N); 7.65 (d, 4H, J = 10 Hz, H-20); 7.52 (s, 2H, H-6); 7.29 (t, 4H, J = 10 Hz, H-
30); 7.13 (s, 2H, H-2); 7.01 (t, 2H, J = 10 Hz, H-40); 3.95 (s, 6H, OCH3). 13C NMR
(DMSO-d6, 125 MHz): 148.4 (CH@N); 146.2 (C-3), 142.1 (C-4); 139.7 (C-40);
128.9 (C-30); 125.7 (C-6); 125.3 (C-10); 124.1 (C-5); 122.8 (C-1); 120.4 (C-20);
108.7 (C-2); 56.6 (OCH3). HRMS calcd for C28H26N4O4 482.1954 found (M+1):
483.2013. 3. 1H NMR (DMSO-d6, 500 MHz): 12.00 (s, 2H, NH); 9.01 (s, 2H, H-
50); 8.72 (d, 2H, J = 5 Hz, H-20); 8.31 (s, 2H, CH@N); 8.22 (d, 2H, J = 10 Hz, H-40);
7.55 (dd, 4H, J = 10 and 5 Hz, H-30); 7.39 (s, 2H, H-6); 7.10 (s, 2H, H-2); 3.90 (s,
6H, OCH3). 13C NMR (DMSO-d6, 125 MHz): 161.8 (C@O); 152.5 (C-40); 149.5 (C-
3), 149.0 (CH@N); 148.7 (C-50); 147.0 (C-4); 135.8 (C-20); 129.9 (C-5); 125.6 (C-
10); 125.2 (C-6); 124.8 (C-1); 123.9 (C-30); 108.4 (C-2); 56.5 (OCH3). HRMS
calcd for C28H24N6O6 540.1757 found (M+1): 541.1863. 4 1H NMR (DMSO-d6,
300 MHz): 10.00 (s, 2H, NH); 8.74 (br. s, 2H, OH); 7.76 (s, 2H, CH@N); 7.39 (s,
2H, H-6); 6.97 (s, 2H, H-2); 6.45 (br. s, 4H, NH2); 3.89 (s, 6H, OCH3). 13C NMR
(DMSO-d6, 75 MHz): 155.7 (C@O); 150.4 (CH@N); 148.4 (C-3); 147.6 (C-4);
125.7 (C-5); 124.7 (C-6); 124.2 (C-1); 118.44 (C-2); 56.6 (OCH3). HRMS calcd
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.04.
120.
References and notes
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for
C18H20N6O6 416.1444 found (M+1): 417.1732. 5
1H NMR (DMSO-d6,
400 MHz): 12.10 (s, 2H, NH); 9.00 (br. s, 2H, OH); 8.08 (s, 2H, CH@N); 7.72 (d,
2H, J = 8 Hz, H-60); 7.40 (d, 2H, J = 8 Hz, H-30); 7.31 (s, 2H, H-6); 7.29 (t, 2H,
J = 8 Hz, H-40); 7.13 (s, 2H, H-2); 7.09 (t, 2H, J = 8 Hz, H-50); 3.93 (s, 6H, OCH3).
13C NMR (DMSO-d6, 125 MHz): 167.3 (C-10); 150.4 (C-3); 148.4 (C-4); 146.3
(CH@N); 126.3 (C-20 and C-70); 125.9 (C-1); 125.3 (C-5); 123.2 (C-30 and C-60);
121.9 (C-6); 121.8 (C-20); 108.5 (C-2); 56.3 (OCH3). HRMS calcd for
C
30H24N6O4S2 596.1300 found (M+1): 597.1379. 6
1H NMR (DMSO-d6,
400 MHz): 11.93 (br. s, 4H, NH2); 9.00 (br. s, 2H, NH); 8.08 (s, 2H, CH@N);
7.51 (s, 2H, H-6); 7.19 (s, 2H, H-2); 3.91 (s, 6H, OCH3). 13C NMR (DMSO-d6,
100 MHz): 155,3(s, C-8); 147.8 (s, C-3); 147.0 (s, CH@N); 146.6 (s, C-4); 125.2
(s, C-5); 124.2 (s, C-6); 123.8 (s, C-1); 108.8 (s, C-2); 56.1 (s, OCH3). HRMS calcd
for C18H22N8O4 414.1764 found (M+1): 415.1836.
13. Spectroscopic measurements: Metal cations (Fe3+ Cr3+ Al3+
, , ) as nitrate or
chloride salts were used to obtain solutions of concentration of 10ꢀ4 M in
MeOH or acetonitrile. UV spectra were recorded using a Shimadzu UV-2600
spectrometer. Fluorescence spectra were recorded using a Varian Cary Eclipse
fluorimeter. Titrations were performed by adding aliquots of M3+ (10ꢀ3 M in
CH3CN) in a solution of ligand (10ꢀ5 M) in DMSO.
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DMSO (10ꢀ5 M). The UV spectra were recorded in 1-cm path length cells at
25 °C (thermostatted). Representation of absorbance at the appropriate
wavelength vs. concentration of simulant allowed the limit of detection to
be calculated.
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