Imidazoanthraquinone derivatives for the chromofluorogenic sensing of basic anions and trivalent metal cations

Article abstract of DOI:10.1021/jo501515e

Four imidazoanthraquinone derivatives (2a-d) were synthesized and characterized and their coordination behavior against selected anions and cations tested. Acetonitrile solutions of probes showed charge-transfer absorptions in the 407-465 nm range. The four probes emitted in the 533-571 nm interval. The recognition ability of 2a-d was evaluated in the presence of F^-, Cl^-, Br^-, I^-, OCN^-, BzO^-, ClO₄^-, AcO^-, HSO₄^-, H₂PO₄^-, and CN^-. Only F^-, AcO^-, and H₂PO₄^- induced a new red-shifted absorption band that was attributed to a deprotonation process involving the amine moiety of the imidazole ring. Moreover, upon increasing quantities of F^-, AcO^-, and H₂PO₄^-, moderate quenching was induced in the emission of 2a-d together with the appearance of a new red-shifted band. The UV-visible and emission behavior of the four probes in the presence of Cu²⁺, Co²⁺, Mg²⁺, Fe³⁺, Ba²⁺, Fe²⁺, Ni²⁺, Ca²⁺, Zn²⁺, Pb²⁺, Cd²⁺, Cr³⁺, Al³⁺, K⁺, and Li⁺ was also assessed. Only addition of Fe³⁺, Cr³⁺, and Al³⁺ caused a new blue-shifted band in 2a-d that was ascribed to a preferential coordination with the acceptor part of the probes. Moreover, an important quenching of the emission was observed which was ascribed to the interaction between these trivalent cations and 2a-d.

Full text of DOI:10.1021/jo501515e

Article
pubs.acs.org/joc
Imidazoanthraquinone Derivatives for the Chromofluorogenic
Sensing of Basic Anions and Trivalent Metal Cations
Cristina Marín-Hernandez,†,‡ Luis E. Santos-Figueroa,†,‡ María E. Moragues,†,‡ M. Manuela M. Raposo,*,§
́
Rosa M. F. Batista,§ Susana P. G. Costa,§ Teresa Pardo,†,‡ Ramon Martínez-Manez,*,†,‡
́
́
̃
and Felix Sancenon†,‡
́
́
†Centro de Reconocimiento Molecular y Desarrollo Tecnolog
́
ico (IDM), Unidad Mixta Universidad de Valencia-Universidad
́
Politecnica de Valencia, Camino de Vera s/n, 46022 Valencia, Spain
‡CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN)
§Centro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
S
* Supporting Information
ABSTRACT: Four imidazoanthraquinone derivatives (2a−d)
were synthesized and characterized and their coordination
behavior against selected anions and cations tested. Acetoni-
trile solutions of probes showed charge-transfer absorptions in
the 407−465 nm range. The four probes emitted in the 533−
571 nm interval. The recognition ability of 2a−d was evaluated
−
−
−
−
in the presence of F−, Cl−, Br−, I−, OCN−, BzO−, ClO4 , AcO−, HSO4 , H2PO4 , and CN−. Only F−, AcO−, and H2PO4
induced a new red-shifted absorption band that was attributed to a deprotonation process involving the amine moiety of the
imidazole ring. Moreover, upon increasing quantities of F−, AcO−, and H2PO4 , moderate quenching was induced in the
−
emission of 2a−d together with the appearance of a new red-shifted band. The UV−visible and emission behavior of the four
probes in the presence of Cu2+, Co2+, Mg2+, Fe3+, Ba2+, Fe2+, Ni2+, Ca2+, Zn2+, Pb2+, Cd2+, Cr3+, Al3+, K+, and Li+ was also
assessed. Only addition of Fe3+, Cr3+, and Al3+ caused a new blue-shifted band in 2a−d that was ascribed to a preferential
coordination with the acceptor part of the probes. Moreover, an important quenching of the emission was observed which was
ascribed to the interaction between these trivalent cations and 2a−d.
about the formation of host−anion complexes and how this
knowledge can be used for the design of selective anion
receptors.8 The most widely approach to design probes is the
use of the “binding site-signaling subunit” paradigm, in which
the “‘binding site”’ is covalently connected to an optical
“‘signaling subunit”’ in such a way that the interaction of certain
species with the coordination site induces electronic modu-
lations in the signaling unit, resulting in color or emission
changes.9 Inspired by these concepts, authors have designed a
number of probes for anions using, in most cases, well-known
binding interactions such as hydrogen bonding and electrostatic
forces.10,11
Imidazole derivatives have been shown to be effective in
coordinating anions.12 Besides, acidity of the NH protons
affects the hydrogen-bonding ability of the imidazole group. Its
acidity can be modulated by the presence of easily delocalizable
heteroaromatic rings, such as thiophene, pyrrole, and furan,
electronically connected to the imidazole group, as a way to
enhance intramolecular electronic delocalization.13
INTRODUCTION
■
The design of new molecular probes to detect anions, cations,
and neutral species has gained primary significance in recent
years due to the necessity to detect certain target analytes in
environmental and biological samples.1 In this context, these
probes transform probe−analyte interactions into a signal
which allows analyte detection via optical or electrochemical
changes.2 Among these particular output signals, optical
responses are highly appealing due to the opportunity of
using low-cost, extensively accessible instrumentation, and they
offer, in certain circumstances, the possibility of detecting target
species “to-the-naked-eye”.3 Moreover, chromofluorogenic
chemosensors displaying a displacement of the absorption or
emission band are of importance for the development of
ratiometric procedures.4 Optical detection probes for cations
were developed before 20 years ago,5 whereas the anionic ones
have only been investigated during recent years.6 In general,
anion sensing is more challenging than cation detection.
Comparing ions, anions usually show stability constants lower
than those of metal cations, and some of them display a
complex pH-dependence, and varied shapes, that make the
design of selective receptors for anions more difficult than for
cationic species.7 However, despite these shortcomings, the
design of anion probes has advanced and gained importance in
recent years helped by the progress made in the understanding
On the other hand, trivalent metal cations play crucial roles
in biological processes, and their detection is a timely topic. For
instance, iron is the most abundant transition metal in cellular
Received: July 14, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501515e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Synthesis of Imidazoanthraquinone Receptors 2a−d
Table 1. Spectroscopic Data for the Interaction of 2a−d with Fluoride Anion
absorbance data
fluorescence data
a
a
λab LH (nm)
log ε
λab L− (nm)
Δλab (nm)
λex LH (nm)
λem LH (nm)
λem L− (nm)
Δλem (nm)
Stokes shift (cm−1
)
2a
2b
2c
2d
407
435
465
441
4.25
4.30
4.22
4.13
479
490
514
501
72
55
49
60
438
465
458
467
544
571
533
568
588
608
609
621
44
37
76
53
6188
5506
3123
4658
a
Measured upon addition of 50 equiv of fluoride anion.
systems. More specifically, Fe3+ is an essential element in the
growth and development of living systems as well as in many
biochemical processes at the cellular level,14 and its deficiency is
associated with several diseases (anemia, hemochromatosis,
diabetes, Parkinson’s, and dysfunction of heart, pancreas, and
liver).15 On the other hand, aluminum is the third most
abundant element in earth and the most abundant metallic
element. Aluminum is highly used in several commercial
applications such as water treatment, food additives, medicines,
and metallic devices. Besides, some studies indicate that
abnormal levels of aluminum ions in certain human tissues
and cells could induce Alzheimer’s and Parkinson’s diseases.16
Finally, Cr3+ is one of the most important nutrients in human
and animal diet and plays a fundamental role in the metabolism
of carbohydrates, proteins, lipids, and nucleic acids.17 Its
deficiency is associated with the development of diabetes and
some cardiovascular diseases.18 Moreover, its use in the metal
industry has resulted in increased levels of chromium in the
environment, and today has come to be regarded as a
pollutant.19
From a different point of view, some anthraquinone
derivatives have been recently reported as suitable systems for
the colorimetric sensing of certain anions and have also been
used for metal ion recognition.20 Anthraquinones have been
widely used in the manufacture of pigments,21 fibers, and
paper22 in the textile industry23 and of semiconductors in the
electronic industry.24 More recently, anthraquinones have
attracted increasing research interest due to their bioactive
properties, and some of their derivatives have been reported to
be used as antiviral,25 antibacterial,26 antiparasitic,27 insectici-
dal,28 fungicidal,29 antimalarial,30 and anticancer agents.31
Taking into account the above-mentioned facts, and our
interest in the development of optical probes,32 we report
herein the synthesis and characterization of a new family of
imidazoanthraquinone derivatives functionalized with aromatic
and heterocyclic groups (i.e., biphenyl, N-methylpyrrole,
thiophene, and furan). The spectroscopic behavior of the
designed probes in the presence of selected anions and cations
was studied.
RESULTS AND DISCUSSION
■
Synthesis and Characterization. The formyl precursor 1c
was synthesized through Suzuki−Miyaura cross-coupling
reaction of 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-pyrrole with bromobenzene in dry DME with
Pd(PPh3)4 as catalyst and Na2CO3, followed by Vilsmeier
formylation. The new imidazoanthraquinone derivatives 2a−d
with biphenyl, phenylthiophene, phenylpyrrole, and phenyl-
furan substituents as π-conjugated groups were synthesized in
moderate to good yields (32−71%). In a typical synthesis,
aldehydes 1a−d and 1,2-diaminoanthraquinone were heated for
15 h in ethanol at reflux using formic acid as catalyst, to yield
the respective imines that were subsequently cyclized to the
corresponding imidazoanthraquinones 2a−d in the presence of
lead tetraacetate in acetic acid as solvent and at room
temperature (see Scheme 1). For all reactions, the crude
products were purified by column chromatography on silica
with chloroform or through recrystallization with dichloro-
methane to finally give the pure compounds. The four 2a−d
1
receptors were characterized by H, 13C NMR, and HRMS.
The obtained data are in agreement with the expected
structures (see Supporting Information and Experimental
Section for details).
1
One of the most relevant characteristics in the H NMR
spectrum of this group of imidazoanthraquinone derivatives
was that corresponding to N−H protons of the imidazole
heterocycle which appeared as singlets downfield in the 12.74−
13.38 ppm range. These values suggested the formation in
solution of an intramolecular hydrogen bond between the NH
of the imidazole ring and the neighboring quinone carbonyl
group.33
B
dx.doi.org/10.1021/jo501515e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 1. HOMO (left) and LUMO (right) orbitals for probe 2a.
Figure 2. Color changes observed for probe 2a (1.0 × 10−4 mol dm−3 in acetonitrile) upon addition of 10 equiv of the selected anions.
Figure 3. UV−vis titration profiles of receptor 2b (1.0 × 10−5 mol dm−3 in acetonitrile) obtained upon the addition of F− (left) and AcO− (right)
anions.
Spectroscopic Characterization. Acetonitrile solutions of
imidazoanthraquinone derivatives 2a−d presented a strong
absorption (log ε ≈ 4.2) in the 400−470 nm interval (see Table
1). The position of the visible absorption band in the receptors
was clearly related to the electron donor strength of the
aromatic or heterocycle system (pyrrole ≫ furan > thiophene >
benzene) used as π-bridge linked to the imidazoanthraquinone
moiety. In particular for 2a, bearing a benzene π-bridge, the
absorption band was centered at 407 nm. Upon changing the π-
bridge to thiophene (2b) and furan (2d), the absorption
maximum suffered a moderate bathochromic shift to 435 and
441 nm, respectively. Moreover when a N-methylpyrrole was
used as a π-bridge (2c), the probe displayed a significant
bathochromic shift to 465 nm. Additionally, upon excitation in
the corresponding wavelength maximum for the four probes, a
broad unstructured emission in the 540−580 nm region
appeared (see Table 1).
The HOMO and LUMO differences in energy for probes
2a−d were determined by quantum chemical studies at the
semiempirical level using the PM3 model and with RMS
gradient of 0.001. For the four receptors, the HOMO orbitals
are mainly situated in the imidazole moiety and the heterocyclic
rings (donor part of the molecule), whereas the LUMO orbitals
are located in the anthraquinone moiety (acceptor fragment
common to the four probes). These data indicated that the
electronic transition between the HOMO and the LUMO has a
charge-transfer character. As an example, Figure 1 shows the
HOMO and LUMO orbitals for probe 2a.
Spectroscopic Behavior of 2a−d in the Presence of
Anions. In a first step, the ability of receptors 2a−d to detect
anions was studied. In typical experiments, the UV−vis
spectrum of the probes was monitored in acetonitrile solutions
at 25 °C in the presence of chosen anions of different sizes and
shapes (i.e., F−, Cl−, Br−, I−, OCN−, BzO−, ClO4 , AcO−,
−
−
−
HSO4 , H2PO4 , and CN−). The chromogenic response
observed with compounds 2a−d was quite similar, and in all
−
cases only addition of F−, AcO−, and H2PO4 anions induced
color changes that were especially visible to the naked eye in
the presence of F− anion. As an example, Figure 2 shows the
color modulations observed for probe 2a upon addition of 10
equiv of selected anions.
As shown in Figure 2, acetonitrile solutions of probe 2a were
yellow and turned orange upon addition of F− anion. Upon
addition of AcO− and H2PO4− anions, a moderate color change
from yellow to dark yellow occurred. Other anions were unable
to induce remarkable color changes. A similar behavior was
observed for probes 2b, 2c, and 2d; i.e., clear color modulations
in the presence of F− and only a moderate color change in the
−
presence of AcO− and H2PO4 anions.
C
dx.doi.org/10.1021/jo501515e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Once the responses for 2a−d probes toward anions were
assessed, changes in the UV−visible spectrum in the presence
of F−, AcO−, and H2PO4 were studied in more detail. UV−
−
visible titration profiles of probe 2b with F− and AcO− anions
are shown in Figure 3 as an example. Acetonitrile solutions of
probe 2b displayed an intense band at 435 nm that, upon
addition of increasing quantities of F− anion, decreased in
intensity while a new red-shifted band grew at 490 nm. In
contrast, the addition of AcO− and H2PO4 anions induced
−
only moderate changes in the UV−visible profiles of probe 2b.
As shown in Figure 3, addition of increasing amounts of AcO−
anion resulted in a hypochromic effect for the band at 435 nm
together with the appearance of a broad shoulder centered at
−
ca. 520 nm. Similar titration profiles were obtained for H2PO4
anion and 2b.
UV−visible titration experiments carried out with probes 2a,
2c, and 2d showed the same behavior as that observed for 2b,
i.e., only the addition of F− anion caused a remarkable decrease
in the visible band of the receptor with a concomitant clear
increase of a new red-shifted absorbance (see Supporting
Figure 4. Absorbance of receptor 2a (1.0 × 10−5 mol dm−3) at 479 nm
alone and upon the addition of 10 equiv of F− anion and 10 equiv of
−
−
Br−, Cl−, I−, OCN−, BzO−, ClO4 , HSO4 , and CN− anions in
acetonitrile.
−
Information). Addition of AcO− and H2PO4 anions to
corresponding isosbestic point observed in the UV−visible
titrations. The obtained response with the four probes was
quite similar and, as an example, Figure 5 shows the emission
acetonitrile solutions of 2a, 2c, and 2d induced small changes
in the UV-profiles, similar to those depicted in Figure 3 for 2b
(data not shown).
The fact that color modulations in the four probes were
induced by the addition of basic anions (F−, AcO−, and
−
H2PO4 ) pointed to a ground-state proton shift as the
mechanism for the chromogenic response observed.34 In this
scenario, addition of F− anion would induce the deprotonation
of the N−H moiety of the imidazoanthraquinone fragment,
which is common to all four probes. The mechanism of the
chromogenic response was assessed with additional titration
experiments carried out with probes 2a−d and tetrabutylam-
monium hydroxide that showed an identical behavior to that
found in the presence of F− anion (see Supporting
Information). On the whole, the results were in agreement
with the expectation that the deprotonation of a donor group in
a push−pull system by an electron-rich anion would be
expected to induce a bathochromic shift of the absorption band.
Indeed, other benzimidazole-, urea-, thiourea-, amide-, pyrrole-,
benzimidazole-, or thiosemicarbazone-containing probes have
been reported to cause similar shifts upon addition of
Figure 5. Emission spectra of probe 2a (1 × 10−5 mol dm−3) in
acetonitrile upon addition of increasing quantities of F− anion
(excitation at 438 nm). The inset shows the change in the intensity
of the 544 nm band upon addition of increasing quantities of F− anion.
fluoride.35 Besides, AcO− and H2PO4 showed a less relevant
−
response with the probes as expected because they are not as
basic as F− anion.36 One striking feature of probes 2a−d is their
lack of response upon addition of the basic and nucleophilic
CN− anion. However, this lack of response has also been
described in other anthraquinone-containing probes.37
changes for probe 2a upon addition of increasing quantities of
F−. As shown, probe 2a showed a broad emission band at 544
nm (λex = 438 nm), the intensity of which gradually decreased
as the amount of F− anion increased. Together with this
quenching effect, a progressive bathochromic shift of the
fluorescence was observed (from 544 to 588 nm upon addition
of 2 equiv) with an isoemissive point at 576 nm.
As a general trend, the remaining probes 2b−d also showed a
moderate bathochromic shift and a simultaneous partial
quenching of their original emission band upon addition of
increasing quantities of F− anion. However, a more detailed
look at the titration experiments indicated that, to induce the
same behavior, larger amounts of fluoride were necessary for
receptor 2b, 2c, and 2d than for receptor 2a. Emission data of
the four probes alone and in the presence of F− anion are
shown in Table 1.
The chromogenic behavior of 2a−d toward F− was rather
selective, and for instance the intensity of the red-shifted
absorption band obtained upon addition of 10 equiv of this
anion is identical to that obtained in mixtures containing 10
equiv of fluoride and 10 equiv of Cl−, Br−, I−, OCN−,BzO−,
−
−
ClO4 , HSO4 , and CN− anions (see Figure 4). Besides, the
limits of detection of 2a−d for F− were also determined from
the corresponding titration profiles. The values obtained were
quite similar for the four probes and around 10 μM.
Once the UV−visible behavior of 2a−d probes was assessed,
more detailed fluorogenic studies with F− anion were carried
out. F− was selected because this was the anion that induced
the most remarkable changes in the UV−visible of the four
probes. Emission titrations were carried out in acetonitrile
solutions in the presence of F− and using as λex the
The emission changes observed for the four probes in the
presence of F− anion were quite similar to those observed for
related derivatives.38 For 2a−d, the quenching of the initial
D
dx.doi.org/10.1021/jo501515e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 2. Logarithms of the Stability Constants Measured for the Interaction of Probes 2a−d with F− Anion
2a
2b
2c
2d
log K
4.208 0.006
3.308 0.007
3.819 0.071
3.381 0.071
fluorescence band together with the appearance of the red-
shifted emission was ascribed to a proton transfer process that
yielded the deprotonated probes. This mechanism was
proposed, for instance, by Han and co-workers for the
interaction of fluoride with phenyl-1H-anthra(1,2-d)imidazole-
6,11-dione, a probe closely related to 2a−d.39 The four probes
alone are highly emissive. In the excited state, fluoride anion
induced the loss of the proton of the N−H group, and the
formed HF binds, through the formation of a weak hydrogen
bond, with the deprotonated receptor. This complex is not
stable; as a consequence, a deprotonation process takes place
and the formed complex loses the HF molecule, yielding the
also emissive anionic form of the corresponding probe. The
lifetimes of the hydrogen bonded complexes are too short and
are not observed experimentally in the emission titration
profiles. The negative charge generated upon the proton
transfer process induced a new emission band that corresponds
to the deprotonated form which emits at a wavelength longer
than that of the neutral probe.
The optical response of 2a−d was also studied in mixed
acetonitrile:water solutions. However, it was found that
addition of more than 2% of water to acetonitrile disabled
the chromofluorogenic response observed upon addition of F−
anion. This could be ascribed to the fact that F− has a high free
energy of solvation (−465 kJ mol−1) and hence a strong affinity
for coordinating water molecules rather than the N−H moiety
of the four probes. The formation of a dense water shell around
fluoride anion decreased significantly its basicity and, as a
consequence, the proton transfer process was disabled.
molecule and that of the deprotonated form.13 Calculations for
probes 2a−d (assuming that the N−H moiety of the four
receptors was deprotonated) were carried out using a PM3
semiempirical model, and the results are shown in Table 3.
Table 3. Stabilization Energy of the Deprotonation for
Probes 2a−d
−
−
receptor E(LH) (kcal/mol) E(L ) (kcal/mol) E(LH) − E(L ) (kcal/mol)
2a
2b
2c
2d
−5735.5
−5343.6
−5725.9
−5374.3
−5724.9
−5336.0
−5721.9
−5365.8
−10.6
−7.6
−4.0
−8.5
Data in Table 3 indicated that the most acidic probe was 2a.
This was in agreement with the stability constants calculated
above for the deprotonation process of the probes in the
presence of fluoride. However, for the remaining chemosensors,
there was not a clear correlation between the acidity predicted
by quantum chemical calculations (i.e., 2d > 2b > 2c) and that
found from titration experiments (i.e., 2c > 2d > 2b). This is
most likely due to the different conditions in which the
calculations were performed (gas for quantum calculations vs
acetonitrile solutions for stability constants).
Spectroscopic Behavior of 2a−d with Cations. Probes
2a−d contain in their structures two oxygen and two nitrogen
atoms that could be able to coordinate with transition metal
cations.42 For this reason, the interaction of probes 2a−d with
selected cations (Cu2+, Co2+, Mg2+, Fe3+, Ba2+, Fe2+, Ni2+, Ca2+,
Zn2+, Pb2+, Cd2+, Cr3+, Al3+, K+, and Li+) in acetonitrile was
studied upon addition of 10 equiv of the corresponding cation.
Only addition of trivalent cations (Fe3+, Al3+, and Cr3+) induced
color changes in the acetonitrile solutions of the four probes.
Once the selective chromogenic response of 2a−d to
trivalent cations was assessed, more detailed studies of the
four probes with Fe3+, Al3+, and Cr3+ were performed via UV−
visible titrations. As a general trend, addition of increasing
amounts of these cations induced a progressive reduction in
absorption of the visible band concomitant with the growth of a
new blue-shifted band. As an example of this behavior, Figure 6
shows the UV−visible titration profile of probe 2a with Fe3+
cation. The absorption at 407 nm progressively decreased when
increasing quantities of Fe3+ cation were added. At the same
time, a new absorption band at 371 nm (Δλ = 36 nm) was
formed. These changes were reflected in a color modulation
from yellow to colorless.
Determination of Stability Constants with Anions and
Quantum Mechanical Studies. As stated above, basic anions
(such as F−, AcO−, and H2PO4 ) induced proton transfer
−
processes in the probes 2a−d. This proton transfer equilibrium
is represented in eq 1 in which LH is the probe and A−
represents a basic anion such as fluoride.
−
−
LH + 2A ⇆ L + A2H−
(1)
To complete the characterization of the interaction among
2a−d with anions, the deprotonation process was studied by
the determination of the stability constants from UV−vis
spectroscopic titrations, using the HypSpec software.40 The
studies were performed using F− because this was the anion
that induced the most remarkable changes in the UV−visible
(vide ante). The results are shown in Table 2.
The logarithms of the stability constants for probes 2b, 2c,
and 2d in their interaction with F− were rather similar and
lower than log K = 4. Moreover, when the π-bridge was a
biphenyl system, the acidity of the N−H moiety was enhanced
(pK of 4.208). This observed enhancement was clearly related
to the lower electron donor character of the benzene ring, when
compared with the pyrrole (2c), furan (2d), and thiophene
(2b) heterocycles. Despite this fact, the logarithms of the
stability constants for the proton transfer reactions for probes
2a−d are of the same order of magnitude and similar to those
reported for related compounds.41
The emission behavior of 2a−d in the presence of trivalent
cations was also studied. The four probes presented a very
similar response upon addition of Fe3+, Al3+, and Cr3+ cations,
namely a marked emission quenching. As an example, Figure 7
shows the titration obtained for probe 2a and Fe3+ cation. As
shown, the emission at 543 nm (λex = 396 nm) was
progressively quenched upon addition of increasing amounts
of Fe3+. Changes in the UV−visible and emission of probes 2a−
d in the presence of trivalent cations are summarized in Table
4. Furthermore, the limits of detection of the four probes
toward trivalent metal cations were evaluated from fluorescence
It has been reported that the hydrogen bond-donating or
-accepting ability of a molecule can be studied from quantum
chemical calculations as a difference between the energy of the
E
dx.doi.org/10.1021/jo501515e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 5. Limits of Detection for 2a−d Probes to Trivalent
Cations (μM) from Emission Titrations
receptor
Fe3+
Al3+
Cr3+
2a
2b
2c
2d
1.43
2.10
1.65
1.81
1.78
2.46
−
0.98
3.10
1.89
1.85
1.35
group, and the results strongly suggested an interaction of the
metal cations with this moiety.
1H NMR Spectroscopic Studies in the Presence of
Cations. To study, in more depth, the coordination mode of
probes 2a−d with trivalent cations, 1H NMR titration
experiments were performed. For this purpose, we selected
Figure 6. UV−visible titration of probe 2a (1.0 × 10−5 mol dm−3)
with Fe3+ in acetonitrile. The inset shows the absorbance changes at
371 and 407 nm vs Fe3+ concentration.
1
receptor 2a, and changes in H NMR spectra (in CD3CN)
upon addition of increasing quantities of Al3+ cation were
studied.
1
The H NMR spectrum of 2a in CD3CN (see Figure 8 for
proton assignation) showed the signals of the monosubstituted
benzene ring centered at 7.45 (t, Ha), 7.53 (t, Hb), and 7.80 (d,
Hc) ppm. Protons of the 1,4-disubstituted benzene ring
appeared at 7.90 (m, Hd overlapped with Hi) and at 8.38
(He) ppm whereas protons of the anthraquinone moiety
appeared at 7.90 (m, Hi overlapped with Hd), 8.13 (d, Hf),
8.21 (d, Hg), and 8.31 (dd, Hh) ppm. As a general trend,
addition of Al3+ cation induced downfield shifts of the signals of
probe 2a (see Figure 8). Besides, the shifts of the proton
resonances stopped upon addition of 1 equiv of Al3+ cation,
suggesting the formation of 1:1 (probe−cation) complexes.
The more remarkable shifts observed upon Al3+ addition
were those of protons Hd, Hf, Hg, and He that are located in
the 1,4-disubstituted benzene ring of the biphenyl system and
in the anthraquinone aromatic ring fused with the imidazole
heterocycle (see Figure 8). More in detail, the Hg signal shifted
from 8.21 to 8.27 ppm, whereas Hf was displaced from 8.13 to
8.27 ppm. On the other hand, the protons of the biphenyl
group centered at 7.90 (Hd) and 8.38 (He) ppm shifted to 8.08
and 8.51 ppm, respectively. These observed shifts are
tentatively ascribed to a preferential coordination of Al3+ cation
with one of the nitrogen atoms of the imidazole ring.
Figure 7. Emission spectra (excitation at 396 nm) of receptor 2a (1.0
× 10−5 mol dm−3) in acetonitrile upon addition of increasing
quantities of Fe3+ cation. The inset shows the changes in the emission
intensity at 543 nm vs Fe3+ concentration.
Table 4. Spectroscopic Data for Probes 2a−d with Trivalent
Cations
Finally, the 1:1 stoichiometry of the complex formed
between probes 2a−d and Al3+, Fe3+, and Cr3+ was assessed
by the method of continuous variation (Job’s plot). The Job’s
plot for the interaction between 2a and Fe3+ cation is shown in
Figure 9. In all cases, the formation of 1:1 (probe−trivalent
cation) complexes was confirmed.
a
absorption wavelength (nm)
emission wavelength (nm)
LH-
Al3+
LH-
Cr3+
LH-
Fe3+
LH-
Al3+
LH-
Cr3+
LH-
Fe3+
receptor LH
LH
2a
2b
2c
2d
407
435
465
441
371
410
429
419
372
410
429
419
371
410
428
419
544
571
533
580
544
559
533
558
543
562
534
556
543
563
534
555
Stability Constants with Cations. To complete the
characterization of the interaction between probes 2a−d and
cations, the corresponding stability constants for the formation
of 1:1 complexes were determined from UV−visible spectro-
scopic titrations using the HypSpec software. The results are
shown in Table 6. As shown, the stability constants determined
for probes 2b, 2c, and 2d were of the same order of magnitude
and were in the 3.74−4.52 range. Compared with these data, 2a
formed, in general, stronger complexes with values of the
logarithms of the stability constants of 5.28, 4.80, and 4.49 for
the coordination with Al3+, Cr3+, and Fe3+, respectively. The
fact that 2a forms complexes with trivalent metal cations
stronger than that of 2b−d may be tentatively ascribed to the
presence of N-methylpyrrole, thiophene, and furan heterocycles
in 2b−d that may inhibit, to some extent, the coordination with
the trivalent cations.
a
Measured upon excitation at isosbestic point in the UV−vis titration.
titration profiles. The values obtained were quite similar for all
2a−d probes and are shown in Table 5.
The blue shift of the visible band of 2a−d observed upon
addition of trivalent cations was indicative of a preferential
coordination with the donor part of the probes.43 In fact, the
results are in agreement with the expectation that the
interaction between an electron-acceptor cation and a donor
group in a push−pull system will induce a blue shift. The
common donor fragment in the four probes is the imidazo
F
dx.doi.org/10.1021/jo501515e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
Figure 8. H NMR spectra of probe 2a in CD3CN alone and in the presence of increasing quantities of Al3+ cation.
(AcO− and H2PO4 ) induced moderate changes in the UV−
visible and emission profiles of the probes. On the other hand,
of all the cations tested, only Al3+, Fe3+, and Cr3+ induced
changes in the UV−visible and fluorescence of 2a−d. In
particular, addition of trivalent cations to solutions of the four
probes induced a remarkable blue shift of the absorption band
and a partial quenching of the emission. The spectroscopic
changes observed with of Al3+, Fe3+, and Cr3+ were ascribed to
−
1
the formation of 1:1 (probe−cation) complexes. H NMR
measurements suggested that trivalent cations coordinated with
the donor part of the probes, i.e., the imidazole group.
Receptors 2a−d are rare dual probes that can be used as both
anion (F−) or cation (Al3+, Fe3+, and Cr3+) chemosensors.
EXPERIMENTAL SECTION
Figure 9. Job’s plot for the complexation of 2a with Fe3+ cation
determined by UV−visible spectrophotometry in acetonitrile at 371
nm and [2a] + [Fe3+] = 1.0 × 10−3 mol dm−3.
■
Materials and Methods. General. TLC analyses were carried out
on 0.25 mm thick precoated silica plates, and spots were visualized
under UV light. NMR spectra were obtained at an operating frequency
1
of 300 or 400 MHz for H and 75.4 or 100.6 MHz for 13C using the
Table 6. Logarithms of the Stability Constants Calculated for
the Probes 2a−d with Trivalent Cations (C3+ = Al3+, Cr3+,
and Fe3+) Interactions
solvent peak as internal reference at 25 °C. All chemical shifts are
given in ppm using δH Me4Si = 0 ppm as reference, and J values are
given in hertz. Precursors 1a, 1b, 1d, and 1,2-diaminoanthraquinone
are commercially available and were used as received.
Synthesis of Formyl Precursor 1c. The synthesis of compound 1c
includes two steps: (i) Suzuki−Miyaura cross-coupling to obtain the
intermediate 1-methyl-2-phenyl-1H-pyrrole followed by (ii) Vilsmeier
formylation to obtain the formyl precursor 1-methyl-5-phenyl-1H-
pyrrole-2-carbaldehyde.
i. Suzuki−Miyaura Cross-Coupling. To bromobenzene (0.112 g,
0.72 mmol) in DME (6 mL) were added 1-methyl-2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (0.193 g, 0.93 mmol,
1.3 equiv), Pd(PPh3)4 (0.050 g, 0.06 equiv), and 2 M Na2CO3 (0.72
mL, 2 equiv). The mixture was stirred at 80 °C under an argon
atmosphere during 15 h until disappearance of the halide. The mixture
was cooled to room temperature, and a saturated solution of NaCl (10
mL) and ethyl acetate (30 mL) were added. The two phases were
separated, and the organic phase was extracted with ethyl acetate (3 ×
20 mL), washed with water and then with aqueous NaOH (10%),
dried with anhydrous magnesium sulfate, and evaporated to dryness.
The obtained residue was purified by column chromatography, using
LH + C3+ ⇆ LH···C3+
Al3+
Cr3+
Fe3+
2a
2b
2c
2d
5.28 0.02
4.44 0.04
4.23 0.04
4.52 0.04
4.80 0.02
3.74 0.05
4.34 0.03
4.19 0.05
4.49 0.02
4.52 0.03
4.40 0.03
4.01 0.07
CONCLUSION
A family of imidazoanthraquinone probes (2a−d) was
synthesized and characterized. Moreover, their interactions
■
1
with ions were studied via UV−visible, fluorescence, and H
NMR spectroscopy. Among the anions tested, F− induced a
clear deprotonation process for 2a−d that was reflected in a
red-shift of the absorption and in a moderate quenching of the
emission intensities of the four probes. Other basic anions
G
dx.doi.org/10.1021/jo501515e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mixtures of diethyl ether and light petroleum ether of increasing
polarity, and 1-methyl-2-phenyl-1H-pyrrole was obtained as a yellow
oil44 (0.085 g, 76%).
155.7, 182.2, 183.1 ppm. HRMS: (FAB) m/z (%) for C25H14N2O3;
calcd 390.1004; found 390.0986.
Physical Measurements. Stock solutions of the anions (F−, Cl−,
−
−
−
Br−, I−, OCN−, BzO−, ClO4 , AcO−, HSO4 , H2PO4 , and CN− as
tetrabutylammonium salts) and cations (Cu(ClO4)2·6H2O, Co-
(ClO4)2·6H2O, Mg(ClO4)2, Fe(ClO4)3·xH2O, Ba(ClO4)2, Fe-
(ClO4)2·xH2O, Ni(ClO4)2·6H2O, Ca(ClO4)2·4H2O, Zn(ClO4)2·
6H2O, Pb(ClO4)2·xH2O, Cd(ClO4)2·xH2O, Cr(ClO4)3·6H2O, Al-
(ClO4)3·9H2O, KClO4, and LiClO4) were prepared at 10−3 mol
dm−3 in acetonitrile. The concentrations of ligands used in
spectroscopy measurements were ca. 1 × 10−4 and 1 × 10−5 mol
dm−3. The quantity of anion solutions added did not exceed 10% of
the volume of the compounds 2a−d to avoid relevant changes in the
total solution concentration. For the probes that required the addition
of excess of ions (30 equiv), corrections of the volume and
concentration were made. The UV−vis and fluorescence titrations
were measured at room temperature (25 °C).
ii. Vilsmeier Formylation. POCl3 (0.079 mL, 1.20 mmol) was
added to DMF (0.056 mL, 1.20 mmol), and the mixture was stirred for
15 min at 0 °C. 1-Methyl-2-phenyl-1H-pyrrole (0.062 g, 0.39 mmol)
dissolved in DMF (1 mL) was added dropwise with stirring. The
mixture was heated for 2 h at 60 °C. The solution was then poured
slowly into a saturated sodium acetate aqueous solution (5 mL) and
stirred during 30 min. The organic layer was diluted with diethyl ether
(20 mL), washed with saturated NaHCO3 aqueous solution (10 mL),
and dried with anhydrous MgSO4. The organic extract was filtered,
evaporated under reduced pressure, and purified by column
chromatography, using mixtures of diethyl ether and light petroleum
ether of increasing polarity, yielding 1-methyl-5-phenyl-1H-pyrrole-2-
carbaldehyde (1c) as colorless oil (0.073 g, 90%).45 1H NMR (400
MHz, CDCl3) δ = 6.31 (d, 1H, J = 4.0 Hz, H-4), 6.98 (d, 1H, J = 4.0
Hz, H-3), 7.40−7.47 (m, 5H, H-2′, H-3′, H-4′, H-5′ and H-6′), 9.59
(s, 1H, CHO) ppm.
General Procedure for the Synthesis of Imidazoanthraquinones
2a−d. i. Preparation of the Imines. The aldehydes 1a−d (0.20
mmol) and 1,2-diaminoanthraquinone (0.24 mmol) were dissolved
separately in ethanol (4 mL/mmol). The ethanolic solution of
aldehyde and formic acid (0.04 mL/mmol of aldehyde) was added to
the solution of 1,2-diaminoanthraquinone heated at reflux. The
reaction mixture was heated under reflux overnight.
ii. Cyclization of the Imines. After cooling, the ethanolic solution
was evaporated and the crude imine was dissolved in a small volume of
acetic acid (5 mL/mmol of imine). To this solution was added lead
tetraacetate (0.20 mmol), and the mixture was stirred overnight at
room temperature. The mixture was poured into water (20 mL) and
extracted with chloroform (2 × 50 mL). The organic layer was dried
with magnesium sulfate and evaporated under reduced pressure to give
compounds 2a−d, which were purified by column chromatography on
silica with chloroform as eluent.
2-([1′,1″-Biphenyl]-4′-yl)-1H-anthra[1,2-d]imidazole-6,11-dione
(2a). Yellow solid (55 mg, 65%). Mp: 267−269 °C (269−270 °C46).
1H NMR (400 MHz, DMSO-d6) δ = 7.40−7.44 (m, 1H), 7.49−7.53
(m, 2H), 7.79 (dd, 2H, J = 8.4 and 1.2 Hz), 7.87 (d, 2H, J = 8.4 Hz),
7.91−7.95 (m, 2H), 8.07−8.14 (m, 2H), 8.19−8.24 (m, 2H), 8.52 (d,
2H, J = 8.0 Hz), 13.23 (s, 1H) ppm.
Theoretical Studies. Quantum chemical calculations were carried
out in vacuum with Hyperchem V6.03 with a semiempirical level
(PM3, within restricted Hartree−Fock level). For optimization, the
Polar−Ribiere algorithm was used. The convergence limit and the
RMS gradient were set to 0.01 kcal mol−1. Stability constants were
calculated with the HypSpec Software V1.1.18 and using the data of
the titration of receptors with target anions and cations.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H NMR spectra of compounds 1c and 2a, 1H and 13C spectra
of probes 2b−d. UV−vis and emission titration profiles.
Cartesian coordinates of the optimized geometries. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: rmaez@qim.upv.es.
*E-mail: mfox@quimica.uminho.pt.
■
Notes
The authors declare no competing financial interest.
2-(5′-Phenylthiophen-2′-yl)-1H-anthra[1,2-d]imidazole-6,11-
1
dione (2b). Orange solid (53 mg, 71%). Mp: 269−271 °C. H NMR
ACKNOWLEDGMENTS
We thank the Spanish Government (project MAT2012-38429-
■
(300 MHz, DMSO-d6) δ = 7.34−7.39 (m, 1H), 7.43−7.48 (m, 2H),
7.63 (d, 1H, J = 3.9 Hz), 7.74 (d, 2H, J = 7.2 Hz), 7.86−7.93 (m, 2H),
8.02 (s, 2H), 8.15−8.21 (m, 2H), 8.50 (d, 1H, J = 3.9 Hz), 13.38 (s,
1H) ppm. 13C NMR (75.4 MHz, DMSO-d6) δ = 118.3, 121.2, 124.3,
125.2, 125.7, 126.2, 126.8, 127.9, 128.6, 129.3, 131.3, 131.6, 132.8,
132.9, 133.0, 133.1, 134.2, 134.4, 147.4, 149.2, 152.7, 182.2, 183.1
ppm. MS (FAB) m/z (%): 407 ([M + H]+, 25), 406 (M+, 9), 307
(33), 289 (17), 166 (13), 155 (30), 154 (100). HRMS: (FAB) m/z
(%) for C25H15N2O2S; calcd 407.0854; found 407.0847.
́
C04) for support. C. Marın-Hernan
́
dez thanks the Spanish
Ministry of Economy and Competitiveness for her grant. We
also gratefully acknowledge financial support from Fundacion
́
Carolina and UPNFM-Honduras for a predoctoral grant to L.
E. Santos-Figueroa and from Spanish Ministry of Science and
Innovation for a FPU grant to M. E. Moragues. Thanks are also
given to the Fundaca
and FEDER-COMPETE for financial support through the
̧
o para a Cien
̂
cia e Tecnologia (Portugal)
̃
2-(1′-Methyl-5′-phenyl-1H-pyrrol-2′-yl)-1H-anthra[1,2-d]-
imidazole-6,11-dione (2c). Dark red solid (24 mg, 32%). Mp: 246−
1
́
Centro de Quımica - Universidade do Minho, Project PEst-C/
248 °C. H NMR (400 MHz, DMSO-d6) δ = 4.08 (s, 3H), 6.39 (d,
1H, J = 4.0 Hz), 7.39−7.44 (m, 1H), 7.48−7.56 (m, 4H), 7.59 (d, 1H,
J = 4.0 Hz), 7.88−7.93 (m, 2H), 8.04 (s, 2H), 8.19−8.24 (m, 2H),
12.74 (s, 1H) ppm. 13C NMR (100.6 MHz, DMSO-d6) δ = 35.2,
109.8, 115.5, 117.7, 121.0, 123.3, 123.8, 126.2, 126.8, 127.3, 127.8,
128.7, 128.9, 131.9, 132.3, 133.1, 133.3, 134.2, 134.4, 140.2, 149.8,
152.3, 182.2, 183.2 ppm. HRMS: (FAB) m/z (%) for C26H17N3O2;
calcd 403.1321; found 403.1307.
QUI/UI0686/2013 (FCOMP-01-0124-FEDER-037302) and a
Postdoctoral grant to R.M.F. Batista (SFRH/BPD/79333/
2011). We are also grateful to the Instituto da Educaca̧ o of
̃
Universidade do Minho for providing the laboratory infra-
structure necessary for the development of this work.
REFERENCES
■
2-(5′-Phenylfuran-2′-yl)-1H-anthra[1,2-d]imidazole-6,11-dione
1
(2d). Dark orange solid (38 mg, 33%). Mp: 250−252 °C. H NMR
(1) Kaur, K.; Saini, R.; Kumar, A.; Luxami, V.; Kaur, N.; Singh, P.;
Kumar, S. Coord. Chem. Rev. 2012, 256, 1992−2028.
(400 MHz, DMSO-d6) δ = 7.22 (d, 1H, J = 4.0 Hz), 7.38 (t, 1H, J =
8.0 Hz), 7.50 (t, 2H, J = 8.0 Hz), 7.84 (d, 1H, J = 4.0 Hz), 7.87−7.89
(m, 2H), 7.94 (d, 2H, J = 8.0 Hz), 8.01−8.06 (m, 2H), 8.15−8.19 (m,
2H), 13.27 (s, 1H) ppm. 13C NMR (100.6 MHz, DMSO-d6) δ =
108.5, 116.7, 118.5, 121.2, 124.3, 124.6, 126.2, 126.8, 128.0, 128.6,
129.0, 129.3, 132.4, 133.0, 133.1, 134.2, 134.5, 143.6, 149.1, 149.5,
(2) (a) Rurack, K. Spectrochim. Acta, Part A 2001, 57A, 2161−2195.
́
(b) Lloris, J. M.; Martninez-Manez, R.; Padilla-Tosta, M. E.; Pardo, T.;
̃
̃
Soto, J.; Beer, P. D.; Cadman, J.; Smith, D. K. J. Chem. Soc., Dalton
Trans. 1999, 14, 2359−2369.
(3) Miyaji, H.; Sessler, J. L. Angew. Chem., Int. Ed. 2001, 40, 154−157.
H
dx.doi.org/10.1021/jo501515e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(4) (a) Yuan, L.; Lin, W.; Zheng, K.; Zhu, S. Acc. Chem. Res. 2013, 46,
1462−1473. (b) Doussineau, T.; Schulz, A.; Lapresta-Fernandez, A.;
(23) (a) Chen, M.; Zhang, C.; Shen, Y.; Zu, G. Adv. Mater. Res. 2013,
610−613, 9−14. (b) Gomes, A. C.; Nunes, J. C.; Simoes, R. M. S. J.
Hazard. Mater. 2010, 178, 57−65.
(24) (a) Zhu, H.; Yang, Y.; Hyeon-Deuk, K.; Califano, M.; Song, N.;
Wang, Y.; Zhang, W.; Prezhdo, O. V.; Lian, T. Nano Lett. 2014, 14,
1263−1269. (b) Rabache, V.; Chaste, J.; Petit, P.; Della Rocca, M. L.;
Martin, P.; Lacroix, J.-C.; McCreery, R. L.; Lafarge, P. J. Am. Chem. Soc.
2013, 135, 10218−10221. (c) Darwish, N.; Díez-Perez, I.; Da Silva, P.;
́
Tao, N.; Gooding, J. J.; Paddon-Row, M. N. Angew. Chem., Int. Ed.
2012, 51, 3203−3206.
(25) (a) Liu, Z.; Wei, F.; Chen, L.-J.; Xiong, H.-R.; Liu, Y.-Y.; Luo, F.;
Hou, W.; Xiao, H.; Yang, Z.-Q. Molecules 2013, 18, 11842−11858.
(b) Li, D.; Zhang, N.; Cao, Y.; Zhang, W.; Su, G.; Sun, Y.; Liu, Z.; Li,
F.; Liang, D.; Liu, B.; Guo, M.; Fu, Y.; Zhang, X.; Yang, Z. Eur. J.
Pharmacol. 2013, 705, 79−85.
(26) (a) Claes, P.; Cappoen, D.; Uythethofken, C.; Jacobs, J.;
Mertens, B.; Mathys, V.; Verschaeve, L.; Huygen, K.; De Kimpe, N.
Eur. J. Med. Chem. 2014, 77, 409−421. (b) Yildiz, E.; Keles, M.; Kaya,
A.; Dincer, S. Chem. Sci. Trans. 2013, 2, 547−555. (c) Kardong, D.;
Upadhyaya, S.; Salkia, L. R. J. Pharm. Res. 2013, 6, 179−182.
(27) Patil, A. G.; Joshi, K. A.; Patil, D. A.; Phatak, A. V.; Naresh, C.
Pharmacogn. J. 2009, 1, 267−272.
(28) (a) Ayo, R. G. J. Med. Plants Res. 2010, 4, 1339−1348. (b) Ee,
G. L. C.; Ng, K. N. Asian J. Chem. 2004, 16, 429−433.
(29) (a) Shah, A.; Varma, O.; Patankar, S.; Kadam, V. Curr. Bioact.
Compd. 2013, 9, 288−305. (b) Khamthong, N.; Rukachaisirikul, V.;
Phongpaichit, S.; Preedanon, S.; Sakayaroj, J. Tetrahedron 2012, 68,
8245−8250.
Moro, A.; Korsten, S.; Trupp, S.; Mohr, G. J. Chem.Eur. J. 2010, 16,
̈
10290−10299. (c) Wang, S.; Li, N.; Pan, W.; Tang, B. Trends Anal.
Chem. 2012, 39, 3−37.
(5) See for example: (a) Kaur, N.; Kumar, S. Tetrahedron 2011, 67,
9233−9264. (b) Prodi, L.; Montalti, M.; Zaccheroni, N.; Dolci, L. S.
Top. Fluoresc. Spectrosc. 2005, 9, 1−57. (c) Fabbrizzi, L.; Poggi, A.
Chem. Soc. Rev. 1995, 24, 197−202. (d) Okamoto, K.; Araki, Y.; Ito,
O.; Fukuzumi, S. J. Am. Chem. Soc. 2004, 126, 56−57. (e) Okamoto,
K.; Fukuzumi, S. J. Am. Chem. Soc. 2004, 126, 13922−13923.
(6) (a) Suksai, C.; Tuntulani, T. Chem. Soc. Rev. 2003, 32, 192−202.
(b) Snowden, T. S.; Ansyn, E. V. Curr. Opin. Chem. Biol. 1999, 3, 740−
746. (c) Wiskur, S. L.; Ait-Haddou, H.; Lavigne, J. J.; Anslyn, E. V. Acc.
Chem. Res. 2001, 34, 963−972. (d) Fukuzumi, S.; Ohkubo, K.;
D’Souza, F.; Sessler, J. L. Chem. Commun. 2012, 48, 9801−9815.
(7) Beer, P. D.; Gale, P. A. Angew. Chem., Int. Ed. 2001, 40, 486−516.
(8) (a) Santos-Figueroa, L. E.; Moragues, M. E.; Climent, E.;
Agostini, A.; Martínez-Man
́
ez, R.; Sancenon
́
, F. Chem. Soc. Rev. 2013,
̃
42, 3489−3613. (b) Moragues, M. E.; Martínez-Manez, R.; Sancenon
́
́
,
̃
F. Chem. Soc. Rev. 2011, 40, 2593−2643.
(9) Martínez-Manez, R.; Sancenon, F. Chem. Rev. 2003, 103, 4419−
́
́
̃
4476.
(10) (a) Schug, K. A.; Lindner, W. Chem. Rev. 2005, 105, 67−113.
(b) Blondeau, P.; Segura, M.; Perez-Fernandez, R.; de Mendoza, J.
́
́
Chem. Soc. Rev. 2007, 36, 198−210. (c) Gale, P. A.; García-Garrido, S.
E.; Garric, J. Chem. Soc. Rev. 2008, 37, 151−190. (d) Steed, J. W.
Chem. Soc. Rev. 2009, 38, 506−519.
(30) (a) Abdissa, N.; Induli, M.; Akala, H. M.; Heydenreich, M.;
Midiwo, J. O.; Ndakala, A.; Yenesew, A. Phytochem. Lett. 2013, 6, 241−
245. (b) Choomuenwai, V.; Andrews, K. T.; Davis, R. A. Bioorg. Med.
Chem. 2012, 20, 7167−7174.
(11) (a) Dydio, P.; Lichosyt, D.; Jurczak, J. Chem. Soc. Rev. 2011, 40,
2971−2985. (b) Sessler, J. L.; Camiolo, S.; Gale, P. A. Coord. Chem.
Rev. 2003, 240, 17−55. (c) Bondy, C. R.; Loeb, S. J. Coord. Chem. Rev.
2003, 240, 77−99. (d) Choi, K.; Hamilton, A. D. Coord. Chem. Rev.
2003, 240, 101−110.
(31) (a) Shrestha, J. P.; Fosso, M. Y.; Bearss, J.; Chang, C.-W. T. Eur.
J. Med. Chem. 2014, 77, 96−102. (b) Wei, W.-T.; Lin, S.-Z.; Liu, D.-L.;
Wang, Z.-H. Oncol. Rep. 2013, 30, 2555−2562.
(12) (a) Yoon, J.; Kim, S. K.; Singh, N. J.; Kim, K. S. Chem. Soc. Rev.
2006, 35, 355−360. (b) Xu, Z.; Kim, S. K.; Yoon, J. Chem. Soc. Rev.
2010, 39, 1457−1466.
(32) See for example: (a) Agostini, A.; Campos, I.; Milani, M.;
Elsayed, S.; Pascual, L.; Martínez-Manez, R.; Licchelli, M.; Sancenon,
́
́
̃
́
(13) (a) Raposo, M. M. M.; García-Acosta, B.; Abalos, T.; Calero, P.;
Martínez-Manez, R.; Ros-Lis, J. V.; Soto, J. J. Org. Chem. 2010, 75,
F. Org. Biomol. Chem. 2014, 12, 1871−1874. (b) Climent, E.;
Mondragon, L.; Martínez-Manez, R.; Sancenon, F.; Marcos, M. D.;
Murguía, J. R.; Amoros ez-Paya, E. Angew. Chem.,
Int. Ed. 2013, 52, 8939−8942. (c) Santos-Figueroa, L. E.; Gimenez, C.;
Agostini, A.; Aznar, E.; Marcos, M. D.; Sancenon, F.; Martínez-Manez,
R.; Amoros, P. Angew. Chem., Int. Ed. 2013, 52, 13712−13716.
(d) Climent, E.; Groninger, D.; Hecht, M.; Walter, M. A.; Martínez-
́
̃
́
́
́
̃
2922−2933. (b) Santos-Figueroa, L. E.; Moragues, M. E.; Raposo, M.
M. M.; Batista, R. M. F.; Costa, S. P. G.; Ferreira, R. C. M.; Sancenon
F.; Martínez-Manez, R.; Ros-Lis, J. V.; Soto, J. Org. Biomol. Chem.
́
, P.; Rurack, K.; Per
́
́
́
,
́
́
̃
́
́
̃
2012, 10, 7418−7428.
́
(14) Winter, W. E.; Bazydlo, L. A.; Harris, N. S. Lab. Med. 2014, 45,
92−102.
̈
Man
́
ez, R.; Weller, M. G.; Sancenon
́
, F.; Amoros
Chem.Eur. J. 2013, 19, 4117−4122. (e) Moragues, M. E.; Esteban, J.;
Ros-Lis, J. V.; Martínez-Manez, R.; Marcos, M. D.; Martínez, M.; Soto,
́
, P.; Rurack, K.
̃
(15) von Haehling, S.; Anker, S. D. Dtsch. Med. Wochenschr. 2014,
139, 841−844.
́
̃
(16) (a) Perl, D.; Brody, A. Science 1980, 208, 297−299.
(b) Belojevic, G.; Jakovljevic, B. Srp. Arh. Celok. Lek. 1998, 126,
283−289. (c) Perl, D.; Gajdusek, D.; Garruto, R.; Yanagihara, R.;
Gibbs, C. Science 1982, 217, 1053−1055.
J.; Sancenon
(f) Climent, E.; Marcos, M. D.; Martínez-Man
Soto, J.; Rurack, K.; Amoros
8522.
́
, F. J. Am. Chem. Soc. 2011, 133, 15762−15772.
ez, R.; Sancenon, F.;
, P. Angew. Chem., Int. Ed. 2009, 48, 8519−
́
́
̃
́
(17) Mertz, W. J. Nutr. 1993, 123, 626−633.
(33) Saha, S.; Ghosh, A.; Mahato, P.; Mishra, S.; Mishra, S. K.;
Suresh, E.; Das, S.; Das, A. Org. Lett. 2010, 12, 3406−3409.
́
(34) Amendola, V.; Esteban-Gomez, D.; Fabbrizzi, L.; Licchelli, M.
(18) Wallach, S. J. Am. Coll. Nutr. 1985, 4, 107−120.
(19) Szczygiel, J.; Dyrek, K.; Kruczala, K.; Bidzinska, E.; Brozek-
Mucha, Z.; Wenda, E.; Wieczorek, J.; Szymonska, J. J. Phys. Chem. B
2014, 118, 7100−7107.
Acc. Chem. Res. 2006, 39, 343−353.
(35) (a) Moragues, M. E.; Santos-Figueroa, L. E.; Abalos, T.;
Sancenon, F.; Martínez-Manez, R. Tetrahedron Lett. 2012, 53, 5110−
́
(20) (a) Langdon-Jones, E. E.; Pope, S. J. A. Coord. Chem. Rev. 2014,
269, 32−53. (b) Batista, R. M. F.; Costa, S.P. G.; Raposo, M. M. M.
Sens. Actuators, B 2014, 191, 791−799. (c) Batista, R. M. F.; Oliveira,
E.; Costa, S. P. G.; Lodeiro, C.; Raposo, M. M. M. Supramol. Chem.
2014, 26, 71−80. (d) Saini, R.; Kaur, N.; Kumar, S. Tetrahedron 2014,
70, 4285−4307.
́
́
̃
5113. (b) Batista, R. M. F.; Oliveira, E.; Costa, S. P. G.; Lodeiro, C.;
Raposo, M. M. M. Tetrahedron 2011, 67, 7106−7113. (c) Santos-
Figueroa, L. E.; Moragues, M. E.; Batista, R. M. F.; Costa, S. P. G.;
Raposo, M. M. M.; Ferreira, R. C. M.; Sancenon
R.; Ros-Lis, J. V.; Soto, J. Tetrahedron 2012, 68, 7179−7186.
(d) Aldrey, A.; Nunez, C.; García, V.; Bastida, R.; Lodeiro, C.;
́
, F.; Martínez-Manez,
́
̃
(21) (a) Stathopoulou, K.; Valianou, L.; Skaltsounis, A.-L.;
Karapanagiotis, I.; Magiatis, P. Anal. Chim. Acta 2013, 804, 264−
272. (b) Shindy, H. A. Mini-Rev. Org. Chem. 2012, 9, 361−373.
(22) (a) De Almeida, D. P.; Gomide, J. L. Papel 2013, 74, 53−56.
(b) Song, W.; Liu, J. J. Chem. Pharm. Res. 2013, 5, 1217−1221.
́
̃
Macías, A. Tetrahedron 2010, 66, 9223−9230. (e) Atta, A. K.; Ahn, I.-
H.; Hong, A.-Y.; Heo, J.; Kim, C. K.; Cho, D.-G. Tetrahedron Lett.
2012, 53, 575−578. (f) Amendola, V.; Fabbrizzi, L.; Mosca, L.;
Schmidtchen, F.-P. Chem.Eur. J. 2011, 17, 5972−5981. (g) Amen-
dola, V.; Bergamaschi, G.; Boiocchi, M.; Fabbrizzi, L.; Milani, M.
Chem.Eur. J. 2010, 16, 4368−4380.
(c) Alfaro, A.; Lop
P. Cell. Chem. Technol. 2013, 47, 765−775.
́ ́
ez, F.; Perez, A.; García, J. C.; Pelach, M. A.; Mutje,
I
dx.doi.org/10.1021/jo501515e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(36) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456−463. The pKa of
acetic and hydrofluoric acids in DMSO are 12.3 and 15.2, respectively.
Taking into account this value, fluoride is a stronger base than acetate
in organic solvents and the extension of the proton shift observed with
the former anion is larger than that observed for the latter.
(37) Batista, R. M: F.; Oliveira, E.; Costa, S. P. G.; Lodeiro, C.;
Raposo, M. M. M. Org. Lett. 2007, 9, 3201−3204.
(38) Peng, X.; Wu, Y.; Fan, J.; Tian, M.; Han, K. J. Org. Chem. 2005,
70, 10524−10531.
(39) Li, G.-Y.; Zhao, G.-J.; Liu, Y.-H.; Han, K.-L.; He, G. Z. J.
Comput. Chem. 2010, 31, 1759−1765.
(40) HyperChem 6.03 Molecular Modeling System, Hypercube Inc.,
Gainesville, FL.
(41) (a) Kumari, N.; Jha, S.; Bhattacharya, S. J. Org. Chem. 2011, 76,
8215−8222. (b) Batista, R. M. F.; Costa, S. P. G.; Raposo, M. M. M. J.
Photochem. Photobiol., A 2013, 259, 33−40.
(42) (a) Chawla, H. M.; Shukla, R.; Shubha, P. Tetrahedron Lett.
2012, 53, 2996−2999. (b) Yang, H.; Zhou, Z.-G.; Xu, J.; Li, F.-Y.; Yi,
T.; Huang, C.-H. Tetrahedron 2007, 63, 6732−6736. (c) Yoshida, K.;
Mori, T.; Watanabe, S.; Kawai, H.; Nagamura, T. J. Chem. Soc., Perkin
Trans. 2 1999, 393−398.
(43) Valeur, B.; Leray, I. Coord. Chem. Rev. 2000, 205, 3−40.
(44) Wen, J.; Qin, S.; Ma, L.-F.; Dong, L.; Zhang, J.; Liu, S.-S.; Duan,
Y.-S.; Chen, S.-Y.; Hu, C.-W.; Yu, X.-Q. Org. Lett. 2010, 12, 2694−
2697.
(45) Carson, J. R.; Jetter, M. C.; Lee, J. S.; Youngman M. A. U.S.
Patent Appl. 20040192720 A1 20040930, 2004.
(46) da Silva, E. N.; Guimaraes, T. T.; Menna-Barreto, R. R. S.; Pinto,
M. D. F. R.; de Simone, C. A.; Pessoa, C.; Cavalcanti, B. C.; Sabino, J.
R.; Andrade, C. K. Z.; Goulart, M. O. F.; de Castro, S. L.; Pinto, A. V.
Bioorg. Med. Chem. 2010, 18, 3224−3230.
J
dx.doi.org/10.1021/jo501515e | J. Org. Chem. XXXX, XXX, XXX−XXX