Colorimetric probes based on anthraimidazolediones for selective sensing of fluoride and cyanide ion via intramolecular charge transfer

Article abstract of DOI:10.1021/jo201290a

Probes based on anthra[1,2-d]imidazole-6,11-dione were designed and synthesized for selective ion sensing. Each probe acted as strong colorimetric sensors for fluoride and cyanide ions and exhibited intramolecular charge transfer (ICT) band, which showed significant red-shifts after addition of either the F^- or CN^- ion. One of the probes (2) showed selective colorimetric sensing for both cyanide and fluoride ions. In organic medium, 2 showed selective color change with fluoride and cyanide, whereas in aqueous organic medium it showed a ratiometric response selectively for cyanide ion.

Full text of DOI:10.1021/jo201290a

ARTICLE
pubs.acs.org/joc
Colorimetric Probes Based on Anthraimidazolediones for
Selective Sensing of Fluoride and Cyanide Ion via Intramolecular
Charge Transfer
Namita Kumari,† Satadru Jha,† and Santanu Bhattacharya*,†,‡
†Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
‡Chemical Biology Unit, Jawaharlal Nehru Centre of Advanced Scientific Research, Bangalore 560 012, India
S Supporting Information
b
ABSTRACT: Probes based on anthra[1,2-d]imidazole-6,11-
dione were designed and synthesized for selective ion sensing.
Each probe acted as strong colorimetric sensors for fluoride and
cyanide ions and exhibited intramolecular charge transfer (ICT)
band, which showed significant red-shifts after addition of either
the Fꢀ or CNꢀ ion. One of the probes (2) showed selective
colorimetric sensing for both cyanide and fluoride ions. In
organic medium, 2 showed selective color change with fluoride
and cyanide, whereas in aqueous organic medium it showed a ratiometric response selectively for cyanide ion.
’ INTRODUCTION
Chart 1. Molecular Structures of the Sensors
Anions play a fundamental role in many biological and
chemical processes.1 Various anions have their different roles
and importance. Thus, the design and synthesis for the molecular
sensors that can detect the anions selectively are always of major
interest. In current research, the anion-sensing using fluorescent
and colorimetric sensors are important, as they do not require
expensive instruments. The colorimetric sensors are even better
as the signaling event can be detected by naked eye itself.
The fluoride ion is one of the most important anions because
of to its role in dental care and in the treatment of osteoporosis.2
Fluoride is also present in many anesthetic, hypnotic, and in
psychiatric drugs. Fꢀ ion sensors should also be useful in the
detection of uranium enrichment via hydrolysis of UF6 or in the
detection of chemical warfare agent sarin, as Fꢀ ion is released
upon its hydrolysis.3 Among various anions, cyanide is another
important ion which needs to be detected at very low concentra-
tions, since CNꢀ is one of the most toxic ions known to
mankind.4 It inhibits the cellular respiration in mammalian cells
by interacting with the active site of cytochrome a3, which makes
even a small amount of cyanide very lethal to human beings.5
Many reports have appeared in the literature describing the
detection of either Fꢀ or CNꢀ ion,6 but examples of a sensor
which can detect both anions are relatively less known.7
We have previously developed sensors and functional assem-
blies that are made up of peptide- or ligand-based frameworks.8
Herein we introduce new anthraimidazoledione based sensors
1ꢀ4 (Chart 1) that can detect both Fꢀ and CNꢀ ion via an
intramolecular charge-transfer (ICT) process. ICT works on the
“pushꢀpull” effect of the donor (D) and the acceptor (A) moiety
present in the sensor. So far, only a few sensors have been
reported for the anion sensing which works via the ICT
mechanism because the weak binding with anion results in a
feeble spectroscopic signal.9 The negatively charged analyte can
bind with the electron-deficient acceptor site of a receptor. This
can in turn alter the “DꢀA” to a “DꢀD” system and thereby
reduce the charge-transfer character, weakening the signal.10
Received: June 30, 2011
Published: September 05, 2011
r
2011 American Chemical Society
8215
dx.doi.org/10.1021/jo201290a J. Org. Chem. 2011, 76, 8215–8222
|

The Journal of Organic Chemistry
ARTICLE
The benzimidazole system is well-known to detect fluoride ion
via deprotonation of its NH proton.11 But none of the systems
reported so far uses ICT for anion detection. ICT exerts a
significant role on either a chromogenic or a fluorescent molecule,
as it causes a shift in the absorption and fluorescene emission band,
respectively. The shift of an absorption and/or emission band
reflects the strength of the DꢀA interaction, and hence, this could
be used for modulating the spectral properties of a molecule.12 We
report herein the interesting effect of variation of donor system on
the ICT band. Toward this end, the “anthraquinone” part of the
anthraimidazoledione is chosen for the first time as an electron-
deficient acceptor to which different N-substituted aromatic units
are linked in conjugation as donor sites. The receptors having
electron-rich aromatic units containing the anionic moiety at the
donor site show particularly pronounced red-shifted CT bands.
Scheme 1. Synthetic Routes to Compounds 1ꢀ4
’ RESULTS AND DISCUSSION
Synthesis. All the four receptors were synthesized as shown in
Scheme 1. First, each aldehyde precursor was synthesized via
VilsmeierꢀHaack reaction, and then each aldehyde was oxida-
tively coupled with 1,2-diaminoanthraquinone in nitrobenzene to
furnish the desiredproducts.13 All ofthe receptors wereadequately
characterized using 1H and 13C NMR and mass spectral methods.
Colorimetric and UVꢀvis Spectral Response. Absorption
spectra of 1ꢀ4 in acetonitrile showed the presence of an ICT band
in each case. However, the maximum red-shift was shown by the
receptor containing the anionic moiety at the donor site. Between
the receptors that contain anionic moiety, i.e., 2 and 3, the latter
showed a more red-shifted CT band than the former in the absence
of any added ion. However, after addition of fluoride ion, the
maximum red-shift was found in the deprotonated (benzimidazole)
species of 2. The presence of electronegative oxygens at the ortho
position of the donor site in 3 might have reduced the negative
charge density on the donor site in this molecule. Thus, both the
resonance (+R) as well as the inductive effect (ꢀI) of the
substituent on the aromatic unit appear to influence the ICT here.
Each compound showed colorimetric response upon addition of
either Fꢀ or CNꢀ ion in contrast to other anions. The anions were
added in the form of their tetrabutyl ammonium salts in actonitri-
leꢀDMSO (95:5) mixure. After the addtion of either Fꢀ or CNꢀ ion
to each receptor, the ICT band was found to be red-shifted. Of these
2 showed a remarkable and selective color change from light yellow
to dark blue upon the addition of Fꢀ ion and from light yellow to red
upon the addition of CNꢀ ion (Figure 1). The spectral responses
were further investigated using UVꢀvis spectroscopy. Compound 2
(50 μM) showed bathochromic shifts (Δλmax) of ∼120 nm and
∼81 nm in presence of Fꢀ ion and CNꢀ ion, respectively (Figure 1).
Other receptors also showed noticeable changes upon addition of
either Fꢀ or CNꢀ ion and only a very small change in presence of
AcOꢀ and H2PO4ꢀ ion (Figure S2ꢀS4, Supporting Information).
Selective Sensing of Fluoride Ion. Each receptor was found
tobesensitivetowardboth the Fꢀ as wellasCNꢀ ion. Importantly,
2 and 3 were able to detect the Fꢀ even in presence of CNꢀ ion in
the medium (Figure 2). Other receptors, however, showed very
little changes uponaddition ofFꢀ ion inpresence ofexcessofCNꢀ
ion in the medium (Figure S13 and S14, Supporting Information).
Effect of an Anionic Moiety on the Charge-Transfer Spectra.
Among the four receptor molecules, only 2and 3 showed maximum
shifts upon addition of Fꢀ ion. The common feature in both 2 and 3
is that the donor sites of the molecules have negative charges on
them. To probe the effect of negative charge, we compared the
UVꢀvis spectra of these two molecules with their neutral precur-
sors, i.e., the ethyl esters of 2 and 3 (Figures 3 and S15, Supporting
Information). The charge-transfer band of 2 has a maximum at
468 nm compared to 450 nm with its ethyl ester. This confirms that
the negative charge on the donor site has a significant role on the CT
band. The effect became more pronounced after the addition of Fꢀ
ion to it. The observed red-shift of the ester of 2 was only 40 nm
compared to ∼120 nm shift in case of 2. The comparison between 3
and its ethyl ester also showed similar results (Figure S15, Support-
ing Information). Thus, the build-up of negative charge on the
molecule helps the formation of a more red-shifted CT band.
Job’s plot involving each receptor confirmed its 1:1 stoichio-
metric interaction with either Fꢀ or CNꢀ ion (Figures S16ꢀS19,
Supporting Information). This suggests an interaction of the
added anion with the benzimidazole proton as this is the most
labile proton in these compounds. The deprotonation of the
benzimidazole upon addition of Fꢀ ion was eventually confirmed
by 1H NMR titration as given below.
1H NMR Titration Experiments. 1H NMR titrations of each of
the four receptors were performed in the DMSO-d6 because of the
limited solubility of such compounds in CD3CN. With the
addition of only 0.5 equiv of Fꢀ ion, the peak due to the
benzimidazole NH broadened, indicating a hydrogen-bonding
interaction involving the fluoride with that of the NꢀH proton
(Figure4). Afteradditionof 3 equivofFꢀ, one triplet signal started
developing at ∼16.3 ppm, which became quite prominent after
addition of 5 equiv of Fꢀ ion. Appearance of this triplet suggests
the formation of HF2ꢀ ion and confirms the deprotonation of the
benzimidazole NꢀH. This was also supported by the upfield shifts
of the (c, d) protons of the anthraquinone nucleus (Figure 4).
8216
dx.doi.org/10.1021/jo201290a |J. Org. Chem. 2011, 76, 8215–8222

The Journal of Organic Chemistry
ARTICLE
Figure 1. Colorimetric (above) and below (a) UVꢀvis spectral responses of 2 (50 μM) in CH3CN (5% DMSO) after addition of 50 equiv of different
anions (inset: Changes in Δλmax after addition of different anions). (b) UVꢀvis titration of 2 with fluoride ion.
Figure 2. Changes in the UVꢀvis spectra of 2 and 3 (50 μM) upon addition of 2.5 mM CNꢀ first and then upon addition of 50 equiv of Fꢀ ion in
CH3CN (5% DMSO).
Each receptor showed similar results, and appearance of the
triplet corresponding to the benzimidazole proton was observed
(Figures S20ꢀS23, Supporting Information). To investigate why
receptor 2 showed maximum change among all the receptors, the
1H NMR spectrum of each compound was compared. The only
structural difference in each of the compounds was due to the
variationsintheN-orO-substituents on the substituted phenyl ring.
We looked at the effect on the ꢀCH2 protons attached to the N-
substituent of the ligand. The chemical shifts of the ꢀCH2 protons
were different as they were attached to different functionality. The
ꢀCH2 protons were shifted upfield upon addition of the Fꢀ ion as a
result of the deprotonation of the benzimidazole NH. But the extent
of shift was different for each compound. The upfield shifts for 1
and 4 were found to be ∼0.1 and ∼0.2 ppm, respectively, having
ꢀCH2CO and ꢀCONH moieties next to the ꢀCH2 group.
It appears that the ꢀI effects of these functional groups
Figure 3. UVꢀvis spectra of 2 and its ester alone and after addition of
50 equiv of Fꢀ ion in CH3CN (5% DMSO).
minimize the negative field generated on the ꢀCH2 protons after
8217
dx.doi.org/10.1021/jo201290a |J. Org. Chem. 2011, 76, 8215–8222

The Journal of Organic Chemistry
ARTICLE
Figure 4. Partial 1H NMR (400 MHz) spectra of receptor 1 in DMSO-d6 in the absence and presence of 0.5, 1, 3, and 5 equiv of [(n-Bu)4N]+Fꢀ.
the deprotonation of the benzimidazole NH of 1 and 4. A
maximum upfield shift (>0.5 ppm) of ꢀCH2 protons was found
in receptor 2 (Figure 5). It could be because the ꢀCH2 protons in
2 are attached to a COOꢀ group, which is already in possession of
negative charge. So this could not stabilize the negative charge
generated on the ꢀCH2 protons. In 3, the upfield shift was only
0.2 ppm (Figure S22, Supporting Information). The difference
between 2 and 3 lies in the presence of a ꢀOCH2COOꢀ moiety
on the substituted phenyl ring. Hence, an ꢀI effect of the oxygen
could be responsible for the charge stabilization. To explain the
effect of CNꢀ addition, 1H NMR titration of 3 was performed by
adding CNꢀ ion. The anthraquinone protons shifted only by
0.1 ppm compared to ∼0.3 ppm shift observed with the fluoride
addition. Also, no sign of deprotonation was visible even after the
addition of 10 equiv of CNꢀ ion. The ꢀCH2 proton peaks at
4 ppm were broadened and shifted upfield by 0.1 ppm after addition
of 10 equiv of CNꢀ (Figure S24, Supporting Information).
These results suggest that in receptor 2, when Fꢀ is added,
maximum negative charge density is developed on the ꢀCH2
protons. Due to this, the red-shift of the CT band is maximum in
case of 2 which results in a pronounced color change from yellow
to intense blue. However, in other receptors, the color change
was relatively modest, i.e., from yellow to red.
Figure 5. Partial 1H NMR (400 MHz) spectra of 2 in DMSO-d6 in the
absence and presence of 0.5, 1, 3, and 5 equiv of [(Bu)4N+]Fꢀ. (Arrow
shows the shift of the CH2 protons from ∼4 ppm to ∼3.4 ppm upon
addition of Fꢀ.)
followed by its deprotonation upon excess addition of Fꢀ. To
further prove this deprotonation phenomenon, we checked the
interaction of the receptors with hydroxide ion in the same medium.
With addition of 50 equiv of hydroxide ion, all the compounds
showed red-shifts of ∼30ꢀ50 nm (Figure S25, Supporting In-
formation). It confirms that the change in the absorbance, due to the
addition of fluoride ion, occurs through the deprotonation process.
Thus, both UVꢀvis and 1H NMR studies show first the
association with the benzimidazole proton with 1 equiv of Fꢀ ion
8218
dx.doi.org/10.1021/jo201290a |J. Org. Chem. 2011, 76, 8215–8222

The Journal of Organic Chemistry
ARTICLE
1
The change in the charge-transfer band for the hydrogen-bonded
complex with Fꢀ anion was very small. Hence, the equilibrium
constant (Ka) could not be determined reliably from the UVꢀvis
spectral titrations. However, the dissociation of the benzimidazole
proton caused a huge red-shift of the charge transfer maximum, and
the corresponding equilibrium constant could be determined. The
dissociation constants (Kd) of each sensor with fluoride ion are com-
piled in the Table 1. The Kd values represent the ground-state
dissociation constants.11 The higher log Kd values also demonstrate
the selectivity of receptor 2 toward Fꢀ over other receptors.
Responses in Aqueous Medium. We also checked the
applicability of the above probes in aqueous medium. The introduc-
tion of water made the probes insensitive to the fluoride ion.
This is because the Fꢀ ion is highly solvated in water and loses its
basicity due to hydration. In aqueous medium, water competes with
the sensors for the Fꢀ ion.15 But each probe showed changes due to
CNꢀ addition in aqueous CH3CN (9:1) medium. The compara-
tively lower hydration energy for the cyanide ion (ΔHhyd =ꢀ67 kJ/
mol) than that of the fluoride ion (ΔHhyd = ꢀ505 kJ/mol) explains
the selectivity of cyanide ion.16 A maximum shift of 40 nm was
observed with the probe 2 without any interference from other
anions (Figure 6). The other probes showed only small changes
upon CNꢀ addition (Figure S26, Supporting Information).
The titration with progressive addition of cyanide to the probe
2 showed decreases in the absorption band at 464 nm and
increases at 504 nm (Figure 7a). The change in absorbance was
complete with addition of just 5 equiv of cyanide. The plot of the
Kd from Absorption Spectra. The UVꢀvis and H NMR
titrations both indicated an involvement of a two-step mechan-
ism in the above processes. This involves first the hydrogen
bonding of the fluoride ion with the benzimidazole proton, and in
the second step, deprotonation takes place upon addition of
excess Fꢀ. Such a two-step process has also been observed in the
anion-induced urea deprotonation by Fabbrizzi et al.14 The first
equilibrium exists for the complexation of the ligand with the
anion via hydrogen bonding, and then the ligand undergoes
dissociation after addition of the anion in excess. A similar
phenomenon was reported for the benzimidazole moiety also.11
All four receptors follow a similar mechanism and show a
dissociation induced by Fꢀ ion as described in the scheme below.
Ka
LH þ Xꢀ a½LH Xꢁꢀ
ð1Þ
3 3 3
Kd
½LH Xꢁꢀ þ Xꢀ a Lꢀ þ ½HX2ꢁꢀ
ð2Þ
3 3 3
Table 1. Proton Dissociation Constants of Each Receptor
upon Interaction with Added Fꢀ Anion
receptor
dissociation constant (log Kd)
1
2
3
4
4.38 ( 0.03
4.59 ( 0.02
4.52 ( 0.04
3.28 ( 0.07
Figure 6. (a) UVꢀvis spectral responses of 2 (10 μM) in 9:1 CH3CNꢀwater (1% DMSO) after addition of 50 equiv of anions. (b) Normalized changes
in absorbance at 518 nm after addition of anions.
Figure 7. (a) UVꢀvis titration of 2 with cyanide ion (0ꢀ6 equiv). (b) Ratiometric response with added cyanide ion.
8219
dx.doi.org/10.1021/jo201290a |J. Org. Chem. 2011, 76, 8215–8222

The Journal of Organic Chemistry
ARTICLE
ratio of the absorbance at 504 and 464 nm with the cyanide ion
concentration showed a ratiometric response (Figure 7b). It
indicated that cyanide ion can be detected using probe 2 even in
aqueous medium at low concentration level selectively without
any interference from other anions.
3H), 11.14 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.2, 53.9, 60.9,
61.3, 66.1, 112.9, 117.7, 118.8, 121.3, 122.0, 125.0, 126.4, 127.5, 128.2,
133.3, 133.4, 133.7, 134.1, 134.3, 142.7, 149.3, 156.5, 168.2, 170.8, 182.6,
185.2; MS(ESI) m/z 636 (M + Na)+; HRMS m/z calcd for
C33H31N3O9 (M + Na)+ 636.1958, found 636.1959.
Compounds 2 and 3. Compound 5 or 6 (0.5 mmol) was taken in
MeOH (4.5 mL). and to it aq NaOH or KOH solution (0.3 mL, 3 M of
NaOH for 5; 0.4 mL, 5 M of KOH for 6) was added dropwise at rt and
the mixture refluxed for 2 h. After the mixture was cooled to rt, a solid
separated out which was filtered. The solid was then washed with MeOH
and dried until TLC indicated it to be pure.
’ CONCLUSIONS
In summary, we have synthesized new colorimetric probes,
which can detect both Fꢀ as well as CNꢀ ions. Fꢀ ions interact
with the benzimidazole NH of the probe molecule, and the
observed change in color is based on an intramolecular charge
transfer. The anthraquinone part of each molecule has an acceptor
moiety, whereas a substituted nitrogen-linked aromatic unit forms
the donor site. Among the various donor moieties, the sites having
negative charges on them were found to disperse greater electron
density on them. Thus, the accumulation of negative charge
density on the donor site leads to a red-shift in the CT band.
Amongthe variousanions, onlyFꢀ ionshowedmaximumred-shift
because it was able to cause deprotonation of the benzimidazole
NH due to its high electronegativity and basicity. Among the four
receptors, 2 showed a maximum red-shift in the ICT band after the
addition of Fꢀ ion. Using this, one can detect both Fꢀ and CNꢀ
ion selectively as it changes to a distinctly different color with Fꢀ
ion (yellow to blue) and CNꢀ ion (yellow to red). Further, the
probes showed selective detection of cyanide ion in aqueous
medium too. Probe 2 showed a red-shift of 40 nm with the
cyanide ion selectively in aqueous medium. It showed the ratio-
metric detection of the cyanide, which makes it a more reliable
sensor in water as well.
Compound 2: yield 90%; red solid; mp >250 °C; IR (KBr, cmꢀ1
)
3302.7, 1663.1, 1604.8, 1584.5, 1489.9, 1394.4, 1290.1, 1208.9, 717.1;
1H NMR (400 MHz, D2O) δ 3.95 (s, 4H), 6.51 (t, J = 7.6 Hz, 2H), 7.1
(s, 1H), 7.24 (s, 3H), 7.35 (s, 1H), 7.44 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, D2O) δ 55.6, 111.4, 114.1, 121.5, 125.5, 125.9, 126.4, 128.9,
131.1, 131.5, 134.1, 134.4, 151.3, 157.7, 178.5, 182.7, 183.2; HRMS m/z
calcd for C25H15N3Na2O6 (M + Na)+ 522.0654, found 522.0656.
Compound 3: yield 80%; red solid; m. >250 °C; IR (KBr, cmꢀ1
)
3381.2, 3255.8, 1640.0, 1607.3, 1589.0, 1403.0, 1328.2, 1289.8, 1248.5,
1200.6, 720.9; 1H NMR (400 MHz, D2O): δ 3.94 (s, 4H), 4.44 (s, 2H),
6.68 (d, J = 8.4 Hz, 1H), 7.02 (s, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.37 (s,
3H), 7.52 (s, 2H), 7.64 (s, 1H); 13C NMR (100 MHz, D2O) δ 58.0, 69.4,
113.2, 117.9, 118.1, 119.2, 122.9, 124.3, 127.0, 127.7, 132.7, 132.9, 135.5,
135.8, 144.8, 149.0, 149.9, 158.6, 165.5, 178.1, 180.4, 184.2, 184.7; MS
(ESI) m/z 644 (M + H)+; HRMS m/z calcd for C27H16K3N3O9 (M +
K) + 681.9435, found 681.9439.
Compound 4. A mixture of 5 (0.15 g, 0.3 mmol) and 2-aminoethanol
(3.75 mL) in CH3CN (10 mL) was refluxed under N2 for 2 h. The
reaction mixture was cooled, and excess 2-aminoethanol was removed by
evaporation. A solid started to appear after the residue was scratched
using 1:1 EtOAc/MeOH. The resulting solution was filtered and dried:
yield 80%; red solid; mp >250 °C; IR (KBr, cmꢀ1) 3439.9, 3397.6,
3303.4, 3071.9, 2920.1, 1661.8, 1638.5, 1614.9, 1488.5, 1325.8, 1291.2,
’ EXPERIMENTAL SECTION
1
1241.4, 1060.0, 716.9; H NMR (400 MHz, DMSO-d6) δ 3.19ꢀ3.21
Synthesis. General Procedure for the Synthesis of 1, 5, and 6.
Each substituted benzaldehyde (7 or 8 or 9) (1.0 mmol) and 1,2-
diaminoanthraquinone (1.0 mmol) was heated in nitrobenzene (4 mL)
at 130 °C for ∼8 h.13 Then the reaction mixture was cooled to rt, and
hexane was added to get a solid precipitate which was washed several
times with hexane. The precipitate was finally purified by column
chromatography (2ꢀ3% CH3OH/CHCl3) to get the desired product.
(m, 4H), 3.39ꢀ3.44 (m, 4H), 4.17(s, 4H), 4.67ꢀ4.70 (t, J = 5.2 Hz, 2H),
6.58ꢀ6.67 (m, 2H), 8.04ꢀ8.10 (m, 2H), 8.13 (d, J = 8.4 Hz, 2H),
8.23ꢀ8.30 (m, 2H), 8.91 (d, J = 5.2, 2H), 12.84 (br s, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 41.5, 56.0, 59.7, 111.2, 117.1, 117.9, 120.9,
123.8, 126.1, 126.7, 127, 129.4, 133.0, 133.1, 133.2, 134.1, 134.3, 149.5,
149.8, 158.3, 170.2, 182.2, 183.2; HRMS m/z calcd for C29H27N5O6Na
(M + Na)+ 564.1859, found 564.1859.
Compound 1: yield 80%; red solid; mp 186ꢀ187 °C; IR (KBr, cmꢀ1
)
Compound 7.17 To a solution of N,N-bis[(hydroxyethyl)amino]benzene
(4.23 g, 23.4 mmol) in CH2Cl2 (32 mL) were consecutively added Ac2O
(7.32 g, 71.8 mmol) and pyridine (5.3 g, 66.8 mmol) dropwise at 0 °C. Then
the reaction mixture was stirred overnight at rt. The mixture was washed with
water and dried. This was further purified by column chromatography (94:6
hexane/EtOAc) to obtain the intermediate as a pale yellow oil (5.7 g): yield
92%; IR (neat, cmꢀ1) 2958.8, 1739.7, 1599.4, 1505.9, 1379.9, 1232.3, 1036.7,
749.6; 1H NMR (300 MHz, CDCl3) δ 1.97 (s, 6H), 3.55 (t, J = 6.15 Hz,
4H), 4.16 (t, J = 6.45 Hz, 4H), 6.62ꢀ6.69 (m, 3H), 7.16 (dd, J = 8.7, 1.8 Hz,
2H); MS(ESI) m/z 266 (M + H)+, 288 (M + Na)+.
The intermediate was then formylated using DMF (5.6 mL, 72.4
mmol) and POCl3 (3.54 g, 23.0 mmol) upon stirring for 30 min at rt
followed by heating at 90 °C for 2 h. Then the reaction was allowed to
come to rt and iceꢀwater was added. The mixture was neutralized to pH
7 by addition of solid sodium acetate. It was then extracted with EtOAc,
washed with water, and dried. Final purification was done on a silica gel
column (98:2 CHCl3/CH3OH): yield 90%; mp 57ꢀ58 °C; IR
(neat, cmꢀ1) 2959.7, 2737.0, 1740.4, 1670.6, 1597.8, 1559.7, 1524.0,
1386.8, 1230.7, 1171.1, 1048.3, 819.5; 1H NMR (300 MHz, CDCl3) δ
2.01 (s, 6H), 3.68 (t, J = 6.15 Hz, 4H), 4.24 (t, J = 6.3 Hz, 4H), 6.78 (d,
J = 9.3 Hz, 2H), 7.16 (dd, J = 9.3, 3.0 Hz, 2H), 9.72 (s, 1H); MS(ESI) m/
z 294 (M + H)+, 316 (M + Na)+.
3418.0, 2956.0, 1732.2, 1721.9, 1660.7, 1607.3, 1593.7, 1488.3, 1296.5,
1244.4, 1044.2, 710.7; 1H NMR (400 MHz, DMSO-d6) δ 2.02 (s, 6H),
3.73 (t, J = 5.4 Hz, 4H), 4.23 (t, J = 5.6 Hz, 4H), 6.95 (d, J = 8.8 Hz, 2H),
7.93ꢀ7.95 (m, 2H), 8.01ꢀ8.07 (m, 2H), 8.21ꢀ8.30 (m, 4H), 12.83 (s,
1H); 13C NMR (100 MHz, DMSO-d6) δ 20.6, 48.7, 60.9, 111.4, 116.1,
117.8, 120.9, 123.6, 126.1, 126.7, 126.9, 129.5, 133.0, 133.1, 133.2, 134.1,
134.3, 149.6, 149.9, 158.4, 170.3, 182.1, 183.2; HRMS m/z calcd for
C29H26N3O6 (M + H)+ 512.1821, found 512.1814.
Compound 5: yield 96%; red solid; mp 214ꢀ215 °C; IR (KBr, cmꢀ1
)
3443.7,2978.9, 1751.7, 1739.4, 1661.1, 1606.3, 1487.9, 1441.3, 1290.0,
1203.3, 1179.3, 1006.6, 718.9; 1H NMR (300 MHz, CDCl3) δ 1.29 (t,
J = 7.2 Hz, 6H), 4.18- 4.28 (m, 8H), 6.73 (d, J = 8.4 Hz, 2H), 7.77 (d, J =
6.9 Hz, 2H), 8.01 (d, J = 8.4 Hz, 3H), 8.13- 8.32 (m, 3H), 11.13 (br s.,
1H); 13C NMR (100 MHz, CDCl3) δ 14.2, 53.3, 61.4, 112.5, 117.4,
118.0, 121.8, 124.6, 126.3, 127.4, 127.8, 128.6, 133.2, 133.4, 133.5, 133.9,
134.2, 149.8, 150.3, 157.1, 170.1, 182.5, 185.1; HRMS m/z calcd for
C29H25N3O6 (M + H)+ 512.1821, found 512.1818.
Compound 6: yield 80%; red solid; mp 222ꢀ224 °C; IR (KBr, cmꢀ1
)
3345.1, 2977.4, 1751.0, 1737.1, 1664.5, 1579.3, 1495.4, 1421.7, 1324.6,
1293.1, 1190.7, 1176.0, 1028.2, 716.1; 1H NMR (300 MHz, CDCl3) δ
1.18ꢀ1.28 (m, 9H), 4.13- 4.23 (m, 10H), 4.72 (s, 2H), 6.87 (d, J = 8.4
Hz, 2H), 7.55ꢀ7.75 (m, 4H), 7.98 (d, J = 8.4 Hz, 1H), 8.13ꢀ8.28 (m,
8220
dx.doi.org/10.1021/jo201290a |J. Org. Chem. 2011, 76, 8215–8222

The Journal of Organic Chemistry
ARTICLE
Compound 8.18 Synthesis of 8 was accomplished by substitution of
aniline by ethyl bromoacetate followed by formylation as described in
case of 7. The crude intermediate was purified by column chromatog-
raphy on silica gel (99:1 EtOAc/hexane): pale yellow oil (99% yield); IR
(neat, cmꢀ1) 2981.2, 1745.2, 1733.6, 1600.6, 1508.0, 1386.5, 1172.5,
1024.0, 748.2; 1H NMR (300 MHz, CDCl3) δ 1.29 (t, J = 5.4 Hz, 6H),
4.18 (s, 4H), 4.19ꢀ4.24 (q, 4H), 6.63 (d, J = 8.1 Hz, 2H), 6.80 (t, J = 7.35
Hz, 1H), 7.21ꢀ7.26 (m, 2H); MS(ESI) m/z 266 (M + H)+, 288 (M +
Na)+; HRMS m/z calcd for C14H19NO4Na (M + Na)+ 288.1212, found
288.1213.
J. Coord. Chem. Rev. 2003, 240, 77. (d) Martínez-Man^ez, R.; Sancenon,
F. Chem. Rev. 2003, 103, 4419. (e) Suksai, C.; Tuntulani, T. Chem. Soc.
Rev. 2003, 32, 192. (f) Beer, P. D.; Gale, P. A. Angew. Chem., Int. Ed.
2001, 40, 486.
(2) (a) Jentsch, T. J. Curr. Opin. Neurobiol. 1996, 6, 303.(b) Kirk,
K. L. Biochemistry of the Halogens and Inorganic Halides; Plenum Press:
New York, 1991; p 58.
(3) Hudnall, T. W.; Chiu, C.-W.; Gabbai, F. P. Acc. Chem. Res. 2009,
42 (2), 388.
(4) Kulig, K. W. Cyanide Toxicity; U. S. Department of Health and
Human Services: Atlanta, GA, 1991.
Purification of the product obtained upon formylation was carried out
by chromatography on a silica gel column (98:2 CHCl3/CH3OH) to
afford a solid (92% yield): mp 63ꢀ64 °C; IR (neat, cmꢀ1) 3478.9,
2919.2, 2829.0, 2749.7, 1742.3, 1672.0, 1596.1, 1525.5, 1385.9, 1320.5,
1167.0, 1020.5, 961.1, 812.6; 1H NMR (300 MHz, CDCl3) δ 1.26 (t, J =
7.0 Hz, 6H), 4.17ꢀ4.25 (m, 8H), 6.63 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4
Hz, 2H), 9.76 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 14.1, 53.3, 61.5,
111.7, 127.3, 131.9, 152.5, 169.6, 190.4; MS(ESI) m/z 294 (M + H)+,
316 (M + Na)+; HRMS m/z calcd for C15H19NO5Na (M + Na)+
316.1161, found 316.1162.
(5) Cyanide in Biology; Vennesland, B., Comm, E. F., Knownles, J.,
Westly, J., Wissing, F., Eds.; Academic: London, 1981.
(6) (a) Xu, Z.; Chen, X.; Kim, H. N.; Yoon, J. Chem. Soc. Rev. 2010,
39, 127. (b) Chen, X.; Nam, S-W; Kim, G-H; Song, N.; Jeong, Y.; Shin,
I.; Kim, S. K.; Kim, J.; Park, S.; Yoon, J. Chem. Commun. 2010, 46, 8953.
(c) Bhalla, V.; Singh, H.; Kumar, M. Org. Lett. 2010, 12 (3), 628. (d) Qu,
Y.; Hua, J.; Tian, H. Org. Lett. 2010, 12 (15), 3320. (e) Wang, Q.; Xie, Y.;
Ding, Y.; Li, X.; Zhu, W. Chem. Commun. 2010, 46, 3669. (f) Bhosale,
S. V.; Bhosale, S. V.; Kalyankar, M. B.; Langford, S. J. Org. Lett. 2009, 11
(23), 5418. (g) Xu, Z.; Kim, S. K.; Han, S. J.; Lee, C.; Kociok-Kohn, G.;
James, T. D.; Yoon, J. Eur. J. Org. Chem. 2009, 3058. (h) Cametti, M.;
Rissanen, K. Chem. Commun. 2009, 2809. (i) Cho, D.-G.; Kim, J. H.;
Sessler, J. L. J. Am. Chem. Soc. 2008, 130 (36), 12163. (j) Cametti, M.;
Cort, A. D.; Mandolini, L.; Nissinen, M.; Rissanen, K. New J. Chem.
2008, 32, 1113. (k) Lin, Z.-H.; Ou, S.-J.; Duan, C.-Y.; Zhang, B.-G.; Bai,
Z.-P. Chem. Commun. 2006, 624. (l) Tomasulo, M.; Sortino, S.; White,
A. J. P.; Raymo, F. M. J. Org. Chem. 2006, 71, 744. (m) Gale, P. A. Coord.
Chem. Rev. 2003, 240, 191. (n) Martinez-Manez, R.; Sancenon, F. Chem.
Rev. 2003, 103, 4419. (o) Choi, K.; Hamilton, A. D. Coord. Chem. Rev. 2003,
240, 101. (p) Sessler, J. L.; Camiolo, S.; Gale, P. A. Coord. Chem. Rev. 2003,
240, 17. (q) Schmidtchen, F. P.; Berger, M. Chem. Rev. 1997, 97, 1609.
(7) (a) Hudnall, T. W.; Gabbai, F. P. J. Am. Chem. Soc. 2007,
129, 11978. (b) Kumar, V.; Kaushika, M. P.; Srivastava, A. K.; Pratapa,
A.; Thiruvenkatamb, V.; Guru Row, T. N. Anal. Chim. Acta 2010,
663, 77. (c) Aldrey, A.; Nunez, C.; Garca, V.; Bastida, R.; Lodeiro, C.;
Macıas, A. Tetrahedron 2010, 66, 9223.
(8) (a) Bhattacharya, S.; Gulyani, A. Chem. Commun. 2003, 1158.
(b) Singh, Y.; Gulyani, A.; Bhattacharya, S. FEBS Lett. 2003, 541, 132.
(c) Bhattacharya, S.; Thomas, M. Tetrahedron Lett. 2000, 41, 10313. (d)
Bhattacharya, S.; Snehalatha, K.; Kumar, V. P. J. Org. Chem. 2003,
68, 2741. (e) Bhattacharya, S.; Snehalatha, K.; George, S. K. J. Org. Chem.
1998, 63, 27. (f) Bhattacharya, S.; Mandal, S. S. Chem. Commun.
1996, 1515. (g) Bhattacharya, S.; Kumari, N. Coord. Chem. Rev. 2009,
253, 2133.
(9) (a) Xu, Z.; Singh, N. J.; Kim, S. K.; Spring, D. R.; Kim, K. S.;
Yoon, J. Chem.—Eur. J. 2011, 17, 1163. (b) Wu, J.; Liu, W.; Ge, J.;
Zhang, H.; Wang, P. Chem. Soc. Rev. 2011, 40 (7), 3483. (c) Thiagarajan,
V.; Ramamurthy, P.; Thirumalai, D.; Ramakrishnan, V. T. Org. Lett.
2005, 7 (4), 657. (d) Kobiro, K.; Inoue, Y. J. Am. Chem. Soc. 2003,
125, 421. (e) Gunnlaugsson, T.; Kruger, P. E.; Jensen, P.; Pfeffer, F. M.;
Hussey, G. M. Tetrahedron Lett. 2003, 44, 8909.
Compound 9.18 o-Aminophenol (0.89 g, 8.17 mmol) and bromoa-
cetic acid (5.678 g, 40.85 mmol) were added to a solution of NaOH
(2.29 g, 57.2 mmol) in 10 mL of H2O and heated at 100 °C. Solid NaOH
was then added slowly to maintain the pH at 10 and then it was heated
for 1 h. The reaction mixture was cooled and dried. Absolute EtOH
(29 mL) and H2SO4 (3.3 mL, 62.9 mmol) were added to the residue,
and the mixture was refluxed for 3 days. The reaction mixture was cooled
and filtered to leave a residue, which was dissolved in EtOAc and washed
successively with 10% NaOH and brine. This afforded an oily material
which was purified by chromatography on silica gel (hexane/EtOAc
(5:95, v/v) as eluant): yield 40%; IR (neat, cmꢀ1) 2983.0, 1747.0,
1598.2, 1504.5, 1184.9, 1026.3, 749.4; 1H NMR (300 MHz, CDCl3) δ
1.21ꢀ1.30 (m, 9H), 4.10ꢀ4.24 (m, 10H), 4.62 (s, 2H), 6.79ꢀ6.99 (m,
4H); MS(ESI) m/z 368 (M + H)+, 390 (M + Na)+.
Similarly, the intermediate was formylated by the procedure men-
tioned above: yield 40%; mp 55ꢀ56 °C; IR (neat, cmꢀ1) 1748.3, 1671.2;
1H NMR (300 MHz, CDCl3) δ 1.25ꢀ1.31 (m, 9H), 4.19ꢀ4.27 (m,
10H), 4.65 (s, 2H), 6.80 (d, J = 8.1 Hz, 1H), 7.26 (s, 1H), 7.40 (d, J = 8.1
Hz, 1H); MS(ESI) m/z 390 (M ꢀ C2H5 + Na)+.
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental section,
b
changes in color, absorption spectra upon addition of different
anions, and titration study of 1, 3, and 4 described in this paper.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
(10) Kovalchuk, A.; Bricks, J. L.; Reck, G.; Rurack, K.; Schulz, B.;
Szumnac, A.; Weißhoff, H. Chem. Commun. 2004, 1946.
(11) Peng, X.; Wu, Y.; Fan, J.; Tian, M.; Han, K. J. Org. Chem. 2005,
70, 10524.
Corresponding Author
*E-mail: sb@orgchem.iisc.ernet.in.
(12) Chen, C.-Y.; Ho, J.-H.; Wang, S.-L.; Ho, T.-I. Photochem.
Photobiol. Sci. 2003, 2, 1232.
(13) (a) Chaudhuri, P.; Majumder, H. K.; Bhattacharya, S. J. Med.
Chem. 2007, 50, 2536. (b) Chaudhuri, P.; Ganguly, B.; Bhattacharya, S.
J. Org. Chem. 2007, 72, 1912.
(14) (a) Gꢀomez, D. E.; Fabbrizzi, L.; Licchelli, M. J. Org. Chem. 2005,
70, 5717. (b) Gꢀomez, D. E.; Fabbrizzi, L.; Licchelli, M.; Monzani, E. Org.
Biomol. Chem. 2005, 3, 1495. (c) Amendola, V.; Boiocchi, M.; Fabbrizzi,
L.; Palchetti, A. Chem.—Eur. J. 2005, 11, 120. (d) Boiocchi, M.; Del Boca,
L.; Gꢀomez, D. E.; Fabbrizzi, L.; Licchelli, M.; Monzani, E. Chem.—Eur. J.
2005, 11, 3097. (e) Boiocchi, M.; Del Boca, L.; Gꢀomez, D. E.; Fabbrizzi,
L.; Licchelli, M.; Monzani, E J. Am. Chem. Soc. 2004, 126, 16507.
’ ACKNOWLEDGMENT
S.B. thanks DST (J.C. Bose Fellowship) for financial support
of this work. N.K. thanks UGC for an SRF. We also thank the
NMR center, I.I.Sc., for help with the 1H NMR titration studies.
’ REFERENCES
(1) (a) Martínez-Man^ez, R.; Sancenꢀon, F. J. Fluoresc. 2005, 15, 267.
(b) Gale, P. A., Ed. Special issue: 35 years of Synthetic Anion Receptor
Chemistry. Coord. Chem. Rev. 2003, 240, 1. (c) Bondy, C. R.; Loeb, S.
8221
dx.doi.org/10.1021/jo201290a |J. Org. Chem. 2011, 76, 8215–8222

The Journal of Organic Chemistry
ARTICLE
(15) (a) Sathish, R. S.; Sujith, U.; Rao, G. N.; Janardhana, C.
Spectrochim. Acta Part A 2006, 65, 565. (b) Boiocchi, M.; Del Boca,
L.; Gomez, D. E.; Fabbrizzi, L.; Licchelli, M.; Monzani, E. J. Am. Chem.
Soc. 2004, 126, 16507–16514. (c) Black, C. B.; Andrioletti, B.; Try, A. C.;
Ruiperez, C.; Sessler, J. L. J. Am. Chem. Soc. 1999, 121, 10438.
(16) (a) Saha, S.; Ghosh, A.; Mahato, P.; Mishra, S.; Mishra, S. K.;
Suresh, E.; Das, S.; Das, A. Org. Lett. 2010, 12, 3406.(b) Housecroft,
C. E.; Sharpe, A. G. In Inorganic Chemistry, 3rd ed.; Pearson Education,
Ltd.: Harlow, 2008; p 537.
(17) Qi, X.; Jun, E. J.; Xu, L.; Kim, S.-J.; Hong, J. S. J.; Yoon, Y. J.;
Yoon, J. J. Org. Chem. 2006, 71, 2881.
(18) Wang, J.; Qian, X. Org. Lett. 2006, 8, 3721.
8222
dx.doi.org/10.1021/jo201290a |J. Org. Chem. 2011, 76, 8215–8222