Colorimetric detection of cyanide with N-nitrophenyl benzamide derivatives

Article abstract of DOI:10.1016/j.tet.2009.02.023

A series of structurally simple N-nitrophenyl benzamide derivatives have been developed as chemosensors toward cyanide in aqueous environment by taking advantage of the cyanide's strong affinity toward the acyl carbonyl carbon. The high selectivity of these compounds toward CN^- makes it a practical system for monitoring CN^- concentrations in aqueous samples.

Full text of DOI:10.1016/j.tet.2009.02.023

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Tetrahedron 65 (2009) 3480–3485
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Colorimetric detection of cyanide with N-nitrophenyl benzamide derivatives
*
Yue Sun, Guofeng Wang, Wei Guo
School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of structurally simple N-nitrophenyl benzamide derivatives have been developed as chemo-
sensors toward cyanide in aqueous environment by taking advantage of the cyanide’s strong affinity
toward the acyl carbonyl carbon. The high selectivity of these compounds toward CNꢀ makes it a prac-
tical system for monitoring CNꢀ concentrations in aqueous samples.
Received 11 November 2008
Received in revised form 7 February 2009
Accepted 13 February 2009
Available online 20 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cyanide sensing
UV–vis spectra
N-Nitrophenyl benzamide derivatives
Naked-eye recognition
1. Introduction
characteristic features such as analyte-specific response and
little competition from the aqueous media, which are highly
Anion recognition is an area of growing interest in supramo-
lecular chemistry due to its important role in a wide range of
environmental, clinical, chemical, and biological applications, and
considerable attention has been focused on the design of artificial
receptors that are able to selectively recognize and sense anion
species.1 Among various anions, cyanide is one of the most con-
cerned anions because it is being widely used in synthetic fibers,
resins, herbicide, and the gold-extraction process.2 Unfortunately,
cyanide anion is extremely detrimental, and could be absorbed
through lungs, gastrointestinal track, and skin, leading to vom-
iting, convulsion, loss of consciousness, and eventual death.3
According to the World Health Organization (WHO), only water
desirable features for an efficient recognition and detection
system. Based on this idea, nucleophilic addition of cyanide to
oxazine,6 pyrylium,7 squarane,8 trifluoroacetophenone,9 acyl-
trazene,10 acridinium,11 salicylaldehyde,12 and carboxamide13
has been reported in recent few years, in which the interference
by other anions, such as Fꢀ and AcOꢀ, can be efficiently
minimized.
Recently, we developed a structurally simple chemical system
integrating both nitroaniline chromophore and activated amide
functionality for cyanide sensing (Scheme 1). We were attracted to
this system because (1) it can be obtained by simple synthetic
procedures, (2) it contains an active amide carbonyl group as an
electrophile13 for the cyanide anion and a nitroaniline group as
a latent chromogenic moiety, and (3) various control compounds,
with other modifications of the skeleton, would be readily avail-
able, supplying a base for systematic studies toward recognition
motifs for cyanide. It is expected that cyanide is detectable by
nucleophilic attack toward the activated amide carbonyl function
followed by fast proton transfer of the acidic amide hydrogen to
the developing alkoxide anion of this compound.12 The proton
transfer may trigger the latent chromogenic nitroaniline group
into an active state (its anionic state), thus resulting in the en-
hancement of the push–pull character of the intramolecular
charge transfer (ICT) transition, which is possibly reflected in the
new red-shifted absorption. Herein, we wish to report the design,
synthesis of these probes, and their unique interaction mode with
cyanide.
with cyanide concentration lower than 1.9 m
M is able to drink.4
Thus, there exists a need for an efficient sensing system for cy-
anide to monitor cyanide concentration from contaminant
sources.
Many of the cyanide anion receptors reported to date have
relied on hydrogen-bonding motifs and, as a consequence, have
generally displayed poor selectivities relative to other anions.5
To overcome this limitation, reaction-based receptors, rationally
designed cyanide anion indicators, have been developed re-
cently.6–13 This reaction-based recognition mode takes advan-
tage of the particular feature of the cyanide ion: its nucleophilic
character, and enables the recognition system with some
* Corresponding author. Tel./fax: þ86 351 7011600.
E-mail address: guow@sxu.edu.cn (W. Guo).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.023

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Y. Sun et al. / Tetrahedron 65 (2009) 3480–3485
3481
O
N
O
N
O
N
NO2
Cl
NO2
NO2
NO2
H
H
H
NO2
1
NO2
2
NO2
3
O
N
O
N
O
N
NO2
NO2
NO2
NO2
H
H
H
NO2
4
6
5
Scheme 1. The chemosensors evaluated in this study.
2. Results and discussion
2.1. Synthesis and crystal structure
Figure 2, compound 1 displayed an obvious absorption at 441 nm,
giving a yellow solution in 9:1 DMSO–H2O. However, with further
increase of water, the absorption band fades along with a blue shift,
giving a pale yellow solution. In 1:1 DMSO–H2O (v/v), the absorp-
tion band completely disappeared, giving an almost colorless
solution.
The synthesis of these receptors is straightforward. Treatment of
4-substituted benzoyl chloride with corresponding aromatic
amines in CH2Cl2 in the presence of triethylamine afforded the
objective compounds (1–5). A control compound (6) was also
synthesized according to the same procedures. All of the com-
pounds were characterized by NMR, IR, and MS spectroscopy, and
elemental analysis. Crystal of receptor 1 suitable for X-ray crystal-
lography was also obtained on slow evaporation of MeOH solution
of 1. In an attempt to characterize the conformation, the crystal
structure of 1 was determined by single crystal X-ray diffraction, as
shown in Figure 1. The most interesting feature of the structure is
the coplanarity of amided2,4-dinitrophenyl unit, indicating the
optimal conformation for ICT process resulting from the de-
localization of electron on the nitrogen of amide group toward
electron-withdrawing 2,4-dinitrophenyl unit.
We speculate that the color change of 1 observed in the mixture
of DMSO–H2O should be originated from a deprotonated species
due to an acidic ionization, that is, the corresponding anion of 1,
which enhanced the charge-transfer interactions between the
electron-rich donor unit and the electron-deficient 2,4-dini-
trophenyl moiety, resulting in a visible color change. The assump-
tion could be supported by the following facts: upon addition of
acid, such as TsOH or HCl, to the mixture of 9:1 DMSO–H2O solution
of 1, the absorption at 441 nm disappears; however, upon addition
of base, such as Et3N or NaOH, to the mixture of 1:1 DMSO–H2O
solution of 1, the strong absorption at 405 nm is observed (see Figs.
S1 and S2). It appears that water plays a key role in inhibiting the
acidic ionization of 1, as shown in 1:1 DMSO–H2O. While the de-
tailed mechanism on water effect is plausible at present, the feature
has been utilized by us to sense cyanide with high selectivity.
Next, in order to gain systematic knowledge on the effect of
water on the binding affinity and selectivity for cyanide, we chose
DMSO–H2O mixtures as solvents (9:1, 7:3, and 1:1 of DMSO–H2O
(v/v), respectively) and various anions of present interest, namely,
CNꢀ, Fꢀ, Clꢀ, Brꢀ, Iꢀ, ClO4ꢀ, AcOꢀ, H2PO4ꢀ, NO3ꢀ, and Nꢀ3 as their so-
dium salts were added to the solution of 1, respectively. The cor-
responding absorption spectra upon addition of different anions in
DMSO–H2O mixtures are shown in Figure 3. In 9:1 DMSO–H2O,
compound 1 displayed a strong absorption band at 441 nm, and
CNꢀ, Fꢀ, and AcOꢀ showed slight effect to the band, whereas less
basic anions such as Clꢀ, Brꢀ, Iꢀ, ClOꢀ4 , H2POꢀ4 , NO3ꢀ, and Nꢀ3 showed
less or no effect (Fig. 3a). In 7:3 DMSO–water, only CNꢀ, Fꢀ, and
AcOꢀ showed obvious interaction with the sensor 1 (Fig. 3b), but,
the selectivity for CNꢀ was rather poor due to the interference of Fꢀ
and AcOꢀ. However, to our delight, a remarkably higher selectivity
for CNꢀ over the other anions were obtained in 1:1 DMSO–H2O, and
other anions tested did not cause any significant changes in the
absorption intensity, even at a concentration of 100 equiv of guests
(Fig. 3c).
2.2. UV–vis titration studies of compound 1
The UV–vis absorption is one of the most interesting output
signals not only because the instrumentation is widely available,
but also because it would be possible to sense target species with
the naked eye. In order to obtain the systematic knowledge on the
photochemical properties of these sensing systems in solution and
to estimate the possible absorption mechanism, we first studied the
absorption spectra of 1 in various DMSO–H2O mixtures [9:1, 8:2,
7:3, 6:4, and 1:1 of DMSO–H2O (v/v), respectively]. As shown in
The above results indicate that the selectivity for CNꢀ is greatly
influenced by water. In 1:1 DMSO–H2O, anions such as Fꢀ and AcOꢀ
could interact with the aqueous medium through H-bonding, and
this salvation leads to a decrease in their basicity, thus, resulting in
the poor deprotonation reaction. In contrast, cyanide has much
weaker H-bonding ability in comparison with Fꢀ and AcOꢀ but has
stronger carbonyl carbon affinity, which results in the addition
reaction of CNꢀ to carbonyl carbon. Subsequent proton transfer of
amide hydrogen to the developing alkoxide anion of 1 produces an
active state (its anionic state) of 1, which enhanced the charge-
transfer interactions between the electron-rich and electron-
Figure 1. The single crystal X-ray structure of sensor 1.

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Y. Sun et al. / Tetrahedron 65 (2009) 3480–3485
0.6
0.5
0.4
0.3
0.2
0.1
0.0
(a)
DMSO: H2O=9:1
DMSO: H2O=8:2
DMSO: H2O=7:3
DMSO: H2O=6:4
DMSO: H2O=5:5
(b)
250
300
350 400
Wavelenth/nm
450
500
550
Figure 2. (a) Absorption spectra of sensor 1 (20 mM) in different DMSO–H2O systems. (b) Color changes in the mixture of DMSO–H2O, from left to right: 9:1, 8:2, 7:3, 6:4, 1:1 of
DMSO–H2O (v/v), respectively.
deficient moieties, resulting in a visible color change (Scheme 2). In
addition, 1H NMR titration experiments were carried out by addi-
tion of cyanide to the mixture of deuterated DMSO–water. With the
increasing addition of cyanide, all the aromatic protons exhibited
an upfield shift to different extent (Fig. 4). This upfield shift is due to
the fact that after the addition reaction of CNꢀ to carbonyl carbon
and subsequent proton transfer of amide hydrogen to the de-
veloping alkoxide anion of 1, the electron density in the aromatic
ring increases, which results in an upfield shift of the protons. The
formation of cyanide adduct was further confirmed by mass spec-
troscopy. The electrospray ionization mass spectrum of the cyanide
adduct showed a molecular mass of 652 (Fig. S3), which corre-
sponds to the formula of [cyanide adductþBu4Nþþ2CNꢀ]. The
above results clearly demonstrate that a highly selective detection
system for cyanide can be developed on the basis of the specific
chemical reaction.
To quantitatively study the cyanide-sensing ability of 1 in 1:1
DMSO–H2O mixture, UV–vis monitoring was performed by using
20 mM solution of 1 at room temperature. Upon addition of cya-
nide anions, the absorption peak at 305 nm decreased, and a new
peak appeared at 405 nm, red-shifted by a Dlmax of 100 nm; the
absorption intensity at 405 nm increased 60-fold and was satu-
rated at 20 equiv of cyanide (Fig. 5a). The isosbestic point at
376 nm indicated a clean conversion throughout the titration
process. Job analysis for the complexation of 1 and cyanide
corroborated the 1:1 binding stoichiometry (Fig. 5b). Nonlinear
least-squares regression analysis14 of these changes gave a binding
constant of 1.1ꢁ105 Mꢀ1
.
(a)
0.6
-
(b)
H2PO4-, ClO4
CN-, F-, AcO-
0.3
0.2
0.1
0.0
0.5
0.4
0.3
0.2
0.1
0.0
-
NO3-, N3
CN-
1, Cl-, Br-, I-
F-
AcO-
500
1, Cl-, Br-, I-, ClO4
,
-
-
H2PO4-, NO3-, N3
300 350
250
300
350
400
Wavelenth/nm
450
500
550
400
450
Wavelenth/nm
550
(c)
(d)
0.5
0.4
0.3
0.2
0.1
0.0
CN-
1, F-, Cl-, Br-, I-, ClO4
-
AcO-, H2PO4-, NO3
-
-
N3
250
300
350
400
Wavelenth/nm
450
500
550
Figure 3. Absorption spectra of 1 (20
(c) 1:1 DMSO–H2O, 10 equiv of CNꢀ and 100 equiv of other anions; (d) the corresponding color changes in (c), vials from the left: only 1, CNꢀ, Fꢀ, Clꢀ, Brꢀ, Iꢀ, ClO4ꢀ, AcOꢀ, H2PO4ꢀ, NOꢀ3
and Nꢀ3
mM) on addition of various anions in different DMSO–H2O (v/v). (a) 9:1 DMSO–H2O, 10 equiv of anions; (b) 7:3 DMSO–H2O, 10 equiv of anions;
,
.

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Y. Sun et al. / Tetrahedron 65 (2009) 3480–3485
3483
O
N
CN
C
O
NO2
H+ transfer
CN
O2N
N
H
NO2
O2N
H
NO2
NO2
CN
C
OH
CN
C
OH
O
hv
N
N
NO2
O2N
N
NO2
O
NO2
NO2
Scheme 2. The proposed sensing mechanism of 1 for cyanide.
The selectivity of the system for cyanide was then examined by
competition experiments. Figure 6 shows UV–vis intensity changes
upon addition of cyanide when 100 equiv of Fꢀ, Clꢀ, Brꢀ, Iꢀ, ClO4ꢀ,
AcOꢀ, NOꢀ3 , and N3ꢀ except for H2POꢀ4 are also present. The ab-
sorption intensity was almost identical to that obtained in the ab-
sence of anions. However, H2POꢀ4 caused a decrease in absorption
intensity when 10 equiv of it were added, possibly resulted from
the protonation of the cyanide adduct by H2POꢀ4 , thus, decreasing
the absorption intensity, which is consistent with our proposed
mechanism depicted in Scheme 2.
indicate the poor sensitivities of these compounds to cyanide
[binding constants (Mꢀ1): 3.4ꢁ104, 4.9ꢁ103, 2.9ꢁ102 and 5.5ꢁ102
for 2–5, respectively]. It seems that the electron-withdrawing
substituted groups in benzamide unit can activate the amide car-
bonyl, favoring nucleophilic addition reaction of cyanide, while in
aniline unit will favor the proton transfer of amide hydrogen to the
developing alkoxide anion upon cyanide attack, both of which are
important to develop such type of chemosensors toward cyanide. In
addition, the strongly electron-withdrawing nitro group in benza-
mide unit is important for the charge-transfer interaction in our
studies. For example, when the sensing ability of 6 was evaluated,
no any discernible spectral change could be induced upon addition
of various anions.
The limits for detecting cyanide by using 1 as a colorimetric
sensor were also determined. A plot of (AꢀA0) versus [CNꢀ] in
DMSO–water (1:1, v/v) gave a linear relationship (see Fig. S4). The
detection limit in DMSO–H2O (1:1, v/v) was determined to be
0.87 mM, which corresponds to 1.74 m
M of [CNꢀ] in pure water.
3. Conclusions
Therefore, the system base on 1 can be used to detect the WHO
suggested maximum allowed cyanide concentration in drinking
water (1.9 mM).
In conclusion, we have developed a series of simple nitroaniline-
based benzamide compounds (1–5) for the ‘naked-eye’ detection of
cyanide in aqueous environment with high selectivity. These
compounds react with CNꢀ in a 1:1 stoichiometric manner, a pro-
cess which induces a large enhancement in absorption intensity
and a marked color changes from colorless to yellow in DMSO–H2O
(1:1, v/v) at room temperature. Importantly, the selectivity of this
system for CNꢀ over other anions is extremely high. In addition, the
detection limit of 1 for CNꢀ falls below the WHO detection level.
Therefore, the chemosensor 1 appears to be a practical system for
monitoring CNꢀ concentrations in aqueous samples.
2.3. Anion binding studies of 2–5
In order to obtain the knowledge on the effect of substituted
groups on the binding affinity and selectivity for cyanide, we re-
peated these measurements using compounds 2–5 in 1:1 DMSO–
H2O system (Figs. S5–S8). Similar to the case of 1, high selectivity for
cyanide was also observed for all these compounds. However, the
lower binding constants for 2–5 toward cyanide compared with 1
4. Experimental
4.1. General
Commercially available compounds were used without further
purification. Solvents were dried according to standard procedures.
All reactions were magnetically stirred and monitored by thin-layer
chromatography (TLC) using Huanghai GF254 silica gel coated
plates. Flash chromatography (FC) was carried out using silica gel
60 (230–400 mesh). Absorption spectra were taken on a Varian
Cary 300 absorption Agilent 8453 UV–vis spectroscopy system
using a 1-cm quartz cell. The 1H NMR and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively. The following abbrevi-
ations were used to explain the multiplicities: s¼singlet;
d¼doublet; t¼triplet; q¼quartet; m¼multiplet; br¼broad. Mass
spectra were recorded by EI method.
4.2. General procedure for the preparation of compounds 1–6
Under nitrogen atmosphere, a mixture of substituted aniline
(10 mmol), substituted benzoyl chloride (12 mmol), and Et3N
(15 mmol) in dry CH2Cl2 (200 mL) was stirred at room temperature
for 6 h, and then under reflux condition for another 12 h. After
completion of reaction (monitored by TLC), the volatile was
Figure 4. Plots of 1H NMR spectra of 1 on addition of cyanide in the mixture of
deuterated DMSO–water.