Synthesis of Novel D–π–A Dyes for Colorimetric Cyanide Sensing Based on Hemicyanine–Functionalized N-(2-Pyridyl)pyrazoles

Article abstract of DOI:10.1002/ejoc.201901178

Novel integrated N-(2-pyridyl)pyrazole-hemicyanine dyes (PH) were synthesized as promisor chemodosimeters for colorimetric and ratiometric CN^– detection. These dyes, obtained by a three-step sequence starting from acetophenones in up to 69 % overall yield, are donor–π–acceptor (D–π–A) systems consisting of indolium-salts bearing a modular donor aryl group on its pyrazole ring PHa–e. The salts displayed high selectivity and sensitivity for CN^– (LOD of up to 9.9 × 10^–7 m), as determined by interrupting the modular D–π–A system by nucleophilic attack of the cyanide on its iminium group; the mechanism of this process was confirmed by Job′s plot experiment, spectral analysis, cyclic voltammetry studies and TD-DFT calculations. This probe changes its color from deep yellow to colorless and can be used for in-the-field measurements without special equipment, since this change can be easily observed by the naked eye; indeed, yellow test strips were suitably used to detect CN^– in water.

Full text of DOI:10.1002/ejoc.201901178

A Journal of
Accepted Article
Title: Synthesis of novel D–π–A dyes for colorimetric cyanide sensing
based on hemicyanine–functionalized N-(2-pyridyl)pyrazoles
Authors: Luz-Mery Garzón and Jaime Portilla
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901178
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10.1002/ejoc.201901178
European Journal of Organic Chemistry
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Synthesis of novel D–π–A dyes for colorimetric cyanide sensing based on
hemicyanine–functionalized N-(2-pyridyl)pyrazoles
Luz-Mery Garzón[a] and Jaime Portilla*[a]
Abstract: Novel integrated N-(2-pyridyl)pyrazole–hemicyanine dyes (PH) were synthesized as promisor chemodosimeters for colorimetric and ratiometric
CN– detection. These dyes, obtained by a three-step sequence starting from acetophenones in up to 69% overall yield, are donor–π–acceptor (D–π–A)
systems consisting of indolium-salts bearing a modular donor aryl group on its pyrazole ring PHa–e. The salts displayed high selectivity and sensitivity for
CN– (LOD of up to 9.9 × 10-7 M), as determined by interrupting the modular D–π–A system by nucleophilic attack of the cyanide on its iminium group; the
mechanism of this process was confirmed by Job's plot experiment, spectral analysis, cyclic voltammetry studies and TD–DFT calculations. This probe
changes its color from deep yellow to colorless and can be used for in-the-field measurements without special equipment, since this change can be easily
observed by the naked eye; indeed, yellow test strips were suitably used to detect CN– in water.
π–acceptor (D–π–A) type dyes usually suffer from an intramolecular
Introduction
charge transfer (ICT) process with a ratiometric response that allows
two points to follow-up and thus provides an integrated correlation
for environmental interference.[9–11]
In recent years, studies on chemosensors based on optical responses
have attracted the attention of researchers in the fields of chemistry,
environmental science, biology, and engineering.[1] There are two
general types of optical detection, a colorimetric detection where
changes in color are produced that are visible to the naked eye and
fluorimetric detection based on emission changes. A plethora of
probes with diverse chromophores or fluorophores have been
developed and used in the detection of different cations, anions,
bioactive species, etc.[1,2] For example, the contamination of water by
ionic species has a high environmental impact; one of the most toxic
species is cyanide ion (CN–), whose salts have been used in the
production of herbicides and fibers, the extraction of gold, the
petrochemical industry and electroplating and metallurgy.[3]
Cyanide is extremely toxic to physiological systems and is mainly
absorbed by skin and inhalation; indeed, in the bloodstream, it can
inhibit the respiratory chain due to the formation of a stable complex
leading to cytotoxic hypoxia and cellular asphyxiation.[4] The maximum
permissible level of CN– in drinking water established by the World
Health Organization (WHO) is 19.0 × 10-7 M;[5] thus, there are several
methods for CN– sensing, such as electrochemistry, gas
chromatography and the use of optical molecular sensors. These
optical molecular sensors are chemosensors that have been widely
studied as simple, selective and sensitive systems and consist of dyes
formed by recognition and signaling units.[6] Among optical sensors,
colorimetric probes are especially promising since the color change
can be observed by the naked eyes, thus requiring less labour in
measurements and not requiring any equipment.[7]
Detection of a specific analyte based on hemicyanines is generally
achieved by adjusting the sensor molecule charge transfer process. It
is possible to modulate the properties of this system type by changing
the donor fragment,[9] and therefore, the optical response (λab, λem
)
leads to colorimetric and ratiometric changes for a specific detection.
However, some limitations of the hemicyanines should be overcome,
such as unwanted aggregation in aqueous solution, Stokes shifts ˂ 25
nm and poor photostability.[12] The D–π–A organic dyes are important
chemicals in elucidating the relations of push-pull chromophores with
their optoelectronic properties,[13] which have been used in the design
of fluorescent sensors,[14] dye-sensitized solar cells (DSSCs)[15] and
organic light-emitting diodes (OLED).[16] Various heterocyclic cores,
such as carbazole, coumarin, triazole, pyrazolo[1,5-a]pyrimidine and
pyrazole, have been used as donor moieties in the construction of D–
π–A systems.[17] Among them, pyrazole derivatives have been proven
to be are good chromophores and show efficient electronic transfer.
Consequently, pyrazoles have important photophysical properties, are
used as optical whiteners in detergents, serve as UV stabilizers, and
can be used in electrophotography and electroluminescence fields.[18]
Some probes for anions can differentiate selectively between
species with similar basicity and surface load density. There are
diverse systems for CN– detection, based on the displacement of
metals in complexes, aldehydes activated by hydrogen bonds and
nucleophilic addition reactions, but some have drawbacks such as low
selectivity and hydrophilicity and high detection limits (LOD).[8] Thus,
research on methods for CN– sensing based on small molecules is
highly desirable; in fact, our lab recently reported two new probes,
pyrazole derivatives bearing conjugated dicyanovinylidene DP[9] or an
indolium salt (hemicyanine moiety) PpHe[10] (Scheme 1). These donor–
[a] Departamento de Química, Universidad de los Andes, Carrera 1 Nº
18A-12, Bogotá, Colombia
E-mail: jportill@uniandes.edu.co
Scheme 1. Synthesis of probes for cyanide detection based on the pyrazole
derivatives DP, PpHe and PH.
https://academia.uniandes.edu.co/AcademyCv/jportill
† Supporting information (SI) for this article is available on the WWW under
http://dx.doi.org/
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10.1002/ejoc.201901178
European Journal of Organic Chemistry
FULL PAPER
Considering the aforementioned aspects together with our interest in
developing efficient methods to prepare ion chemosensors,[9,10,19] we
proposed the synthesis of novel hemicyanine–functionalized N-(2-
pyridyl)pyrazoles PHa–e with a modular-donor aryl group at its
pyrazole ring (Scheme 1c). In our previous works, formylpyrazole 1b
was used to obtain a DP probe that acts quickly since the 2-pyridyl
group of the pyrazole ring favors its reactivity,[9,20] while the 3-
formylpyrazolo[1,5-a]pyrimidine Pp reacted with indolium salt 2 to
obtain PpHe, which acts more slowly.[10] The PpHe probe showed a
lower LOD value that DP, probably because the structure of PpHe
contains higher π-conjugation (Scheme 1a-b). Therefore, we expect
that the new synthesized PHa–e probes have a shorter response time
in CN− sensing with than does PpHe, as well as lower LODs than DP,
since PHa–e combine the best structural properties found in our
previous works.[9,10]
Scheme 3. Synthesis of the colorimetric probes PHa–e from 4-formylpyrazoles 1a–e.
Conditions: 4-formylpyrazole 1a–e (0.50 mmol), indolium salt 3 (0.65 mmol) and
Results and discussion
[a]
NaOAc (0.65 mmol) in 2.0 mL of acetic anhydride. Photograph of PHa–e dissolved
in ethanol (4.0 × 10-5 M) under natural light.
Synthesis and characterization
Photophysical and sensing properties
The novel colorimetric probes PHa–e were successfully synthesized as
orange-red solids (deep yellow in ethanolic solution, 75–88% yield) by
the Knoevenagel reaction of the appropriate 4-formylpyrazole 1a-e
with indolium salt 2 (Scheme 3). In the complete synthetic route of
PHa–e shown in Scheme S1 of the Supporting Information (SI†), we
can observe that PHa–e were obtained via three reaction steps
starting from acetophenones 3a-e and 2-hydrazinylpyridine (4). The
synthesis of precursors 1a–e occurred in the first two steps (Scheme
2). The first step included a condensation reaction between 3a–e and
UV−vis and fluorescence spectra of PHd-e were obtained in toluene
(PhMe), dichloromethane (DCM), acetonitrile (ACN), dimethyl
sulfoxide (DMSO), ethanol (EtOH) and water (H2O) at 1.0 × 10-5
M
(Figs. S23–S27 and Table S1, SI†). The UV–Vis spectra of PHa–e show
two absorption bands, one at approximately 300 nm attributed to
π→π* transitions and the other in the range of 400 to 450 nm
attributed to So→ICT transitions caused by an ICT from the pyrrole-
type N atom of the pyrazole ring to the C=N+ group (Scheme 1c). Thus,
the absorption spectra of compounds PHa–e are largely influenced by
4
to form hydrazones 5a–e in high yields, followed by a
the polarity of the microenvironment, and in this case,
a
Vilsmeier−Haack reaction (formylation-cyclization-formylation) to give
the desired aldehydes in good yields. As a result, the novel hybrid
compounds PHa–e were obtained in good overall yields (52–69%).
hypsochromic shift is observed as the polarity of the solvent increases.
These findings are explained by the ionic nature of the salts PHa–e,
which have greater dipole moments in the ground state than in the
excited state, and upon excitation, the molecular dipole weakens and
reorients.[12,21] As expected, the ICT bands of PHa–e were
bathochromically shifted by increasing the donor nature of the aryl
group (i.e., 2-OAc < 4-OAc < H < 3,4,5-(MeO)3 < 4-MeO).[17,22]
Regarding the fluorescence experiments of PHa–e, the results
were not significant in any of the evaluated solvents, as all compounds
showed low quantum yields (Table S1, SI†), possibly due to the
formation of nonfluorescent aggregates.[23] Notably, decreasing the
donor nature of the aryl group of the pyrazole ring results in a greater
Stokes shift (Table S1, SI†). It is possible that the ICT phenomenon in
PHd (pyrazole→C=N+) is better than that in PHa (Ar→C=N+).
Considering the revealed photophysical properties of these D–π–A
systems, we decided to study the potential use of these materials in
the design of colorimetric chemosensors for anion detection. These
salts have moderate solubility in water; thus, an EtOH:H2O (1:1)
mixture (easily accessible and easy to handle) was selected for later
studies. This study was carried out because PHa–e possesses a
hemicyanine electrophilic group H conjugated with a donor pyrazole
moiety Pa–e. Accordingly, the addition of a suitable nucleophile could
interrupt the ICT between these two structural moieties Pa–e→H,
leading to the loss of its absorption properties.[10,23]
Scheme 2. Synthesis of 3-aryl-1-pyrydin-2-yl-1H-pyrazole-4-carbaldehyde 1a-e.
Conditions: (i) 3a–e (4.58 mmol) and 4 (4.58 mmol) in EtOH:HCl (5:1 v/v) under
microwave irradiation at 95 °C for 10 min; (ii) 5a–e (2.50 mmol) and POCl3/DMF
(12.5/7.5 mmol, 1.17/0.58 mL) in DMF (5 mL).
The structures of all synthetized compounds (PHa–e, 1a–e and
5a–e) were elucidated by NMR spectroscopy and HRMS analysis (Figs.
S2–S22, SI†). TGA of the probes was carried out to verify their high
thermal stability and low solvent residues (Fig. S1, SI†), which is
important for subsequent photophysical studies. It should be noted
that hydrazones 5a–e were obtained through microwave (MW)
irradiation with higher yields, shorter reaction times and easier
purification processes that in our previous work.[9] Furthermore, in the
case of compounds PHd–e, acetylation of the OH group in their
respective precursors also occurred, while the Knoevenagel reaction
did not occur under conditions similar to those used in our other
previous work (MW in acetic acid)[10] (Schemes 1 and 3).
To evaluate the use of PHa–e salts in anion sensing, UV-vis
absorption spectra of PHa–e (4.0 × 10-5 M in ethanol) were measured
after 10 min of reaction at room temperature with 3 equiv of CN− or
−
−
−
−
−
−
other anions (OAc−, Br−, HSO4 , NO3 , ClO3 , F−, H2PO4 , I−, N3 , NO2 ,
S2 , SCN−, SO42−) dissolved in water, achieving EtOH:H2O (1:1 v/v) final
−
solutions. No significant change in the absorption band was observed
for any of the anions tested except for CN−, with the disappearance of
the ICT band (approximately 420 mm) and an increase in the intensity
at approximately 300 nm (Figs. S28−S32, SI†). Consequently, the
designed molecules are colorimetric and ratiometric probes of CN−,
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10.1002/ejoc.201901178
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where nucleophilic addition of this anion to the C=N+ moiety blocks
formation of these D–π–A systems, which is accompanied by
important photophysical changes and a fast color change (deep yellow
to colorless) that is visible to the naked eye (Fig. 1). It is important to
note that PHe exhibited lower selectivity than PHa–d (Figs. S28−S32,
SI†). It is possible that the ICT process in PHe (Ar→C=N+) is weakened
by the acetyl group effect, while in PHa–d, there are electronic and
conformational phenomena that favor this process (Fig. S46, SI†).
versus reaction time, finding strong changes after 5 min and an
equilibrium at nearly 10 min (Fig. 3a). Likewise, the selectivity of PHd
towards CN− at various pH values (from 2 to 11) was explored, with
good cyanide recognition achieved in a pH range of 7−9 in phosphate
buffer solutions (Fig. 3b). Finally, Job’s plot method (absorbance) was
used to determine the recognition stoichiometry using the reaction of
PHd with cyanide ions.[25] The curve obtained in this experiment
showed a maximum at approximately 0.5, suggesting a stoichiometric
ratio PHd:CN− of 1:1 (Fig. S35).
Figure 3. (a) Time-dependent absorption intensity ratio for PHd upon addition of 1.0
equiv of CN– (4.0 × 10−5 M in EtOH:H2O, 1:1). (b) Absorption intensity ratio of PHd (4.0
× 10−5 M) and PHd–CN (4.0 × 10−5 M each) as a function of pH in EtOH:H2O (1:1).
Figure 1. (a) Absorption spectra of PHd (4.0 × 10-5 M) with CN– and different anions (3
equiv, 1.2 × 10-4 M) in EtOH:H2O (1:1). (b) Log(A293/A417) of PHd in the presence of 3
equiv of different anions. (c) Photograph of color changes under natural light with 3
equiv of the respective anion.
On the other hand, since the designed colorimetric probes rapidly
change their color from deep yellow to colorless and this change can
be easily detected by the naked eye, we conducted a preliminary
study to achieve quantitative measurements of CN− without special
equipment. Thus, yellow test strips of chemodosimeter PHd were
prepared by immersing white filter paper into an ethanolic solution
(1.2 × 10-4 M) and drying in an oven at 40 °C for 20 min. Then, the test
strips were dipped into aqueous solutions of CN− with varying
concentrations (0.00, 0.25, 0.50, 0.75, and 1.00 equiv), and obvious
color changes from deep yellow to white were observed (Fig. 4a). To
further confirm the practical applicability of PHd for CN– detection,
qualitative studies of both selective and competition were carried out
using 3 equiv of interfering anions (Fig. 4b). Only the addition of CN–
can lead to important color changes, but the other tested anions did
not exhibit any influence. These results confirmed that PHd has higher
selectivity towards CN– than towards the other tested anions.
Probes PHb and PHd exhibited the highest selectivity towards CN−
(Figs. 1, S29 and S31); thus, we further studied the reaction using
these salts (4.0 × 10-5 M in ethanol) to determine the needed amount
of CN− to achieve total disappearance of the ICT band. UV−vis spectra
were recorder after 1 min of reaction, and an excellent linear
relationship (R2 = 0.999 and R2 = 0.996) was observed between
PHb
PHd
Log(A1/A2 and the CN– ion concentration after progressive addition of
this anion (0.1 to 1.0 equiv) to salt solutions (Figs. 2 and S33−S34).
From this linearity, the limit of detection for each probe was
determined using the formula LOD = 3σ/k, where σ is the standard
deviation from 10 measurements and k is the slope of the line. The
LOD of an analytical method is the lowest amount of analyte in a
sample that can be detected but not necessarily quantitated as an
exact value.[24] The results indicate that LODPHb = 11.5 × 10-7 M and
LODPHd = 9.9 × 10-7 M are well below 19.0 × 10-7 M, which is the
maximum concentration permitted for drinking water by the WHO.[5]
Figure 4. (a) Detection of CN– in water at different concentrations using yellow test
strips of PHd (1.2 × 10-4 M). (b) Selectivity (1) and competition (2) of PHd towards CN–
(1 equiv) with other anions (3 equiv) using yellow-test strips of PHd.
Frontier molecular orbital studies
Cyclic voltammetry (CV) was employed to study the electrochemical
properties of the probes PHa–e and of the addition product PHb–CN
and hence to estimate their HOMO (highest occupied molecular
orbital) and LUMO (lowest unoccupied molecular orbital) energy
levels. This study was carried out at room temperature using solutions
of each compound in acetonitrile (10-4 M) with TBAPF6 (0.1 M) as the
supporting electrolyte. Oxidation and reduction potentials were
measured against a Ag/AgCl reference electrode using ITO as the
working electrode and a platinum wire as the counter electrode. The
Figure 2. (a) UV–Vis absorption titration spectra of PHd (4.0 × 10-5 M) in the presence
of CN– (0–1 equiv) in EtOH:H2O (1:1). (b) Linear relationship of Log(A293/A417) versus
[CN–]. (c) Photograph of color changes (by titration) under natural light.
Additional studies were performed using the chemodosimeter PHd to
better understand the response of this probe type to cyanide ions
(Figs. 3 and S35). For instance, we investigated the time influence of
time on the sensing system results by plotting the absorption intensity
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FULL PAPER
one-electron oxidation of PHx+ generates the resultant PHx·2+ [26]
.
The
group in PHb experienced important changes upon addition of the
anion. In addition, the protons of the geminal methyl groups show the
incorporation of CN− in the C=N+ because in PHb–CN, these groups are
not equivalent, while in CN–PHb, they are equivalent. In addition, no
signal for the methino proton (H*) was observed at low field,[10] which
confirms the formation of PHb–CN (Scheme 5 and Figs. S36–S37 in the
SI†).
voltammograms of PHa–e show irreversible oxidation-reduction
processes possibly due to rapid dimerization (radical-radical coupling)
of the corresponding radical dications (Fig. S40–S44, SI†),[23,27] while
for PHb–CN a reversible process is shown (Fig. S45, SI†).
The introduction of donor groups in the pyrazole moiety results in
a decrease in the oxidation potential (Table S2, SI†), and on the basis
of the determined oxidation potential, the HOMO energy was
estimated using the formula HOMO = −(EOxPHa–e + 4.8ev − EOxF),[28] with
ferrocene (F) as an external standard (Fig. S38, SI†). Subsequently, the
bandgap[29] was estimated with the UV–Vis spectra, and with this
value, the LUMO energy was estimated using the formula LUMO =
HOMO + Eg (Table S2). As expected, the results show that probes
substituted with the most donor groups have lower energy HOMO
and smaller bandgaps than the other probes. Additionally, the frontier
orbital energy levels of these D–π–A systems are suitable for hole and
electron injection, such as in push-pull chromophores with
optoelectronic activity.[13]
Scheme 5. Selectivity of the CN– addition over PHb and proposed sensing mechanism.
To gain deeper insight into the electronic properties of the six
studied compounds PHa–e and PHb–CN, time-dependent density
functional theory (DFT) calculations were performed in acetonitrile.
The λmax values were obtained from the theoretical UV–vis spectra
with a theory level of B3LYP/6-31G (d,p). The maximum calculated UV
absorptions, the theoretical electronic excitation energies, the
calculated oscillator forces and the electronic gas phase transitions
are detailed in Table S3 of the SI†. The band at approximately 420 nm
is assigned mainly to HOMO-1→LUMO transitions in PHa, HOMO-
2→LUMO in PHb, HOMO-3→LUMO in PHc, HOMO-1→LUMO
transitions in PHd, and HOMO-1→LUMO transitions in PHe, indicating
that these are So→ICT in nature.
According to the diagrams of frontier orbitals of these transitions
(Fig. S46, SI†), it can be observed how the electronic nature of the aryl
groups has a great influence on the ICT towards the C=N+, except for
PHd, where the transfer occurs from the pyrrole-type N atom of the
pyrazole ring. It is possible that the steric effect that occurs between
the pyridine-type N atom of the pyrazole (free electron pair) and the
acetocyl group of PHd is responsible for this fact, since its molecular
conformation prevents π conjugation from the acetocyl towards the
C=N+. The theoretical results corroborate the trend of PHd < PHe <
PHa < PHc < PHb for the energy value of the HOMO estimated by CV
and in turn the value of the bandgap (ΔE) in the synthesized probes
(Scheme 4 and Table S3 of SI†).
This mechanism is consistent with all the results obtained herein and
those previously reported by us,[8d,9,10] since the addition of CN− to
PHa–e blocks formation of the D–π–A system together with the ICT
process, which leads to important photophysical changes. In addition,
this mechanism explains the competition with respect to other
nucleophilic anions and why some probes (i.e., PHa, PHc and PHe)
were less selective. It is possible than the 2-pyridyl group of the
pyrazole ring and certain arylic substitutions in this heterocycle make
the C=N+ more electrophilic and selective. As shown in the molecular
orbital diagram (Scheme 4), it is probable that PHd is more selective
because its charge density is lower (the bets reactivity) than those of
the other probes because of the steric effect on its aryl group (2-
OAcPh), which induces a conformation that blocks π-conjugation;
while the high selectivity of PHb is due to the best donor effect (the
bets ICT process) of its 3-aryl group (4-MeOPh).
Conclusions
In summary, novel D–π–A chemodosimeters PHa–e for cyanide ion
detection based on hybrid pyrazole–hemicyanine systems have been
synthesized by a three-step sequence in up to 69% overall yield. These
probes have a modular donor aryl group at the pyrazolic ring that
promotes high selectivity and sensitivity towards CN– versus other
anions with LODs as low as 9.9 × 10-7 M, which is crucial for studies in
aqueous samples.[5] The sensing mechanism (verified by MS and NMR)
consists of the regioselective CN– addition to the C=N+ moiety of the
probes yielding products PH–CN, resulting in an increase in the π→π*
band and a decrease in the So→ICT band with a ratiometric response.
Moreover, CV experiments and TD-DFT calculations established that
the selectivity and sensitivity of the probes depends on the type of
substituent in the donor moiety and that there was an ICT obstruction
in PH–CN. Thus, PHa–e appear to be good models for the
development of simple and practical colorimetric probes for in-the-
field measurements without special equipment.
Scheme 4. Estimation of HOMO and LUMO of compounds PHa–e and PHb–CN.
Proposed sensing mechanism for CN–
Experimental Section
Based on the results obtained, we have more deeply studied and
verified the CN– sensing mechanism via MS analysis and 1H NMR
experiments of the product PHb–CN (easier 1H NMR spectra). The
electrospray ionization mass spectrum (MS-ESI) confirmed the
formation of the expected product (Fig. S38). The ion peak at m/z
476.25 (intensity of 10%) corresponds to the product obtained by CN−
addition to the C=N+ moiety of PHb [PHb–CN]H+ (calcd, 476.24). The
1H NMR spectrum confirms the regioselectivity of the CN– addition
reaction (Fig. S37, SI†), since the aromatic protons and the methylene
General
All reagents were purchased from commercial sources and used without
further purification. The reactions were monitored by thin-layer
chromatography (TLC) and visualized by a UV lamp (254 or 365 nm). Column
flash chromatography was performed on silica gel (230–400 mesh). Microwave
(MW) irradiation of the reactions was performed using a sealed reaction vessel
(10.0 mL, max pressure = 300 psi) containing a Teflon-coated stir bar (obtained
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10.1002/ejoc.201901178
European Journal of Organic Chemistry
FULL PAPER
from CEM) and a CEM DiscoverTM focused MW reactor (ν = 2.45 GHz) equipped
with a built–in pressure measurement sensor and a vertically focused IR
temperature sensor. Controlled temperature, power, and time settings were
used for all reactions. The NMR spectra were recorded on a Bruker Avance 400
(400.13 MHz for 1H; 100.61 MHz for 13C) at 298 K. The NMR spectroscopic data
were recorded in CDCl3 with the residual non–deuterated signal for 1H NMR
and the deuterated solvent signal for 13C NMR as internal standards. Melting
points were determined using a capillary melting point apparatus and are
uncorrected. The high-resolution mass spectra (HRMS) were obtained on an
Agilent Technologies Q−TOF 6520 spectrometer via electrospray ionization (ESI).
The mass spectrum of PHb−CN was recorded on a Thermo-Scientific LCQ
FleetTM ion-trap mass spectrometer using positive ion mode ESI and a direct
inlet system. The UV-vis absorption and fluorescence spectra were recorded at
room temperature (approximately 20 °C) on Varian Cary 100 and Cary Eclipse
spectrophotometers, respectively (both are Agilent Technologies devices) using
quartz cuvettes with a path length of 1 cm. For fluorescence measurements,
both the excitation and emission slit widths were 5 nm.
m, 3H), 1.74 (s, 6H), 3.93 (br s, 9H), 4.99 (br m, 2H), 6.87 (s, 2H), 7.32 (br m, 1H),
7.52–7.57 (br m, 4H), 7.91–8.00 (br m, 2H), 8.18–8.27 (br m, 2H), 8.60 (br s, 1H),
10.35 (s, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 14.2 (CH3), 27.4 (CH3),
44.2 (CH2), 51.9 (C), 56.9 (CH3), 61.1 (CH3), 106.4 (CH), 112.0 (CH), 114.1 (CH),
114.3 (CH), 119.1 (C), 122.7 (CH), 123.3 (CH), 126.8 (C), 129.4 (CH), 129.8 (CH),
133.2 (CH), 139.1 (CH), 139.6 (C), 140.5 (C), 143.0 (C), 146.7 (CH), 149.1 (CH),
150.2 (C), 153.9 (C), 156.3 (C), 181.0 (C) ppm. HRMS (ESI+): calcd. For
C31H33N4O3+ 509.2547 [M – I ]+; found 509.2556.
(E)-1-Ethyl-3,3-dimethyl-2-(2-(3-(2-hydroxyphenyl)-1-(pyridin-2-yl)-1H-
pyrazol-4-yl)vinyl)-3H-indolium iodide (PHd): By following the general
procedure in the reaction with 3-(2-hydroxyphenyl)-1-(pyridin-2-yl)-1H-
pyrazole-4-carbaldehyde (1d, 133 mg, 0.5 mmol), the salt PHd was obtained as
a red solid (256 mg, 85%): Mp 145–146 °C. 1H NMR (400 MHz, CDCl3): δ = 1.50 (t,
J = 7.1 Hz, 3H), 1.71 (s, 6H), 2.09 (s, 3H), 4.80 (m, 2H), 7.31 (m, 2H), 7.43–7.59
(m, 7H), 7.68 (d, J = 15.9, 1H), 7.88 (t, J = 7.5 Hz, 1H), 8.14 (m, 2H), 8.57 (br s,
1H), 10.27 (s, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 14.0 (CH3), 21.0
(CH3), 27.0 (CH3), 43.7 (CH2), 52.1 (C), 111.5 (CH), 113.5 (CH), 114.5 (CH), 119.6
(C), 122.7 (CH), 123.1 (CH), 123.5 (CH), 125.0 (C), 126.6 (CH), 129.5 (CH), 129.6
(CH), 131.1 (CH), 131.6 (CH), 139.0 (CH), 140.2 (C), 143.1 (C), 146.4 (CH), 148.7
(C), 148.9 (CH), 150.1 (C), 151.7 (C), 169.0 (C), 181.3 (C) ppm. HRMS (ESI+):
calcd. For C30H29N4O2+ 477.2285 [M – I]+; found 477.2289.
Synthesis and characterization of PHa–e and PHb–CN
The chemodosimeters PHa–e were synthesized in good yields (75–88%) by the
Knoevenagel reaction between the appropriate 4-formylpyrazole 1a–e and the
indolium salt 2 (Scheme 2). The detailed synthetic route of PHa–e starting from
freshly synthesized 2-hydrazinylpyridine (4)[20] and commercial acetophenones
3a–e is shown in the SI† (Scheme S1). The experimental results and structural
characterization data of the precursors 5a–c and 1a–c are consistent with our
recently reported data,[9] while the results for the novel precursors 5d–e and
1d–e are detailed in the SI†. The structures of PHa–e and precursors (1 and 5)
were elucidated by 1H and 13C NMR spectroscopy (Figs. S2–S11, SI†) and HRMS
analysis (Figs. S12–S22, SI†). Thermogravimetric analysis (TGA) of PHa–e
indicated that these salts exhibit high thermal stability and low solvent residues
(Figs. S1, SI†).
(E)-1-Ethyl-3,3-dimethyl-2-(2-(3-(4-hydroxyphenyl)-1-(pyridin-2-yl)-1H-
pyrazol-4-yl)vinyl)-3H-indolium iodide (PHe): By following the general
procedure in the reaction with 3-(4-hydroxyphenyl)-1-(pyridin-2-yl)-1H-
pyrazole-4-carbaldehyde (1e, 133 mg, 0.5 mmol), the salt PHe was obtained as
a red solid (266 mg, 88%): Mp 105–106 °C. 1H NMR (400 MHz, CDCl3): δ = 1.55 (t,
J = 7.3 Hz, 3H), 1.73 (s, 6H), 2.34 (s, 3H), 4.86 (m, 2H), 7.29 (m, 3H), 7.48–7.60
(m, 4H), 7.70 (d, J = 8.6, 2H), 7.18 (d, J = 16.2 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H),
8.20 (m, 2H), 8.54 (d, J = 4.8 Hz, 1H), 10.24 (s, 1H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ = 14.2 (CH3), 21.2 (CH3), 27.2 (CH3), 44.0 (CH2), 51.9 (CH3), 111.8 (CH),
113.7 (CH), 114.4 (CH), 118.8 (C), 122.4 (CH), 122.7 (CH), 123.1 (CH), 128.9 (C),
129.5 (CH), 129.7 (CH), 130.1 (CH), 132.9 (CH), 139.1 (CH), 140.2 (CH), 142.9 (C),
146.1 (C), 148.9 (CH), 150.0 (C), 151.7 (CH), 154.9 (C), 169.3 (C), 180.9 (C) ppm.
HRMS (ESI+): calcd. For C30H29N4O2+ 477.2285 [M – I]+; found 477.2287.
General procedure for the synthesis of the Integrated pyrazole–hemicyanine
systems PHa–e: A mixture of 1a–e (0.50 mmol), freshly synthesized 1-ethyl-
2,3,3-trimethyl-3H-indol-1-ium iodide (2)[30] (2, 205 mg, 0.65 mmol) and sodium
acetate (53 mg, 0.65 mmol) in acetic anhydride (2.0 mL) was refluxed for 3 h.
Subsequently, the reaction was allowed to cool to room temperature and was
concentrated under reduced pressure, and the solid residue was directly
purified by flash chromatography on silica gel (eluent, CH2Cl2) to afford the pure
products PHa–e in good yields as red-orange solids.
Synthesis of (E)-1-ethyl-2-(2-(3-(4-methoxyphenyl)-1-(pyridin-2-yl)-1H-pyrazol-
4-yl)vinyl)-3,3-dimethylindoline-2-carbonitrile (PHb–CN): A solution containing
PHb (100 mg, 0.173 mmol) and NaCN (15 mg, 0.306 mmol) in ethanol:water
(10:1 v/v) was stirred at 20 °C for 10 min. The product was extracted with DCM
and the organic phase was concentrated under reduced pressure to afford the
pure product PHb–CN (81 mg, 98%) as a yellow solid. Mp 120–121 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.18 (t, 3H), 1.31 (t, J = 7.2, 3H), 1.51 (s, 3H), 3.20 (m, 2H),
3.86 (s, 3H), 6.11 (d, J = 16.2, 1H), 6.62 (d, J = 7.6, 1H), 6.83 (d, J = 7.7 Hz, 1H),
7.00–7.25 (m, 6H), 7.66 (d, J = 8.7, 2H), 7.80 (t, J = 7.3, 1H), 8.08 (t, J = 8.1, 1H),
8.42 (d, J = 4.0, 1H), 8.77 (s, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 14.6
(CH3), 23.2 (CH3), 24.3 (CH3), 41.0 (CH2), 49.2 (C), 55.3 (CH3), 79.8 (C), 108.2 (CH),
112.6 (CH), 114.3 (CH), 118.3 (C), 118.4 (C), 119.7 (CH), 121.6 (CH), 121.8 (CH),
123.6 (CH), 124.9 (C), 125.2 (CH), 125.8 (CH), 128.2 (CH), 129.6 (CH), 136.3 (C),
138.2 (C), 148.0 (CH), 151.1 (C), 152.5 (C), 160.0 (C) ppm. MS (ESI) m/z = 476.25
(MH+, 10%) and 449.28 (MH+ – HCN, 100%); m/z calcd. (C30H30N5O+) = 476.24
[MH]+ and 449.23 [M – HCN]+ (Figs. S35 and S37, SI†).
(E)-1-Ethyl-3,3-dimethyl-2-(2-(3-phenyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl)vinyl)-
3H-indolium iodide (PHa): By following the general procedure in the reaction
with 3-(phenyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde (1a, 125 mg, 0.5
mmol), the salt PHa was obtained as an orange solid (205 mg, 75%): Mp 245–
244 °C. 1H NMR (400 MHz, CDCl3): δ = 1.59 (t, J = 7.1 Hz, 3H), 1.72 (s, 6H), 4.98
(m, 2H), 7.31 (t, J = 5.7 Hz, 1H), 7.49–7.57 (m, 7H), 7.68 (d, J = 7.0, 2H), 7.91 (t, J
= 7.0 Hz, 1H), 7.98 (d, J = 16.0 Hz, 1H), 8.20 (d, J = 16.0 Hz, 1H), 8.26 (d, J = 8.3
Hz, 1H), 8.60 (d, J = 4.1 Hz, 1H), 10.38 (s, 1H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ = 14.2 (CH3), 27.4 (CH3), 44.1 (CH2), 51.9 (C), 111.8 (CH), 113.8 (CH),
114.5 (CH), 118.9 (C), 122.6 (CH), 123.1 (CH), 129.0 (CH), 129.1 (CH), 129.4 (CH),
129.6 (CH), 129.7 (CH), 131.3 (C), 132.8 (CH), 139.0 (CH), 140.3 (C), 142.9 (C),
146.5 (CH), 150.1 (C), 156.0 (C), 181.0 (C) ppm. HRMS (ESI+): calcd. For
C28H27N4+ 419.2236 [M – I]+; found 419.2244
Photophysical properties of salts PHa-e
(E)-1-Ethyl-3,3-dimethyl-2-(2-(3-(4-methoxyphenyl)-1-(pyridin-2-yl)-1H-
pyrazol-4-yl)vinyl)-3H-indolium iodide (PHb): By following the general
procedure in the reaction with 3-(4-methoxyphenyl)-1-(pyridin-2-yl)-1H-
pyrazole-4-carbaldehyde (1b, 140 mg, 0.5 mmol), the salt PHb was obtained as
a red solid (214 mg, 77%): Mp 160–161 °C. 1H NMR (400 MHz, CDCl3): δ = 1.59 (t,
J = 7.0 Hz, 3H), 1.73 (s, 6H), 3.91 (s, 3H), 4.98 (m, 2H), 7.09 (d, J = 8.4 Hz, 2H),
7.31 (t, J = 6.2 Hz, 1H), 7.51–7.64 (m, 6H), 7.90 (t, J = 7.5 Hz, 1H), 7.97 (d, J =
16.0 Hz, 1H), 8.20 (d, J = 16.0 Hz, 1H), 8.25 (d, J = 4.5 Hz, 1H), 8.59 (s, 1H), 10.33
(s, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 14.2 (CH3), 27.4 (CH3), 44.0
(CH2), 51.8 (C), 55.5 (CH3), 111.6 (CH), 113.9 (CH), 114.3 (CH), 114.5 (CH), 119.0
(C), 122.6 (CH), 123.1 (CH), 123.6 (C), 129.3 (CH), 129.7 (CH), 130.4 (CH), 132.9
(CH), 139.0 (CH), 140.4 (C), 142.9 (C), 146.9 (CH), 149.0 (CH), 150.2 (C), 156.0 (C),
160.8 (C), 181.3 (C) ppm. HRMS (ESI+): calcd. For C29H29N4O+ 449.2336 [M – I]+;
found 449.2332.
UV-vis absorption and fluorescence studies: The solvatochromic studies of the
compounds PHa–e were carried out in 1.0 × 10-5 M solutions using different
solvents (Figs. S23–S27), such as toluene (PhMe), dichloromethane (DCM),
acetonitrile (ACN), dimethylsulfoxide (DMSO), ethanol (EtOH), and water (H2O).
Determination of quantum yields: The quantum yields were obtained (Table S1,
SI†) by using quinine sulfate (ϕF = 0.50 in H2SO4 0.5 M at 300 nm) as a
reference and calculated according to the equation[24,31]
where x and st indicate the sample and standard solution, respectively, ϕ is the
quantum yield, F is the integrated area of the emission, A is the absorbance at
the excitation wavelength, and η is the refraction index of solvents.
(E)-1-Ethyl-3,3-dimethyl-2-(2-(3-(3,4,5-trimethoxyphenyl)-1-(pyridin-2-yl)-1H-
pyrazol-4-yl)vinyl)-3H-indolium iodide (PHc): By following the general
procedure in the reaction with 3-(3,4,5-trimethoxyphenyl)-1-(pyridin-2-yl)-1H-
pyrazole-4-carbaldehyde (1c, 170 mg, 0.5 mmol), the salt PHc was obtained as a
red solid (264 mg, 83%): Mp 150–151 °C. 1H NMR (400 MHz, CDCl3): δ = 1.61 (br
Design of the PHa–e Chemosensors
Response detection of PHa–e: The solutions of probes PHa–e (4.0 × 10-5 M)
were prepared in ethanol-water (99:1, v/v at pH = 7.05, 20 °C). The salts used in
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10.1002/ejoc.201901178
European Journal of Organic Chemistry
FULL PAPER
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EtOH) was obtained by 3α/k, where α is the standard deviation of the blank
measurements (10 times), and k is the slope from the plot Log(A1/A2) versus
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solution (1.2 × 10-4 M) of the probe PHd, and dried in an oven at 40 °C for 20
min. Then, the test strips were immersed in aqueous solution containing 0.00
to 1.00 equiv of CN− ions (Fig. 3a). Likewise, the test strips were used with 3
−
equiv of interfering anions (OAc−, Br−, HSO4−, NO3−, ClO3−, SO42−, F−, H2PO4
,
HSO3−, I−, N3−, NO2−, S2−, SCN−) in studies of both selective and competition (Fig.
3b). This method could be used for the selective CN− recognition in different
water samples.
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(CV) experiments were performed on an Autolab PGSTAT302N potentiostat.
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We wish to thank the Chemistry Department and Vicerrectoría de
Investigaciones from Universidad de los Andes for financial support.
We express our gratitude to the Colombian Institute for Science and
Research (COLCIENCIAS, project code 120465843502) for financial
support. We also wish to thank Diana Pinilla and Edwin Guevara (both
of Universidad de los Andes) for acquiring the thermograms and mass
spectra, respectively.
Keywords: Chemodosimeter
• Charge transfer • Cyanide •
Hemicyanine • N-(2-pyridyl)pyrazole
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&
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Entry for the Table of Contents
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Key Topic*
* Hemicyanine–functionalized N-(2-
pyridyl)pyrazoles, cyanide sensing
Luz-Mery Garzón and Jaime Portilla*
Page No. – Page No.
Title Synthesis of novel D–π–A dyes for
colorimetric cyanide sensing based on
hemicyanine–functionalized N-(2-pyridyl)pyrazoles
Herein, a novel family of D–π–A organic dyes for colorimetric cyanide sensing based on
hemicyanine–functionalized N-(2-pyridyl)pyrazoles are provided. These dyes displayed
high selectivity and sensitivity for CN– (LOD of up to 9.9 × 10-7 M) by interrupting the D–
π–A system by nucleophilic attack of the anion on the iminium group of the dyes.
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