A smart sensor for rapid detection of lethal hydrazine in human blood and drinking water

Article abstract of DOI:10.1039/C8NJ06230G

Hydrazine exposure leads to damage of all vital organs of humans and animals, which demands the discovery of a method for the rapid and quantitative detection of hydrazine. Newly designed and synthesized receptor-bearing phenolic-OH,-Br,-CN,-ester and ben

Full text of DOI:10.1039/C8NJ06230G

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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A smart sensor for rapid detection of lethal hydrazine in human
blood and drinking water
Sima Paul,aRajesh Nandi,aKakali Ghoshal,b Maitree Bhattacharyya,band Dilip K. Maiti*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Hydrazine exposure leads to damage of all vital organs of the human and animal, which demands discovery of a rapid and
quantitative detection method for it. A newly designed and synthesizedreceptor bearing phenolic -OH, -Br, -CN, -ester and
benzthiazole moieties displayed brilliant naked eye fluorescent sensing towards hydrazine with rapid reactivity and very
good selectivity over several cations, anions, thiols and amines containing compounds. Theprobe showed good cell
permeability, low cytotoxicity, fast fluorogenic recognition and “naked eye” detection of hydrazine below the TLV levels
which is available in the living cells, drinking water and industrial effluent.
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Introduction
Hydrazine (H2N-NH2) is a chemically strong base, nucleophile
and reducing agent and its high reactivity leads to wide range
of application especially in the industries for large scale
production of high value aerospace propellants,
pharmaceuticals, agrochemicals, polymers, dyes and chemicals
.1Flammable and detonable hydrazine is employed as an
ingredient for rocket-fuels and air bag,2 syntheses of
H2
N
N
OH
Br
N
CN
N2H4
C2H5OOC
H
OH
Br
N
S
H
S
azobisformamide(AC),3diisopropyl
carbonate
inhibitor for
No color and Fluorescence
Yellow color and Blue Fluorescence
andtoluenesulfonhydrazide(TSH),4corrosion
Scheme 1: Proposed mechanism for sensing hydrazine
nuclear and electrical power plants,5 foaming polymers and
alternative energy source to innovative new generation fuel
cells. In spite of widespread application, hydrazine, its vapor
and water solutions are explosive and poisonous in nature,
which can be absorbed to humans and animals on exposure
through dermal, oral and inhalation.6 The highly toxic
hydrazine reduces the average life span of the industrial
workers and damages their livers, kidneys, lungs, central
nervous and respiratory systems.7 The TLV threshold limit
value of hydrazine in drinking water must not be greater than
10 ppb.8 Thus, instantaneous detection of extremely
hazardous hydrazine has significant interest and it is especially
crucial in controlling its concentration levels in the industrial
area, quantitative detection in human blood and drinking
water.
chemiluminescence,12 chromatography,13and
surface-
enhanced Raman spectroscopy14 are not viable for in vivo
analyses. In this regards, modern fluorescent techniques are
simple, inexpensive, rapid and real-time monitoring, which is
ideal technique for in vivo detection of hydrazine.15 Thus,
deprotection-based fluorescence sensing for hydrazine has
emerged as an important tool utilizing acetyl,16 4-bromo
butyrate,17
levulinate,18
phthalimides,19
aldehydes,20
malononitriles,21 benzoic acids,22 γ-oxo-1-pyrenebutyrates,23
trifluoroacetylacetonates24 and acetylacetonates.25 However,
most of these fluorescent probes suffers from longer detect
time.26-27 Recently, Chow et al.26 reported ethylcyanoacetate
protected probe for hydrazine having detection limit 12μM
and detect within 8 min. This probe shows very poor water
solubility as titration was done in buffer: DMSO (1:9). Due to
lack of poor water solubility these probe may not be suitable
for biological application. Li et al.27 also reported similar
protected probe for hydrazine having detection limit 1.6 μM
and detect within 15 min. In case of this probe, absorption and
fluorescence titration was carried out in water/DMSO (4:6). Lei
and coworkers28 found a relatively fast detection protocol
through electrochemical oxidation of pure hydrazine in neutral
water by TiO2–Pt nanomaterials without showing any practical
The qualitative and quantitative detection of hydrazine by the
conventional titrimetry,9 spectrochemistry,10
a. University of Calcutta, 92 Acharya Prafulla Chandra Road, Kolkata 700009, India
b. University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, India
† Email : maitidk@yahoo.com, Fax : + 91-33-23519755
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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application to detect hydrazine from drinking water and/or
blood samples. This electrochemical process will not be viable
for testing aforementioned samples which are possessing
interfering ions, oxidizable organic matters and non neutralpH.
Our target is to design and synthesize almost completely water
soluble probe as an efficient ‘‘naked-eye’’ indicator and
chemodosimeter for rapid recognition of hydrazine present in
human blood drinking water and other samples with quite low
detection limit (Scheme 1).
The benzothiazole moiety was installed in our designed probe
ethyl 3-(3-(benzo[d]thiazol-2-yl)-5-bromo-2-hydroxyphenyl)-2
cyanoacrylate (3, BBHC, Scheme 1) to achieve an excited state
intramolecular photon transfer (ESIPT) process upon
photoexcitation.29 ESIPT leads to making “O” atom in the
phenolic OH highly electronegative, which in turn will induce
more positive character in carbon atom of -CN. In the presence
of –Br and -CN, electrophilic nature of the C=C double bond is
drastically enhanced towards nucleophilic hydrazine for rapid
formation of colored hydrazone, 2-(benzo[d]thiazol-2-yl)-4-
bromo-6-(hydrazonomethyl) phenol (4, BBHP). As a result, this
recognition even observable through naked eye and
fluorescence change, which will be help to detect hydrazine
View Article Online
DOI: 10.1039/C8NJ06230G
Methods for the preparation of Probe
Synthesis of 2-(benzo[d]thiazol-2-yl)-4-bromophenol (BBP).A
solution of 2- aminothiophenol (2 mL, mmol) and
2
5
bromosalicyldehyde (400 mg, 2 mmol) in EtOH (5 mL), aqueous
H2O2 (30%, 12.0 mmol) and aquousHCl (37%, 8.5 mmol) was stirred
for 6 h at ambient temperature. The solution was quenched by 10
mL H2O. The precipitated compound was filtered through a filter
paper and washed with EtOH (2x5mL). Now, the obtained product
dried under vacuum and recrystallized from EtOH to afford the
desired product as a white solid (480mg, 79.47% yield).1H NMR
(CDCl3, 300 MHz) δ (ppm): 12.556 (s, 1H), 7.946 (q, 2H, 8.1 Hz),
7.770 (s, 1H), 7.461 (m, 3H), 6.989 (d, 1H, 4.2 Hz). 13C NMR (CDCl3,
75 MHz): 167.62, 156.89, 151.50, 135.16, 132.48, 130.33, 126. 78,
125.80, 122.23, 121.47, 119.67, 118.18, 110.89. HRMS (ESI TOF):
(m/z, %): 305.9734 [(BBP + H+), 100 %], Calculated value : 305.9731.
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Synthesis
hydroxybenzaldehyde (BBHB). The compound 1 (420 mg, 1.2
mmol), hexamethylenetetramine (420 mg, mmol), and
of
3-(benzo[d]thiaol-2-yl)-5-bromo-2-
3
trifluoroacetic acid (5 mL) were mixed into a r. b flask. The mixture
was allowed to reflux overnight. Then the mixture was cooling
down, the solution was neutralized with aqueous KOH solution. The
precipitated mass was collected through filtration on a filter paper
under sucction, and washed with water (3x10mL). After drying
under vacuum, compound 2 was obtained in 91% yield, and had the
following spectral properties.1H-NMR (CDCl3, 300 MHz) δ (ppm):
12.578 (s, 1 H), 10.479 (s, 1H), 7.943 (m, 2H), 7.782 (s, 1H), 7.470
(m, 2H), 7.003 (d, 1H, J = 6 Hz).13C NMR (CDCl3, 75 MHz): 188.90,
165.63, 159.29,151.20, 127.10, 126.86, 126.29, 125.88, 125.48,
122.54, 122.29, 121.64, 120.60, 119.72. HRMS (ESI TOF): 333.1278
[(BBHD+H+),100 %], Calculated value: 333.1275
calorimetrically and fluorogenically in
measurement.
a
quantitative
Step 1
OH
N
OH
H2O2, HCl, rt, 6 h
NH2
SH
CHO
S
Yield: 79%
Br
Br
(1)
Hexamine,
TFA, 80 °C,
24 h
Step 2
Yield: 91%
EtO2C
H
CN
OH
Step 3
Ethyl cyanoacetate
OH
N
N
OHC
S
S
Piperidine (10 mol%),
EtOH, Reflux, 12 h
Br
Yield: 82 %
Br
Synthesis of receptor (BBHC).The compound 2 (100 mg, 0.3 mmol),
ethylcyanoacetate (68 μL, 0.6 mmol), and 2-3 drops piperidine were
dissolved in 10 mL EtOH. The mixture was allowed to reflux for 3 h
at 80 °C and cooled down to room temperature. The final product
(probe BBHC, 110 mg, 82%) was obtained by filtration and being
washing with ethanol for 3 times.1H NMR (CDCl3, 300 MHz) δ (ppm):
8.989 (s, 1H), 8.503 (s, 1H), 8.147 (d, 2H, J = 8.1 Hz), 8.014 (d, 1H, J =
7.8 Hz), 7.948 (d, 1H, J = 8.4 Hz), 7.851 (s, 1H), 7.843 (s, 1H), 4.454
(2H, q, J = 7.2 Hz), 1.306 (3H, t, J = 7.4 Hz).13C NMR (CDCl3, 75 MHz)
δ (ppm): 167.65, 159.24, 156.90, 151.51, 151.16, 135.19, 133.97,
132.89, 132.49, 127.06, 126.81, 126.24, 125.84, 125.44, 120.55,
119.69, 118.21, 65.72, 15.15. HRMS (ESI TOF): 427.9680 [BBHC],
Calculated value : 427.9671.
(2)
(3, BBHC)
Scheme 2: Synthetics routes to BBHC receptor (3)
Experimental Section
General Methods.
Solvents and Chemicals were taken from various commercial
sources and were used without further purification. 1H-NMR and
13C-NMR spectra were recorded by using Brucker 300 MHz
instruments. CDCl3 was used as solvent for NMR spectra. UV-vis
titration experiments were done by using Perkin Elmer Lambda 750
spectrophotometer. Fluorescence experiments wereperformed
byusing Perkin Elmer LS 55 with a fluorescence cell of 10 mm path.
Silica gel (100−200 mesh) was used to perform Column
chromatography. Fluorescence lifetime experiment was performed
by using TCSPC (Time-correlated single photon counting) set-up.
Synthesis
of
2-(benzo[d]thiazol-2-yl)-4-bromo-6-
(hydrazonomethyl) phenol (BBHP).The probe (BBHC) was mixed
with 1 equivalents of hydrazine in CH3CN at room temperature to
give a yellow solution. Upon removing the solvent, a solid product
was obtained which was used for 1H-NMR, 13CNMR and mass
spectroscopy. 1H NMR (CDCl3, 300 MHz) δ (ppm): 8.524 (s, 1H),
8.058 (d, 2H, J = 7.8 Hz), 7.868 (d, 2H, J = 7.5 Hz), 7.757 (s, 2H),
7.548 (s, 1H), 5.852 (s, 2H). 13C NMR (CDCl3, 75 MHz) δ (ppm):
2 | J. Name., 2012, 00, 1-3
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165.56, 155.55, 153.75, 139.32, 134.29, 133.93, 132.03, 129.33, The probe (BBHC) in CH3CN−H2O solution (1:9, v/v, HEPES, pH 7.1)
View Article Online
128.78, 125.20, 124.75, 121.90, 121.46, 121.18. HRMS (ESI TOF): was taken for carried out UV titration. TwoDmOaI:jo1r0.a10b3s9o/rCp8tiNoJn06b2a3n0dGs
346.3275, Calculated : 346.3271.
General method of UV-vis and fluorescence titrations by UV-vis
and fluorescence.
were observed at 352 and 408 nm upon addition of hydrazine (1
equiv.) to a solution of the probe (3), which are due to a π-π*
transition and an ICT transition, respectively. The absorption
maximum at 352 nm diminished with gradually increase of peak at
408 nm along with an isobestic point at 366 nm (Fig S1a, ESI). This
observation supports a clean conversion of the receptor (3) into
BBHC–hydrazine adduct, BBHP (4, Scheme 1). The colorless solution
of probe changed into light yellow color as soon as hydrazine was
added. The absorbance ratio changed 0.5304 to 0.73229 with
Stock solution of chemodosimeter was prepared (c = 2 x 10-5 ML-1)
in Acetonitrile: Water (1:9, v/v). The solution of the guest ions and
amine containing compounds were prepared (2 x 10-4 ML-1) in
Acetonitrile: Water (1:9, v/v) immediately before perform
experiment. The solution of probe, guest ions and amine containing
compounds were made ready by appropriate dilution technique.
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Details of live-cell imaging
To estimate the efficiency of BBHC to detect hydrazine
endogenously 5 mL of venous blood was obtained from a healthy
volunteer donor (Male, 32 year) with his informed consent.
Peripheral blood mononuclear cells or PBMCs (lymphocytes and
monocytes) were isolated within one hour of sampling by density
gradient-based centrifugation utilizing histopaque-1077 at 400 ×g
for 30–40 min at room temperature. The middle layer or ‘buffy
coats’ contains the PBMCs which were collected carefully and
washed twice in phosphate buffered solution (PBS, pH 7.4). PBMCs
were re-suspended in PBS and divided in six sets. All Cells were
addition of hydrazine (Fig S1b, ESI).
Fig 1: The variation of absorbance for probe BBHC in a CH3CN–H2O
solution (1:9, v/v, and 10 mM HEPES, pH 7.1) in the presence of
various cations and anions.
o
incubated at 37 C for 1hr in dark with 10, 20, 30, 40 and 50 µM of
The interaction between the receptor and hydrazine was
investigated through fluorescence spectral titration experiments in
Acetonitrile: water (1:9, v/v, 10mM HEPES, pH 7.1). Upon excitation
at 366 nm, the probe solution displayed two emission band
centered at 448 nm and 531 nm. The emission peak at 448 nm
shifted to 464 nm, and drastically enhanced with a clear pseudo iso-
emission point at 510 nm upon gradual addition of hydrazine to the
solution of probe (Fig 2).
N2H4 respectively along with 5 µM of BBHC. A separate PBMCs set
was incubated simultaneously with 5 µM of BBHC but without N2H4.
Intracellular fluorescence intensity was detected by fluorescence
microscope (Carl Zeiss HBO 100) under 40X magnification in filter
set 49 DAPI which gives emission peak for 464nm.
To determine cell viability against BBHC, PBMCs were treated with
different concentrations of BBHC solution (2-20µM) for 1 h at 37 oC
against control cell suspension with no added BBHC. Cell density
remains 106 cells per well in a 96- well plate. 100µl of MTT solution
(5mg/mL) was added to each well including control and incubated
for 4 h. at 37 oC. The purple colored form zan crystals were
dissolved with 100µl DMSO and the absorbance were measured at
570 nm. All experiments were performed in accordance with the
guidelines of Biosafety and Indian Ethics. Experiments were
approved by the Biosafety and Ethics Committee at Calcutta
University. Informed consent for participation in the study was
obtained from each individual participating in this study.
Method for the preparation of TLC plate sticks.
Fig 2:Fluorescence emission spectra of BBHC (c=2.0×10−5 M) with
gradual addition of hydrazine (c=2.0×10−4 M, λex = 366 nm); naked
eye fluorescence color change, inset.
Test strips were prepared by immersing TLC plate into the
acetonitrile solution of the probe and to evaporate the solvent it is
expose to air. Now, the probe coated TLC plates are dipped in
various concentration of hydrazine solution for detection of
hydrazine using strips.
Interestingly this fluorescent spectral alternation led to an obvious
color change from transparent to blue (Fig 2, inset). The emission
titration spectra showed the saturation point with 1.1 equiv. of
hydrazine, which in turn confirmed high reactivity of the probe to
the health hazard. The emission intensity of the probe at 464 nm
was brilliantly enhanced (17-fold, 7.03882 to 121.8073, Fig S2, ESI).
Results and discussion
Optical Response of Probe (BBHC) towards hydrazine
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To our pleasure, the detection limit of BBHC for hydrazine was Fig 3:(a) The time vs. fluorescence spectra of BBHC (c =Vie2w.0ArXtic1le0O-5nMline)
-4
DOI: 10.1039/C8NJ06230G
found to be 0.43 µM, which lies below the safe hydrazine level (10 in the presence of 1 equiv. of hydrazine (c=2.0X10 M) at different
ppb), indicates that the probe BBHC may further be developed for time [a, 0; b, 5; c, 10; d, 20; e, 30; f, 40; g, 50; h, 60 s. (b)
the detection of hydrazine in practical applications. This detection Fluorescence decay curves for BBHC and BBHP.
value is also quite low compare to the previously reported two
probes by Chow et al. 26 and Li et al.27
Sensing Mechanism Studies
9
The time-resolved fluorescence response of BBHC towards 1H NMR and ESI-MS spectrum analysis was performed to
hydrazine was investigated in CH3CN-H2O (1:9, v/v) solution. BBHC understand the sensing mechanism of BBHC toward hydrazine.
was initially non-fluorescent. Upon addition of hydrazine, the With the addition of hydrazine, NC-CH2-CO2Et was released from
fluorescence intensity of BBHC at 464 nm was rapidly (<1 min) the probe by the reaction of hydrazine. The aromatic CH protons of
enhanced to maximum with rate constant 18X10-2 S-1 (Fig 3a and S3, adduct BBHP were up field shifted with respect to probe BBHC
ESI), which established BBHC as a fast responsive fluorescent along with disappearance of δ 4.45 and δ 1.30 of ester (-
chemodosimeter for hydrazine. This detection time is quite low CO2CH2CH3) and appearance of –CH=NNH2 at δ 8.52 and δ 5.85,
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1
compared to previously report two similar type probe by Chow et respectively (ESI). From the H NMR experiments, we had reasons
al26 and Li et al.27 The fluorescence lifetime of BBHC in the presence to conclude that BBHP might be the obtained from BBHC by
and absence of hydrazine was detected by time resolved reacting with N2H4. BBHC showed a peak at 427.9680 before
fluorescent spectra (Fig 3b). The fluorescence decay curves of the addition of hydrazine in mass spectra which is the correct mass of
compounds were fitted by utilizing monoexponential functions the probe and emission spectra.
(ESI). The radiative rate constant30 kr and the total nonradiative rate
constant knr of BBHC and hydrazine-adduct BBHP were 0.675 ns and Interference of common ions in the detection of hydrazine
6.035ns, respectively.
(a)
No significant changes were observed with other environmentally
important cations and anions such as Ag+, Cd2+, Co2+, Cu2+, Fe3+,
(b)
Mn2+, Pd2+, Cl-, Br-, I-, SO42- and S2- (Fig S4). The probe BBHC was also
treated with amine analogues such as NH3, NH2OH,
ethylenediamine, acetyl hydrazine, urea, thiourea, cysteine, lysine,
glutamine and glutathione and desired fluorescence was not
observed (Fig S5, ESI). These results confirmed that BBHC is a highly
selective probe for hydrazine recognition. Competitive experiments
were carried out for double checking and there was no interference
to determine hydrazine in the presence of possible analytes present
in drinking water, industrial effluents and human blood (Fig 4). High
reactivity and existence of related binding sites in the receptor are
responsible for passing through a possible transition state (BBHC-
NH2,TS, Scheme 1), which explain the outstanding selectivity and
anti-interference of the probe to hydrazine.
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Fig 5:Photograph of BBHC towards various concentrations of N2H4
View Article Online
(×10−5 mol) of (a) 0, (b) 2, (c) 20, (d) 100, anDdO(eI:)1200.1003in9/sCo8lNutJi0o6n23a0nGd
in TLC plates
6
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Cell cytotoxicity and bioimaging application of Probe (BBHC)
8
9
BBHC is found as an excellent intracellular probe to detect N2H4 for
its permeability and stability. The Figure 6A depicts the bioimaging
of human PBMCs by BBHC, if there was no added N2H4 from
outside. Herein cells have shown no significant blue fluorescence.
The figure 6B-F have displayed gradually enhanced blue
fluorescence with increasing concentration of N2H4 from 10µM to
50µM. Cell viability was represented in Fig 7, where up to 20µM
concentrations of BBHC showed around 76.336 % of viable cells
predicting it is as a safe probe to use in a biological system. We
used 5µM BBHC solutions for imaging, which were fairly high
number of viable cells (90.667 %). This observation also confirmed
its nontoxic nature (Fig 7).
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Fig 4: The fluorescence intensity of BBHC (2.0×10−5 M) toward
Hydrazine (1equiv) containing 10 equiv of various cations (upper)
and anions (lower) (λex = 366 nm).
Application
The practical application of the colorimetric and fluorometric sensor
was investigated by immersing filter papers as a test strips into a
Acetonitrile/Water (1:9, v/v) solution of probe BBHC and air drying.
A blue color under UV lamp was observed in the presence of
hydrazine (Fig S6, ESI). Such dip strips development is useful for
instant qualitative information about existence of hydrazine in
thetesting sample without resorting and waiting for instrumental
analysis. Industrial processes involving hydrazine can pollute water-
bodies and affects the ecological milieus severely. Practical
applications of our probes have been extended towards the
detection of hydrazine even in dirty pond water. Both the industrial
waste water and drinking water were used for the analysis through
adding probe BBHC to samples containing hydrazine in both pond
and drinking water. Our fluorescence spectroscopy experiments
clearly showed that the BBHC probe is highly efficient to detect
hydrazine in drinking as well as industrial waste water (Fig S7, ESI).
The probe coated strips were immersed in drinking water samples
possessing low concentration of hydrazine (<LVT), an instant
development of the blue color was observed with increasing
intensity with concentration of hydrazine (b-e, Fig 5). Development
of such dipsticks is useful as instant qualitative information which is
obtained without resorting to instrumental analyses.
Fig 6:Human PBMCs (40X) treated with 5 µM of BBHC under 464nm
fluorescence emission; [A] No added N2H4, [B-F] with 10, 20, 30, 40
and 50 µM of N2H4 respectively.
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We designed, synthesized and discovered a brilliant colorimetric
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and selectivity towards recognizing
a serious health hazard
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hydrazine over various cations, anions, thiols and amines containing
compounds. This probe showed good cell-permeability, low
cytotoxicity, rapid recognition, and detection of hydrazine even
much below the TLV levels in the living cells, which will find great
application as a ‘‘naked-eye’’ indicator in solution and dip strips and
chemodosimeter for convenient monitoring of hydrazine present in
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Research fellowships toSP(SERB-NPDF) andRN(UGC), Govt.
of India are gratefully acknowledged.
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New Journal of Chemistry
View Article Online
DOI: 10.1039/C8NJ06230G
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A smart sensor for rapid detection of lethal hydrazine in human blood and drinking
water
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Sima Paul,a Rajesh Nandi,a Kakali Ghoshal,b Maitree Bhattacharyyab and Dilip K. Maitia*
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A newly designed and synthesized probe showed good cell-permeability, low cytotoxicity, fast fluorogenic
recognition, and ‘‘naked-eye’’ detection of a lethal health hazard hydrazine even much below the TLV levels
present in the living cells, drinking water and industrial effluent.