Metal-Organic Framework Showing Selective and Sensitive Detection of Exogenous and Endogenous Formaldehyde

Article abstract of DOI:10.1021/acs.inorgchem.8b02411

In this work, we report a new hydrazine-functionalized Al(III)- based metal-organic framework having MIL-53 (MIL = Material of Institute Lavoisier) framework topology for the sensitive and selective detection of formaldehyde (FA). The phase purity of the

Full text of DOI:10.1021/acs.inorgchem.8b02411

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Metal−Organic Framework Showing Selective and Sensitive
Detection of Exogenous and Endogenous Formaldehyde
Soutick Nandi,† Ena Sharma,† Vishal Trivedi,‡ and Shyam Biswas*,†
‡
†Department of Chemistry and Malaria Research Group, Department of Biosciences and Bioengineering, Indian Institute of
Technology Guwahati, Guwahati, 781039 Assam, India
S
* Supporting Information
ABSTRACT: In this work, we report a new hydrazine-
functionalized Al(III)- based metal−organic framework
having MIL-53 (MIL = Material of Institute Lavoisier)
framework topology for the sensitive and selective detection
of formaldehyde (FA). The phase purity of the thermally
activated and as-synthesized forms of the material was
examined by X-ray powder diffraction experiments, Fourier
transform infrared spectroscopy, and thermogravimetric
analysis. The desolvated material (1′) showed great potential
for the selective sensing of FA in the existence of other
potentially competitive aldehydes in both aqueous and 10 mM
HEPES buffer (pH = 7.4) media. The fluorescence “turn-on”
behavior of the reaction-based probe can be ascribed to the
inhibition of the photoinduced electron transfer process (from the hydrazine group to the phenyl ring) because of the formation
of the hydrazone moiety. The detection limit of the probe toward FA in HEPES buffer is 8.37 μM (0.25 ppm), which lies below
the intracellular concentration of FA (100−400 μM). A very short response time (1 min) has been displayed by 1′ for FA
sensing. Moreover, a remarkable enhancement in the emission intensity (sevenfold and fourfold in aqueous and HEPES buffer
media, respectively) of 1′ was observed after 1 min of FA addition. Furthermore, the ability of the probe to detect FA in the
vapor phase was demonstrated. Interestingly, the material is also capable to detect endogenous FA in cancer cells. All the above
discussed features clearly reveal that the present material has a huge potential for selective recognition of FA in both real water
and biological samples.
nature, FA can easily bind with the nucleophilic site of DNA
and proteins, which causes cellular dysfunction. The abnormal
concentration of FA in the human body is responsible for
various types of diseases such as cancer,18,19 diabetes,20
cirrhosis, and cardiovascular and neurological disorders.21 In
recent years, FA is identified as a major component for sick-
building syndrome.22−24 It can cause strong irritation of
mucous membranes and eyes.24 According to the World
Health Organization (WHO), the permissible limit of exposure
to FA is 0.08 ppm for 30 min.25 On the other hand, the US
National Institute for Occupation Safety and Health (NIOSH)
has set a maximum of 0.016 ppm as the long-term exposure
limit for FA.26
After taking the above-mentioned facts into account, the
detection of FA has been explored in the last few years. A
variety of techniques have been employed such as spectropho-
tometry,27 colorimetry,28 gas chromatography,29 high-perform-
ance liquid chromatography,30 ion chromatography,31 and
polarography32 for the quantification and detection of FA.
Unfortunately, all of these methods demand well-trained
INTRODUCTION
■
Formaldehyde (FA) is the simplest aldehyde among all the
reactive carbonyl species (RCS).1 It is involved in the
methylation and demethylation of DNA and RNA.2,3 Hence,
it plays beneficial roles in the activation and suppression of
gene activities, brain function, and memory formation.4−6
Despite its beneficial roles, FA has been recognized as the most
harmful RCS. It has been extensively utilized as a potent
preservative. It is also widely employed in household goods
such as adhesives, cosmetic items, particle boards, paints,
textiles, and so forth. From these materials, FA can emit as a
volatile species into the indoor environment.7−11 It can also be
released into the environment by some natural processes (e.g.,
degradation of humic substances, emission by microbes,
combustion of biomass, etc.) as well as by anthropogenic
activities (e.g., tobacco smoke, automobile exhaust, etc.).9,12
Moreover, FA can be produced endogenously by the oxidase
and demethylase enzymes such as JmjC domain-containing
protein13,14 and lysine specific demethylase 1.15,16 Owing to
the degradation reaction by FA dehydrogenase, the physio-
logical concentration of FA can range from 100 to 400 μM.4,17
Moreover, in cancer cells, the endogenous concentration of FA
can reach up to 1000 μM.18 Owing to its high electrophilic
Received: August 27, 2018
© XXXX American Chemical Society
A
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operators, bulky and expensive instrumentation, high power
consumption, and destruction of biospecimens. Hence, these
traditional methods are unsuitable for the spatiotemporal
sensing of FA. Recently, the fluorescence sensing technique has
drawn more attention than the conventional methods because
of its simple operation, high selectivity, sensitivity, fast
response, and nondestructive detection of biospecimens.33
Generally, two types of mechanisms have been reported for the
fluorometric sensing of FA. In one kind of mechanism, the
fluorescent properties of the fluorogenic core present in the
molecule can be restored by disrupting the photoinduced
electron transfer (PET) process,34,35 either via condensation
reaction or via 2-aza-Cope reaction after the initial
condensation reaction.36,37 In the second type of mechanism,
a drastic fluorescence enhancement is observed because of the
condensation reaction between FA and primary amines which
causes a rhodamine unit transformation from spiro to open-
ring conformation through a cyclization reaction.38 A variety of
fluorescent probes have been explored for the purpose of
sensing FA, which include organic small molecules,39 organic−
inorganic hybrid materials,40 and metal−organic framework
(MOF) compounds.41−44
MOFs are a new class of functional porous materials having
extended crystalline frameworks, comprising metal ions and
organic linkers.45 Owing to the tunable functionality and
porosity, chemical stability as well as highly conjugated
backbones, MOF materials have been widely employed in
chemical sensing,46,47 gas storage and separation,48 catalysis,
and49,50 drug delivery.51 Till now, only four MOF materials
have been employed for the fluorogenic sensing of FA.41−44
Here, we report the synthesis, comprehensive characterization,
and fluorescence sensing properties of a new Al(III) MOF, (1)
having MIL-53 (MIL = Material of Institute Lavoisier)
framework topology and containing the hydrazine-function-
alized H2BDC−N2H3 (H2BDC−N2H3 = 2-hydrazinyl-1,4-
benzenedicarboxylic acid) ligand. In its thermally activated
form (1′), the material acts as an efficient probe for detecting
FA (in aqueous and HEPES buffer media and the vapor phase)
with remarkable sensitivity and selectivity (Scheme 1). The
compounds were utilized previously for the sensing of FA
(Table S1, Supporting Information), some of them require the
incorporation of guest metal ions (i.e., Ag+, Eu3+, etc.) for the
sensing of FA. However, 1′ can successfully detect FA by
functional group interconversion without incorporation of any
metal ion. Moreover, some of the MOF materials were
employed for the aqueous-phase sensing and few of them were
utilized for the vapor-phase sensing of FA. However, 1′ was
successfully employed for both aqueous- and gas-phase sensing
of FA. The capability of none of the MOF materials was
examined for the detection of FA in living cells, whereas 1′ has
the ability to detect FA in cancer cells. Furthermore, 1′ showed
selectivity toward FA over a wide number of other aldehydes
(oxaldehyde, acetaldehyde, butyraldehyde, propionaldehyde,
valeraldehyde, crotonaldehyde, benzaldehyde, 4-chlorobenzal-
dehyde, and anisaldehyde). Such a vast number of competitive
aldehydes were not utilized during the selectivity study for the
other reported MOF materials. In addition, the response time
(60 s) of 1′ toward FA is also lower than the other MOF-based
FA sensors. Hence, an easy synthetic procedure, sensing of FA
in a versatile medium and fast response and high selectivity
toward FA over other aldehydes make 1′ a superior FA sensor
over the reported MOF probes.
EXPERIMENTAL SECTION
■
Preparation of [Al(OH)(BDC−N2H3)]·0.85DEF·1.0H2O (Al-
MIL-53-N2H3; 1). In a Pyrex tube, Al(NO3)3·9H2O (57 mg, 0.15
mmol) and the H2BDC−N2H3 (30 mg, 0.15 mmol) ligand were
placed. Then, 3 mL of the DEF/H2O (1 mL/2 mL) mixture was
poured into the tube, which was sealed and sonicated for 15 min.
Afterward, it was heated at 120 °C for 24 h using a block heater. The
resulting yellow colored material was obtained by filtration and dried
inside an air oven at 70 °C for 6 h. Yield: 30 mg (0.08 mmol, 53%).
The yield was calculated on the basis of the aluminum salt. FT-IR
(KBr, cm−1): 3426 (br), 2968 (sh), 2934 (w), 2851 (w), 1657 (m),
1628 (sh), 1580 (vs), 1505 (w), 1430 (s), 1381 (sh), 1313 (w), 1265
(m), 1216 (w), 1098 (m), 1003 (m), 853 (w), 804 (m), 768 (m), 678
(m), 578 (br), 481 (br).
Activation of the Material. At first, heating of the as-synthesized
compound (100 mg) was conducted at 150 °C for overnight in 20 mL
of N,N-dimethylformamide by using a Teflon-lined stainless steel
autoclave. Later, stirring of the filtered compound was carried out in
acetone (50 mL) for overnight at room temperature. In the third step,
heating of the filtered material at 130 °C for overnight was performed
using a high vacuum pump. The guest-free material is named as 1′.
Fluorescence Sensing Experiments in the Aqueous Me-
dium. The probe (5 mg) was placed in a glass vial and water or 10
mM HEPES buffer (5 mL each) was added. The preparation protocol
for the HEPES buffer solution has been reported by us previously.47
The mixture was sonicated for 1 h. After keeping for one day at room
temperature, a stable suspension was obtained.
Scheme 1. Fluorogenic “Turn-On” Sensing of FA by the
Activated Al-MIL-53-N2H3 (1′) Probe at Physiological
Conditions
The above-mentioned suspension (200 μL) of the probe (in water
or HEPES buffer) was placed inside a quartz cuvette. Then, we have
added 2800 μL of deionized water or HEPES buffer to the
suspension. All the fluorescence titration measurements were carried
out using the resulting suspension. These experiments involved
addition of the solutions of various aldehydes (20 mM) to the
suspension (3 mL) of the probe. FA, oxaldehyde, acetaldehyde, and 4-
chlorobenzaldehyde are readily soluble in water. Therefore, 20 mM
aqueous or HEPES buffer solutions of these aldehydes were prepared
in pure deionized water. The other aldehydes (butyraldehyde,
propionaldehyde, valeraldehyde, crotonaldehyde, benzaldehyde, and
anisaldehyde) are insoluble in water. For them, the required amount
of an aldehyde (for 20 mM solution) was dissolved in a minimum
amount of distilled ethanol. Then, deionized water or HEPES buffer
was added to fulfil the required volume.
endogenous FA in breast cancer cells can be efficiently
detected by this MOF probe. Moreover, the compound has the
potential to detect the change in concentration of FA in cancer
cells. It should be noted that the H2BDC−N2H3 ligand has
never been utilized for the preparation of any MOF material.
Therefore, 1′ is the first example of a hydrazine-functionalized
Al(III) MOF which possesses the 1,4-benzenedicarboxylate
(BDC)−N2H3 ligand and exhibits selective fluorescence
sensing properties toward FA. Though several MOF
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Cell Culture and Imaging Experiments. The culture of the
MDAMB-231 breast cancer cells was performed in DMEM:F12
media consisting of 10% fetal bovine serum and 1% antibiotic cocktail
as described formerly.52 Cells were loaded with 1′ (0.5 mg/mL) for
10 h in serum-containing media. To remove the excess probe, the
washing of the cells was carried out with phosphate-buffered saline
(PBS) thrice. Then, the cells were treated with FA (50 μM) for 60
min at 37 °C in PBS. The cancer cells were observed in the bright
field and the blue channel (λex = 390 nm, λem = 430 nm) using a
Cytell cell imaging system (GE Healthcare), and images were
captured from randomly selected fields.
RESULTS AND DISCUSSION
■
Fourier Transform Infrared Spectroscopy. The Fourier
transform infrared (FT-IR) spectra (Figure S5, Supporting
Information) of the activated and as-synthesized forms of 1
were recorded to ensure the incorporation of the ligand in the
MOF structure during the solvothermal reaction and the
complete elimination of guest molecules from the voids of the
MOF after thermal activation. In the FT-IR spectra of the as-
synthesized 1 and activated 1′, strong absorption bands at
around 1580 and 1430 cm−1 were noticed, which can be
ascribed to the asymmetric and symmetric −CO2 stretching
vibrations of the coordinated BDC−N2H3 ligand, respec-
tively.53 The carbonyl stretching vibration of the trapped DEF
molecules gives rise to the medium absorption band at 1657
cm−1 in the IR spectrum of the as-synthesized form of the
material.54 This absorption band is totally vanished in the IR
spectrum of activated 1′, indicating entire elimination of DEF
molecules from the pore of the material.
Structure Description. The hydrazine-functionalized Al-
MIL-53 (1) exhibits the same framework topology as the
unfunctionalized compound. The framework structure of Al-
MIL-53 has been previously described by Loiseau et al.55
Briefly, the structure of Al-MIL-53 is constructed by the
interconnection of infinite trans chains of corner-sharing (via
OH groups) [AlO4(OH)2] octahedra by the BDC ligands to
form a three-dimensional (3D) framework containing one-
dimensional (1D) rhombic pores. For the presented
compound (1), the BDC−N2H3 ligand molecules replace the
BDC ligands of the Al-MIL-53 framework. The as-synthesized
form of 1 incorporates guest (DEF and water) molecules
inside the pores under ambient conditions. Furthermore, the
hydrazine groups attached with the coordinated BDC−N2H3
ligands point toward the interior of the pores.
From Figure 1, it is obvious that the experimental X-ray
powder diffraction (XRPD) pattern of the as-synthesized title
compound shows great similarity with the XRPD pattern of the
unfunctionalized Al-MIL-53 compound. Therefore, 1 is
isostructural with unfunctionalized Al-MIL-53. Furthermore,
the XRPD pattern of the thermally activated 1′ (Figure S6,
Supporting Information) shows remarkable similarity with that
of the as-synthesized 1, which suggests that the structural
integrity of the compound is retained after the thermal
activation procedure. The XRPD pattern of 1′ was also
recorded after the FA sensing process. As can be seen from the
XRPD pattern, the crystallinity (and thus structural robust-
ness) of 1′ remains intact after the sensing experiment,
indicating that 1′ is efficient for practical sensing applications.
Thermal Stability. Thermogravimetric analyses (TGA)
were carried out for investigation of the thermal stability of the
as-synthesized and thermally activated forms of 1 in the
temperature range of 25−800 °C under an air atmosphere.
According to the TG curve (Figure S7, Supporting
Figure 1. Calculated (black) XRPD pattern of Al-MIL-53 and the
experimental (red) XRPD pattern of the as-synthesized Al-MIL-53-
N2H3.
Information), the compound displays high thermal stability
up to 480 °C under an air atmosphere.
In the TG trace of the as-synthesized 1, the first weight loss
of 5.1 wt % in the temperature range of 25−130 °C can be
attributed to the elimination of one guest water molecule per
formula unit (calcd: 5.2 wt %). The next weight loss of 25.3 wt
% in the temperature range of 130−360 °C can be attributed
to the removal of 0.85 DEF molecule per formula unit (calcd:
25.1 wt %). After 480 °C, the compound starts to decompose
because of the removal of coordinated ligand molecules from
the framework.
Surface Area Analysis. In order to prove permanent
microporosity, N2 sorption studies were carried out with 1′.
The compound showed type-I N2 sorption isotherms (Figure
S8, Supporting Information), which are characteristics of
microporous materials. For the presented material, the
Brunauer−Emmett−Teller (BET) surface area and micropore
volume were found to be 958 m2 g−1 and 0.51 cm3 g−1 (at p/p0
= 0.50), respectively. The BET surface area of 1′ is comparable
with those of the other functionalized Al-MIL-53 com-
pounds.56,57
Particle Size Measurement. The morphology of 1′ was
investigated using the field emission scanning electron
microscopy (FE-SEM) technique. The FE-SEM images
(Figure S9, Supporting Information) reveal that the particles
of 1′ display rod-like morphology and are almost uniform in
size. The average diameter of the particles is about 600−700
nm. The shape and size of the particles are very similar with
previously reported MIL-53(Al).58
The average particle size measured by the dynamic light
scattering (DLS) method is 741 nm for the ethanolic
dispersion of 1′ (Figure S10, Supporting Information). The
polydispersion index (0.31) value signifies narrow distribution
of the particle size. Moreover, the average particle size obtained
from the DLS study is in good agreement with the FE-SEM
results.
Sensing of FA in the HEPES Buffer Medium. For the
carcinogenic effect of FA, its real-time detection has become a
highly demanding task. As a result, a huge number of
fluorescent probes based on small organic molecules have
been developed in the last few years.34−38,59 Unfortunately, the
number of existing MOF-based fluorescent probes for FA is
very less (Table S1, Supporting Information).41−44 Al(III)-
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based MOFs are always preferable to MOFs containing other
metal ions for their high hydrolytic stability, nontoxic nature,
and biofriendly behavior.46 All the above facts motivated us to
examine the efficacy of the new hydrazine-functionalized
Al(III)-based MIL-53 compound for sensitive and selective
sensing of FA in both aqueous and physiological media
(HEPES buffer, pH = 7.4).
compounds (oxaldehyde, acetaldehyde, butyraldehyde, propio-
naldehyde, valeraldehyde, crotonaldehyde, benzaldehyde, 4-
chlorobenzaldehyde, and anisaldehyde) in both HEPES buffer
and aqueous media. From Figures 3 and S12−S14 (Supporting
Fluorescence experiments were performed to evaluate the
detection performance of FA by the presented material. Prior
to the introduction of FA, the hydrazine-functionalized 1′ was
in the fluorescent “turn-off” state because of PET from the
hydrazine moiety to the phenyl ring.34 However, after the
addition of FA, the hydrazine functionality is transformed to
the hydrazone moiety, which suppresses the PET process and
restores the fluorescence property of the fluorogenic core.
Consequently, a drastic enhancement in the fluorescent
emission intensity was detected for the material in the
presence of FA.
For the time-dependent study, 500 μL of 20 mM FA was
introduced to the suspension of 1′ in the HEPES buffer
medium, and fluorescence spectra were collected upon
excitation at 330 nm at a regular time interval of 1 min up
to 10 min. Figure 2 reveals that saturation of the emission
Figure 3. Relative fluorescence turn-on signal of 1′ toward the
addition of different aldehydes (20 mM, 500 μL) in HEPES buffer.
Information), it becomes obvious that the fluorescence
intensity (monitored at 436 nm) of the Al-MIL-53-N2H3
probe changed hardly in the presence of other aldehyde
compounds. Only FA was capable of enhancing the emission
intensity of the compound. As the bulky and polar hydrazine
functionality is grafted with the BDC ligand, a highly polar
environment has been generated in the MOF structure.
Moreover, the interconnection of infinite trans chains of
corner-sharing (via OH groups) [AlO4(OH)2] octahedra by
the BDC−N2H3 ligands forms a 3D framework containing 1D
channels. Furthermore, the hydrazine groups attached with the
coordinated BDC−N2H3 ligands point toward the interior of
the pores, which is not possible in the discrete H2BDC−N2H3
ligand. On the other hand, as FA is the smallest and highest
electrophilic aldehyde among other competitive aldehydes, it
can easily diffuse through the porous channel of the MOF
material and react with the nucleophilic hydrazine functional
group present to form the hydrazone moiety. Other aldehyde
molecules having larger sizes are unable to diffuse through the
pore channel. These competitive aldehydes can hardly react
with the hydrazine functional group owing to their lower
electrophilic nature as compared to FA. A careful inspection of
Figure 3 reveals that both oxaldehyde and acetaldehyde show
similar enhancement in emission intensity which is lower than
the emission intensity of 1′ in the presence of FA. This is
because of the larger size and lower electrophilic nature of
acetaldehyde and oxaldehyde as compared to FA. Therefore,
the selective response of FA toward 1′ can be assigned to the
highly polar environment and porous structure of the MOF
material as well as the smallest size and highest electrophilic
character of FA over other aldehydes.60
Figure 2. Increment in the emission intensity of 1′ (in HEPES buffer)
after the introduction of 20 mM FA (500 μL) from 1 to 10 min. Inset
plot shows the enhancement in emission intensity as a function of
time (monitored at 436 nm).
intensity occurred within 60 s with fourfold increment as
compared to the initial intensity. Another fluorescence
experiment was performed by replacing the HEPES buffer
medium with the aqueous medium (Figure S11, Supporting
Information). In this case, the fluorescence intensity also
attained saturation within 60 s, but a remarkably higher fold
increment (sevenfold) was noticed for the aqueous medium
than the HEPES buffer. It can be accounted for the higher
stability of the hydrazone moiety at lower pH (water at pH =
7.0) than higher pH (HEPES at pH = 7.4) of the medium.59
Though the fold increment in the fluorescence intensity in the
aqueous medium is reasonably superior to the HEPES buffer
medium, we have employed HEPES buffer for the subsequent
fluorescence experiments as the biological conditions are more
accurately mimicked by the later medium.
Another set of fluorescence experiments was performed to
examine the selectivity of the probe toward FA in the presence
of other aldehyde compounds in both HEPES buffer and
aqueous media. For these experiments, FA was added to the
suspension of 1′ which already contained other competing
aldehydes. From Figures 4 and S15−S17 (Supporting
Information), it becomes clear that FA is capable to enhance
the emission intensity of the suspension of the probe in both
HEPES buffer and aqueous media, even though other
aldehydes exist in the system. Hence, we can conclude that
the present probe has shown remarkable selectivity toward FA
even in the existence of other competing aldehyde compounds.
An ideal fluorescent sensor should exhibit high selectivity
toward the desired analyte over other competing species.
Hence, we have examined the selectivity of the MOF probe
toward FA with respect to other common aldehyde
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concentration in drinking water and food stuffs as set by
WHO/EPA (86 μM). Moreover, the LOD values are lower
than the intracellular concentration of FA (100−400 μM).4,17
It is interesting to note that the structural integrity of the MOF
material was retained throughout the sensing event (Figure S6,
Supporting Information).
To examine the retention of shape and size of the particles of
the material in HEPES buffer, 1′ was soaked in the HEPES
buffer medium for 12 h (as the cells were loaded with 1′ for 10
h and afterward, FA was treated and incubated for 1 h before
the imaging experiment). Then, 1′ was collected by filtration
and dried in a conventional oven at 60 °C for 12 h. The FE-
SEM images of the HEPES buffer-soaked material (Figure S21,
Supporting Information) reveal that the overall morphology of
the material is very similar with the activated material (Figure
S9, Supporting Information). Hence, no alteration in shape
and size of the particles of the material was detected even after
soaking the material in HEPES buffer. Moreover, we have
recorded the XRPD pattern of 1′ obtained after soaking in
HEPES buffer. Figure S22 (Supporting Information) suggests
that the framework topology of 1′ is unchanged even after
soaking in HEPES buffer for 12 h.
Figure 4. Relative fluorescence turn-on signal (monitored at 436 nm)
of 1′ toward FA (20 mM, 500 μL) in the presence of other possibly
intrusive aldehydes (20 mM, 500 μL) in HEPES buffer.
To quantify the detection process of FA by the probe, a
concentration-dependent fluorescence titration experiment was
performed. Figure 5 reveals that with incremental introduction
Sensing of FA in the Vapor Phase. The permanent
porosity and efficient solid-state emission of 1′ inspired us to
investigate the vapor-phase fluorimetric sensing of FA. The
time-dependent fluorescence profile (Figure S23, Supporting
Information) of the 1′-coated quartz slide clearly signifies that
with gradual exposure of FA vapor, the emission intensity of
the film-coated quartz slide increased and saturation in the
fluorescence intensity occurred within 20 min of addition of
FA. Moreover, around threefold increment in the fluorescence
emission intensity was noticed within 20 min of exposure
(monitored at 486 nm). Noticeably, in the solid-state emission
spectrum of 1′, a large bathochromic shift (50 nm) in the λmax
value was observed as compared to the solution state. This
large shift in the λmax value may be attributed to the strong
intermolecular interactions, that is, hydrogen bonding, van der
Waals interactions, and so forth, in the solid state.61
High selectivity toward FA vapor over the vapors of other
competitive aldehydes is necessary for an ideal FA sensor.
Hence, we have conducted a selectivity test with other liquid
aldehydes. The 1′-coated film on the quartz slide was first
exposed to the vapors of different aldehydes for 20 min, and
then, the fluorescence spectra were recorded. Figures S24−S32
(Supporting Information) reveals that the vapors of all other
aldehydes failed to enhance the emission intensity of the 1′-
coated film significantly as compared to FA. Only acetaldehyde
was able to enhance the emission intensity of the 1′-coated
film by 1.8-fold with respect to its initial intensity. The lower
boiling point (20.2 °C) and smaller size of acetaldehyde as
compared to other aldehydes may be the possible reason
behind the higher fold increment in emission intensity of the
1′-coated film in the presence of acetaldehyde vapor. The 1′-
coated film showed higher fold increment (threefold) toward
FA vapor than acetaldehyde vapor (1.8-fold). It is important to
mention that for the vapor-phase sensing of FA, the fold
increment (threefold) of emission intensity is lower and the
response time (20 min) is considerably higher than the
aqueous-phase sensing of FA, where increment in the
fluorescence intensity is sevenfold and response time is 1
min. Nevertheless, the vapor-phase sensing of FA by the 1′-
coated film is particularly interesting because of its high
Figure 5. Enhancement of the fluorescence emission intensity of 1′
(HEPES buffer) upon gradual addition of 20 mM FA solution.
of FA in the HEPES buffer suspension of 1′, the fluorescence
intensity also enhanced gradually. A similar outcome was
observed when the concentration-dependent fluorescence
titration experiment was conducted with the aqueous
suspension of the MOF material (Figure S18, Supporting
Information).
In order to determine the limit of detection (LOD) of 1′
toward FA, the fluorescence intensity of the HEPES buffer
suspension of the compound was monitored upon incremental
addition of very low concentrations of FA solution. When the
emission intensity of 1′ versus the concentration of FA was
plotted, a linear curve (R2 = 0.99) having a slope (m) of 200
262.98 was obtained (Figure S19, Supporting Information).
The standard deviation (σ) was determined from eight blank
measurements with the MOF probe. The LOD value was
calculated by employing the formula: LOD = 3σ/m. The
calculated LOD value of 1′ for FA sensing in HEPES buffer
was 8.37 μM (0.25 ppm). It is worthy to note that the LOD
value of the probe for FA in the aqueous medium (Figure S20,
Supporting Information) was estimated to be 2.14 μM (64.33
ppb). These values fall within the permissible limit of FA
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selectivity toward FA over the vapors of other aldehydes and
application potential for real-world sensing of FA vapor.
Sensing of FA in Live Cancer Cells. After achieving
excellent selectivity and sensitivity of 1′ for FA sensing in both
HEPES buffer and aqueous media, we next examined its
detection performance in a more complicated and challenging
medium like breast cancer cells. The cancer cells without the
MOF probe were observed in both the bright field and blue
channel. These cells were found to be healthy and they did not
exhibit any fluorescence (Figure 6a−c). When the cancer cells
the mode of their uptake depends on size.65−67 Smaller objects
(nm range) are mostly taken up by pinocytosis, whereas large
objects (1−3 μm) are taken by phagocytosis.68,69
Mechanism of FA Sensing. As the mechanism for FA
detection, we expected that the hydrazine functionality present
in the BDC−N2H3 ligand of the MOF material is converted to
the hydrazone moiety in the presence of FA during the sensing
process. Owing to this functional group conversion, the PET
process from the hydrazine group to the phenyl ring is
prohibited. As a result, dramatic enhancement in the emission
intensity of the compound was observed because the
fluorogenic core restored its fluorescence property. The
formation of the hydrazone moiety was verified by mass
spectrometry. The peak at m/z = 195.0374, which was
observed in the mass spectrum of digested 1′ (Figure S33,
Supporting Information), signifies the (M−H)− ion of the
H2BDC−N2H3 ligand (M = mass of the H2BDC−N2H3
ligand). In the mass spectrum of digested FA-treated 1′
(Figure S34, Supporting Information), the peak at m/z =
207.0586 represents the (M−H)− ion of the hydrazone-
functionalized H2BDC ligand (i.e., H2BDC−NHNH = CH2).
Hence, it can be concluded that during the detection process,
FA is converted to the hydrazone moiety from the hydrazine
moiety. The reaction-based sensing mechanism for FA by 1′
was further investigated by an inhibition experiment with a
quencher of FA such as NaHSO3.59,70 From Figure S35
(Supporting Information), it becomes evident that FA was
unable to increase the emission intensity of the suspension of
1′ when it was pretreated with NaHSO3. As NaHSO3 is
strongly nucleophilic in nature, it readily reacts with highly
electrophilic FA and inhibits its reactivity toward the
hydrazine-functionalized MOF compound. Therefore, negli-
gible increment in the fluorescence intensity occurred for the
NaHSO3-pretreated suspension of 1′ as compared to the
untreated suspension of 1′. However, no inhibition in the
activity of FA occurred when NaHSO3 solution was added
after the addition of FA to the suspension of 1′ (Figure S36,
Supporting Information). This observation signifies that FA
transformed the hydrazine group to the hydrazone moiety, and
consequently, the emission intensity of the compound was
enhanced. Hence, the posttreatment by NaHSO3 solution did
not cause a significant change in the emission intensity. To
ensure that only the hydrazine group is responsible for the
interaction and enhancement of the emission intensity in the
presence of FA, a sensing experiment was carried out with
unfunctionalized and amine-functionalized Al-MIL-53. It can
be observed from Figures S37−S39 (Supporting Information)
that no observable “turn-on” response was obtained from
unfunctionalized and amine-functionalized Al-MIL-53 in the
presence of FA. Hence, it can be inferred that only the
hydrazine group is responsible for the “turn-on” response
because of the conversion to the hydrazone moiety and
consequently inhibition of the PET process in the presence of
FA.
Figure 6. Detection of FA in MDAMB-231 breast cancer cells by the
Al-MIL-53-N2H3 probe. MDAMB-231-unloaded cells (a−c), probe-
loaded cells (d−f), and probe-loaded cells treated with 50 μM FA (g−
i) for 1 h at 37 °C in the complete medium. The probe-loaded cancer
cells display bright blue fluorescence, whereas the addition of FA
causes marginal increase in the fluorescence signal. The superposition
of bright field and fluorescence indicates that the signal arises from the
cell-associated probe.
were incubated with the suspension of the fluorescent probe
1′, it was taken up by the cells. The probe did not affect the
cellular viability, but the cellular morphology was affected
because of the uptake of the probe. Furthermore, it did not
cause any morphological change to the mammalian cells, as
evident from the bright field imaging (Figure 6d). Interest-
ingly, the cells could detect endogenous FA in cancer cells and
exhibited a blue fluorescence signal (Figure 6e,f). The probe-
loaded cells, after treatment with FA (50 μM) for 60 min, gave
marginal increase in the blue fluorescence signal as compared
to the probe-loaded cells (Figure 6h,i). Our results clearly
indicate that the probe 1′ has the potential to detect the
intracellular FA in cancer cells and could be able to respond to
the change in intracellular FA levels.
It is worthy to mention that we have carried out the imaging
experiment by the MDAMB-231 cells. The mean diameter of
these cells is in the range of 10−20 μM.62−64 Hence, the probe
with the average particle size of 741 nm (as measured by the
DLS method) can easily be taken up by MDAMB-231 cells.
Actually, the mammalian cells can take up extracellular
molecules in the range of nanometers to micrometers and
The recyclability of the reaction-based fluorescent probe was
examined up to six cycles of sensing experiments. As shown in
Figure S40 (Supporting Information), the fluorescence turn-on
response of 1′ toward FA was significantly reduced after the
first cycle and became almost negligible in the subsequent
cycles. The poor recyclability of the MOF material for the
detection of FA can be attributed to the fact that the hydrazine
functional group was converted to the hydrazone moiety
through the reaction with FA during the first cycle of sensing
F
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Inorganic Chemistry
Article
experiments. Therefore, the hydrazine-functionalized 1′
showed negligible fluorescence turn-on responses in the
subsequent cycles of sensing experiments. Thus, the poor
recyclability of the Al-MIL-53-N2H3 probe for FA sensing is
consistent with the proposed sensing mechanism.
The fluorescence turn-on sensing of FA by MOFs is still in
the stage of infancy. There is a huge scope for the development
of new MOF probes and evaluation of their performances in
terms of detection limit, fold increment, response time, and so
forth. Hence, we believe that our work will stimulate
tremendous research interest in the field of MOF-related
sensors for FA.
Experimental Support for the PET Mechanism. Time-
resolved fluorescence experiments can provide invaluable
information when more than one emitting species are present
in the system.71 To ensure the involvement of the PET process
from the hydrazine group to the phenyl moiety in 1′, we have
performed fluorescence lifetime studies. Time-resolved fluo-
rescence lifetime decay profiles of the aqueous suspension of 1′
were collected before and after the addition of FA (20 mM,
500 μL) at different emission wavelengths. The fluorescence
lifetime decay profiles (Figure S41, Supporting Information)
and the fitted results (Table S2, Supporting Information)
clearly signify that before the addition of FA, the fluorescence
decayed (λem = 436 nm) in a three-exponential manner with
lifetime values of 13.19 ns (63.06%), 0.39 ns (18.97%), and
4.31 ns (17.97%). Such a three-exponential decay profile
indicates the contribution from three components. After
addition of FA, the lifetime decay profiles were measured at
different emission wavelengths (Table S2, Supporting In-
formation). Upon the addition of FA (λem = 436 nm), the two
short-lived components almost completely disappeared, and
the percentage of the long-lived component increased with an
increase of its lifetime value from 13.19 to 19.01 ns. In the
presence of FA, the increase in the lifetime value of the long-
lived component and the disappearance of the two short-lived
components confirm the inhibition of the PET process.72
Moreover, the large difference in the time-resolved fluores-
cence decay profiles (Figure S41, Supporting Information) of
1′ before and after the addition of FA suggests the formation of
imine bonds.73
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.8b02411.
NMR, FT-IR, and mass spectra, TG curves, XRPD
patterns, fluorescence spectra, FE-SEM images, DLS
spectra and N2 sorption isotherms (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sbiswas@iitg.ernet.in. Phone: (+)91-3612583309.
Fax: (+)91-3612582349.
ORCID
Shyam Biswas: 0000-0001-7103-9939
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are highly thankful to the Science and Engineering
Research Board (SERB; grant no. EEQ/2016/000012), New
Delhi, for generous financial support. The Ministry of Human
Resource Development is thankfully acknowledged for the
Center of Excellence in FAST (F. no. 5-7/2014-TS-VII).
CONCLUSIONS
■
We have judiciously designed, synthesized, and comprehen-
sively characterized a hydrazine-functionalized Al(III) MOF
material having MIL-53 topology. As confirmed by the TGA,
the compound shows high thermal stability up to 480 °C in an
air atmosphere. According to the N2 sorption measurements,
the compound after activation (1′) possesses a BET surface
area of 958 m2 g−1. Compound 1′ can be utilized as a
fluorescence turn-on probe for the selective detection of FA (in
aqueous and HEPES buffer media and the vapor phase), even
in the presence of potentially intrusive species. The
fluorescence turn-on phenomenon can be explained by the
inhibition of the PET event (from the hydrazine group to the
phenyl ring) owing to hydrazone formation. The anticipated
mechanism has been confirmed by mass analyses as well as by
the specially designed inhibition experiments. The Al-MIL-53-
N2H3 probe exhibits a short response time (1 min) for FA in
10 mM HEPES buffer. It is also highly sensitive for FA having
a detection limit of 8.37 μM (0.25 ppm) in HEPES buffer. In
addition to the solution phase, the probe is capable of
detecting FA in the vapor phase. Moreover, intracellular FA in
breast cancer cells can be efficiently sensed by the material. As
corroborated by the XRPD experiments, the crystallinity (and
hence structural robustness) of 1′ remains intact after the
fluorescence sensing experiments. Therefore, 1′ is a potential
probe for the real-time detection of FA in aqueous, vapor, and
simulated physiological media as well as inside cancer cells.
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