Design and synthesis of a new class of 2,4-thiazolidinedione based macrocycles suitable for Fe3+ sensing

Article abstract of DOI:10.1039/c8nj01536h

A new class of three 2,4-thiazolidinedione based macrocycles (3a-c) have been synthesized and then characterized from spectral data and X-ray crystallography. The fluorescence quenching of the compounds caused by the addition of nineteen separate metal cations to their solutions in ethanol-water (3 : 1) was investigated, when it was observed that among the cations, the response to Fe³⁺ was distinctive. Again, among the macrocycles, 3c gave the best result.

Full text of DOI:10.1039/c8nj01536h

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Design and synthesis of a new class of 2,4-thiazolidinedione based
macrocycles suitable for Fe3+ sensing
Nayim Sepay, Sumitava Mallik, Pranab C. Saha and Asok K. Mallik*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A new class of three 2,4-thiazolidinedione based macrocycles (3a-c) have been synthesized and they have been
characterized from spectral data and X-ray crystallography. The fluorescence quenching of the compounds by addition of
nineteen metal cations separately to their solutions in ethanol-water (3:1) was investigated, when it was observed that
among the cations, response of Fe3+ was distinctive. Again, among the macrocycles, 3c gave the best result.
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Introduction
Iron, present in both +2 and +3 oxidation states in nature,
is an essential element for the vital activity in the biology of
living organisms on the planet Earth.1 It is the most abundant
transition metal in human body and plays key roles in various
enzyme catalysis, electron transfer, energy generation,
neurotransmission, cellular metabolism, gene expression and
DNA, RNA synthesis.2 Anemia and hemochromatosis are the
common disorders for the deficiency or overload of this metal.
Iron deficiency stress found in most organisms is because of
poor water-solubility of trivalent iron species (most existent
iron) in oxidative environmental conditions of the earth.1 In
order to observe the various activities of Fe+3 ions, it is very
important to recognize this metal ion qualitatively and
quantitatively with reference to the broad areas of chemistry,
geography and biology.3 Thus, development of molecules as
sensors, biomolecule separation tools, diagnostic and
therapeutic agents for iron species is of great demand.
containing nitrogen and sulfur and possess a wide range of
promising biological activities, e.g., antimicrobial,7a anti-HIV,7b,c
In comparison to acyclic molecules, macrocyclic molecules
have less conformational freedom and they show high affinity
toward metal ions for greater thermodynamic stability of the
complex.4 Therefore, designing of macrocycles having selective
fluorescence response for Fe3+ ion is greatly desirable because
fluorescence spectroscopy has advantages like high sensitivity,
tunability and easy detection.5 Identification of the metal ions
by an enhancement or quenching of the emitted fluorescence
intensity of the fluorophore attached with macrocycle is due
to selective fluorophore–ionophore interaction. In recent
years, various fluorescent macrocyclic molecules have been
designed and successfully synthesized for detection of Fe3+
ions (Figure 1).6a-e Parrallely, work on designing of acyclic Fe3+
sensor molecules is also an active area of research.6f-i
e
anti-convulsant,7d cytotoxic7 and anti-dengue-viral7f activities
to name a few. They can be easily synthesized using readily
available starting materials, and, in fact, the most common
method for getting the parent compound
simply refluxing of a mixture of chloroacetic acid and thiourea
in aqueous acidic medium.7a The reactive sites in
are the
nitrogen atom and the CH2 group (positions 3 and 5,
respectively). Thus, good number of examples of N-
alkylation7e,f and Knoevenagel condensation7a,e on
are known
1 in high yield is
1
a
1
to convert it to its derivatives in search of newer biologically
important compounds. It is very encouraging to consider that
the existence of two reactive sites in
1 gives a possibility of
building macrocyclic systems incorporating this unit. Such
consideration prompted us to undertake a synthesis of
2,4-Thiazolidinediones (1) are five-membered heterocycles
macrocycles of the type
2 starting from 2,4-thiazolidinedione
(
1) and 2-hydroxybenzaldehydes (Scheme 1) and study of
binding of
2
having electronegative atoms directed inward
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with different metal cations. It may be mentioned here that
the choice for 2-hydroxybenzaldehyde derived dialdehydes is
based on our experience of synthesis of macrocyclic
compounds using them.8 As an outcome of this study, we have
been able to synthesize several new macrocycles with (CH2)n
spacers (n=3-5) and show that they can selectively bind to Fe3+.
Results and discussion
Synthesis
The strategy undertaken for synthesis of one category (
the targeted macrocycles is shown in Scheme 2. It involves
preparation of the precursors and through alkylation
3) of
2
UV-vis study for Fe3+ sensing
4
5
reactions and then their two-stage Knoevenagel condensation
(first intermolecular and then intramolecular) under high
In UV-vis absorption spectrum of each of the macrocyclic
molecules of the series in ethanol-water (3:1) medium (5
dilution condition. Thus, three compounds of the series
3 were
3
synthesized and characterized from their spectral data along
with the X-ray crystallographic studies of one of them. The
μM), one absorption maximum at ~348 nm with a peak
shoulder at 312 nm was observed (red line in Figure 1). There
were no notable changes in the UV-vis absorption spectra of
the macrocycles upon addition of Li+, Na+, K+, Ag+, Mg2+, Ca2+,
Ba2+, Pb2+, Zn2+, Co2+, Cd2+, Hg2+, Ni2+, Mn2+, Cr3+, Al3+, Sn2+ or
Fe2+ ions in the same medium. In case of addition of Fe3+ ion, it
was found that for these compounds the absorption intensity
of both the peaks increased. To get a detailed understanding
of the effects of Fe3+ ion on absorption of the compounds, a
titration experiment was performed. It was observed that for
all the compounds increase of intensity of the peak at 312 nm
was higher than that of the peak at 348 nm on gradual
observed low yield of
some polymeric products. Configuration of the double bonds
in was found to be Z as reported previously for formation of
acyclic Knoevenagel condensation products involving 1 7a,e
3 (17-34 %) may be due to formation of
3
.
Selective recognition of Fe3+ ions by the macrocycle 3a-c
The sensing potential of all the three synthesized macrocycles
3a-c towards various metal ions was investigated with the help
of UV-vis and fluorescence experiments in their solutions in
ethanol-water (3:1) at room temperature. The sensibility was
found to be good for Fe3+ ion in all cases, and 3c gave the best
result.
addition of Fe3+
(Figure 2). At the end point (saturation point),
the peak at 312 (which was originally a shoulder peak) became
the main peak with a 12 nm blue shift and the peak at 348 nm
2 | J. Name., 2012, 00, 1-3
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(the original main peak) was transformed to a shoulder peak of in their nature other than declining intensity as shown in
the new 300 nm peak with a 3 nm blue shift. This indicated the Figure 3. Furthermore, no formation of any exiplex was
formation of a complex of Fe3+ ion with the macrocycles and indicated by the non-appearance of any peak at low energy
the resulting complexes show UV-vis absorption in the 300 nm region on Fe3+ addition. The data obtained from the
region. The peaks at 312 and 348 nm are possibly due to the π- experiment were analyzed by calculating Stern-Volmer
π* and n-π* transitons of the enamide part of the quenching constant Ksv in the Stern-Volmer equation.9a
macrocycles. Since n-electrons are considered to be more
involved in metal binding than π-electrons, the hypsochromic
F0/F = 1 + Ksv[Q]
(1)
shift of 12 nm for 312 nm peak and 3 nm for the 348 nm peak
is somewhat unexpected. A conformational factor may be where F0 and
F signify fluorescence intensity of the
responsible for this.
macrocycles before and after addition of Fe3+, respectively,
and Q the concentration of Fe3+ in the medium. The values of
Ksv were found to be 7.32×103, 7.70×103 and 8.11×103 M-1 for
Fluorescence study for Fe3+ sensing
3a, 3b and 3c, respectively. Moreover, the natures of Stern-
The fluorescence spectra of 3a-c and their complexes were Volmer plots were found to be linear in each case. Thus, it may
recorded by excitation at 300 nm which corresponds to the be inferred that the compounds 3a-c can be used as specific
absorption of Fe3+-macrocycle complex. The emission spectra sensors for Fe3+ ion. In addition, binding constants of the
show a three-hump pattern with peaks at 338, 410 and 433 macrocycles with Fe3+ ion have also been determined using
nm in ethanol-water (3:1) medium. The fluorescence spectra non-linear fit9b and here also 3c was found to be the best in
of 3a-c with increasing Fe3+ concentration exhibited no change the series with a K1 value of 5.19×103 M-1 (See ESI).
It is possible that quenching of fluorescence of the
macrocycle by metal ions proceeds through formation of non-
emissive complex with charge transfer from an excited
macrocycle to the Fe3+ ion. An increase of ISC to the triplet
state due to heavy atom effect and paramagnetic interaction
may be other reasons for such fluorescence quenching.
The selectivity of the macrocycles 3a-c for Fe3+ over other
metal ions such as Li+, Na+, K+, Ag+, Mg2+, Ca2+, Ba2+, Pb2+, Zn2+,
Co2+, Cd2+, Hg2+, Ni2+, Mn2+, Cr3+, Al3+, Sn2+ and Fe2+ was
investigated (Figure 4). Among all the competitive ions, only
Fe3+ was able to make a significant decrease of fluorescence
intensity of the macrocycles. The decrease of fluorescence
intensity caused by Fe2+ ion is greater than that done by the
other metal ions, but the value is sufficiently smaller as
compared to that of Fe3+ ion.
Thus, the new 2,4-thiazolidinedione based macrocycles 3a-
c
are good additions to the existing list of Fe3+ sensors. In fact,
they can bind Fe3+ more strongly than a number of reported
iron sensors of both cyclic and acyclic verities (See ESI). In
order to determine their sensitivity, fluorescence titrations of
3a-c
(1×10−6 M) with Fe3+ (1×10−6 M) in ethanol-water (3:1)
medium were performed. From this study, the limit of
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detection (LOD: 3.3σ/S) and limit of quantification (LOQ:
10σ/S) of the macrocycle 3c for Fe3+ were found to be 9.8 µM
and 30 µM, respectively (See ESI). It is interesting to note that
the LOD and LOQ values are quite good compared to a number
of reported sensors of both cyclic and acyclic verities (See ESI).
Theoretical study
The structures of the macrocycles 3a-c were optimized
with Density Functional Theory (DFT) using the B3LYP/6-311G
level of theory. The optimized structures are shown in Figure
5a. The bond lengths and bond angles of 3b from DFT
calculations were found to be quite consistent with the values
obtained from the x-ray crystallography.11 The compound 3a is
a twenty-one membered macrocycle and the other two are
twenty-two membered. Such ring sizes are expected to create
a large cavity, but actually the cavity is smaller due to the
three dimensional arrangements of the molecules and the
presence of two amide carbonyls directed inward (evident
from both the DFT optimized and x-ray crystal structures).
Molecular electrostatic potential (MEP) calculations show the
electron dense atoms (red and yellow) in the macrocycles
available for metal coordination (Figure 5b). These are the said
carbonyl oxygens (red) and two ether oxygens (yellow) at the
wall of the cavity. On the basis of this information, the
Proposed recognition mechanism
The two possible ways for accommodation of Fe3+ in the
cavity of the host are shown in Figure 7. Between them, the
latter is expected to be more favourable as the former involves
formation of two four-membered rings with a tightly packed
arrangement. This is indicated by the results of MEP study of
3a-c also (Figure 5b). In order to establish the presence of
solvent molecules (either water or ethanol or both) in 3c-Fe3+
complex under the sensing conditions, mass spectral study
was done. This study showed peaks at 699.1591, 643.7680 and
671.3739 (among which the former was of highest intensity)
indicating of the formation of 3c-Fe3+ complex containing two
molecules of ethanol (i: calculated mass 699.1497), two
optimized structure for the Fe3+-3a
/3b/3c complex in aqueous
molecules of water (ii: calculated mass 643.5270) and one
molecule of each of them (iii: calculated mass 671.1184),
respectively (Figure 7b).
ethanol medium (in which the UV-vis and fluorescence studies
were done) was calculated by DFT method (Figure 5c).
The HOMO and LUMO of the compound 3b are shown in
Figure 6, where it is clear that the HOMO distribution of 3b is
located on one benzylidene moiety while the LUMO
distribution is on the other. These distributions indicate that
the π-π* and n-π* transitions and the energy difference
between HOMO and LUMO of the molecule correspond to the
band gap associated with its UV-vis spectrum.11
When the MEP pictures of 3a-c are compared (Figure 5b),
it is found that the cavity sizes follow the order 3b>3c>3a. In
the case of 3c, the portion bearing the alkylated salicylidene
moieties is of largest size which possibly makes it more flexible
to accommodate a Fe3+ ion. This may be the reason for the
highest binding constant of this compound. Again, considering
3a and 3b, the polymethylene unit attached to the two 2,4-
thiazolidinediones of the latter will have greater flexibility
enabling 3b to accommodate Fe3+ in a better way. This is
reflected in the relative magnitudes of the Ksv values of these
two compounds. To get a better understanding of the
situation, the Gibbs free energy changes were calculated for
the three complexes presented in Figure 5c. The calculations
showed that the complex 3c-Fe3+ is more stable than both of
3b-Fe3+ and 3a-Fe3+ (ΔG = -123.61 and -143.50 kcal/mol,
respectively). Again, the complex 3b-Fe3+ is slightly more stable
than 3a-Fe3+ (ΔG = -19.89 kcal/mol). These ΔG values also
support the order of Ksv.
Scope of this study
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At this point it may be stated that there is ample scope for thiazolidinedione.16 A solution 2,4-thiazolidinedione (20 mmol)
structural variation of the 2,4-thiazolidinedione based and KOH (25 mmol) in ethanol (12 mL) was refluxed for 30 min
macrocycles by changing the spacers which may be composed and then cooled to 0 °C. The precipitate of the potassium salt
of different acyclic, carbocyclic or heterocyclic units. of 2,4-thiazolidinedione was filtered and washed with cold
Moreover, the 2-hydroxybenzylidene unit can be replaced by ethanol. The solid thus obtained was taken in DMF (10 mL)
its analogs. Thus, synthesis of a large number of newer with α,ω-dibromoalkane (8 mmol) and refluxed for 3 h. The
macrocycles having selective binding ability to different metal reaction mixture was then cooled; water was added to it and
cations may be achieved. Another interesting aspect is that the extracted with ethyl acetate (3 x 20 mL). The combined organic
final compounds containing the 2,4-thiazolidinedione moiety layer was collected, dried over anhydrous Na2SO4 and the
might show some biological activities.7
solvent was distilled off. The resulting crude material was
subjected to column chromatography over silica gel to obtain
the pure product (4). The synthesized compounds, 4a and 4b,
were characterized from their 1H NMR spectral data.
Experimental
General
1
3,3'-(Propane-1,3-diyl)bis(thiazolidine-2,4-dione) (4a)
:
Mps were recorded on a Köfler block and are uncorrected. H
and 13C NMR spectra were recorded in CDCl3 on a Bruker AV-
300 (300 MHz) spectrometer. Mass spectra were acquired on a
Waters Xevo G2QTof HRMS spectrometer. Analytical samples
were dried in vacuo at room temperature. Microanalytical data
were recorded on a Perkin-Elmer 2400 Series II C, H, N
analyzer. Column chromatography was performed on silica gel
(100-200 mesh) using petroleum ether (60-80 °C) and
petroleum ether-ethyl acetate mixtures as eluents. TLC was
done with silica gel G. X-ray crystallographic studies were done
by using a Bruker APEX II single crystal X-ray diffractometer.
Bis-(2-formylphenoxy)alkanes used (4a [alkane = butane] and
4b [alkane = pentane]) were prepared by a known method
previously developed by us.8 The UV-vis absorption and
Colourless needles, m.p. 94-95 ○C, 1H NMR (300 MHz, CDCl3): δ
= 1.83 (2H, br. s, N-CH2-CH2
4.01 (4H, br. s, N-CH2 CH2-CH2
3,3'-(Butane-1,4-diyl)bis(thiazolidine-2,4-dione) (4b)
Colourless needles, m.p. 104-105 ○C, 1H NMR (300 MHz,
CDCl3): δ = 1.61 (4H, br. s, -N-CH2-CH2 CH2 CH2-N-), 3.63 (2H, s,
S-CH2 C=O), 3.95 (4H, br. s, N-CH2 CH2-CH2-CH2 N).
-CH2-N), 3.61 (2H, s, S-CH2
-C=O),
-
-N).
:
-
-
-
-
-
General procedure for synthesis of macrocyclic compounds
(3a-c)
A mixture of bis-(2,4-thiazolidinedion-1-yl)alkane (4a/4b, 0.5
mmol) and bis-(2-formylphenoxy)alkane8 (5a/5b, 0.5 mmol)
was taken in toluene and catalytic amount of piperidine (10
drops) was added to it. The solution was diluted by addition of
toluene to make the total volume 300-320 mL. The mixture
was then refluxed with stirring for 50 h. After completion of
the reaction as indicated by TLC, the reaction mixture was
cooled and the solvent was distilled off. The crude mixture
thus obtained was subjected to column chromatography to
separate the desired product (3a-c) from the reaction mixture.
fluorescence spectra were taken with
a
UV-2450
spectrophotometer (Shimadzu, Japan) and a Perkin-Elmer LS-
55 spectrofluorimeter (Perkin-Elmer, USA), respectively.
Computational Methods
GAUSSIAN 09 program package12 was used for all
A
calculations in this paper. For the DFT calculation Becke three
parameters hybrid exchange13 and the Lee–Yang–Parr
correlation functionals14
(B3LYP) were used as functionals. The
Spectral data of 3a-c
Compound 3a: Colorless crystalline solid, m.p. 268-269 ○C, H
1
DFT method was used to optimize the geometry of the
molecule using 6-311G level of theory. For Fe3+ ion lanl2dz and
for C, N, O and S atoms 6-31+G (d,p) basis set was used.
Hartree-fock method with STO-3G basis set was used also for
calculation of MEP for the compound. 6-311G level of theory
was used for time dependent DFT calculations.
NMR (300 MHz, CDCl3): δ 2.16 (4H, br. s, O-CH2-CH2-CH2-CH2-
O), 2.46-2.50 (2H, m, N-CH2-CH2-CH2-N), 3.74 (4H, t, J = 6.0 Hz,
N-CH2-CH2-CH2-N), 4.12 (4H, br. s, O-CH2-CH2-CH2-CH2-O), 6.93
(2H, br. d, J = 8.2 Hz, Ar-H), 7.04 (2H, br. t, J = 7.5 Hz, Ar-H),
7.39 (2H, br. t, J = 7.6 Hz, Ar-H), 7.47 (2H, br. d, J = 7.5 Hz, Ar-
H), 8.38 (2H, s, =CH-); 13C NMR (75MHz, CDCl3): δ 23.3, 27.0,
37.5, 68.0, 111.8, 120.8, 121.7, 123.0, 128.7, 129.3, 132.0,
158.2, 165.9, 168.8; Elemental analysis (%) for C27H24N2O6S2,
calculated C, 60.43; H, 4.51; N, 5.22, found C, 60.33; H, 4.23; N,
5.09; HRMS calcd for C27H25N2O6S2 (M+H)+: 537.1154, found:
537.1617.
Synthesis of 2,4-thiazolidinedione
An aqueous solution of chloroacetic acid (50 mmol) and
thiourea (55 mmol) was stirred for 15 minutes when a white
precipitate separated out accompanied by considerable
cooling. Concentrated HCl (50 mL) was added and the mixture
was refluxed with stirring for 8 h and then cooled to obtain
2,4-thiazolidinedione as a white precipitate which was filtered
out, dried and crystallised from ethanol, Yield: 85%, M.p. 126-
127 ○C (Lit.15 125-126○C).
Compound 3b: Colorless crystalline solid, m.p. 276-277 ○C, H
1
NMR (300 MHz, CDCl3): δ 1.71 (4H, br. s, N-CH2-CH2-CH2-CH2-
N), 2.07 (4H, br. s, O-CH2-CH2-CH2-CH2-O), 3.81 (4H, br. s, N-
CH2-CH2-CH2-CH2-N), 4.11 (4H, br. s, O-CH2-CH2-CH2-CH2-O),
6.96 (2H, d, J = 8.5 Hz, Ar-H), 7.05 (2H, t, J = 7.5Hz, Ar-H), 7.34-
7.43 (4H, m, Ar-H), 8.31 (2H, s, =CH-); 13C NMR (75 MHz,
CDCl3): δ 24.6, 26.2, 41.0, 68.1, 111.9, 120.9, 122.0, 123.2,
128.8, 130.2, 132.0, 157.8, 166.2, 168.7; Elemental analysis (%)
General procedure for synthesis of 4.
Two compounds of the series
4 have been synthesized by
following a recently reported method for alkylation of 2,4-
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Wang and H. Xu., Bioorg. Med. Chem., 2013, 21, 508; (f) J. H.
Xu, Y. M. Hou, Q. J. Ma, X. F. Wu and X. J. Wei, Spectrochim.
Acta A, 2013, 112, 116, (g) V. Bravo, S. Gil, A. M. Costero, M.
N. Kneeteman, U. Llaosa, P. M. E. Mancini, L. E. Ochando and
M. Parra, Tetrahedron, 2012, 68, 4882.
for C28H26N2O6S2, Calculated C, 61.08; H, 4.76; N, 5.09. Found
C, 61.27; H, 4.51; N, 4.81, HRMS calcd for C28H26N2NaO6S2
(M+Na)+: 573.1130, found: 573.1931.
1
Compound 3c: Colorless crystalline solid, m.p. 280-281 ○C, H
NMR (300 MHz, CDCl3): δ 1.28-1.36 (2H, m, O-CH2-CH2-CH2-
CH2-CH2-O), 1.72-1.74 (4H, m, O-CH2-CH2-CH2-CH2-CH2-O),
2.35-2.43 (2H, m, N-CH2-CH2-CH2-N), 3.79 (4H, br. t, J = 5.2 Hz,
N-CH2-CH2-CH2-N), 4.32 (4H, t, J = 5.6 Hz, O-CH2-CH2-CH2-CH2-
CH2-O), 6.95 (2H, d, J = 8.4 Hz, Ar-H), 7.01 (2H, t, J = 7.2 Hz, Ar-
H), 7.33 (2H, t, J = 7.5 Hz, Ar-H), 7.42 (2H, d, J = 7.2 Hz, Ar-H)
8.21 (2H, s, =CH-); 13C NMR (75 MHz, CDCl3): δ 23.8, 27.1, 29.2.
41.3, 66.8, 113.8, 121.6, 122.1, 123.8, 129.5, 129.9, 131.7,
157.7, 166.7, 168.8; Elemental analysis (%) for C28H26N2O6S2,
Calculated C, 61.08; H, 4.76; N, 5.09. Found C, 61.03; H, 4.57;
N, 5.17; HRMS calcd for C28H26N2NaO6S2 (M+Na)+: 573.1130,
found: 573.1343.
3
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Conclusions
In summary, we have devised new fluorosensors for Fe3+
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two 2,4-thiazolidinedione moieties, two 2-hydroxybenzylidene
moieties and two polymethylene units. The fluorescence of the
fluorophore decreases significantly upon binding with the
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Conflicts of interest
There are no conflicts to declare.
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Delhi to the Department of Chemistry, Jadavpur University is
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6 | J. Name., 2012, 00, 1-3
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New Journal of Chemistry
View Article Online
DOI: 10.1039/C8NJ01536H
Design and synthesis of a new class of 2,4-thiazolidinedione based
macrocycles suitable for Fe3+ sensing
Nayim Sepay, Sumitava Mallik, Pranab C. Saha and Asok K. Mallik*a
Three 2,4-thiazolidinedione based macrocycles, very good Fe3+ sensors in aqueous-ethanol medium,
have been synthesized. X-ray crystallography, DFT calculations and MEP analysis have been used for
their structural confirmation and understanding their behavior towards Fe3+.