Effect of solvent on the photophysical properties of isoxazole derivative of curcumin: A combined spectroscopic and theoretical study

Article abstract of DOI:10.1016/j.jphotochem.2021.113164

The present work aims to decipher the photophysics of a β-diketo modified curcumin analog named isoxazole derivative of curcumin (IOC). IOC itself happens to be a potential drug molecule possessing numerous biological applications such as; anti-cancer, an

Full text of DOI:10.1016/j.jphotochem.2021.113164

Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
Contents lists available at ScienceDirect
Journal of Photochemistry & Photobiology, A: Chemistry
journal homepage: www.elsevier.com/locate/jphotochem
Effect of solvent on the photophysical properties of isoxazole derivative of
curcumin: A combined spectroscopic and theoretical study
Manisha Sharmaa, Uttam Palb, Mamta Kumaria, Damayanti Bagchic, Swati Rania,
Dipanjan Mukherjeec, Arpan Berac, Samir Kumar Palc, Tanusree Saha Dasguptad,
,
Subho Mozumdara *
a Department of Chemistry, University of Delhi, Delhi, 110007, India
b Technical Research Centre, S. N. Bose National Centre for Basic Sciences, Block JD, Sector III, Salt Lake, Kolkata, West Bengal, 700106, India
c Department of Chemical, Biological & Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Block JD, Sector III, Salt Lake, Kolkata, West Bengal,
700106, India
d Department of Condensed Matter Physics and Material Sciences, S. N. Bose National Centre for Basic Sciences, Block JD, Sector III, Salt Lake, Kolkata, West Bengal,
700106, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
The present work aims to decipher the photophysics of a β-diketo modified curcumin analog named isoxazole
derivative of curcumin (IOC). IOC itself happens to be a potential drug molecule possessing numerous biological
applications such as; anti-cancer, anti-malarial, anti-Alzheimer’s, anti-Parkinson’s etc. Herein, the photophysical
properties of IOC have been explored in various sets of solvents. In order to investigate, steady state and time
resolved spectroscopy have been utilized as a tool. To elucidate the experimental observations at molecular level,
electronic structure calculations with density functional theory (DFT) as well as classical molecular dynamics
(MD) simulations in explicit solvents have been deployed. The DFT has established that the most stable ground
state electronic structure of the IOC molecule is the all trans- planar conformation where the conjugated pi-
electrons are delocalized over the entire molecule. The MD simulations have provided an insight into the spe-
cific and non-specific interactions with the solvent molecules. Steady state spectroscopic techniques have shown
that both the absorption and emission maxima experienced a traditional red shift upon increase in the solvent
polarity. The absorption maxima for IOC got red shifted from 332 nm in hexane to 344 nm in DMSO. However,
the red shift in the emission maxima is more pronounced than that of absorption maxima starting from 356 nm in
hexane to 431 nm in water. The value of molar extinction coefficient has also been determined for IOC in
different solvents from the concentration dependent absorption spectra. The time correlated single photon
counting (TCSPC) data has revealed that the excited state of IOC molecule could relax via three probable
pathways. Also, the overall process of decay of the excited state is comparatively slower in case of non-polar
solvents. On the other hand, the fluorescence lifetime has been observed to be unusually low in case of
dimethyl sulfoxide (DMSO) as compared to its other fellow polar aprotic solvents.
Spectroscopy
Photophysics
TCSPC
DFT calculation
MD simulations
1. Introduction
solute with its immediate environment [3]. The study of photophysical
profile of fluorescent molecules in presence of different solvents helps in
The term solvatochromism is defined as the phenomenon where the
position and intensity of electronic bands are dependent on the solvents
[1,2]. During this process, the absorption and emission spectra, the
steady state fluorescence intensity as well as the excited state lifetime of
the fluorophore also get perturbed [3]. These photophysical properties
of a fluorophore are governed by the intermolecular interaction of the
scrutinizing the phenomenon of solvatochromism. The solvatochromic
fluorophores have been enormously investigated because of their
capability to act as polarity-sensitive molecular probes [4]. The photo-
physical properties of various fluorophores have been reported to pro-
vide crucial contributions in the field of optoelectronic, analytical and
biomedical sciences [5–7]. The idea of investigation of photophysics of
* Corresponding author.
E-mail address: subhomozumdar@yahoo.com (S. Mozumdar).
https://doi.org/10.1016/j.jphotochem.2021.113164
Received 24 November 2020; Received in revised form 13 January 2021; Accepted 22 January 2021
Available online 26 January 2021
1010-6030/© 2021 Elsevier B.V. All rights reserved.

M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
solvatochromic fluorophores which are biologically active have attrac-
ted immense attention from the scientific community. The information
about the photophysical properties helps in monitoring the various
biochemical processes and hence, reveals details about the mechanism
of the drug activities of the molecules. The detailed insight about the
solvatochromism of various biologically efficient molecules that have
been reported include various coumarin derivatives like 7-aminocou-
marin [8], coumarin-1 [9], coumarin-6 [10], coumarin-151 [11],
along with others such as; sulphonated aluminium phthalocyanin [12],
Chlorin e6 [13], merocyanin 540 [14], camptothecin [15], and many
more. Based on the solvent dependent studies on the coumarin, de-
rivatives, Karcz and Cravean et al. have done multiple investigation
showing the photophysical and biological properties of widespread
coumarin derivatives along with their metal complexes as well as thia-
diazole derivatives [16–19]. Besides all these molecules, the medicinal
pigment which has been extensively investigated for the study of pho-
tophysical properties in presence of solvents of varying polarity is cur-
cumin [20–22].
the rotational freedom of the molecule. It has been reported that the
isoxazole derivative of curcumin (IOC) is known to have modest inhib-
itory activity against HIV-1 and HIV-2 proteases [37]. Chakraborty et al.
have reported that as compared to curcumin, IOC has better in-vitro
anti-proliferative activity [38]. Selvam et al. have reported that IOC
exhibits significantly higher inhibitory activity towards the COX-2
enzyme as compared to curcumin [39]. IOC exhibits increased
anti-tumor activity against hepatocellular carcinoma HA22T/VGH cell
line [40]. It has also been evaluated for lipoxygenase inhibitory activity,
cytotoxic activity, anti-tumor activity against breast cancer cell lines
(MCF-7, SKBR3) and anti-malarial activity [41,42]. In a recent report,
Shaikh et al. have extensively studied the in-vitro antioxidant and
anti-radical activity of the IOC drug molecule. They have reported that
these properties of IOC are even better than those of curcumin [43]. The
preliminary studies on the interaction mechanism of IOC have been
performed with various proteins such as; BSA [44], HSA [45,46],
β-lactoglobulin [47] as well as with calf thymus DNA [48] but the
detailed insight into the photophysics has not been done till date.
Now, in order to elucidate the fundamental understanding about the
medicinal effects of the IOC drug molecule, its photochemistry and
photophysics must be exploited. In order to serve this purpose, firstly the
DFT calculations have been deployed to get an idea about the most
stable ground state stereoisomer of the IOC molecule. Later, the inter-
action mechanism of IOC molecule with various solvents has been
explored. The solute-solvent interaction can provide us with the infor-
mation about the structural changes that occur in the molecule upon
excitation in the presence of different microenvironments. The present
study aims to study the process of solvatochromism for this potential
drug molecule (IOC) in the presence of various solvents categorized into
three different sets of solvents such as non-polar, polar protic and polar
aprotic solvents. The steady state absorption and emission properties of
this drug molecule have been investigated in wide range of solvents. The
MD simulations have been performed on the IOC molecule in presence of
six different solvents like water, methanol, DMSO, acetonitrile, benzene
and hexane to get an idea about the type of interactions happening
between the solute and solvent. The fluorescence transients of IOC in
different solvents have also revealed the type of processes involved for
the deactivation in their excited state. This has been done to acquire a
microscopic understanding of the intermolecular effects of various
physico-chemical parameters like solvent polarity, dielectric constant,
hydrogen bonding ability etc. on the photophysics of IOC. Furthermore,
to study the effect of hydrogen bonding on the solubility as well as
photophysics of IOC along with the effect of deuteration has also been
analyzed in depth.
Curcumin is a polyphenolic compound found in the rhizome of
Curcuma longa Linn exhibiting widespread biological applications like
anti-cancer, anti-oxidant, anti-proliferative, anti-inflammatory etc.
[23–25]. This phytochemical is also used in the treatment of skin cancer
(through phytodynamic therapy), cystic fibrosis, Parkinson’s disease as
well as Alzheimer’s disease [26–28]. The extraordinary pharmacolog-
ical activities of curcumin are attributed to its unique structure in which
the β-diketo moiety is attached to the phenolic groups on its both sides
through an α,β unsaturated carbon chain [29]. A widespread photo-
physical studies have been done on curcumin so as to understand its
biological efficiency. In general, curcumin displays strong absorption
peaks in both UV and visible region. However, these absorption peaks
are strongly influenced by the micropolarity of the environment of the
curcumin molecules [30]. The absorption peak of curcumin has been
reported to exhibits a solvent dependency by displaying a red shift in the
absorption maxima in case of polar solvents. Khopde et al. have outlined
that curcumin shows a red shift from 408 nm in cyclohexane to 430 nm
in DMSO. Similar results were obtained for emission spectra where the
emission maxima experiences a red shift from 446 nm in cyclohexane to
560 nm in methanol [20,21]. Moreover, it has also been reported that
the curcumin molecule possesses low quantum yield as well as low
excited state lifetime in the picosecond time scale. The fast decay of the
fluorescence excited state has been attributed to the ultrafast Hydrogen
atom transfer in the excited state (commonly known as ESIPT process)
[31].
Despite all these beneficial advantages, curcumin could not be
translated into a drug because upon oral administration (up to 8 g per
day), the compound is poorly absorbed with only trace appearing in the
blood [32]. The biological efficacy of curcumin has been limited by
various factors such as poor aqueous solubility, lack of bioavailability
and rapid degradation at physiochemical conditions [33,34]. The most
pivotal factor responsible for its rapid degradation in aqueous medium
has been assigned to the keto-enol tautomerization of the β-diketo
moiety of the curcumin molecule [35]. Hence, in order to achieve
maximum benefits of curcumin, extensive research has been carried out
to design various diketo analogs of curcumin.
2. Experimental
2.1. Materials
Curcumin, Hydroxylamine Hydrochloride (NH2OH.HCl) and Ethanol
were purchased from Sigma Aldrich. All the solvents used were of
analytical grade. All the chemicals were used as obtained without any
further purification.
Numerous studies have reported that isoxazole derivatives of
different drug molecules possess various biological applications
including anti-bacterial, anti-fungal, anti-inflammatory, anti-convul-
sant, anti-viral and immunological activities [36]. Also, isoxazoles are
inhibitors of p38 kinase, estrogen synthase, factor Xa enzyme, cyto-
megalovirus DNA polymerase and multidrug-resistance protein (MRP1)
[36]. Because of all these applications immense research has been going
on to discover new isoxazole derivatives which could be used as
important pharmacophores in the modern drug discovery. Therefore, in
order to cease the process of keto-enol tautomerization occurring in
curcumin; the strategy to convert the diketo group of curcumin into an
isoxazole ring has been utilized. This structural modification restricts
2.2. Synthesis of isoxazole derivative of curcumin
In a typical synthesis procedure, 1 mmol of curcumin was dissolved
in 10 mL of ethanol and was allowed to stir for 15 min. To the resulting
mixture, catalytic amount of acetic acid was added, followed by addition
of 1.5 mmol of hydroxylamine hydrochloride (NH2OH.HCl) [42]. The
reaction mixture was allowed to stir at 80 ◦C for 24 h under N2 atmo-
sphere (Scheme 1). The progress of the reaction was monitored by TLC.
After the completion of the reaction, the reaction mixture was trans-
ferred to a beaker containing ice cold water. As a result, light yellow
color precipitates were formed which were extracted via centrifugation.
The crude obtained was recrystallized in methanol and hence, the pure
2

M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
Scheme 1. Diagrammatic representation of β-diketone modification of curcumin into IOC along with schematic representation of the synthesis of IOC.
form of IOC was obtained. The prepared compound was characterized
using 1H NMR, 13C NMR, and ESI-MS (SI: Note 1).
the corresponding samples.
The classification of solvents based on hydrogen bonding ability has
been done in Table 1. This classification into the type of solvents has
been referred from the literature [49].
2.3. Preparation of solution of IOC in different solvents
The values of solvent polarity parameter (ET(30)) for each solvent
has been taken from the literature [50]. The values of dimensionless
In order to prepare the solutions of IOC in different solvents, firstly, a
stock solution of IOC in methanol was prepared. Then, required amount
of methanolic solution of IOC was poured in a vessel and the methanol
was allowed to evaporate leaving behind a thin film of IOC. This thin
film was scratched from the vessel and dissolved in appropriate amount
of solvents. The solutions were ultrasonicated for about an hour to
achieve maximum possible solubilization. Then after, the solutions were
normalized solvent polarity (ETN) has been determined by using Eq. (1)
which was proposed by Reichardt. In this equation, water and tetra-
methylsilane (TMS) are considered as extreme reference solvents with
(ENT ) values of 1 and zero, respectively [51].
ET(solvent) ꢀ ET(TMS)
ET(water) ꢀ ET(TMS)
ET(solvent)-30.7
32.4
ETN
=
=
(1)
filtered through a 0.45
μ filter and were used for further characteriza-
tions. For the photophysical studies, the amount of IOC that was added
The reaction field parameter (Δf) for different solvents has been
to different solvents to prepare solutions was according to 2 μM con-
calculated using the Lippert-Mataga equation described below [52].
centration. However, the concentration of IOC inside different solutions
varied in accordance to its solvent dependent extent of solubility.
ε
-1
n2-1
Δf (
ε
, n ) =
ꢀ
(2)
2n2 + 1
2
ε
+ 1
2.4. Characterization techniques
Where,
ε
and n are the static dielectric constants and refractive index of
and n of pure solvents have
the solvents; respectively. The values of
ε
The absorption spectra were measured with Shimadzu spectropho-
tometer (UV-2600) in the range of 200–800 nm. All the spectra were
recorded using 1 cm path length quartz cuvettes. The steady state
emission spectra were recorded using Varian Carry Eclipse Fluorescence
spectrophotometer at the absorption maxima of the respective samples
in the range of 355ꢀ 800 nm. During the measurements, both the exci-
tation and emission slits were kept at 10 nm. The excitation spectra were
obtained using Horiba fluorolog instrument at the emission maxima of
been taken from the literature [13,53,54].
The fluorescence quantum yield of IOC in different solvents has been
calculated using the equation written below [55].
(
) (
) (
)
2
Ax
As
Abss
Absx
ηx
ηs
ɸx = ɸs
(3)
In the above-mentioned equation, the symbols ɸ, A, Abs. and
η
Table 1
The values of characteristic properties of each solvent along with the steady state spectral properties of IOC.
Solvent
Type of
Dielectric
Refractive
Viscosity
Δf
λmax (abs.)
λmax (emsn.)
ε
(Mꢀ 1 cm-1
)
Stokes shift
ETN
solventc
constant (
ε
)
Index (n)
(η
)
(nm)
(nm)
(×104)
(cmꢀ 1
)
Acetonitrile
Benzene
HBA-HBDd
Ar-NHB-
HBAe
38.8
2.28
1.34
0.37
0.65
0.466
0.111
0.30763
0.00265
333
336
419
387
6.38
6164
3922
1.501
3.942
aDCM
NHBc
9.08
4.335
47.24
38.66
1.88
32.7
20.3
7.52
80.7
–
1.424
1.356
1.479
1.431
1.37
0.45
0.24
1.987
1.61
0.31
0.547
2.3703
0.55
0.89
–
0.3086
0.1173
0.4444
0.7901
0.0062
0.7654
0.5525
0.2068
1
0.21842
0.16557
0.26337
0.27522
0.00041
0.30859
0.27673
0.20895
0.32132
–
334
335
344
340
332
337
339
339
333
340
331
403
388
422
430
356
429
414
404
431
420
427
4.229
4.568
5.721
4.299
2.298
4.521
4.415
4.493
1.757
–
5126
4078
5373
6156
2031
6364
5344
4746
6828
5602
6792
aDEE
HBAc
aDMSO
HBAc
aEG
HBA-Dc
NHBc
Hexane
Methanol
2-Propanol
aTHF
HBA-Dc
HBA-Dc
HBAc
1.3284
1.3776
1.407
1.33
Water
HBA-Dc
–
bDMSO-d6
bMethanol-
d4
–
–
–
–
–
–
–
–
–
a
The abbreviations in the table corresponds to DCM = Dichloromethane, DEE = Diethyl ether, DMSO = Dimethyl sulfoxide, EG = Ethylene Glycol and
THF = Tetrahydrofuran.
b
DMSO-d6 = Deuterated DMSO and Methanol-d4 = Deuterated methanol.
c
HBA = Hydrogen bond acceptor, HBD = Hydrogen bond donor, NHB = Non-hydrogen bonding, HBA-D = amphiprotic hydrogen bond acceptor and donor,
Ar = Aromatic solvents.
d
e
This solvent usually act as non-hydrogen bonding solvents, but has shown weak HBD properties with strong HBA indicator solutes.
This aromatic solvent is usually weak hydrogen bond acceptors, but has also sometimes behaved as non-hydrogen-bonding solvents.
3

M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
corresponds to fluorescence quantum yield, integrated area under the
curve of fluorescence spectra, absorption intensity and refractive index;
respectively. The subscripts “x” has been designated for the unknown
sample and “s” stands for standard. The standard used for these calcu-
lations is Quinine sulfate in 0.1 N H2SO4 having quantum yield value of
0.546 [56].
orders were assigned and force field specific partial charges were
generated using the default preparation wizard and manually verified.
For the simulation in different explicit solvents, the simulation box was
filled with the respective pre-optimized solvent models (water, meth-
anol, acetonitrile, DMSO, benzene and n-hexane). Pre-optimized solvent
models for simple point charge (SPC) water, DMSO and methanol was
available by default. Solvent models for acetonitrile, benzene and
n-hexane were built by optimizing 512 solvent molecules each in cubic
periodic boxes. All the solvated IOC systems were electroneutral and
therefore no ions were required to balance the charge: no salt has been
added either. The simulations were run in OPLS (optimized potential for
liquid simulations) force field [65]. The systems were equilibrated
following the default five step relaxation protocol starting with Browa-
nian dynamics for 100 ps with restraints on solute heavy atoms at NVT
(with T =10 K) followed by 12 ps dynamics with restraints at NVT (T
=10 K) and then at NPT (T =1 K) using Berendsen method. Then the
temperature was raised at 300 K for 12 ps followed by 24 ps relaxation
step without restraints on the solute heavy metal [66]. The final MD
simulations were run in NPT ensemble with constant pressure of 1 bar
and temperature of 298.15 K for 1.2 ns each. RESPA (reference system
propagator algorithm) integrator was used with near, far and out time
steps of 2, 2 and 6 fs; respectively. The isotropic pressure was applied
using the Martyna-Tobias-Klein barostat method with relaxation time of
2 ps. The Nose-Hoover chain thermostat method was used with relaxa-
tion time of 1 ps. Long-range coulombic interaction was treated with the
PME (particle mesh Ewald) method. For short-range coulombic in-
teractions, the cut off radius was 9 Å [64,67]. Interaction energies (van
der Waals’ and Coulombic), radial distribution function (RDF; g(r)) were
computed on the simulation trajectories.
For the picosecond resolved excited state lifetime measurements, the
commercial time-correlated single- photon counting (TCSPC) set up
from Edinburgh instruments with MCP-PMT detectors was used. Details
of the time resolved fluorescence set up have been discussed in previous
publications by Pal et al. [57]. For TCSPC measurements, the picosecond
pulsed laser diode was employed as the excitation source of 375 nm with
instrument response function (IRF) of 75 ps. The decay was obtained at
emission wavelength of 500 nm at the polarizer angle of 55◦ while the
excitation was vertically polarized. In order to eliminate all the possi-
bility of the scattered excitation light, a long pass filter with cut-off at
400 nm was incorporated in the emission channel. The obtained pico-
second resolved fluorescence transients were fitted using
multi-exponential functions. The average lifetime of decay for IOC
molecule has been determined using the equation described below [55].
τavg. = a1τ1 + a2τ2 + a3τ3
(4)
The values of rate constant for radiative and non-radiative decay
process have been determined using the two equations mentioned below
[55].
ɸF
τavg.
1
τavg
kr =
and
= kr + knr
.
(5)
Here, τ1, τ2 and τ3 are the three components of the decay time of IOC in
presence of different solvents and an represents their corresponding
relative weightage. Here, kr and knr are the radiative and non-radiative
decay rate constants, respectively. The symbols ɸF and τavg corre-
sponds to the fluorescence quantum yield and average lifetime of the
excited state of IOC molecule.
3. Results and discussion
The primary aim of the study was to get basic understanding about
the stereochemistry of the ground state of the IOC molecule and then to
explore the phenomena of solvatochromism on the IOC molecule. The
extent and reasons of effect of solvent polarity on the photophysical
properties of IOC has also been scrutinized with the help of various
theoretical and experimental techniques.
All the measurements were done at 25 ◦C.
2.5. Computational studies
Structure of the stereoisomers of isoxazole derivative of curcumin
(IOC) were geometry optimized at the level of density functional theory
(DFT) using CAM-B3LYP exchange correlation functional and Pople’s
double zeta basis set 6ꢀ 31+g(d) with diffuse and polarization function
on heavy atoms [58]. CAM-B3LYP uses the long range corrected version
of B3LYP with Coulomb-attenuating method (CAM- B3LYP) [59,60].
Apart from the gas phase (in vacuo) calculations, all the optimizations
were done in polarizable continuum model (IEFPCM) of respective sol-
vents, where the molecule was placed in a solvation cavity and a con-
stant dielectric field was assumed on the outside [61,62]. In addition to
water, DMSO and methanol explicit solvent molecules hydrogen bonded
with IOC (three for water, two for DMSO and one for methanol) were
also used besides the implicit solvent model. UV–vis spectra of the most
stable conformation of IOC was computed using time dependent density
functional theory (TD-DFT) on the ground state equilibrium geometries
with same exchange correlations and basis sets, with which the geom-
etry was optimized [63]. In TD-DFT, vertical excitation was calculated
with linear response solvation followed by state specific solvation
correction. For emission calculations, a TD-DFT geometry optimization
with equilibrium linear response solvation was performed. The band-
width used for the calculation of both absorption and emission spectra is
0.333 eV.
3.1. DFT calculations
The first step in acquiring fundamental knowledge about a new
molecule is to know about its ground state structure. In order to explore
the ground state geometry of the IOC molecule, the DFT calculations
have been used as a tool. These calculations revealed that the isoxazole
derivative of curcumin (IOC) could probably exists in a planar confor-
mation where the electrons could get delocalized over the entire mole-
cule. Conceptually, in order to experience complete electron
delocalization over the molecule, the isoxazole ring of the IOC molecule
must be aromatic and for that the oxygen atom must donate its lone pair
of electrons. This has been depicted in Fig. 1a and it can be mentioned
that subsequent to electron donation, it is possible for the oxygen atom
to acquire a partial positive charge and the nitrogen atom to get a partial
negative charge. Further, in the ground state it is possible for the
molecule to exist in the zwitter ionic form, with the overall molecule
remaining electrically neutral in nature. This hypothesis has been very
well augmented by the calculation of Mulliken charge densities (in
vacuo) on each atom of the molecule through DFT calculations and is
represented in Fig. 1b. Computed charge densities showed similar trend
in implicit polar as well as non-polar solvents and the results have been
tabulated in supplementary information (SI: Table S1).
Classical MD simulations were performed using Desmond molecular
dynamics [64] program as implemented in Schrodinger Maestro mo-
lecular modeling suit (Academic release 2018ꢀ 1). The IOC molecule
was placed in a periodic boundary box with 1 nm buffer region on each
side so that the molecule does not interact with its periodic image. Bond
Fig. 1b shows the ground state optimized geometry of the most stable
stereoisomer of IOC. The ground state geometries of other possible
isomers are shown in Supplementary Information (SI: Fig. S1). Relative
energies and dipole moment of each isomer as calculated by the DFT
have been tabulated in Table S2. The isomers from IOC 1 to IOC 4 show
4

M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
Fig. 1. Electronic structure of the most stable conformation of IOC. (a) Schematic representation of the electronic delocalization over the entire molecule of IOC and
the appearance of partial positive charge on the O atom of the isoxazole moiety; (b) In vacuo ground state optimized geometry of IOC. Here, N in shown in blue and O
in red. Computed partial charges on N and O are shown. Dipole moment vector is shown with the yellow arrow; and (c) Frontier molecular orbitals of IOC.
trans- geometries whereas the isomers from IOC 5 to IOC 8 show cis-
geometries on either of the two double bonds present in the aliphatic
chain of the IOC molecule. The isomer labelled as IOC 4 in which both
the double bonds present in the aliphatic chain were having trans- ge-
ometries, was found to be energetically most favorable with a maximum
dipole moment of 10.48 D. However, the conformers from IOC 1 to IOC 4
are interconvertible by the means of rotation along the single bonds.
Amongst these conformers any conformation is possible but the most
favorable one is the IOC 4. The thermal energy (kBT) at room temper-
ature is 0.59 kcal/mol; therefore, the conversion of IOC 4 to any of the
other three conformations (i.e. IOC 1 to IOC 3) would require extra
amount of energy in terms of heat and light. Moreover, the stereoisomers
Fig. 2. Computed absorption and emission
properties of IOC and the electronic transitions.
(a) Computed absorption and emission spectra
of IOC in gas phase (in vacuo); (b) Natural
transition orbitals of IOC for the electronic
transitions to the first transition state; (c)
Comparison of computed absorption spectra of
IOC in water with that of the experimentally
observed spectrum and (d) Comparison of
computed emission spectra of IOC in water with
that of the experimentally observed spectrum.
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M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
from IOC 5 to IOC 8 are very unlikely as they are all cis- conformers and
since curcumin exists as all trans- conformation; IOC being its derivative
should also exist in trans-geometry. The relative energies of the con-
formers are represented in Table S2. Electron distributions in the fron-
tier molecular orbitals (FMO) of IOC are depicted in Fig. 1c. It is evident
from the figure that electrons in the highest occupied molecular orbital
remains delocalized all over the IOC molecule.
Fig. 2a shows the computed absorption and emission spectra of the
most stable conformer of IOC (i.e. IOC4) in gas phase (in vacuo). Ab-
sorption maxima in gas phase was observed at 314 nm and the emission
maxima was at 365 nm. Large Stokes shift, therefore, may be attributed
to the vibrational relaxation and change in the dipole moment (i.e. from
7.53 D to 7.73 D). Natural transitions orbitals (NTOs) for the S0 to S1
transition is depicted in Fig. 2b. NTOs show marked difference from that
of FMOs. Partial delocalization of electron in NTOs over one side of the
molecule indicates why the IOC shows much blue shifted absorption as
compared to curcumin. Furthermore, in order to have a clear under-
standing, the experimentally obtained absorption and emission spectra
of the synthesized IOC molecule in the presence of water has also been
plotted with the computationally calculated absorption/ emission
spectra (Fig. 2c and d). Fig. 2 clearly shows a very good agreement with
each other reaffirming that the ground state of IOC is planar and it re-
mains in all trans- conformation (E,E) with delocalization of the conju-
gated electrons across the isoxazole ring.
3.2. Steady state photophysical studies
Fig. 3 shows the UV–vis spectra of IOC in different solvents. It is
clearly evident that the molecule could have an absorption maxima in
the range of approximately 332 nm–344 nm (with a shoulder in the
range of 275 nm–300 nm) depending on the solvent polarity. According
to Maity et al., the peak at around 336 nm and the shoulder at around
295 nm (in the case of methanol as a solvent) can be ascribed to the π→
π∗ and n→π∗ transitions, respectively [47]. The values of experimentally
obtained absorption maxima of IOC in different solvents have been
tabulated in Table 1. A large amount of red shift from 332 nm in hexane
to about 344 nm in DMSO could be noticed for the π→
π∗ transitions.
These observations are in accordance with the fact that increment in the
solvent polarity can result in a red shift in the peaks for the π→
π∗
transition [68]. Also, based on the findings of the DFT calculations
depicted in Fig. 2b, it is clearly evident that the peak at around 333 nm
corresponds to the π→
π∗ transition. The shift in the absorption maxima
for DMSO has been found to be quite high in comparison to its fellow
polar aprotic solvents like DCM, THF and acetonitrile. This suggests that
there could be some specific interactions between DMSO and IOC,
probably involving the phenolic or the isoxazole ring of the molecule. In
addition, a large extent of hyperchromic shift could be observed in the
absorption spectra in case of solvents like acetonitrile and diethyl ether.
This could probably be attributed to the enhancement in the molar
excitation coefficient in case of different solvents and should not be
confused with the extent of solubility. Therefore, in order to get a clear
understanding about the extent of solubility, values of molar extinction
coefficient for IOC have been determined in all the aforementioned
solvents. In doing so, the absorption spectra were recorded for the
samples having varying concentration of IOC. Then after, a graph was
plotted between absorbance and concentration of IOC. The overlay of
the absorption spectra along with the linear plots have been provided in
the supplementary information (SI: Note 2 and left-hand sides of Fig. S2
(non-polar solvents), S3 (polar aprotic solvents) and S4 (polar protic
solvents)). These values have been tabulated in Table 1.
Fig. 3. The experimentally obtained absorption spectra of IOC in the presence
of (a) non-polar solvents (Benzene, Diethyl ether and Hexane); (b) polar aprotic
solvents (DCM, Acetonitrile, DMSO and THF) and (c) polar protic solvents
(Ethylene glycol, Methanol, Water and 2-Propanol). Inset in each graph shows
the corresponding intensity normalized graph of IOC in presence of respec-
tive solvents.
solvent polarity and the emission maxima varied in the range of 356 nm
(in hexane) to 431 nm (in water). The values of emission maxima for
each solvent are tabulated in Table 1. It is evident that, a large extent of
red shift for the emission maxima could be observed in case of polar
protic solvents (like ethylene glycol, methanol, 2-propanol and water).
But an intermediate to a very low shift in the emission maxima could be
observed for polar aprotic (like acetonitrile, DCM, DMSO and THF) and
non-polar (like benzene, DEE and hexane) solvents, respectively. Inter-
estingly, in case of polar aprotic and non-polar solvents a shoulder at the
red end of the main peak (around 460 nm) could be observed in the
Fig. 4 shows the fluorescence emission spectra of IOC in different
solvents. The effect of excitation wavelengths on the emission spectra
was also monitored but no change in the nature of spectrum could be
observed and the overlay of excitation wavelength dependent emission
spectra has been depicted in supplementary information (Fig. S5). In
general, the emission maxima for IOC increased with increase in the
6

M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
supplementary information. (SI: right hand sides of Fig. S2 (non-polar
solvents), S3 (polar aprotic solvents) and S4 (polar protic solvents)).
Similarly to the absorption spectra, a linear plot could be obtained for
emission spectra as well, without any significant effect in the emission
maxima or the nature of the emission spectra.
Furthermore, in order to completely overshadow the possibility of
inner filter effect, the overlay of the normalized absorption and emission
spectra of IOC in different solvents have been plotted. This overlay has
been plotted in six different solvents which include benzene, diethyl
ether, acetonitrile, DMSO, methanol and water. The plots have been
represented in the supplementary information (SI: Fig. S6). This figure
clearly demonstrates that the overlap in the absorption and emission
spectra is very small. Also, the samples used for the analysis were very
dilute (2 μM) having optical density ≤ 0.1. Therefore, the chances of
inner filter effect and reabsorption processes could be ruled out in these
cases.
Based on the data obtained from the absorption and emission
spectra, it could be seen that although changes in the polarity of solvents
could lead to very little shifts in the absorption spectra, a large extent of
red shift could be observed in the case of fluorescence spectra due to
solvent relaxation. Computed absorption and emission spectra in pres-
ence of implicit solvents echo these findings. Computed ground state and
excited state dipole moments of IOC in different solvents are listed in
Supplementary Information (SI: Table S3). It shows very small change in
the dipole moment of the excited state as compared to the ground state.
However, marked decrease in the dipole moment is observed in case of
n-hexane and benzene showing much less Stokes shift than in the polar
solvents. This implies that the variation in the solvents is not affecting
the ground state energy distribution significantly probably due to less
polar nature of the ground state than the excited state [21,69]. Using the
obtained values of absorption and emission maxima in the presence of
different solvents, the values of Stokes shift have been calculated and are
tabulated in Table 1 [17,19]. Similar studies have also been reported for
curcumin where depending on the solvent polarity the Stokes’ shift
value have remarkably varied in the range of 2000 cmꢀ 1 to 6000 cmꢀ 1
.
In case of curcumin, the values of Stokes shift have been reported to be
comparatively larger for H-bond donating-accepting solvents like alco-
hols, DMSO etc [70]. The values of Stokes shift somewhat follows similar
trend as that of curcumin. The huge variation in the values of Stokes shift
suggest that the dipole moment of the excited state of the molecule could
be higher than that of the ground state. This assumption is found to be
well augmented by the computed values (SI: Table S3). Plotting the
experimental values of Stokes shift against the ENT values for different
solvents, a linear correlation could be observed with the regression co-
efficient value of 0.75 (Fig. 5a). In order to verify whether this Stokes
shift was because of the solvent polarity (and not due to other factors
like dielectric constant/ viscosity) the values of Stokes shift for different
solvents were plotted against the reaction field parameter (Δf) in
accordance with the Lippert-Mataga equation. A linear increase in the
Stokes shift with the reaction field parameter with the regression coef-
ficient of 0.96 (n = 10) could be observed (Fig. 5b). Deviation from
linearity in this case could be observed in case of aromatic solvents i.e.
benzene. This could probably be because of the hydrophobic (pi-stack-
ing) interactions between the phenyl rings of solvent and that of the IOC
molecule.
Fig. 4. The experimentally obtained emission spectra of IOC in the presence of
(a) non-polar solvents (Benzene, Diethyl ether and Hexane); (b) polar aprotic
solvents (DCM, Acetonitrile, DMSO and THF); and (c) polar protic solvents
(Ethylene glycol, Methanol, Water and 2-Propanol). Inset in each graph shows
the corresponding intensity normalized graph of IOC in presence of respective
solvents. During the measurements, the samples were excited at their respective
absorption maxima and both the emission and excitation slits were kept
at 10 nm.
In order to get information about the emitting species in the excited
state, the excitation spectra were recorded. The excitation spectra of IOC
in different solvents have been provided in the supplementary infor-
mation (SI: Fig. S7). The effect of emission wavelength on the excitation
spectra was also monitored in both the red as well as blue wavelength
ends but no significant change in the nature of spectrum could be
observed. The overlay of the excitation spectra at different emission
wavelength has been specified in the supplementary information (SI:
Fig. S8). However, the width of the excitation spectra was larger as
compared to the absorption spectra. Similar to the absorption spectra,
emission spectra. However, this shoulder was completely absent in the
presence of polar protic solvents. Moreover, in order to check the effect
of concentration of IOC in different solvents on its emission spectra, the
concentration dependent emission measurements have been performed.
The overlay of concentration dependent emission spectra in different
solvents and their respective linear plots have been represented in
7

M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
In order to get information about the probability to find a particle at
a certain distance from the particle used as reference, radial distribution
function (RDF) could be utilized [71]. In MD simulations, the atom-atom
RDF could be used to study the distances between two atoms which give
an atomic level insight into the stable non-bonded interactions [72]. The
solute-solvent radial distribution function; g(r) (RDF) graphs were ob-
tained from MD simulations. Fig. 7 represents the RDFs for IOC in the
presence of various solvents. The RDFs for IOC in presence of water is
represented in Fig. 7a. A peak ~2 Å is clearly visible in this graph which
–
could correspond to the hydrogen bond distance of N atom and OH
group of the IOC molecule with the water molecules. This could be
attributed to the H-bonding between these functional groups and the
water molecules. A small peak at this same position is also observed for
the methoxy (-OMe) group of the IOC. This may probably be due to the
close proximity of the methoxy group with the hydroxyl group of the
IOC molecule that forms a hydrogen bond. A similar kind of RDFs is also
obtained in case of methanol (Fig. 7b). In this case, the peak could be
observed to shift from ~2 Å to ~3 Å which typically corresponds to the
hydrogen bond donar-acceptor distance. In case of polar aprotic solvents
like DMSO and acetonitrile (Fig. 7c & d) the observations are completely
different. The MD simulations have divulged that DMSO being a
hydrogen bond acceptor type of molecule, could form hydrogen bond
with the peripheral hydroxyl group of the IOC molecule. This is evident
from the RDFs in case of DMSO, where there is a peak ~2.5 Å only for
–
the OH group and not for the nitrogen atom. It could be because of
these interactions that DMSO shows such a high red shift in the ab-
sorption as well as emission spectra despite being a polar aprotic solvent.
As apparent from the RDFs in the presence of acetonitrile, there are no
specific strong interactions with the IOC molecule. Furthermore, the
observations in case of benzene are quite surprising (Fig. 7e). The RDFs
shows the formation of somewhat ordered structure of the benzene
solvent molecules surrounding the IOC molecule from the center of mass
of the benzene molecule, the peak is at ~5 Å. This could be attributed to
the π-π stacking of the benzene ring with the phenolic as well as iso-
xazole ring of the IOC molecule. All these observations could also be
observed in the MD simulation snapshots taken at definite time intervals
(SI: Video S1-S6). In case of aliphatic non-polar solvent like hexane also,
the solvent molecules are equidistant from all the atoms/groups of the
IOC molecule but the formation of an ordered structure is missing.
Therefore, these interactions could only correspond to the weak hy-
drophobic type.
Fig. 5. (a) Plot of Stokes shift (cmꢀ 1) vs. ETN values for different solvents and
(b) represents the plot of Stokes shift (cmꢀ 1) vs. Δf (reaction field parameter)
according to the Lippert-Mataga equation.
two peaks in the excitation spectra could be observed, one at around
340 nm and the other one around 290 nm. Therefore, from the ab-
sorption, emission and excitation spectra, it could be concluded that
there was only one specie in the sample and there was no contamination
from any other absorbing or emitting species.
Meanwhile, to complement these results, the H-bond distance cal-
culations with solvents were done using the DFT method. The bond
–
distance between the nitrogen atom and the OH group of the water
and methanol molecule was found to be 1.83 Å and 1.80 Å; respectively.
–
Whereas in case of DMSO, the bond distance between the OH group of
3.3. MD calculations
IOC molecule and the oxygen atom of the DMSO molecule was found to
be 1.77 Å. Therefore, it could be said that the DFT results of bond dis-
tance calculations convey that the strength of H-bond formed by DMSO
is much stronger than that formed by other polar protic solvents like
water and methanol.
The classical MD simulations with explicit solvents have been used to
determine the coulombic as well as van der Waals’ interaction energies
with the solvents. Fig. 6 depicts the graphs showing the interaction
energies of IOC in the presence of different solvents. As clearly shown in
Fig. 6a, both the energies could equally contribute in case of water. In
case of other polar protic solvents like methanol (Fig. 6b), the van der
Waals’ forces have slightly more contribution in the interaction with the
IOC molecule which could probably be due to the presence of additional
methyl group in methanol. In case of polar aprotic solvents like DMSO
and acetonitrile (Fig. 6c & d), the major contribution for interactions
between IOC and solvent molecules was found to be from the van der
Waals’ one. Whereas, in case of non-polar solvents like benzene and
hexane (Fig. 6e & f), since, these solvents cannot have any type of
participation from the coulombic energy, only van der Waals’ forces
were found to be responsible for the interactions between IOC and sol-
vent molecules. With the reducing polarity of the solvent, coulombic
contributions decrease and van der Waals’ interactions increase. These
observations are in synchrony with the expected behavior of a molecule
in solvents with the decreasing polarity.
3.4. Fluorescence quantum yield and time-resolved studies
The fluorescence quantum yield of IOC in presence of all the afore-
mentioned solvents with varying solvent polarity have been calculated
using quinine sulfate in 0.1 N H2SO4 as the reference. The values ob-
tained have been tabulated in Table 2. From the values it could be
observed that the fluorescence quantum yield is lower in non-polar
solvents rather than in polar solvents (including both polar protic and
polar aprotic solvents). Also, the values are even higher in polar protic
solvents (excluding water) like in ethylene glycol, methanol and prop-
anol. The exceptionally high value has been obtained in case of DMSO
indicating the presence of some specific solute-solvent interactions be-
tween DMSO and IOC molecules. Overall, it could be said that IOC has
comparatively higher fluorescence yield in the solvents that falls under
8

M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
Fig. 6. The computed coulombic and van der Waals’ interaction energies of IOC in the presence of (a) water; (b) Methanol; (c) DMSO; (d) Acetonitrile; (e) Benzene
and (f) Hexane as obtained through MD stimulations.
the category of Hydrogen bond accepting-donating type.
THF, acetonitrile etc. (Fig. 8b) gave larger values of average lifetime in
comparison to the polar protic solvents like methanol, ethylene glycol,
water etc. This could be ascribed to the deactivation of the excited state
majorly through non-radiative processes in polar solvents [75]. In other
words, it could be said that the in case of polar solvents, the excited state
of the IOC molecule majorly deactivates through non-radiative pathway
thereby decreasing the average excited state lifetime. Whereas, in case
of non-polar solvents the radiative processes predominates for the
deactivation of the excited state of IOC and therefore, comparatively
higher values of average lifetime could be obtained [76]. It has been
reported that in such cases it is assumed that the nature of excited state
of IOC is different in non-polar solvents than in other solvents [9].
Typically, the trend for the value of average excited state lifetime in
polar protic solvents followed the order as Ethylene Glyco-
l > Methanol > Propanol > Water. Based on this information it could be
interpreted that the fast decay in case of polar protic solvents could
probably be due to the hydrogen bonding between IOC molecule and the
solvent molecules. Moreover, the fastest lifetime could be obtained in
case of DMSO and this could be attributed to the formation of a stronger
H-bond between DMSO and the hydroxyl group of the IOC molecule.
Based on the fluorescence quantum yield and lifetime measurements,
the values of rate constant for the decay of the excited state through
radiative (kr) and non-radiative (knr) pathways have been calculated.
These values have been tabulated in Table 2. It could be observed that
the values of both kr and knr strongly depends on the type of solvent used.
Moreover, in order to get an insight about the excited state dynamics
of the IOC molecule, the picosecond resolved fluorescence decay tran-
sients of IOC molecule under different solvents were recorded (Fig. 8).
Time resolved fluorescence decay of IOC could be characterized by
triexponential fitting parameters. Such kind of transients of IOC in ho-
mogenous solvent have also been observed for some other fluorescent
dyes including some coumarin derivatives [73,74]. This implies that
three different kinds of processes are involved in the deactivation of the
excited state of this potential drug molecule. The values of each
component of the decay profile of IOC molecule along with their per-
centage contribution in different solvents are tabulated in Table 2. While
working with different solvents it could be noted that the first compo-
nent was around 30 ps, the second component ranged from 150
ps-700 ps and the range of the third component was from 1 ns to 3 ns.
Further, while contribution from the third component was almost
negligible for the polar protic and polar aprotic solvents, pronounced
contribution could be articulated by the category of non-polar solvents
(especially hexane). In general, the average lifetime for the decay of the
excited state of IOC molecule was observed to be maximum for
non-polar solvents. Fig. 8a delineates the excited state decay profiles of
IOC in non-polar solvents like benzene, diethyl ether and hexane. The
slowest decay could be observed in case of benzene for which the
average fluorescence lifetime was close to 826 ps. On the other hand,
while dealing with polar solvents, the polar aprotic solvents like DCM,
9

M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
Fig. 7. The computed RDF plots of particular atom/ group of the IOC molecule in the presence of (a) water; (b) Methanol; (c) DMSO; (d) Acetonitrile; (e) Benzene
and (f) Hexane as obtained through MD stimulations.
Table 2
Lifetime of picosecond time-resolved fluorescence transients of IOC in the presence of different solvents.
Sample name
τ1 (ps)
τ2 (ps)
τ3 (ps)
τavg. (ps)
χ2
ɸx
kr (sꢀ 1) (×108)
knr (sꢀ 1) (×109)
Acetonitrile
Benzene
aDCM
30 (78.23)
40 (30.77)
33.5 (65.14)
36.7 (56.31)
30 (81.21)
33 (40.56)
37 (60.91)
32 (71.94)
35.5 (72.26)
32 (81.75)
30 (92.61)
30 (78.65)
32.5 (70.92)
305.5 (15.64)
705.5 (26.92)
361.2 (18.55)
350.3 (17.47)
142.4 (18.18)
178.6 (57.55)
333.5 (20)
1532 (6.12)
1476.6 (42.31)
1461.2 (16.31)
1415.4 (26.21)
1524.1 (0.61
1277.2 (1.89)
3092.1 (19.09)
1099.9 (4.31)
1509.1 (1.46)
1762.8 (5.41)
1964.7 (1.14)
1425 (1.22)
165.07
826.96
327.15
452.9
59.49
140.25
679.5
106.03
99.51
154.45
62.95
70.1
1.077
1.05
0.046
0.04
0.056
0.042
0.076
0.075
0.032
0.06
0.075
0.057
0.004
–
2.82
0.49
1.70
0.93
12.56
5.38
0.47
5.68
7.58
3.72
0.68
–
5.78
1.16
2.89
2.11
15.52
6.61
1.42
8.86
9.29
6.10
15.84
–
1.098
1.019
1.277
1.175
1.046
1.113
1.234
1.137
1.282
1.216
1.122
aDEE
aDMSO
aEG
Hexane
Methanol
2-Propanol
aTHF
149.7 (23.74)
197.2 (26.27)
257 (12.84)
Water
205.5 (6.25)
144.7 (20.12)
172.8 (27.66)
bDMSO-d6
bMethanol-d4
1731.3 (1.42)
95.4
–
–
–
a
The abbreviations in the table corresponds to DCM = Dichloromethane, DEE = Diethyl ether, DMSO = Dimethyl sulfoxide, EG = Ethylene Glycol and
THF = Tetrahydrofuran.
b
DMSO-d6 = Deuterated DMSO and Methanol-d4 = Deuterated methanol. ɸx corresponds to quantum yield of IOC in presence of different solvents.
The values also indicate that the non-radiative processes predominated
over the radiative ones in case of polar protic solvents and therefore, the
lifetime is lower in those solvents.
between the IOC molecules and the various solvent molecules, the effect
of deuteration was studied in detail. With this intention, two deuterated
solvents (DMSO-d6 and Methanol-d4) were chosen on the grounds of
one being from the hydrogen bond acceptor family and another from the
hydrogen bond donor family of solvents. For this analysis, different
steady state and time-dependent spectroscopic techniques were utilized.
Firstly, the steady state absorption spectra of the IOC molecules in the
3.5. Effect of deuterated solvents
In order to gain further insight about the nature of interaction
10

M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
major change in the position of fluorescence maxima (SI: Fig. S9c & d).
This could confirm that intermolecular hydrogen transfer is not the sole
reason for the red shift in the emission maxima for other polar solvents.
Also, it could be said that the solubility of IOC molecule does depend on
the H-bonding ability of the solvent molecules. Based on the absorption
and emission spectra it could be interpreted that deuteration of the
solvents could only affect the ground state of the molecule but not the
excited state. Further, upon deuteration, the nature of excitation spectra
was found to be almost similar to that in the non-deuterated solvents (SI:
Fig. S9e & f).
Fig. S9g (Supplementary Information) shows overlay of the decay
transients of the excited state of IOC molecule upon deuteration. It has
already been established that typically the average lifetime of curcumin
is extremely fast because of the ESIPT (Excited State Intramolecular
Proton Transfer) process [21]. The main contribution of ESIPT is from
the diketo group of this molecule. Therefore, upon deuteration, the
decay of the excited state of curcumin is seen to get slower [20]. Since in
the case of IOC molecule, the diketo group of curcumin is blocked by the
formation of 5-membered isoxazole ring, there should not be any ESIPT
process. This observation could be verified by the TCSPC studies per-
formed on the IOC molecule in presence of non-deuterated as well as
deuterated solvents. The average lifetime of the IOC molecule in the
presence of DMSO and DMSO-d6 as well as in methanol and meth-
anol-d4 were found to be almost equivalent. This could be explained by
the fact that DMSO, being an H-bond acceptor type of solvent, could only
–
form H-bonds with the peripheral OH groups of IOC molecule leaving
the lifetime of the IOC molecule in presence of DMSO-d6 unaltered.
Upon deuteration, the nature and the extent of H-bonding would not be
permuted. However, in case of methanol, it is expected that H-bonding
–
can occur with the solvent molecules utilizing both the OH groups and
through the nitrogen atom of the isoxazole ring of the IOC molecule.
Upon deuteration, though the H-bonding through the nitrogen atom
–
would be disturbed, that with the OH group would still remain intact.
Since the later one is having the major contribution, the average lifetime
in case of methanol-d4 was also found to be equivalent to its
non-deuterated counterpart.
4. Conclusion
The photophysical properties of isoxazole derivative of curcumin
(IOC) have been studied in presence of various polar protic, polar
aprotic and non-polar solvents. Herein, the IOC molecule has been
proved to bear a planar structure where the electron gets delocalized
over the whole molecule. Based on the calculations of the charge dis-
tribution it could be confirmed that the nitrogen acquires a partial
negative charge whereas oxygen of the isoxazole ring remains partially
positively charged. The electronic structure calculations with DFT also
demonstrated that the most stable stereoisomer is the one in which both
the aliphatic double bonds are having trans- geometries; i.e. (E,E).
Studies of solvatochromism on the IOC molecule revealed that both the
absorption and emission maxima experienced a traditional red shift
upon increase in the solvent polarity. In case of DMSO, an unexpectedly
large red shift in both absorption as well as emission spectra has been
analyzed along with the fastest decay of the excited state of the IOC
molecule. Based on the RDF analysis on MD trajectories followed by
DFT, it has been established that being an H-bond acceptor type of
category, DMSO forms a comparatively stronger H-bond with the hy-
droxyl group of the IOC molecule. Moreover, the slowest fluorescence
lifetime of the excited state of IOC has been observed in case of benzene
solvent. The MD calculations have also revealed that benzene forms an
Fig. 8. TCSPC studies performed on the IOC molecule in presence of (a) non-
polar solvents (Benzene, Diethyl ether and Hexane); (b) polar aprotic solvents
(DCM, Acetonitrile, DMSO and THF) and (c) polar protic solvents (Ethylene
glycol, Methanol, 2-Propanol and Water). The fluorescence decay transients
have been obtained at the emission wavelength of 500 nm using a filter
of 400 nm.
deuterated solvents were recorded. Though the variation in the λmax of
the IOC molecules was insignificant as compared to their non-deuterated
counterparts, there was a drastic blue shift in the shoulder (SI: Fig. S9a &
b) together with a profound decrease in the absorption intensity. The
decrease in the intensity of absorption could be ascribed to the low
solubility of IOC molecules in the deuterated solvents. This information
helps us in inferring that the solubility of the IOC molecule in different
solvents depends not only on the polarity but also on the H-bonding
ability of the solvent. Further, in the deuterated solvents, a drastic
decrease in the fluorescence intensity could be observed without any
ordered distribution around the IOC molecule through hydrophobic (π-π
stacking) interactions. The Fluorescence lifetime studies pointed to-
wards the excited state of IOC molecule relaxing via three probable
pathways, with the overall process of decay being comparatively slower
in the case of non-polar solvents. Upon deuteration of solvents, no sig-
nificant changes could be observed in the emission or excitation spectra.
11

M. Sharma et al.
Journal of Photochemistry & Photobiology, A: Chemistry 410 (2021) 113164
[12] A. Beeby, A.W. Parker, M.S. Simpson, D. Phillips, The effect of solvent deuteration
on the photophysics of sulphonated aluminium phthalocyanine, J. Photochem.
Photobiol. B Biol. 16 (1) (1992) 73–81.
Ultimately, from all these results it could be concluded that H-bonding is
not the sole reason for extraordinary photophysics of IOC molecule but
rather there is an interplay of factors like solvent polarity, viscosity,
dielectric constant, hydrogen bonding ability etc.
[13] S. Paul, P.W.S. Heng, L.W. Chan, Optimization in solvent selection for chlorin e6 in
photodynamic therapy, J. Fluoresc. 23 (2) (2013) 283–291.
[14] P.F. Aramendia, M. Krieg, C. Nitsch, E. Bittersmann, S.E. Braslavsky, The
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CRediT authorship contribution statement
[15] J. Dey, I.M. Warner, Spectroscopic and photophysical studies of the anticancer
drug: camptothecin, J. Lumin. 71 (2) (1997) 105–114.
Manisha Sharma: Writing - original draft, Formal analysis, Meth-
odology, Conceptualization, Investigation, Writing - review & editing.
Uttam Pal: Formal analysis, Methodology, Software, Writing - review &
editing. Mamta Kumari: Validation, Investigation, Formal analysis,
Writing - review & editing. Damayanti Bagchi: Validation, Formal
analysis. Swati Rani: Validation, Formal analysis. Dipanjan Mukher-
jee: Validation, Formal analysis, Writing - review & editing. Arpan
Bera: Validation, Formal analysis. Samir Kumar Pal: Conceptualiza-
tion, Resources, Validation, Writing - review & editing. Tanusree Saha
Dasgupta: Conceptualization, Resources, Validation, Software, Writing
- review & editing. Subho Mozumdar: Conceptualization, Resources,
Validation, Writing - review & editing, Supervision.
´
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Declaration of Competing Interest
The authors declare that they have no known competing financial
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Acknowledgements
M.S. acknowledges the UGC, India for the financial support. Thanks
are due to the Department of Chemistry, and U.S.I.C., University of
Delhi, New Delhi as well as Technical cell, S.N.B.N.C.B.S., Kolkata for
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