Synthesis, solution studies and DFT investigation of a tripodal ligand with 3-hydroxypyran-4-one scaffold

Article abstract of DOI:10.1007/s10847-021-01088-0

Hydroxypyranones form very stable complexes and possess varied uses in medical applications. They are promising chelators for treating iron overload diseases as they form stable complexes with Fe³⁺. A novel tripodal ligand tris[(5-hydroxy-4-oxo

Full text of DOI:10.1007/s10847-021-01088-0

Journal of Inclusion Phenomena and Macrocyclic Chemistry
https://doi.org/10.1007/s10847-021-01088-0
ORIGINAL ARTICLE
Synthesis, solution studies and DFT investigation of a tripodal ligand
with 3‑hydroxypyran‑4‑one scafold
Shailza Sharma1 · Minati Baral1 · Dibyajit Dash2 · B. K. Kanungo2
Received: 30 March 2021 / Accepted: 7 June 2021
© The Author(s), under exclusive licence to Springer Nature B.V. 2021
Abstract
Hydroxypyranones form very stable complexes and possess varied uses in medical applications. They are promising chela-
tors for treating iron overload diseases as they form stable complexes with Fe3+. A novel tripodal ligand tris[(5-hydroxy-4-
oxo-pyran-2-yl)methyl] benzene-1,3,5-tricarboxylate (TBHPY) was synthesized and characterized by several spectroscopic
techniques like UV–Vis, FT-IR, 1HNMR, 13CNMR and mass spectrometry. The coordination behavior of the ligand TBHPY
was investigated with proton and trivalent metal ions viz., Fe(III), Al(III) and Cr(III) by potentiometric and spectrophoto-
metric methods. The studies revealed four species viz., L3−, LH2−, LH2− and LH3 for the ligand while ML, MLH and MLH2
species for all the three metal ion complexes. In addition, only aluminium formed MLH−1, MLH−2 and MLH−3. Quantum
mechanical studies at DFT level validated the geometrical, spectroscopic, electronic and photophysical properties of the
neutral and deprotonated states of the ligand, and its metal complexes. The ligand showed a scorpio-type geometry with
the presence of face-to-face stacking and hydrogen bond, whereas the neutral metal–ligand complexes displayed a distorted
octahedral structure.
Keywords Tripodal chelator · Hydroxypyranone · DFT · Potentiometric · Spectrophotometric
Introduction
and analysis of solvent and chelation therapy [2]. Kojic
acid (5-hydroxy-2-hydroxymethylpyran-4-one), belonging
to a class of hydroxypyranone, is a biologically signifcant
fungal secondary metabolite that originated from diferent
genera of fungi, e.g., Aspergillus, Penicillium, and Aceto-
bacter, and possesses plentiful pharmacological properties
[3]. It is renowned for its antibiotic, antibacterial, antifungal
properties and the oxygen uptake rate when the o-dihydroxy
and trihydroxy phenols are oxidized by tyrosinase [4]. It is
widely used to preserve the color of substances in food, such
as preventing oxidative browning on cut fruits, preserving
pink and red colors of seafood, and immensely useful in
cosmetics also as skin whitening agents [5]. More impor-
tantly, it has found great utility as active biological deriva-
tives for chelating Fe(III) [6, 7]. The naturally occurring
metal chelators, siderophores, form stable complexes with
the metal ions with high binding constants. For example,
enterobactin, a fascinating Fe(III) chelator that contains a
tri-lactone ring as a central unit, three pendant side chains
having amide linkage as spacers, and catechol moieties as
the binding units (Fig. 1) show stability constant value of
1049. The unique structures of the siderophores account
for the high thermodynamic stability and kinetic inertness.
Hydroxypyranones and hydroxypyridinones are promising
chelators having hydroxylic and ketonic oxygen atoms at
suitable sites on the heterocyclic systems, forming stable
complexes with metal ions by the formation of fve-mem-
bered chelate rings [1]. Both the chelators have potential
uses and applications [2]. Hydroxypyranones show great
utility in food as natural products and as analytical rea-
gents for spectrophotometric and colorimetric determina-
tion of various elements and in diagnosis and therapy. A
wide range of hydroxypyridinones and their metal com-
plexes can be synthesized from hydroxypyranones precur-
sors; the former fnds useful application in the extraction
Dedicated to Dr. Jacques Vicens
* Minati Baral
minatibnitkkr@gmail.com
1
Department of Chemistry, National Institute of Technology,
Kurukshetra, Haryana 136119, India
2
Department of Chemistry, Sant Longowal Institute
of Engineering & Technology, Longowal 148106, India
Vol.:(0123456789)
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Journal of Inclusion Phenomena and Macrocyclic Chemistry
Fig. 1 Molecular structures of a Kojic acid, b Deferiprone, and c Enterobactin
Considering these facts, many artifcial siderophore mimics
have been developed by utilizing binding units that possess
efective chelating ability towards hard metal ions such as
hydroxypyridinones, hydroxypyranones, 8-hydroxyquino-
line, hydroxamates, catechol, pyrogallol, aminocarboxylates
and hydroxycarboxylates [1]. The toxicity due to the accu-
mulation of metal in specifc organs is of grave concern that
can be controlled by using suitable chelating agents [8, 9].
Thus, from the past few decades, there is an emerging inter-
est in developing chelators to be used in chelation therapy
for treating diseases associated with metal overload [9–11].
The chelating agents nowadays are usually used like des-
feral, deferiprone, and deferasirox; all efective though,
possess some drawbacks [12]. Iron plays a critical role in
various physiological processes like oxygen uptake, oxygen
metabolism, and electron transfer [13, 14]. Excess free iron
helps in the production of Reactive oxygen species (ROS),
which results in severe organism dysfunctions [15]. Iron
overload originates the hereditary hemochromatosis, which
ultimately brings the damage of tissue and fbrosis with
irreparable damage to diferent organs [16]. Iron chelators
are gaining attention in the feld of medicine for the past few
decades to treat iron overload diseases [17, 18]. Aluminum,
a non-essential element, if present in excess, can cause dam-
age to the central nervous system and is probably linked to
various neurodegenerative diseases, like Alzheimer’s disease
and amyotrophic lateral sclerosis [19–21]. Trivalent chro-
mium acts as an essential nutrient and is extensively used
by humans and animals as a nutritional supplement. The
destruction in cultured cells exposed to Cr(III) compounds
in vitro has brought out the introduction of genetic damage,
which highlighted the concern that Cr(III) compounds may
employ genotoxic efects under certain circumstances [22].
Metal complexes formed from tripodal multidentate ligands
like enterobactin unveil unusual coordination, high kinetic
inertness, and thermodynamic stability [23, 24] due to the
unique geometry and saturation with six coordination sites.
A cautious choice of three distinct moieties (central unit,
connecting unit or spacer, and binding unit) is the basis for
designing and synthesizing coordination compounds with
preferred structural features and physicochemical proper-
ties [25] and numerous synthetic chelators diverse chelating
subunits have been developed till now [26].
Keeping in view the above, an attempt has been made
to develop and synthesize a new tripodal chelator, tris[(5-
hydroxy-4-oxo-pyran-2-yl)methyl]benzene-1,3,5-tricarboxy-
late, (TBHPY) (Fig. 2) by utilizing benzene as a central unit,
hydroxypyranone as chelating units connected through ester
link, and study its interaction with trivalent iron, aluminum
and chromium. The ligand-proton and the metal complex
formation equilibria with trivalent metal ions Fe3+, Al3+ and
Cr3+ ions are evaluated by potentiometric and spectrophoto-
metric methods. The Density Functional Theory (DFT) stud-
ies have been complemented to all experimental fndings and
establish the structure and bonding.The ligand-proton and
Fig. 2 Molecular structure of tris[(5-hydroxy-4-oxo-pyran-2-yl)
methyl] benzene-1,3,5-tricarboxylate (TBHPY)
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Journal of Inclusion Phenomena and Macrocyclic Chemistry
the metal complex formation equilibria with trivalent metal
ions Fe3+, Al3+ and Cr3+ ions are evaluated by potentiomet-
ric and spectrophotometric methods. The Density Functional
Theory (DFT) studies have been complemented to all experi-
mental fndings and establish the structure and bonding.
Results and discussion
Synthesis of the ligand TBHPY
To design the new hexadentate tripodal ligand TBHPY, the
benzene-1,3,5-tricarboxylate unit was selected as a basic
skeleton while the three hydroxypyranone subunits act as
binding components. The synthesis of the TBHPY was done
by following a general plan (depicted in Scheme 1). The
synthesis was initiated with the chlorination of the com-
mercially available starting material kojic acid with thionyl
chloride to produce chlorokojic acid by following the pro-
cedure [27]. The chlorokojic acid thus obtained in the frst
step was coupled with three moles of the sodium salt of tri-
mesic acid in DMF by slight modifcations in the procedure
[28]. The compound gave an air-stable brown product (m.p.
158 °C). It is partly soluble in most of the organic solvents
but completely soluble only in DMF or DMSO. The synthe-
Fig. 3 The infrared spectrum of TBHPY
at 3381 cm−1 was attributed to the O–H stretching of the
substituted hydroxypyranone present in the binding moiety.
The appearance of an additional peak at 3232 cm−1 due to
v(O–H) shows the existence of the intramolecular hydro-
gen bonding between two of the substituted hydroxypyra-
none scafolds. The absence of C–Cl stretching in the range
600–800 cm−1 confrms the formation of the product. The
peak at 920 cm−1 was ascribed to the C–H bending vibra-
tions of the aromatic benzene. The C–H bending vibrations
for the CH2 group was observed at 1448 cm−1. The peak at
1625 cm−1 due to the C=C stretching frequency of substi-
tuted hydroxypyranone moiety was also observed. The C–O
(ether) peak of hydroxypyranone binding scafold occurred
at 1103 cm−1.
1
sized ligand was characterized by TLC, FT-IR, H-NMR,
13C-NMR, mass (ESI–MS), UV–Visible spectra.
Characterization
Infrared spectra
1H‑NMR and 13C‑NMR
The FT-IR spectrum of the synthesized ligand was recorded
as KBr pellet and is shown in Fig. 3. The presence of an ester
linkage in the ligand was characterized by a characteristic
sharp peak for C=O stretching vibrations at 1737 cm−1, and
1234 cm−1 for C–O stretching frequency. The broad peak
The different chemical environments of the protons in
TBHPY were found through 1H NMR spectral data recorded
in deuterated DMSO. The spectrum is shown below in Fig. 4.
From the NMR spectrum of the ligand, it was observed that
O
OH
O
O
O
O
O
O
O
COONa
COONa
DMF, 4 hr, 110°C
OH
OH
SOCl 2
1 hr, Roomtemp
NaOOC
O
O
Cl
H O
O
O
O
O
O
O
OH
H O
Scheme 1 Synthesized ligand TBHPY with three hydroxypyranone based binding moieties
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Journal of Inclusion Phenomena and Macrocyclic Chemistry
Fig. 4 1H-NMR spectrum of
ligand TBHPY
there were fve chemically non-equivalent protons present
in the system. The aromatic protons (Ar–H) of TBHPY
in the central unit benzene were observed as triplet due to
meta-meta coupling in the aromatic region of the spectrum
that appeared at 8.69 ppm, 8.71 ppm, and 8.73 ppm (3H,
J=10 Hz). The protons of two methylene groups (−CH2 −)
in the ligand are deshielded one and occurred at 5.33 ppm
(6H, singlet). The proton of the hydroxyl group (−OH) pre-
sent in hydroxypyranone scafold occurred at 9.29 ppm (3H,
singlet). The remaining two chemically non-equivalent pro-
tons of the hydroxypyranone unit occurred at 8.14 ppm and
6.62 ppm.
non-equivalent carbon atoms present in the ligand, and all
could be identifed. The peaks obtained in the range of
112.87–173.53 ppm agree to the carbon of benzene and the
hydroxypyranone moiety. The peak at 62.61 ppm is attrib-
uted to three methylene groups in the spacers. The theoreti-
cal 13C NMR spectrum (Fig. S3) calculated by DFT method
also agree with the experiments.
ESI–MS spectra
The molecular mass spectrum of the ligand was recorded
by the high-resolution electrospray ionization mass spec-
trometer (ESI–MS), is depicted in Fig. 6. It showed a par-
ent molecular peak at m/Z 583.13 (calculated 582.06) for
M+H. The corresponding fragmented peaks are due to the
The carbon framework of the synthesized ligand was
evaluated through 13C-NMR spectral data as depicted in
Fig. 5, taken in deuterated DMSO. There are nine chemically
Fig. 5 13C-NMR spectrum of
ligand TBHPY
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Journal of Inclusion Phenomena and Macrocyclic Chemistry
WATERS,Q-TOF MICROMASS (ESI-MS)
SAIF/CIL,PANJAB UNIVERSITY,CHANDIGARH
Fig. 6 Mass spectrum (ESI–
Shailza S1_ 5 (0.137) Cm (4:9)
100
TOF MS ES+
583.1393
6370
6.37e3
MS) of TBHPY
584.2455
4782
382.2792
3888
459.2088
3494
460.1906
1843
384.2916
1727
338.4534
1261
385.2376
514
461.2152
394
415.2201
378
339.4580
354
335.1541
332
141.0621
281
59.8561
194
285.1101
227
0
m/z
60
80
100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440 460 408 500 520 540 560 580 600
the hydroxypyranone moieties. The protonation equilibria,
represented by Eq. (1)
LHn−1 + H
⇌
LHn
(n = number of protons)
(1)
were calculated by potentiometric titration within pH range
of 2.5–10.5 with KOH from the acidic pH, which was
attained by adding standard 0.1 M HCl at 25 °C (μ=0.1 M
KCl). Refnement of all the titration collected data was
done to evaluate the equilibrium constants by use of Hyper-
quad[30]. The three protonation constants determined are:
log K1 =9.77, log K2 =6.92, log K3 =6.16 correspond to the
three protonation phenolate sites of the compound.
Fig. 7 Electronic spectrum of TBHPY 10–3 M at 298 K
The spectrophotometric titrations were also performed
within the same pH range to supplement the potentiomet-
ric study. Analysis of the spectrophotometric data by using
the global ftting program Hypspec, also produced three
protonation constants. The results are in good agreement
with the results obtained for similar ligands (Table 1). The
electronic spectrum of the ligand TBHPY in its protonated
form exhibits a strong absorption band at 272 nm, ε=2.76 ×
103 M−1 cm−1 assigned to π–π* transition. Deprotonation of
the hydroxyl groups of the hydroxypyranone ring resulted in
a new peak, designated for the expected n-π* shift. The pH-
dependent species distribution curve is depicted in Fig. 8,
which signifes that in the acidic solution, the ligand initially
exists 99% as LH3. On increment of pH after successive
addition of KOH, deprotonation of the ligand occurs at pH
3.15 begins with the formation of LH2 species and exhibited
maximum concentration 54.6% at pH 6.55. Further deproto-
nation formed LH species at pH 5.07, forming a maximum
concentration of 92.39% at pH 8.32. Two isosbestic points
were observed in the pH-dependent electronic spectra of
TBHPY, indicating the presence of three types of absorb-
ing species. The spectrum of each individual species viz.,
fragmentation of the respective hydroxypyranone based
binding units are found at 459.21 and 335.15.
Electronic spectrum
The electronic spectrum of TBHPY recorded in 10–3 M in
pure DMSO is presented in Fig. 7. The UV–visible spectrum
showed a broad band at~272 nm (ε=2.76×103 M−1 cm−1)
due to π–π* transition.
Solution thermodynamics and ligand protonation
constants
The protonation constants of TBHPY were evaluated by
both potentiometry and UV–Visible spectrophotometry
methods [29]. The titrations were done in a highly aque-
ous medium (H2O: DMSO:: 9:1) due to solubility issues.
The neutral ligand is represented as LH3 with three poten-
tial protonation sites due to three hydroxyl oxygen atoms in
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Journal of Inclusion Phenomena and Macrocyclic Chemistry
Table 1 Comparison of protonation constants (Log K) of the ligand
L by potentiometric (A) and spectrophotometric (B) methods, and
some other hydroxypyranones derivatives for –OH protonation sites
of hydroxypyranone scafold reported in literature [31–33]
the metal–ligand system show deviation from the curve of
the ligand at the lower pH (<4) region suggesting complex
formation (Fig. 9).
The possible complex equilibria existed in the solu-
tion were studied. A number of species were assumed to
exist in solution in the entire pH range, and the complete
data were ftted into the global refning program. Difer-
ent models were tried to ft in with the data. The best ft
was obtained when the formation of three complex spe-
cies ML, MLH, and MLH2 was considered for iron and
chromium systems, whereas additional hydrolysis species
were indispensable for the aluminum system to match the
theoretical curve with the experimental one. The acquired
formation constants from the calculation are returned in
Table 2. The speciation curves for all the metal–ligand
systems are shown in Fig. 10. At low pH, all the metal ions
form MLH2 complexes. With the rise in pH, the deproto-
nation occurs from the –OH group of hydroxypyranone
moiety, developing simultaneous coordination to the
metal ion. The MLH2 species formation is predominant
at low pH with a maximum of 100%, whereas the neutral
ML species starts forming at pH > 5 and exists ~ 100% at
higher pH. MLH species for all three metal ions exist at
the intermediate pH with a maximum of nearly 40%. In
the case of aluminum, three additional hydrolysis species
viz.; MLH-1 and MLH-2 and MLH-3 were formed above pH
5 with a population ~ 60%; MLH-3 reaches 100% at higher
pH. In the case of Fe-TBHPY and Cr-TBHPY systems,
there was no formation of hydrolysis species. The stabil-
ity constants (log β) determined for the neutral complexes
of ML type are 26.57 and 25.58 for Fe and Cr systems,
respectively. In contrast, a lower stability constant (11.79)
in Al-TBHPY complex indicated weak complex formation.
The formation constants for all the species are enumerated
in Table 2.
Ligand
Log K1
Log K2
Log K3
9.77(A)
6.92(A)
6.16(A)
9.77(B)
6.90(B)
6.20(B)
Average Log K1–3
7.62
9.91
9.57
6.84
7.44
–
–
9.24
7.04
–
10.10
9.98
–
–
6.91
6.78
9.85
–
7.56
The interactions of the ligand with all the trivalent metal
ions were also evaluated spectrophotometrically (Fig. 11) by
a similar method that described in the proton-ligand equilib-
rium study in the entire pH range. As already discussed, the
ligand shows an absorption band at~272 nm in the UV–Vis-
ible region due to π→π* transition; on coordination to the
metal ions, there was a signifcant change in the absorp-
tion spectra. In all three cases, and at the lower pH~ 3.5,
the prominent π→π* band at~272 was retained. However,
upon successive addition of KOH the intensity of the elec-
tronic absorption band got decreased. With the increase in
pH, the bands got shifted after pH 7 onwards to a higher
wavelength λmax ~320 nm with a concomitant increase in the
absorption band’s intensity. The spectra of all the individual
species that existed during the spectrophotometric titrations
obtained from Hypspec, are shown at (d–f) in Fig. 11. The
log β values of all the complex species of the three metal
ions, obtained by both methods, are listed in Table 2.
−
L3−, LH2−, LH2 and LH3, calculated using the program
Hypspec obtained from the experimental data, are shown
at (b) in Fig. 8.
Complex formation equilibria
The complexation behavior of the ligand with the three
trivalent metal ions [Fe(III), Al(III), and Cr(III)] was also
investigated by potentiometric and spectrophotometric
titration methods. For the potentiometric process, titra-
tions were done in 1:1 metal–ligand molar ratios at 25 °C
in a highly aqueous medium (9:1:: H2O: DMSO) as in the
protonation study. The potentiometric titration curves for
1 3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
Fig. 8 a Absorption spectra of ligand TBHPY as a function of pH. b Absorption spectra of diferent species of the ligand. c Species distribution
curve of the ligand
Molecular modeling and computational methods
An appropriate single crystal could not be grown for X-ray
crystallography by any method, either slow evaporation
or vapor-difusion method when tried with diferent pure
solvents and a mixture of solvents. Therefore, a molecular
modeling study was performed to establish the structure and
bonding of the ligand and its complexes.
Fig. 9 Potentiometric titration curve of ligand and its metal com-
plexes in 1:1 metal to ligand ratio
Table 2 Log β values of the
Species
Fe
Log βA
Al
Log βA
Cr
Log βA
ligand-M(III) complexes
Log βB
Log βB
Log βB
by potentiometric (A) and
spectrophotometric (B) methods
ML
MLH
MLH2
MLH-1
MLH-2
MLH-3
26.57
33.38
39.73
–
–
–
26.55
33.39
39.51
–
–
–
11.79
17.03
21.22
5.63
−1.42
−9.38
11.86
17.19
21.20
5.31
−1.39
−10.01
25.58
31.88
38.10
–
–
–
25.38
32.43
39.18
–
–
–
100
100
80
60
40
20
0
100
80
60
40
20
0
CrLH
FeLH
2
2
AlLH
-
3
FeL
CrL
80
60
40
20
0
AlLH
Al
2
AlLH
AlLH
-
1
-
AlL
2
AlLH
FeLH
CrLH
3
5
7
9
3
5
7
9
3
5
7
9
pH
pH
pH
(a)
(b)
(c)
Fig. 10 Species distribution curves of a Fe(TBHPY), b Al(TBHPY), c Cr(TBHPY) computed by using Hyss
1 3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
Fig. 11 The pH-dependent absorption spectra of a Fe(TBHPY), b Al(TBHPY), c Cr(TBHPY); The absorption spectra of the diferent species
obtained from global ftting program for: d Fe3+, e Al3+ and Cr3+
Prediction of the ligand geometry
The ligand’s molecular structure after the geometry opti-
mization is shown in Fig. 12 along with other deprotonated
species. The molecular structure indicates an intramolecular
hydrogen bonding within the two hydroxypyranone units,
between −OH proton of one and oxygen of oxo group of
another unit. The studies revealed a Scorpio-like structure
for the ligand (LH3) and its ionic species (LH2− and LH2−)
shown in Fig. 12a–c. Whereas in L3− species, all the three
charged hydroxypyranone arms stay away from each other to
The quantum mechanical calculations were done for the
ligand and its deprotonated species were performed by the
DFT method using the hybrid functional GGA-BLYP-D3
employing basis set DZP. It is confrmed that the optimized
geometry of the ligand on potential energy surfaces is present
at true local minima, as evident from the calculated vibra-
tional spectrum, which contains no imaginary frequencies.
Fig. 12 Optimized structures of the ligand TBHPY, and its deprotonated species a LH3, b LH2−, c LH2−, d L3−
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Journal of Inclusion Phenomena and Macrocyclic Chemistry
exert the most negligible repulsion for achieving maximum
stability; hence, no hydrogen bond formation occurs between
the binding units, as displayed in Fig. 12d. The theoretical
results are in good agreement with the observed deprotona-
tion behavior of the ligand, as discussed previously.
The geometry of the molecules retained the same octahe-
dral structure; however, there was minimal change in the
geometrical parameters; for example, in the chromium
complex, the Cr–O bond length varied between 0.001 and
0.036 Å, whereas the O–Cr–O bond angle altered between
0 and 10 degree. Also, the energy of HOMO and LUMO
was decreased in solution resulting in an increase in
HOMO–LUMO energy gap to~0.004 Hartree. The coordi-
nates of the optimized geometry of all the complexes in the
gas phase and also, in the solvent (water) phase along with
their frontier orbital energy are given in the supplimantary
materials Tables S-2 and S3.
Prediction of the geometry of metal complexes
The ligand possesses six oxygen donor sites that can bind
to the metal ions in a hexadentate mode of coordination.
Several possible tridentate modes of coordination were
tried with molecular mechanics calculations by using the
UFF forcefeld and DFTB method, which were sterically
unfavorable; however, the bidentate mode of coordination
of each arm of hydroxypyranone units was favorable. From
the optimized geometry of the complexes, it was observed
that the ligand concentrates only at one side of the metal ion
rather than in an expected octahedron. The bond lengths and
the octahedral angles were far from expected. It is estab-
lished that, for transition metal ions in solution, the solvent
molecules can coordinate to the metal ion to prefer hexaco-
ordination. Keeping in view of above facts, one, two, or three
solvent water molecules were introduced to the coordination
sphere with simultaneous breaking one, two or three M–O
bonds. The molecular mechanics calculations of all probable
structures were performed, and the strain energies were com-
pared and are placed in the supplementary data (Table S1.
On the basis of the minimum strain energies (UFF), the
molecular formulae of the complexes were proposed to be
[Fe(TBHPY)(H2O)2], [Cr(TBHPY)(H2O)] and [Al(TBHPY)
(H2O)]. The DFTB studies also produced similar results. The
optimized hexacoordinate structures obtained from molecu-
lar mechanics and DFTB were further optimized by the DFT
with GGA/BLYP functional and DZ basis set to predict a
suitable structure for the complexes (Fig. 13). These struc-
tures were used for further studies.
DFT predicted IR, 1H NMR, 13C NMR of TBHPY
For confrming the IR frequencies obtained by the experi-
ment, theoretical calculations were performed by DFT at
GGA-BLYP-D3(Generalized Gradient approximation;
Exchange: Becke; Correlation BLYP) /DZP level. It was
found that the calculated IR frequencies differ slightly
from the experimental ones (Table 3); the diference may
be attributed to the fact that the observed spectra were
recorded in solid-phase, whereas theoretical spectra were
1
calculated in the gas phase. The theoretical H NMR and
13C NMR spectra were also evaluated for the ligand in the
gas phase by using GGA/OPBE functional and TZ2P-J basis
1
set (Table 3). The predicted IR, H NMR, and 13C NMR
spectra of the ligand are shown in supplementary informa-
tion at Figures S1–S3, respectively. A comparison of the
data obtained from experimental and theoretical results is
presented in Table 3.
Frontier molecular orbitals (FMO) analysis
Important information about the molecular systems can be
obtained from the frontier molecular orbitals. The global
chemical reactivity, stability, and structures are often
described by the Kohn–Sham density functional theory
using global reactivity parameters [34–42] like chemical
In order to get an insight in the change in the geometry
of the complexes in solution, the calculation was extended
for the optimization in water as solvent using COSMO.
Fig. 13 DFT optimized
structures of metal com-
plexes: Fe[(TBHPY)(H2O)2],
[Cr(TBHPY)(H2O)] and
[Al(TBHPY)(H2O)] obtained
by GGA/BLYP/DZP method.
Hydrogen atoms are kept hidden
for clarity
1 3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
Table 3 Calculated (GGA:
OPBE/TZ2P-J) for NMR,
(GGA-BLYP-D3) for IR and
experimental (d6-DMSO,
1H NMR
13C NMR
IR frequencies
Proton Theoretical Experimental Carbon Theoretical Experimental Theoretical Experimental
500 MHz) 1H NMR and 13
C
H1
H2
H3
H4
H5
8.10
5.38
6.87
7.07
9.44
8.71
5.33
6.62
8.14
9.29
C1
C2
C3
C4
C5
C6
C7
C8
C9
132.98
139.15
168.93
70.56
163.53
142.58
154.39
171.95
121.73
131.18
139.94
160.81
62.61
163.31
130.38
146.04
173.53
112.87
3411
3241
1679
1618
1455
1144
1115
925
3381
3232
1737
1625
1448
1143
1103
920
NMR chemical shifts (ppm) and
IR frequencies (ATR, cm−1) for
TBHPY
potential (μ), global hardness (η), global softness (S), elec-
trophilicity (ω), ionization potential (I), electron afnity (A)
and electronegativity (χ). The high chemical reactivity and
low kinetic stability of a molecule can be determined by the
use of the frontier orbitals energy gap. The HOMO (Highest
occupied molecular orbital) and LUMO (Lowest unoccu-
pied molecular orbital) are related to ionization potential and
electron afnity, respectively. In the ligand TBHPY, HOMO
is MO 108A (E= −5.68 eV) which is mainly a π bonding
molecular orbital comprising of 50.86% py, 26.60% pz and
2.00% px orbitals of the oxygen atom of the hydroxypyra-
none unit, while other contributions are from carbon atoms
of the same ring with 4.07% py, 2.64% pz, 3.63% s (1.99%
from carbon-33 and 1.64% from carbon-35) and 1.05%
essentially an antibonding π* orbital with a major contribu-
tion of pz orbitals (66.04%) of carbon atoms of the central
benzene and carbon of the carbonyl group attached to ben-
zene. The pz orbitals of oxygen atoms of the ester group
contribute 14.25%, and px orbitals of the carbon atom con-
tribute 2.79%. The diagrams of both the molecular orbitals
are depicted in Fig. 14.
The frontier molecular orbitals of iron and chromium
complexes of the ligand were obtained by employing
Restricted Openshell Hartree Fock (ROHF) calculations,
whereas RHF calculations were used for the aluminum
complex. In the complex [Fe(TBHPY)(H2O)2], the HOMO
(MO 121A) is a singly occupied molecular orbital (SOMO)
that has energy−0.147572 eV, and the LUMO (MO 122A)
with energy − 0.143835, resulting in an energy gap of
2
from dz orbitals. The LUMO, MO 109A (E= −3.26 eV) is
Fig. 14 Frontier Molecular Orbitals of TBHPY, [Fe(TBHPY)(H2O)2], [Cr(TBHPY)(H2O)] and [Al(TBHPY)(H2O)]
1 3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
0.101689 eV. The HOMO 121A has got contribution pre-
dominantly from the metal d-orbitals and comprises 41.99%
of dx2 –y2, 11.39% dxz, 3.94% dxy, 3.43% dz2 orbitals of iron,
and the rest contribution is from p- orbitals of carbon and
oxygen atoms of hydroxypyranone moiety. In LUMO 122A,
the metal orbitals have no contribution but contain a higher
π–orbital character with 31.89% C pz, 8.49% O pz, 5.45% of
C px orbitals. The remaining orbital contribution is aided by
p-orbitals of other C and O atoms. For the hexacoordinated
chromium complex, the HOMO is 115A, which is also a
SOMO, containing 67.75% metal d character (40.98% dxy,
17.10% dx2–y2, 6.10% dyz, 1.90% dxy and 1.76% dxz). LUMO
for this complex is 117A that constitutes only ligand orbitals,
mainly the oxygen and carbon p orbitals (>73% of pz orbit-
als). The HOMO–LUMO gap is found to be 0.1983 eV. The
energy of individual MOs is shown in Table 4. In the case
of [Al(TBHPY)(H2O)] complex, the energy gap between
HOMO (MO 112 A, E = − 0.189730 eV) and LUMO
(MO 113 A, E = − 0.137672 eV) is 1.312 eV. In both the
MOs, there was no contribution from the metal orbital. The
HOMO receives greater participation of carbon pz orbitals
i.e., 53.82%, and the rest contribution follows as 6.31% of C
px, 7.52% of O pz and 5.05% of O px orbitals. On the other
hand, LUMO encompasses a contribution from the p- orbit-
als as 27.35% of O px, 26.03% of O pz, 14.35% of O py, 5.65
of C px, 5.42 of C py and 5.06% of C pz orbitals. The frontier
molecular orbital diagrams for all the three complexes are
shown in Fig. 14.
Theoretical electronic spectrum of the ligand TBHPY
Theoretical calculations were also done at DFT level using
GGA-BLYP/TZP to unveil the nature of electronic transi-
tions. The results obtained through theoretical calculations
indicate that the band at 272 nm is due to the electronic tran-
sition between HOMO and LUMO+1 (E=2.42 eV), a π–π*
transition. The NTO (Natural transition orbital) analysis also
revealed the same. The HOMO is mainly comprised of the p
orbitals of oxygen and carbon atoms of the carbonyl group
existing in hydroxypyranone unit (MO 108 A), whereas
LUMO + 1 contains the p orbitals of the carbon atoms of
the benzene ring (MO 110 A) as shown in Fig. 15.
Theoretical electronic spectra of iron, chromium
and aluminum complexes
The theoretical calculations for computing the absorp-
tion spectra of all the metal complexes were also carried
out (Fig. 16) in the gas phase at the DFT level using GGA/
PBE/TZP. An open-shell calculation (UHF) was carried
out for iron and chromium complexes, whereas, for the alu-
minum complex, an RHF calculation was performed. The
results are consistent with the experimental ones. Ofset for
The global descriptive parameters for all the metal com-
plexes were also calculated from the HOMO and LOMO
energies and presented in the Table 4. It is known that the
smaller the energy gap between the HOMO–LUMO, the
more is the reactivity of a molecule. Similarly, a substan-
tial gap corresponds to the high stability, hence the low
reactivity of a molecule. The computationally calculated
results are correlated with the said parameters for the com-
plexes. The results demonstrate the reactivity of the com-
plexes is in the order [Fe(TBHPY)(H2O)2]>[Cr(TBHPY)
(H2O)]>[Al(TBHPY)(H2O)].
Fig. 15 The theoretical absorption spectrum of TBHPY calculated by
DDFT:GGA/BLYP/TZP on DFT:GGA/BLYP/DZ geometry
Table 4 Global reactivity descriptors: HOMO–LUMO gap, chemical potential (μ), chemical hardness (η), electrophilicity (ω), ionization poten-
tial (I), electron afnity (A), and electronegativity (χ) of ligand TBHPY and its metal complexes with trivalent iron, aluminum and chromium
Molecules
HOMO–
Chemical
Global
Global softness
Electrophilicity
(ω)
Ionization
potential (I)
(eV)
Electron
Electron-
LUMO gap (ε) potential
hardness (S)
(η)
afnity (A) egativity
(eV)
(μ)
(eV)
(χ)
TBHPY
[Fe(TBHPY)
(H2O)2]
2.427
0.118
−4.471
−3.597
1.214
0.059
0.824
8.236
132.651
5.684
4.016
3.257
3.898
4.471
3.597
16.947
10.079
1.524
[Cr(TBHPY)
0.198
1.312
−3.997
−4.507
0.099
0.656
80.519
15.478
4.096
5.163
3.898
3.851
3.997
4.507
(H2O)]
[Al(TBHPY)
(H2O)]
1 3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
Fig. 16 Theoretical electronic spectra of a [Fe(TBHPY)(H2O)2], b
[Cr(TBHPY)(H2O)] and c [Al(TBHPY)(H2O)] complexes calculated
by TDDFT:GGA/PBE/TZP on DFT:GGA/BLYP/DZ geometry. Of-
set for [Fe(TBHPY)(H2O)2], [Cr(TBHPY)(H2O)] and [Al(TBHPY)
(H2O)] are−565,−480 and−370 nm respectively. Half bandwidth:
50
[Fe(TBHPY)(H2O)2], [Cr(TBHPY)(H2O)] and [Al(TBHPY)
(H2O)] are−565,−480 and−370 nm respectively, and the
half bandwidth was set to 50 to match with the experimen-
tal spectra.The electronic transitions of the hexacoordinated
complexes showing the wavelengths, oscillator strengths
(fcalc), nature of electronic transitions, the specifc orbit-
als involved in the transitions, the natural transition orbit-
als (NTO) with their percentage contribution are shown in
Table 5
diferent. For iron, HOMO (SOMO) and LUMO are 121A
and 122A orbitals, respectively, whereas, for β orbitals, the
HOMO is 116A. The highest intensity peak was obtained
for 116A to 119A, a SOMO; obviously, one electron transi-
tion occurred from one of the paired orbital to the single
occupied molecular orbital. From the coefcient of atomic
orbitals, it could be revealed that 116A is a ligand molecular
orbital with no contribution from metal, whereas 119A has
2
7.6% contribution from the metal orbital, specifcally dz ,
2
2
Since the calculation of the iron and chromium complexes
was performed by the unrestricted Hartree Fock (UHF)
method, the HOMO and LUMO of the α and β orbitals are
dx
and dxz and 92.4% ligand contribution. Since both
the -lyigand molecular orbitals were π character, the transi-
tion may be attributed to the π →π* along with a minimal
Table 5 Electronic spectra of hexacoordinated Fe[(TBHPY)(H2O)2],
Cr[(TBHPY)(H2O)] and Al[(TBHPY)(H2O)] complexes: wave-
lengths, oscillator strengths (fcalc), electronic transitions and ener-
gies calculated at the GGA/PBE/TZP method, using GGA/BLYP/DZ
ground state geometry
Complexes
λnm (abs)a fcalc
Nature
Transition (% contri- NTO (% contri- Orbital representation of NTO
bution) bution)
Fe[(TBHPY) 245.7
(H2O)2]
0.0243 HOMO-5→HOMO–2
116A→119aA (84.0) NTO1 (84.9)
NTO2 (9.9)
NTO3 (2.4)
NTO1
NTO1
NTO1
Cr[(TBHPY) 274.0
(H2O)]
0.0071 HOMO-2→LUMO+1 114A→118A (75.5) NTO1 (75.9)
HOMO-1→LUMO+3 115A→120A (23.6) NTO2 (23.6)
Al[(TBHPY) 283.1
(H2O)]
0.0030 HOMO-1→LUMO+3 111A→116A (99.3) NTO1 (99.8)
aOfset for Fe[(TBHPY)(H2O)2], Cr[(TBHPY)(H2O)] and Al[(TBHPY)(H2O)] are − 565, − 480 and − 370 nm respectively. Iso value: 0.03. For
iron and chromium complexes, the HOMO and LUMO data have been taken for α orbitals
1 3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
contribution of π→metal d orbitals. Sometimes it is advan-
tageous to present the transition through the natural transi-
tion orbitals (NTO); the NTO transitions are also shown
in Table 5. For chromium and aluminum complexes, the
details of the transitions involved in the electronic spectra
are represented in terms of single orbital contribution and
NTO, which are shown in Table 5.
medium, H2O: DMSO (9:1, v/v). Thermo Scientifc Orion
star A111 pH meter with Ross ultra electrode 8102BNUWP
was used for pH measurement. DFT calculations were per-
formed on a Intel(R) Core(TM) i7-6500U CPU @ 2.40 GHz
using LINUX operating system.
Synthesis of ligand (TBHPY)
Correlation of protonation constants with theoretically
calculated Gibbs Free Energy
Synthesis of tris[(5‑hydroxy‑4‑oxo‑pyran‑2‑yl)methyl]
benzene‑1,3,5‑tricarboxylate (TBHPY)
In order to verify the validity and assignment made for the
experimental formation constants, gas-phase free ener-
gies for the entire representative species were calculated
through GGA/BLYP. The ΔG° of the reactions (Table 6)
were correlated with log K values. A linear correlation was
found between the calculated and experimental data with
R2 =0.96343, establishing a good agreement between them.
In the frst step of the synthesis, 20 ml of thionyl chloride
was added to the kojic acid (5 g, 35.2 mmol). The reaction
mixture was stirred for 1 h at room temperature. The product
thus obtained was collected through fltration and washed
with petroleum ether followed by drying in vacuum, which
was then recrystallized in hot water to give a beige-colored
solid (5.36 g, 95%) with m.p. 162–165 °C.To a magnetically
stirred solution of kojyl chloride (1 g, 6.22 mmol) in dry
DMF (16.5 ml) under nitrogen atmosphere, a sodium salt
of trimesic acid (0.57 g, 2.06 mmol) was added. The reac-
tion mixture was stirred and heated at 110 °C for 4 h. DMF
was evaporated under reduced pressure. The crude product
thus obtained was washed with ethyl acetate followed by
water which produced a brown mud-like product of TBHPY
(0.85 g, 70.8%). The compound was fltered, washed with
ether, and dried in vacuo. m.p. 158 °C. IR (KBr pellet,
cm−1): 3232.7, 1737.9, 1651.1, 1626.0, 1234.4, 1143.8;
1H NMR (DMSO-d6, 500 MHz): 5.33(s,6H), 6.62(s,3H),
8.14(s,3H), 8.71(t,3H), 9.29(s,3H); 13C NMR(DMSO-d6,
500 MHz): 62.61, 112.87, 130.38, 134.18, 139.94, 146.04,
160.81, 163.31, 173.53; Mass spectrum (ESI–MS +):
C27H18O15: 582.1 (calc.), 583.13 (observed).
Experimental
Materials and measurements
The chemicals were purchased from CDH and Sigma
Aldrich and were used without further purifcation. The
reactions were carried out in the nitrogen atmosphere. Ethyl
acetate, DMF, and DMSO were the diferent solvents that
were purchased from CDH, whereas thionyl chloride and
PET ether were purchased from Loba Chemie. For the deter-
mination of the melting points, a melting point apparatus
of Navyug India was used, the melting point was reported
1
here in ºC. The H and 13C NMR measurement was done
using Bruker Advance Neo 500 MHz spectrometer and was
recorded in DMSO-d6. Mass spectra were recorded with the
help of LC–MS Spectrometer Model Q-TOF Micromass
(ESI–MS). Both the mass and NMR spectra were recorded
at Sophisticated Analytical Instrumentation Facilities (SAIF)
of Panjab University, Chandigarh. The FT- IR spectra taken
in transmission mode over a range of 4000–500 cm−1 were
recorded on the Shimadzu FT-IR spectrometer. Evolution
201 Thermoscientifc UV–Vis spectrophotometer was used
for spectrophotometric studies using a quartz cuvette. The
potentiometric titrations were carried out in a highly aqueous
Potentiometric measurements
Determination of the protonation behavior of the hexaden-
tate ligand and its metal complexes were carried out poten-
tiometrically at 25 1 °C in a highly aqueous medium (H2O:
DMSO:: 9:1), using a double wall titration vessel. In the pH
titrations, the classical method was used to calibrate the elec-
trode for getting accurate pH values. 0.1 M KOH and 0.1 M
HCl solutions were prepared and by using 0.1 M KHP, KOH
solution was standardized to get accurate concentration. The
ligand solution of 10–3 M concentration was used in poten-
tiometric measurements, and ionic strength (0.1 M KCl) was
maintained. The ligand solution (10–3 M) was acidifed with
0.1 M HCl acid up to pH 2 to detect the formation of any
species at low pH, and was then titrated against standard
0.1 M KOH solution steadily at 25 1 °C to evaluate the
log K values (pH range 2–11). The complexation behav-
ior of ligand was explored with Fe(III), Al(III) and Cr(III)
by titrating 1:1 metal–ligand solution against 0.1 M KOH.
Table 6 Calculated thermodynamic properties of the neutral ligand
and its deprotonated species at the DFT level
Species
Protonation reactions
ΔGo (kcal/mole)
Log K
LH2 + H+
⇌
LH3
LH3
−
−31.04
− 65.42
− 111.18
6.16
6.90
9.77
−
LH2− + H+ ⇌ LH2
LH2
−
LH2−
L
3− + H+ ⇌ LH2−
1 3

Journal of Inclusion Phenomena and Macrocyclic Chemistry
Ferric chloride, Aluminium sulfate, and chromium acetate
salt solution of 10–3 M concentration were used. The fnal
concentration of the metal salt solution and ligand solution
was kept 10–3 M. Hyperquad 2006 refnement program was
used for determining the equilibrium constants and the dif-
ferent species formed. The species distribution diagrams
were evaluated using Hyss 2009[43].
(H2O)2, [Cr(TBHPY)(H2O)] and [Al(TBHPY)(H2O)]. The
experimental and theoretical electronic spectral studies for
the complexes revealed that the electronic transitions are
intra-ligand (IL) type, predominantly the π–π transitions.
The global reactivity parameters of the ligand and the com-
plexes were correlated with the complex reactivity. The high
formation constants of the complexes infer that this ligand
can become a promising candidate for chelation therapy for
diseases caused due to metal overload; also, it can act as a
metal sequestering agent. Being a good iron chelator, the
ligand TBHPY can also fnd utility in photodynamic therapy.
Spectrophotometric measurements
Spectrophotometric titrations were carried similarly to
potentiometric titrations. The absorption spectrum was
recorded after each addition of KOH by taking the solution
in the quartz cuvette. The aliquot volume was put back to
the titration mixture, and this was carried out very precisely.
The binding constants were evaluated from titration data by
using the global ftting program Hypspec [44].
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s10847-021-01088-0.
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