Synthesis, structural elucidation, intramolecular hydrogen bonding and DFT studies of quinoline-chalcone-chromene hybrids

Article abstract of DOI:10.24820/ARK.5550190.P011.193

Eight hydroxyquinoline-chromene chalcones, of which six were new, were synthesized using the Vilsmeier-Haack reaction and Claisen-Schmidt condensation. These contain either mono or dichromene functionality. The hydroxyl proton chemical shift of both types of compounds at varying temperature indicated weakened hydrogen bonds with an increase in temperature, however there was no significant difference to the slopes of the OH chemical shift curves (3.4 x10^-3 for the 2-methoxychromene derivative and 3.1 x10^-3 for the 6-methoxydichromene derivative. Potential energy scans of these two compounds were obtained using B3LYP/6-311 G level theory in the gas phase, and showed the enol form to be most stable for both molecules and that the energy barrier to make proton transfer possible is 5.076 and 3.989 Kcal mol^-1 for the 2-methoxychromene and 6-methoxydichromene derivatives respectively.

Full text of DOI:10.24820/ARK.5550190.P011.193

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Synthesis, structural elucidation, intramolecular hydrogen bonding and DFT
studies of quinoline-chalcone-chromene hybrids
Lamla Thungatha, Saba Alapour, and Neil A. Koorbanally*
School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X54001, Durban, 4001, South Africa
Email: Koorbanally@ukzn.ac.za
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Abstract
Accepted mm-dd-yyyy
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Eight hydroxyquinoline-chromene chalcones, of which six were new, were synthesized using the Vilsmeier-
Haack reaction and Claisen-Schmidt condensation. These contain either mono or dichromene functionality.
The hydroxyl proton chemical shift of both types of compounds at varying temperature indicated weakened
hydrogen bonds with an increase in temperature, however there was no significant difference to the slopes of
the OH chemical shift curves (3.4 x10-3 for the 2-methoxychromene derivative and 3.1 x10-3 for the 6-
methoxydichromene derivative. Potential energy scans of these two compounds were obtained using
B3LYP/6-311 G level theory in the gas phase, and showed the enol form to be most stable for both molecules
and that the energy barrier to make proton transfer possible is 5.076 and 3.989 Kcal mol-1 for the 2-
methoxychromene and 6-methoxydichromene derivatives respectively.
Keywords: Quinoline, chalcones, chromenes, molecular hybrids, DFT studies, hydrogen bonding
DOI: https://doi.org/10.24820/ark.5550190.p011.193
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Introduction
Quinoline is a heterocyclic aromatic organic molecule with a broad spectrum of pharmacological properties
including antimalarial,1 antibacterial,2-3 antifungal,4 anticancer,5 antitubercular,6 antileishmanial7 and anti-
inflammatory.8 Current pharmaceuticals containing this pharmacophore include Amodiaquine, Chloroquine,
Ciprofloxacin, Levofloxacin and Mefloquine. These drugs have a quinoline core hybridised with other
pharmacophores leading to more potent drugs. Quinoline molecules substituted at C-3 are also known for
their broad range of biological activities. These hybrid molecules include quinoline chalcones synthesised
from 3-quinoline carbaldehydes and have shown promising anticancer,5 antibacterial9 and antiprotozoal10
activities. Quinoline chalcones are also used as precursors for bioactive quinoline pyrazole derivatives.11
Benzopyran on the other hand, consists of a benzene ring fused to a pyran ring and is mostly found in
natural products. They show a broad range of biological activities, such as anticancer12 and anti-inflammatory
activity.13 This scaffold also forms part of the flavones, potent antioxidants and known to have good biological
activity.14
Derivatives of ortho-hydroxy acetophenone, used to synthesise chalcones are known to have
intramolecular hydrogen bonding (IHB) and intramolecular proton transfer (IPT) properties.15 Intramolecular
proton transfer is also known to be enhanced by photoexcitation of the molecule. This concept is known as
the excited state intramolecular proton transfer (ESIPT) and was first studied by Albert Weller.16 IHB and IPT or
ESIPT have since been extensively studied both theoretically and experimentally.17 The two phenomena occur
by interaction of the oxygen atom of the carbonyl group C=O and the hydrogen atom of the hydroxy group in
2-hydroxyacetophenones. IHB and ESIPT are known to affect the physical properties of the molecule as well as
their bioactivity, photochemistry and reactivity, which differ depending on the properties of the molecular
subunits or core structure.18-20 The chalcones reported in this work have a hydroxyl group on the chromene
core adjacent to the carbonyl carbon of the chalcone.
The hydrogen bond is an important intermolecular interaction in biochemical processes.21 NMR chemical
shifts are very sensitive to steric, electronic effects, and molecular interactions.22 It is therefore a good tool to
identify and study hydrogen bond interactions. Hydrogen bonds are classified in two different groups, strong
and weak hydrogen bonds. Strong hydrogen bonds are those in which hydrogen is covalently bound to N, O, or
F and form a second weak interaction to another electronegative atom (N, O, or F).23 Weak hydrogen bonding
is when hydrogen is attached to a spx (x = 1–3) hybridized carbon and forms additional weak interactions with
electronegative atoms.24-25 In a weak hydrogen bond, the hydrogen bond donor must be electron deficient
enough to be attracted to an electron-rich atom.25
We herein report the synthesis of quinoline chromenochalcone hybrid molecules, their structural elucidation
by NMR, and a study of the hydrogen bonding using VT NMR. DFT studies, carried out to understand the
electronic properties of the molecule are also reported.
Results and Discussion
The quinoline-3-carbaldehyde intermediates (1) were synthesised in three steps using the Vilsmeier-Haack
reaction where POCl3 and DMF were reacted with acetanilides (Scheme 1).26-28 The chromene derivatives were
made in a single step, which involved reaction of 2,4-dihydroxy or 2,4,6-trihydroxyacetophenone with 3-
methylcrotonaldehyde to form the desired monochromene (2) or dichromene (3) acetophenone derivatives.
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The final step involved reaction of the quinoline-3-carbaldehydes with the chromeno acetophenones using the
Claisen-Schmidt condensation29 to synthesise quinoline chromenochalcone hybrids (4).
The Vilsmeier-Haack reaction works better in dry conditions and the Claisen-Schmidt condensation does
not work well with some hydroxyacetophenones,30-31 indicated by the low yields of 4a-h (38-46%). This can be
attributed to the competing enolate ion and phenoxide ion of the hydroxyacetophenone arising from the base
abstraction of both the α proton and hydroxy proton of the acetophenone.32
Scheme 1. Synthetic scheme to quinoline chromenochalcones. (i) Acetic anhydride, 6 h; (ii) DMF, POCl3, 80 oC,
18 h; (iii) MeOH, KOH reflux; (iv) 3-methylcrotonaldehyde (1 eq.), pyridine, 150 oC, 12 h; (v) 3-
methylcrotonaldehyde (2 eq.), pyridine, 150 oC, 12 h; (vi) KOH, EtOH, rt, 48 h.
Characteristic resonances for all chalcones were observed. For example in 4f, the two doublets for H-9 and
H-10 occured at  7.97 and 8.27 respectively with large coupling constants of 15.8 Hz, an indication of trans
coupled alkene protons. The formation of these compounds was also confirmed by HMBC correlations of H-9
to C-2 and C-4, and H-10 to C-3. The α,β-unsaturated carbonyl resonance occurred at  193.1. The chromene
rings are characterised by a pair of doublets for each ring (H-10' and H-11' at  5.47 and  6.61, and H-3' and
H-4' at  5.47 and  6.69) and two methyl resonances at  1.45 (H-2a'/H-2b') and  1.54 (H-9a' and H-9b'). The
resonances for each of the pairs of olefinic protons in the chromene rings were paired in the COSY spectrum.
Furthermore, H-9a' and H-9b' showed HMBC correlations to C-10', and H-2a' and H-2b' showed HMBC
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correlations to C-3'. H-4' and H-3' showed HMBC correlations to C-8a' and C-4a' respectively (Figure 1). The
hydroxyl proton H-5a' also showed a correlation to C-4a' confirming the assignment of this system. Both
methyl resonances of the chromene ring adjacent to the hydroxyl group showed NOESY correlations to the
hydroxyl proton H-5a'.
Figure 1. Selected HMBC correlations for 4f
The proton resonances of H-4 to H-8 on the quinoline ring were observed to be more deshielded when a
chloro group was substituted at C-2 than when a methoxy group was substituted at the same position. This is
attributed to the more electronegative chloro group, withdrawing electron density from the quinoline ring as
opposed to the electron donating methoxy group. With the hydroxy proton 5a', the opposite occurs.
Compounds with a chloro group have a more shielded proton resonance for H-5a' than those compounds with
a chloro group. This is indicative of slightly weaker hydrogen bonding between the hydroxy group and
carbonyl group of the α,β-unsaturated moiety (the stronger the hydrogen bonding, the more deshielded the
resonance is) as opposed to when a methoxy is situated at the same position. This is possibly due to the
slightly shorter C=O bond due to the electronegative chloro group. As usual, the β proton, H-9 in the chalcone
moiety is more deshielded than H-10 due to resonance effects.33 These correlations are later confirmed in the
3D crystal and DFT optimised structures. The 13C NMR data is fairly consistent across the series of compounds.
The synthesised compounds formed crystals by slow evaporation in a solution of ethanol. Single crystal X-
ray diffraction data for 4b and 4f (with atom numbering shown in Figure 2 below) show that 4b is monoclinic
and 4f triclinic with space group P21/n and P-1 respectively. In 4b, an intramolecular hydrogen bond is
observed between the hydroxyl proton H2 and the carbonyl oxygen O3 (1.754 Å) and between the same
atoms in 4f between H2 and O5 (1.708 Å) (Figures 2 and 3). The reason for the stronger hydrogen bond when
a second ring is added to the structure is not known, but could involve the additional oxygen present in 4f.
Intermolecular hydrogen bonds are also observed with the methyl groups, nitrogen in the quinoline ring and
oxygen in the hydroxy and methoxy groups and in the chromene ring (Table 1). In 4b, the monochromeno
chalcone (Figure 2), the quinoline ring is situated with the methoxy group (O4-C24) and the nitrogen (N5)
trans to the carbonyl group (C12-O3). This situates the two electronegative oxygen atoms as far apart as
possible. However, in 4f, the dichromenochalcone (Figure 3), the quinoline ring rotates itself 180 (compared
to 4b) around the C9-C10 bond, due to steric hindrance, so as to move out of the way of the dimethyl groups
(C-29 and C-30) and the pyran oxygen (O4) in the angular pyran ring. The methoxy group (O3-C22) and
nitrogen (N1) is now situated cis to the carbonyl group (C7-O5).
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Table 1: Intermolecular hydrogen bonds for 4b and 4f
Compound 4b
Compound 4f
D-H…A
d(H…A)/Å
2.561
2.715
D-H…A
d(H…A)
2.694
2.704
2.484
2.680
2.526
C(24)-H(24b)…O(1)
C(4)-H(4)…O(3)
C(2)-H(2b)…O(3)
C(1)-H(1c)…N(1)
C(15)-H(15a)…N(1)
C(29)-H(29a)…O(5)
C(29)-H(29b)…O(2)
C(30)-H(30c)…O(3)
2.704
Figure 2. Intramolecular and intermolecular hydrogen bonds for 4b
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Figure 3. Intramolecular and intermolecular hydrogen bonds for 4f
Variable Temperature NMR studies
Hydrogen bonding of the O-H proton H-5a' (Figure 1) with the carbonyl oxygen at C-11 was indicated by the
downfield chemical shift between  13.47-14.30, and further suggested by a broad O-H stretching band at
2489-2637 cm-1 in the IR spectrum. Compounds 4b with a single pyran ring and 4f with two pyran rings were
selected to study the strength of the hydrogen bond at different temperatures. Compound 4f with an O-H
chemical shift at  14.30 at room temperature was more deshielded than 4b  13.68 indicating that the extra
pyran ring affected hydrogen bonding in some way. The strength of the hydrogen bond in solution can be
determined by chemical shift variation of a proton in the hydrogen bond donor.23, 34
The chemical shift of the O-H proton decreased linearly with increasing temperature for both compounds
indicating weakening of hydrogen bond interactions with increasing temperature (Figure S40). However, the
slopes of the two compounds 4b (3.4 x10-3 ppm/K) and 4f (3.1 x10-3 ppm/K) did not show a significant
difference, 13.47-13.70 ppm for 4b and 14.10-14.30 ppm for 4f. This indicates that this hydrogen bond in both
compounds were fairly strong and not disrupted by additional heat.
In 4b, the H-9 chemical shift decreases (becomes more shielded) non-linearly with an increase in
temperature (Figure S12), due to a weakening of the H bond. The opposite is observed in 4f (Figure S36),
where the quinoline ring is rotated 180 around the C3-C9 bond compared to 4b (Figure 1). In this case, an
increase in chemical shift is experienced with increase in temperature, due to H-9 being in close proximity to
both the oxygen atoms of the methoxy and carbonyl groups.
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Frontier molecular orbitals and photophysical properties of the molecule
Good agreement in bond lengths and angles between the single crystal X-ray data and DFT calculations were
observed. This indicated that theoretical calculations were a good approximation of the observed values. It
also indicated that solid and gas phase structures are similar. HOMO-LUMO energy values and their band gaps
were obtained for structures 4a-h (Figure 4). The charge distribution of frontier molecular orbitals follows the
same trend. Essentially, the HOMO electron density is mostly distributed on the chromene or dichromene core
and the LUMO electron density on the quinoline core and partially on the benzene ring of the chromene or
dichromene core. The band gaps of the chromene derivatives (4a-4d) are observed to be higher ~3.2 eV
compared to the dichromene derivatives (4e-4h), which is ~2.9 eV. Band gaps are known to be related to
stability of the molecule. The larger the band gap, the more stable the molecule, indicating the greater
stability of the chromene derivative over their dichromene counterparts.
Molecular electrostatic potential (MEP) maps assigns electrostatic potential on each atom of the molecule.
This phenomenon correlates with dipole moment, electronegativity and partial charges,35 and makes it
possible to identify reactive sites of a molecule toward nucleophiles and electrophiles. One can also see how
charge distribution of the molecule can affect inter- and intramolecular interactions. The red shaded portions
indicate negative regions, reactive to electrophiles and the blue shaded portions are positive, reactive to
nucleophiles.36 Figure 5 shows that the 2-hydroxy and carbonyl oxygen atoms are the most electronegative,
being the best electron bond acceptors in the molecule. This results in intramolecular hydrogen bonding
between the O-H proton and carbonyl group oxygen and intermolecular hydrogen bonding between the O-H
oxygen and hydrogen bond donors in adjacent molecules.
Figure 4: Frontier molecular orbitals and energies for 4b and 4f in chloroform
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Figure 5. MEP plots for compound 4b and 4f in chloroform
To understand the intramolecular proton transfer of 4b and 4f, the relaxed potential energy scans of the
optimised molecules were carried out (Figure 6) using B3LYP/6-311 ++G (d, p) level theory in the gas phase.
This involved varying the redundant internal coordinates of the O-H bond from 0.9-1.7 Å, with increment steps
of 0.05 Å. The method was set to optimize the structures at each increment step and perform single point
calculations. The energies were obtained for each bond length of O-H fixed at 0.9-1.7 Å with increment steps
of 0.05 Å. The curve compares the two molecules. Both have the same global minimum, the enol form, which
is the most stable form for both molecules. A slight bend in the curves is observed, which seems to correspond
to local minima. The two molecules show different relative energies at this point 5.076 and 3.989 Kcal/mol for
4b and 4f respectively. These points estimate the energy barrier required to make proton transfer possible.
This means it is easier for 4f to undergo proton transfer and form the ketone than 4b, indicating greater
hydrogen bonding in 4f, corroborating the discussion made earlier.
Figure 6: Potential energy plot for 4b and 4f in chloroform
UV-VIS spectra of all compounds indicate two absorption maxima at 263-280 nm and 359-373 nm,
corresponding to π–π* and n-π* transitions respectively (Figure 7).37 Compounds 4a-d have a stronger
absorption intensity at ~ 359-373 nm (n-π*), while 4e-h have a stronger absorption intensity at ~ 263-280 nm
(π–π*). This is due to extra conjugation brought about by the extra chromene ring in the dichromene
derivatives.
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Figure 7. Overlaid UV-VIS spectra for 4a-h
Conclusions
The hydroxy quinoline-chromene chalcones were successfully synthesised and analysed using spectral
techniques. The presence of hydrogen bonding was initially confirmed by the OH chemical shift of the
compounds. The structural difference of the chromene and dichromene derivatives resulted in observed
1
differences in the H NMR chemical shift of the OH proton. Intramolecular hydrogen bonding was shown to
respond to varying temperature. The O-H proton of both derivatives were observed to shift upfield upon
temperature increase, with slightly different slopes. The potential energy scans further confirm that these
molecules are stable in the enol form. The HOMO-LUMO band gaps suggest that the dichromene derivatives
are less stable. The structural difference of the two derivatives result in an observable effect of the electronic
and physical parameters of the molecule.
Experimental Section
General. Chemicals were purchased from Sigma-Aldrich, South Africa. Thin layer chromatography and column
chromatography were performed using Kieselgel 60 F254 plates and silica gel (60-120 mesh) respectively with
hexane, dichloromethane, ethyl acetate and methanol in various ratios as the mobile phase. All solvents were
dried and redistilled according to standard procedures. Melting points were determined on an Electrothermal
IA9100 melting point apparatus. Infrared data was recorded on a Perkin Elmer Spectrum 100 FT-IR
spectrometer with universal attenuated total reflectance sampling accessory. Ultraviolet spectra were
obtained on a Shimadzu UV-VIS spectrophotometer in ethanol. High-resolution mass data was obtained using
a Waters Micromax LCT Premier TOF-MS instrument, operating at ambient temperatures, with a sample
1
concentration of approximately 1 ppm. H and 13C NMR spectra were recorded at 298 K with 5 to 10 mg
samples dissolved in 0.5 mL of CDCl3 in 5-mm NMR tubes using a Bruker Avance 400-MHz NMR spectrometer
(9.4 T; Bruker, Germany) (400.22 MHz for 1H, 100.63 MHz for 13C and 376.58 Hz for 19F). The FID resolution
was 0.501 Hz/pt for 1H and 0.734 Hz/pt for 13C spectra. Chemical shifts are reported in ppm and coupling
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constants (J) in Hz. 1H and 13C NMR spectra were referenced to the solvent line of 7.24 and 77.0, respectively
for deuterated chloroform.
Synthesis
Acetanilides Acetanilides were prepared according to the procedure of Dulla et al.38 Aniline or p-toluidine (15
mmol) was added to a round bottomed flask containing acetic anhydride (21 mmol) and the reaction stirred at
room temperature for 30 min. Upon completion, the contents were poured in ice water, where white or
creamy precipitates were filtered and recrystallized in water.
2-Chloro-3-formylquinolines (1a and 1b). A modified method of Meth-Cohn et al. 39 was used. Briefly, freshly
dried DMF (33.5 mmol) was transferred to a dry round bottomed flask fitted with a condenser attached to a
drying tube. POCl3 (93.8 mmol) was added dropwise to the DMF at 0-5 °C for 10-15 min. After addition, the
reaction was stirred for 20 min and the acetanilide (13.4 mmol) added. The reaction was stirred at 80-90 °C for
12-16 h. On completion, the reaction mixture was cooled to room temperature and poured in ice water. A
golden yellow precipitate was filtered and recrystallized in ethyl acetate.
2-Methoxy-3-formylquinolines (1c and 1d). A modified method of Waghray et al.40 was used. Briefly, the 2-
chloro-3-formylquinolines 1a (10.4 mmol) and 1b (10.4 mmol) were added to a solution of potassium
hydroxide (15.6 mmol) in methanol (100 mL) and the contents refluxed overnight. Upon completion, the
reaction was cooled to room temperature and cold water added to precipitate the product, which was then
filtered and dried.
1-(5-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)ethanone (2). The method of Gupta et al.41 was employed with
modification. 2,4-Dihydroxyacetophenone (5.00 g, 32.90 mmol) was added to a solution of dry pyridine (3.50
mL) followed by 3-methyl-but-2-enal (3.20 mL, 32.90 mmol). The contents were refluxed for 4 hours at 110 °C,
after which an equivalent amount of 3-methyl-but-2-enal (3.20 mL, 32.90 mmol) was added to the reaction
mixture. The reaction was then refluxed overnight. The product was then dissolved in ethyl acetate and
purified by column chromatography on silica gel using ethyl acetate and hexane (3:7).
1-(5-Hydroxy-2,2,8,8-tetramethyl-2,8-dihydropyrano[2,3-f]chromen-6-yl)ethanone (3). The method outlined
in Pawar and Koorbanally42 was followed. 3-Methyl-but-2-enal (4.70 mL, 47.6 mmol) was added to a stirred
solution of 2,4,6-trihydroxyacetophenone (2.00 g, 11.9 mmol) in dry pyridine (1.37 mL). The reaction was
stirred at 110 °C overnight. After the reactant was completely consumed, the solvent was evaporated and the
thick brown paste purified by column chromatography on silica gel using ethyl acetate and hexane (1:9).
Quinoline chromenochalcones (4a-d) and quinoline dichromenochalcones (4e-h). The method reported by
Lee and Kim43 was adapted. The quinoline aldehyde 1 (1.04 mmol) and chromene 2 or dichromene 3 (0.86
mmol) was added to a solution of potassium hydroxide (8.70 mmol) in ethanol (8.00 mL). The reaction was
stirred at room temperature for 48 h. Upon completion, the contents were poured in cold water and
neutralised with HCl. The resultant precipitate was filtered and dried. The product was purified by column
chromatography using 5% ethyl acetate in hexane as the mobile phase.
(E)-3-(2-Chloroquinolin-3-yl)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl)prop-2-en-1-one (4a). Yellow
crystalline solid; yield 40%; mp 156-157 °C; IR (neat, vmax, cm-1) 1700 (C=O); λmax (log ε): 271 (4.27), 367 (4.51);
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1H NMR (400 MHz, CDCl3) δH 1.46 (6H, s, H-2a'/H-2b'), 5.59 (1H, d, J 10.1 Hz, H-3'), 6.39 (1H, d, J 8.8 Hz, H-8'),
6.74 (1H, d, J 10.1 Hz, H-4'), 7.59 (1H, ddd, J1 8.6 Hz, J2 7.4 Hz, J3 1.0 Hz, H-6), 7.66 (1H, d, J 15.5 Hz, H-10),
7.72 (1H, d, J 8.8 Hz, H-7'), 7.77 (1H, ddd, J1 8.4 Hz, J2 7.3 Hz, J3 1.0 Hz, H-7), 7.87 (1H, d, J 8.1, H-5), 8.02 (1H, d,
J 8.4 Hz, H-8), 8.25 (1H, d, J 15.5 Hz, H-9), 8.47 (1H, s, H-4), 13.47 (1H, s, H-5a'); 13C NMR (100 MHz, CDCl3) δC
28.4 (C-2a'/C-2b'), 78.1 (C-2'), 108.6 (C-8'), 109.5 (C-4a'), 113.9 (C-6'), 115.7 (C-4'), 124.8 (C-10), 127.0 (C-4a),
127.8 (C-6), 128.0 (C-5), 128.1 (C-3), 128.3 (C-3'), 128.5 (C-8), 130.8 (C-7'), 131.7 (C-7), 136.3 (C-4), 138.8 (C-9),
147.9 (C-8a), 150.4 (C-2), 160.3 (C-8'a), 161.1 (C-5'), 191.0 (C-11).
(E)-1-(5-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-methoxyquinolin-3-yl)prop-2-en-1-one (4b). Yellow
crystalline solid; yield 43%; mp 152–153 °C; IR (neat, vmax, cm-1) 1630 (C=O); λmax (log ε): 271 (4.26), 364 (4.56);
1H NMR (400 MHz, CDCl3) δH 1.46 (6H, s, H-2a'/ H-2b'), 4.18 (3H, s, H-2a), 5.58 (1H, d, J 10.4 Hz, H-3'), 6.39 (1H,
d, J 8.9 Hz, H-8'), 6.75 (1H, d, J 10.4 Hz, H-4'), 7.38 (1H, ddd, J1 8.3 Hz, J2 7.7 Hz, J3 1.5 Hz, H-6), 7.63 (1H, ddd, J1
8.3 Hz, J2 7.4 Hz, J3 1.1 Hz, H-7), 7.73 (1H, d, J 8.9 Hz, H-7'), 7.75 (1H, d, J 8.3 Hz, H-5), 7.83 (1H, d, J 8.3 Hz, H-8),
7.87 (1H, d, J 15.8 Hz, H-10), 8.06 (1H, d, J 15.8 Hz, H-9), 8.24 (1H, s, H-4), 13.68 (1H, s, H-5a'); 13C NMR (100
MHz, CDCl3) δC 28.4 (C-2a'/C-2b'), 53.9 (C-2a), 77.9 (C-2'), 108.4 (C-8'), 109.4 (C-4a'), 114.2 (C-6'), 115.9 (C-4'),
120.2 (C-3), 123.5 (C-10), 124.7 (C-6), 125.0 (C-4a), 127.1 (C-8) 128.0 (C-5), 128.2 (C-3'), 130.8 (C-7, C-7'), 138.7
(C-9), 139.1 (C-4), 146.9 (C-8a), 160.0 (C-2), 160.2 (C-8a'), 161.1 (C-5'), 192.1 (C-11); HRMS (neg) m/z 386.1398
[M-H] (calcd. for C24H20NO4: 386.1392).
(E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl)prop-2-en-1-one (4c).
Yellow crystalline solid; yield 38%; mp 189-191 °C; IR (neat, vmax, cm-1) 1631 (C=O); λmax (log ε): 280 (4.36), 359
(4.30); 1H NMR (400 MHz, CDCl3) δH 1.46 (6H, s, H-2a'/H-2b'), 2.53 (3H, s, H-6a), 5.59 (1H, d, J 10.0 Hz, H-3'),
6.39 (1H, d, J 8.9 Hz, H-8'), 6.74 (1H, d, J 10.0 Hz, H-4'), 7.58 (1H, dd, J1 8.6 Hz, J2 1.8 Hz, H-7), 7.62 (1H, s, H-5),
7.63 (1H, d, J 15.4 Hz, H-10), 7.71 (1H, d, J 8.9 Hz, H-7'), 7.89 (1H, d, J 8.6 Hz, H-8), 8.23 (1H, d, J 15.4 Hz, H-9),
8.36 (1H, s, H-4), 13.48 (1H, s, H-5a'); 13C NMR (100 MHz, CDCl3) δC 21.6 (C-6a), 28.4 (C-2a'/C-2b'), 78.1 (C-2'),
108.6 (C-8'), 109.5 (C-4a'), 113.9 (C-6'), 115.8 (C-4'), 124.5 (C-10), 126.8 (C-5), 127.0 (C-4a), 127.8 (C-3), 128.1
(C-8), 128.3 (C-3'), 130.8 (C-7'), 134.0 (C-7), 135.7 (C-4), 137.9 (C-6), 139.0 (C-9), 146.6 (C-8a), 160.3 (C-8a'),
161.1(C-5'), 191.0 (C-11); HRMS (neg) m/z 404.1049 [M-H] (calcd. for C24H19NO3Cl 404.1053).
(E)-1-(5-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-methoxy-6-methylquinolin-3-yl)prop-2-en-1-one (4d).
Yellow crystalline solid; yield 40%; mp 150-151 °C; IR (neat, vmax, cm-1) 1633 (C=O); λmax (log ε): 272 (4.38), 367
(4.53); 1H NMR (400 MHz, CDCl3) δH 1.46 (6H, s, H2a'/H-2b'), 2.47 (3H, s, H-6a), 4.15 (3H, s, H-2a), 5.58 (1H, d, J
10.2 Hz, H-3'), 6.38 (1H, d, J 9.0 Hz, H-8'), 6.74 (1H, d, J 10.2 Hz, H-4'), 7.46 (1H, dd, J1 8.5 Hz, J2 1.9 Hz, H-7),
7.49 (1H, s, H-5), 7.71 (2H, d, J 9.0 Hz, H-7', H-8), 7.85 (1H, d, J 15.6 Hz, H-10), 8.02 (1H, d, J 15.6 Hz, H-9), 8.13
(1H, s, H-4), 13.70 (1H, s, H-5a'); 13C NMR (100 MHz, CDCl3) δC 21.3 (C-6a), 28.4 (C-2a'/C-2b'), 53.8 (C-2a), 77.9
(C-2'), 108.3 (C-8'), 109.4 (C-4a'), 114.2 (C-6'), 115.9 (C-4'), 120.0 (C-3), 123.3 (C-10), 125.0 (C-4a), 126.8 (C-8),
127.0 (C-5), 128.1 (C-3'), 130.8 (C-7'), 132.9 (C-7), 134.3 (C-6), 138.7 (C-4), 138.9 (C-9), 145.2 (C-8a), 159.8 (C-
8a'), 159.9 (C-2), 161.0 (C-5'), 192.2 (C-11); HRMS (neg) m/z 400.1541 [M-H] (calcd. for C25H22NO4 400.1549).
(E)-3-(2-Chloroquinolin-3-yl)-1-(5-hydroxy-2,2,8,8-tetramethyl-2H,8H-pyrano[2,3-f]chromen-6-yl)prop-2-en-
1-one (4e). Brown crystalline solid; Yield 45%; mp 215-217 °C; IR (neat) vmax 1639 cm-1 (C=O); λmax (log ε): 276
(4.66), 364 (4.34); 1H NMR (400 MHz, CDCl3) δH 1.45 (6H, s, H-2a'/H-2b'), 1.53 (6H, s, H-9a'/H-9b'), 5.47 (1H, d,
J 10.0 Hz, H-10'), 5.48 (1H, d, J 10.0 Hz, H-3'), 6.61 (1H, d, J 10.0 Hz, H-11'), 6.68 (1H, d, J 10.0 Hz, H-4'), 7.58
(1H, ddd, J1 8.1 Hz, J2 7.7 Hz, J3 0.9 Hz, H-6), 7.75 (1H, ddd, J1 8.4 Hz, J2 7.7 Hz, J3 1.5 Hz, H-7), 7.81 (1H, d, J 8.1
Hz, H-5), 8.02 (1H, d, J 8.4 Hz, H-8), 8.13 (1H, d, J 15.5 Hz, H-9), 8.19 (1H, d, J 15.5, H-10), 8.41 (1H, s, H-4),
14.14 (1H, s, H-5a'); 13C NMR (100 MHz, CDCl3) δC 28.1 (C-2a'/C-2b'), 28.5 (C-9a'/C-9b'), 78.5 (C-2', C-9'), 102.0
(C-4a', C-8'), 105.8 (C-6'), 116.1 (C-4'), 116.6 (C-11'), 124.8 (C-10'), 125.6 (C-3'), 127.2 (C-4a), 127.6 (C-6), 127.8
(C-5), 128.5 (C-8), 128.9 (C-3), 131.4 (C-7), 131.9 (C-10), 135.7 (C-4), 136.2 (C-9), 147.7 (C-8a), 150.6 (C-2),
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155.6 (C-8a'), 156.9 (C-7'), 161.6 (C-5'), 191.9 (C-11); HRMS (neg) m/z 472.1324 [M-H] (calcd. for C28H23NO4Cl
472.1316).
(E)-1-(5-Hydroxy-2,2,8,8-tetramethyl-2H,8H-pyrano[2,3-f]chromen-6-yl)-3-(2-methoxyquinolin-3-yl)prop-2-
en-1-one (4f). Brown crystalline solid; yield 42%; mp 178-180 °C; IR (neat, vmax, cm-1) 1700 (C=O); λmax (log ε):
263 (4.58), 368 (4.27); 1H NMR (400 MHz, CDCl3) δH 1.45 (6H, s, H-2a'/H-2b'), 1.54 (6H, s, H-9a'/H-9b'), 4.16
(3H, s, H-2a), 5.47 (2H, d, J 10.0 Hz, H-3', H-10'), 6.61 (1H, d, J 10.0 Hz, H-11'), 6.69 (1H, d, J 10.0 Hz, H-4'), 7.38
(1H, ddd, J1 8.0 Hz, J2 7.5 Hz, J3 1.2 Hz, H-6), 7.63 (1H, ddd, J1 8.5 Hz, J2 7.5 Hz, J3 1.2 Hz, H-7), 7.71 (1H, d, J 8.0
Hz, H-5), 7.83 (1H, d, J 8.5 Hz, H-8), 7.97 (1H, d, J 15.8 Hz, H-9), 8.21 (1H, s, H-4), 8.27 (1H, d, J 15.8, H-10),
14.30 (1H, s, H-5a'); 13C NMR (100 MHz, CDCl3) δC 27.9 (C-9a'/C-9b'), 28.4 (C-2a'/C-2b'), 53.9 (C-2a), 78.3 (C-9'),
78.4 (C-2'), 102.6 (C-4a', C-8'), 106.1 (C-6'), 116.3 (C-4'), 116.6 (C-11'), 121.0 (C-3), 124.6 (C-6), 124.9 (C-10'),
125.2 (C-4a), 125.4 (C-3'), 127.0 (C-8), 127.9 (C-5), 130.5 (C-7), 130.7 (C-10), 136.2 (C-9), 138.1 (C-4), 146.7 (C-
8a), 155.4 (C-8a'), 156.2 (C-7'), 160.3 (C-2), 161.4 (C-5'), 193.1 (C-11); HRMS (neg) m/z 468.1821 [M-H] (calcd.
for C30H22NO5 468.1824).
(E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-hydroxy-2,2,8,8-tetramethyl-2H,8H-pyrano[2,3-f]chromen-6-
yl)prop-2-en-1-one (4g). Brown crystalline solid; Yield 46%; mp 189-190 °C; IR (neat, vmax, cm-1) 1700 (C=O);
λmax (log ε): 276 (4.60), 369 (4.51); 1H NMR (400 MHz, CDCl3) δH 1.45 (6H, s, H-2a'/H-2b'), 1.53 (6H, s, H-9a'/H-
9b'), 2.53 (3H, s, H-6a), 5.48 (1H, d, J 10.0 Hz, H-3'), 5.49 (1H, d, J 10.0 Hz, H-10'), 6.61 (1H, d, J 10.0 Hz, H-11'),
6.68 (1H, d, J 10.0 Hz, H-4'), 7.54 (1H, s, H-5), 7.57 (1H, dd, J1 8.4, J2 1.8 Hz, H-7), 7.90 (1H, d, J 8.4 Hz, H-8), 8.11
(1H, d, J 15.7 Hz, H-9), 8.16 (1H, d, J 15.7 Hz, H-10), 8.31 (1H, s, H-4), 14.16 (1H, s, H-5a'); 13C NMR (100 MHz,
CDCl3) δC 21.6 (C-6a), 28.2 (C-9a'/C-9b'), 28.5 (C-2a'/C-2b'), 78.5 (C-2', C-9'), 102.6 (C-8'), 102.7 (C-4a'), 105.9
(C-6'), 116.1 (C-4'), 116.6 (C-11'), 124.8 (C-10'), 125.5 (C-3'), 126.6 (C-5), 127.2 (C-4a), 128.2 (C-8), 128.7 (C-3),
131.6 (C-10), 133.7 (C-7), 135.1 (C-4), 136.4 (C-9), 137.7 (C-6), 146.4 (C-8a), 149.7 (C-2), 155.7 (C-8a'), 156.2 (C-
7'), 161.5 (C-5'), 191.9 (C-11); HRMS (neg) m/z 482.1975 [M-H] (calcd. for C30H28NO5 482.1967).
(E)-1-(5-Hydroxy-2,2,8,8-tetramethyl-2H,8H-pyrano[2,3-f]chromen-6-yl)-3-(2-methoxy-6-methylquinolin-3-
yl)prop-2-en-1-one (4h). Brown crystalline solid; yield 43%; mp 148-149 °C; IR (neat, vmax, cm-1) 1700 (C=O);
λmax (log ε): 266 (4.66), 373 (4.34); 1H NMR (400 MHz, CDCl3) δH 1.44 (6H, s, H-2a'/H-2b'), 1.54 (6H, s, H9a'/H-
9b'), 2.48 (3H, s, H-6a), 4.13 (3H, s, H-2a), 5.47 (2H, d, J 10.0 Hz, H-3', H-10'), 6.61 (1H, d, J 10.0 Hz, H-11'), 6.68
(1H, d, J 10.0 Hz, H-4'), 7.46 (1H, dd, J1 8.6, J2 1.6 Hz, H-7), 7.47 (1H, s, H-5), 7.72 (1H, d, J 8.6 Hz, H-8), 7.97 (1H,
d, J 16.0 Hz, H-9), 8.12 (1H, s, H-4), 8.23 (1H, d, J 16.0 Hz, H-10), 14.31 (1H, s, H-5a'); 13C NMR (100 MHz, CDCl3)
δC 21.3 (C-6a), 28.0 (C-9a'/C-9b'), 28.4 (C-2a'/C-2b'), 53.8 (C-2a), 78.3 (C-2'/C-9'), 102.5 (C-4a'), 102.6 (C-8'),
106.1 (C-6'), 116.3 (C-4'), 116.6 (C-11'), 120.8 (C-3), 124.9 (C-10'), 125.1 (C-4a), 125.4 (C-3'), 126.7 (C-8), 126.9
(C-5), 130.5 (C-10), 132.7 (C-7), 134.2 (C-6), 136.6 (C-9), 137.7 (C-4), 145.1 (C-8a), 155.4 (C-8a'), 156.2 (C-7'),
159.9 (C-2), 161.4 (C-5'), 193.2 (C-11); HRMS (neg) m/z 482.1961 [M-H] (calcd. for C30H28NO5 482.1967).
Computational studies
The 2D structure of the synthesized molecular hybrids 6a-6l were prepared using ChemBioDraw Ultra 13.0 and
optimized using DFT with B3LYP at 6-31G (d, p) level basis sets.44-46 For intramolecular hydrogen bonding
calculations, compounds 4b and 4f were further optimized using 6-311G (d, p).47 The harmonic vibrational
frequency calculations of the optimised molecules were evaluated at the same level of theory as optimisation
and the absence of imaginary frequencies confirmed that the stationary points obtained correspond to the
true minima of the potential energy surface. Symmetry of the molecules was not specified in all calculations.
Software default convergence parameters were used and the optimisations carried out in the gaseous phase.
Calculations were carried out using Gaussian 09 A.02 and visualized using Gauss View 5.0.8 software.48-49 The
final optimised 3D structures were used to obtain frontier molecular orbitals, HOMO-LUMO energies and
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molecular electrostatic potential (MEP) plots. Potential energy scans were determined for 4b and 4f to
investigate the potential energy barrier of the intramolecular proton transfer of the OH proton and its effect
on molecular structure.
Single crystal X-ray diffraction analysis
The compounds were dissolved in methanol and allowed to slowly crystallise at room temperature. Crystal
structures of 4b and 4f were determined on a Bruker Smart APEX II diffractometer with Mo Kα radiation. Data
reduction was carried out using the System Administrator's Integrated Network Tool (SAINT+). SHELXS was
used to solve and refine the structure. Hydrogen atoms were positioned geometrically and refined
isotropically. Crystallographic images were prepared using Mercury 3.9. Crystallographic data has been
deposited with the Cambridge Crystallographic Data Centre, CCDC, 12 Union Road, Cambridge CB21EZ, UK.
Copies of the data can be obtained free of charge on quoting the depository numbers CCDC-1895603 and
1895604 (Fax: +44-1223-336-033; E-Mail: deposit@ccdc.cam.ac.uk http://www.ccdc.cam.ac.uk ).
Acknowledgements
NK thanks the National Research Foundation South Africa for a Competitive Grant for Rated Researchers
(Grant No. 118534) and Incentive Funding for Rated Researchers (Grant No. 114817), and the CSIR Armscor
Ledger Grant for research costs and a bursary for Lamla Thungatha.
Supplementary Material
1
1H and 13C NMR data, High Resolution Mass spectra and graphs depicting the changes in the H NMR chemical
shifts of certain resonances as a function of temperature can be found in the supplementary material file.
References
1. Kaur, K.; Jain, M.; Reddy, R.P.; Jain, R. Eur. J. Med. Chem. 2010, 45, 3245.
https://doi.org/10.1016/j.ejmech.2010.04.011
2. Marella, A.; Tanwar, O.P.; Saha, R.; Ali, M.R.; Srivastava, S.; Akhter, M.; Shaquiquzzaman, M.; Alam, M.M.
Saudi Pharm. J. 2013, 21, 1.
https://doi.org/10.1016/j.jsps.2012.03.002
3. Garudachari, B.; Isloor, A. M.; Satyanarayana, M.N.; Fun, H.-K.; Hegde, G. Eur. J. Med. Chem. 2014, 74, 324.
https://doi.org/10.1016/j.ejmech.2014.01.008
4. Duval, A.R.; Carvalho, P.H.; Soares, M.C.; Gouvêa, D.P.; Siqueira, G.M.; Lund, R.G.; Cunico, W.
ScientificWorldJournal 2011, 11, 1489.
https://doi.org/10.1100/tsw.2011.141
5. Afzal, O.; Kumar, S.; Haider, M.R.; Ali, M.R.; Kumar, R.; Jaggi, M.; Bawa, S. Eur. J. Med. Chem. 2015, 97, 871.
https://doi.org/10.1016/j.ejmech.2014.07.044
6. Candéa, A.L.P.; Ferreira, M.D.L.; Pais, K.C.; Cardoso, L.N.D.F.; Kaiser, C.R.; Henriques, M.D.G.M.D.O.;
Lourenço, M.C.S.; Bezerra, F.A.F.M.; Souza, M.V.N.D. Bioorg. Med. Chem. Lett. 2009, 19, 6272.
https://doi.org/10.1016/j.bmcl.2009.09.098
7. Gopinath, V.S.; Rao, M.; Shivahare, R.; Vishwakarma, P.; Ghose, S.; Pradhan, A.; Hindupur, R.; Sarma, K.D.;
Gupta, S.; Puri, S.K.; Launay, D.; Martin, D. Bioorg. Med. Chem. Lett. 2014, 24, 2046.
https://doi.org/10.1016/j.bmcl.2014.03.065
Page 13
©AUTHOR(S)

Arkivoc 2020, iii, 0-0
Thungatha, L. et al.
8. El-Feky, S.A.H.; El-Samii, Z.K.A.; Osman, N.A.; Lashine, J.; Kamel, M.A.; Thabet, H.K. Bioorg. Chem. 2015, 58,
104.
https://doi.org/10.1016/j.bioorg.2014.12.003
9. Garrison, A.T.; Abouelhassan, Y.; Yang, H.; Yousaf, H.H.; Nguyen, T.J.; Huigens III, R.W. MedChemComm,
2017, 8, 720.
https://doi.org/10.1039/C6MD00381H
10. Ramírez-Prada, J.; Robledo, S.M.; Vélez, I.D.; Crespo, M.D.P.; Quiroga, J.; Abonia, R.; Montoya, A.; Svetaz,
L.; Zacchino, S.; Insuasty, B. Eur. J. Med. Chem. 2017, 131, 237.
https://doi.org/10.1016/j.ejmech.2017.03.016
11. Nikam, M.D.; Mahajan, P.S.; Damale, M.G.; Sangshetti, J.N.; Dabhade, S.K.; Shinde, D.W.; Gill, C.H. Med.
Chem. Res. 2015, 24, 3372.
https://doi.org/10.1007/s00044-015-1385-x
12. Wang, L.; Chen, G.; Lu, X.; Wang, S.; Han, S.; Li, Y.; Ping, G.; Jiang, X.; Li, H.; Yang, J.; Wu, C. Eur. J. Med.
Chem. 2015, 89, 88.
https://doi.org/10.1016/j.ejmech.2014.10.036
13. Wei, Z.; Yang, Y.; Xie, C.; Li, C.; Wang, G.; Ma, L.; Xiang, M.; Sun, J.; Wei, Y.; Chen, L. Fitoterapia 2014, 97,
172.
https://doi.org/10.1016/j.fitote.2014.06.002
14. Dinesh, K.; Pooja, S.; Harmanpreet, S.; Kuna, N.; Girish Kumar, G.; Subheet Kumar, J.; Fidele, N.K. RSC
Advances 2017, 7, 36977.
https://doi.org/10.1039/C7RA05441F
15. Filarowski, A.; Koll, A.; Kochel, A.; Kalenik, J.; Hansen, P.E. J. Mol. Struct. 2004, 700, 67.
https://doi.org/10.1016/j.molstruc.2004.01.033
16. Weller, A. Z. Electrochem., Ber Bunsenges Phys Chem. 1956, 60, 1144.
17. Sobczyk, L.; Chudoba, D.; Tolstoy, P.M.; Filarowski, A. Molecules 2016, 21, 1657.
https://doi.org/10.3390/molecules21121657
18. Kanaani, A.; Ajloo, D.; Ghasemian, H.; Kiyani, H.; Vakili, M.; Mosallanezhad, A. Struct. Chem. 2015, 26,
1095.
https://doi.org/10.1007/s11224-015-0571-2
19. Li, C.; Li, D.; Ma, C.; Liu, Y. J. Mol. Liq. 2016, 224, 83.
https://doi.org/10.1016/j.molliq.2016.09.088
20. Li, H.; Yin, H.; Liu, X.; Shi, Y. J. At. Mol. Sci. 2016, 7, 115-124.
21. Mitchell, J.B.O.; Price, S.L. J. Comput. Chem. 1990, 11, 1217.
https://doi.org/10.1002/jcc.540111014
22. Charisiadis, P.; Kontogianni, V.G.; Tsiafoulis, C.G.; Tzakos, A.G.; Siskos, M.; Gerothanassis, I.P. Molecules
2014, 19, 13643.
https://doi.org/10.3390/molecules190913643
23. Taylor, R. Cryst. Growth Des. 2016, 16, 4165.
https://doi.org/10.1021/acs.cgd.6b00736
24. Desiraju, G.R. Acc. Chem. Res. 1996, 29, 441.
https://doi.org/10.1021/ar950135n
25. Alkorta, I.; Elguero, J. Chem. Soc. Rev. 1998, 27, 163.
Page 14
©AUTHOR(S)

Arkivoc 2020, iii, 0-0
Thungatha, L. et al.
https://doi.org/10.1039/a827163z
26. Rajput, A.P.; Rajput, S.S. Int. J. Pharm. Pharm. Sci. 2011, 3, 346.
27. Rani, K.M.; Rajendran, S.P. Int. J. Innovative Res. Sci. Eng. Technol. 2014, 3, 15966.
28. Venkanna, P.; Rajanna, K.C.; Satish Kumar, M.; Ansari, M.B.; Moazzam Ali, M. Tetrahedron Lett. 2015, 56,
5164.
29. Abonia, R.; Insuasty, D.; Castillo, J.; Insuasty, B.; Quiroga, J.; Nogueras, M.; Cobo, J. Eur. J. Med. Chem.
2012, 57, 29.
https://doi.org/10.1016/j.ejmech.2012.08.039
30. Kulkarni, P.; Swami, P.; Zubaidha, P. Synth. React. Inorg., Met.-Org., Nano-Met. Chem. 2013, 43, 617.
https://doi.org/10.1080/15533174.2012.752392
31. Khan, K.; Siddiqui, Z.N. Appl. Organomet. Chem. 2014, 28, 789.
https://doi.org/10.1002/aoc.3200
32. Patil, C.B.; Mahajan, S.K.; Katti, S.A. J. Pharm. Sci. Res. 2009, 1, 11.
33. Moodley, T.; Momin, M.; Mocktar, C. Kannigadu, C., Koorbanally, N. A. Magn. Reson. Chem. 2016, 54, 610.
https://doi.org/10.1002/mrc.4414
34. Alapour, S.; Farahani, M.D.; Silva, J.R.A.; Alves, C.N.; Friedrich, H.B.; Ramjugernath, D.; Koorbanally, N. A.
Monatsh. Chem. 2017, 148, 2061.
https://doi.org/10.1007/s00706-017-2044-3
35. Gandhimathi, S.; Balakrishnan, C.; Venkataraman, R.; Neelakantan, M.A. J. Mol. Liq. 2016, 219, 239.
https://doi.org/10.1016/j.molliq.2016.02.097
36. Alphonse, R.; Varghese, A.; George, L.; Nizam, A. J. Mol. Liq. 2016, 215, 387.
https://doi.org/10.1016/j.molliq.2015.12.050
37. Li, Q.; Li, B.; Liu, B.; Yu, M. J. Chem. Res. 2010, 34, 379.
https://doi.org/10.3184/030823410X12780936189898
38. Dulla, B., Vijayavardhini, S., Rambau, D., Anuradha, V., Rao, M., Pal, M. Curr. Green Chem. 2014, 1, 73.
https://doi.org/10.2174/22133461114019990002
39. Meth-Cohn, O.; Narine, B.; Tarnowski, B. Tetrahedron Lett. 1979, 20, 3111.
https://doi.org/10.1016/S0040-4039(01)95334-1
40. Waghray, D.; Zhang, J.; Jacobs, J.; Nulens, W.; Basarić, N.; Meervelt, L.V.; Dehaen, W. J. Org. Chem. 2012,
77, 10176.
https://doi.org/10.1021/jo301814m
41. Gupta, S.; Shivahare, R.; Korthikunta, V.; Singh, R.; Gupta, S.; Tadigoppula, N. Eur. J. Med. Chem. 2014, 81,
359.
https://doi.org/10.1016/j.ejmech.2014.05.034
42. Pawar, S.S.; Koorbanally, N.A. Magn. Reson. Chem. 2014, 52, 279.
https://doi.org/10.1002/mrc.4062
43. Lee, Y.R.; Kim, D.H. Synthesis 2006, 603.
https://doi.org/10.1055/s-2006-926294
44. Becke, A.D. J. Chem. Phys. 1993, 98, 5648.
Page 15
©AUTHOR(S)

Arkivoc 2020, iii, 0-0
Thungatha, L. et al.
https://doi.org/10.1063/1.464913
45. Lee, C.; Yang, W.; Parr, R.G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785.
https://doi.org/10.1103/PhysRevB.37.785
46. Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200.
https://doi.org/10.1016/0009-2614(89)87234-3
47. Orio, M.; Pantazis, D.A.; Neese, F. Photosynth. Res. 2009, 102, 443.
https://doi.org/10.1007/s11120-009-9404-8
48. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R. Gaussian 09, 2009,
Gaussian, Inc., Wallingford, CT, USA.
49. Dennington, R.D.; Keith, T.A.; Millam, J.M. GaussView 5.0. 8. 2008. Gaussian Inc.
This paper is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) license
(http://creativecommons.org/licenses/by/4.0/)
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