Journal of Molecular Structure 1253 (2022) 132194

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Journal of Molecular Structure

journal homepage: www.elsevier.com/locate/molstr

Experimental and Theoretical investigations on

(E)-3-(4-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)prop–2-en-1-one
and (E)-3-(naphthalen-2-yl)-1-(2-(trifluoromethyl)
phenyl)prop–2-en-1-one: DNA binding, Urease inhibition and
Promising NLO response
Faiz Rasool a, Ajaz Hussain a,∗, Khurshid Ayub b, Muhammad Tariq a, Khalid Mahmood a,
Sammer Yousuf c, Muhammad Yar b, Muhammad Khalid d, Hafiza Saba Samreen a,
Mehreen Lateef e, Abdul Malik c
a
Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan
b
Department of Chemistry, COMSATS University, Abbottabad, 22060, Pakistan
c
International center for Chemical and Biological Sciences, HEJ Research Institute of Chemistry University of Karachi, Karachi, 75270, Pakistan
d
Department of Chemistry, Khwaja Fareed University of Engineering & Information Technology, Rahim Yar Khan, 64200, Pakistan
e
Multi Disciplinary Research Lab, Medical and Dental College, Bahria University Karachi,75500, Pakistan

a r t i c l e i n f o a b s t r a c t

Article history: In this work, we are presenting preparation of (E)-3-(4-ethoxyphenyl)-1-(2-(trifluoromethyl)phenyl)prop–

Received 14 July 2021 2-en-1-one (1) and (E)-3-(naphthalen-2-yl)-1-(2-(trifluoromethyl) phenyl)prop–2-en-1-one (2) through
Revised 3 December 2021
Claisen-Schmidt reaction. The synthesized compounds were characterized by different analytical tech-
Accepted 13 December 2021
niques (UV–visible, FT-IR 1 HNMR and mass spectrometry). The Urease inhibition, antioxidant potential
Available online 15 December 2021
and DNA binding (Salmon sperm DNA) studies were conducted along with molecular docking for compar-
Keywords: ative analysis of theoretical and experimental findings. The ADMET properties (An acronym for absorp-
Chalcones tion, distribution, metabolism, excretion, and toxicity) of aforesaid compounds were predicted. Density
DNA interactions functional theory (DFT) calculations were performed for FMOs (frontier molecular orbitals) and nonlinear
Enzyme inhibition optical (NLO) properties of 1 and 2. Photophysical properties of title compounds were described by time
Anti-oxidant dependent DFT (TD-DFT). Moreover, energy band gaps of aforementioned compounds were determined
Energy band gap
by Tauc’s plot and were found as (3.0 eV) for 1 and (3.4 eV) for 2 respectively. Additionally, natural
Molecular docking
Pharmacokinetic properties
bond orbitals (NBOs) analysis was applied to evaluate conjugative interactions as well as inter and intra
DFT molecular interactions. The results revealed that 1 exhibits higher stabilization energy of electron’s de-
localization than 2. Moreover, second order NLO properties of 1 (3920.9 a.u.) and 2 (3018.6 a.u.), being
much higher than Urea, reflects that synthesized compounds are potential NLO materials. The experi-
mental data showed that the strong interactions of SS-DNA with entitled compounds took place through
intercalative mode. Moreover, the synthesized compounds showed moderate behavior towards antioxi-
dant assay and Urease inhibition.
© 2021 Elsevier B.V. All rights reserved.

1. Introduction ical activities. The radical scavenging capability of chalcone deriva-

tives containing phenolic moieties have been used in medicines
Chalcones constitute the most prominent class of naturally oc- and food preservatives [1]. Moreover, the chalcone derivatives ex-
curring organic compounds. These are widely found in food prod- hibit enormous applications in arena of medicinal chemistry and
ucts i.e., tea, fruits and vegetables. Chalcones belong to flavonoids seem as future drug candidates due their broad spectrum of
and sometimes categorized as minor flavonoids. Among various or- therapeutic potential. It has been reported that chalcones pos-
ganic molecules the derivatives of chalcones possess unique biolog- sess cytotoxic [2], antitumor [3], antibacterial [4], antidepressant,
anti-inflammatory and analgesic properties [5]. Furthermore, some
∗ chalcone derivatives were reported as anti-Convulsant [6], antigia-
Corresponding author.
E-mail address: drajazhussain@bzu.edu.pk (A. Hussain). rdial [7], antiviral [8], antidiabetic [9], anti–HIV, antileishmanial,

https://doi.org/10.1016/j.molstruc.2021.132194
0022-2860/© 2021 Elsevier B.V. All rights reserved.
F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

δ 6.92–6.94 ppm, (m, 2H J = 6 Hz), δ 7.50–7.54 ppm, (m, 2H

J = 6 Hz), δ 7.52–7.54 ppm, (m, 1H J = 6 Hz) δ 7.65–7.74 ppm,
(m, 2H, J = 3, 9 Hz), δ 7.80–7.82 ppm, (m, 1H, J = 6 Hz); MS (M.+ ),
320.2, 300.2, 291, 275, 251, 223, 195, 175, 147.2, 119, 91, 65, 41.
13 C NMR (101 MHz, CDCl ) δ (ppm): 195.1 (C-7), 161.5 (C-13),
3
147.83 (C-9), 130.45 (C-1), 130.24 (C-6), 129.65 (C11, C-2, C-15),
128.15 (C-8), 127.8 (C-3), 124.75 (C-4), 124.52 (C-10), 114.99 (C-
12,C-5, C-14), 138.5 (C-16), 63.72 (C-17), 14.7 (C-18);

4.2. Spectroscopic characterization of compound 2

Scheme 1. Synthesis of chalcones 1 and 2.

IR ῡ(cm−1 ): 1686 (C = O), 1643, 1587,1462 (C = C), 773 (C-F).
1 HNMR at 300 MHz: δ at 7.21–7.25 ppm, (d, 1H, J = 12 Hz), δ at
antioxidant, antituberculosis, neuroprotective and antiulcer [10]. 7.54–7.58 ppm, (d, 1H, J = 12 Hz), δ at 7.46–7.60 ppm, (m, 3H,
Some of the derivatives of chalcones are known to prevent the J = 3, 9 Hz), δ at 7.71–7.79 ppm, (m, 3H J = 3, 9 Hz), δ at 7.83–
polymerization of tubulin to form microtubules and can be used as 7.89 ppm, (m, 4H J = 3, 9 Hz), δ at 8.00 ppm, (s, 1H J = 3, 9 Hz);
antimitotic agents [11]. Naphthalene based derivatives have been MS (M.+ ), 325.2, 305.2, 256.1, 181.2,173.1, 152.1.
13 C NMR (101 MHz, CDCl ) δ (ppm): 195.12 (C-7), 147.9 (C-9),
involved in treatment of cancer cells by directing tubulin colchicine 3
binding site [12]. Also, these derivatives were used as ingredients 138.96 (C-20), 134.59 (C-11), 133.24 (C-19), 131.68 (C-13), 131.056
in flavoring compounds as well as in perfumes and cosmetics. (C-15), 130.13 (C-14), 129.88 (C-16), 128.93 (C-18), 128.69 (C-1),
The study on account of interactions among chalcones and DNA 128.17 (C-8), 127.83 (C-6), 126.97(C-10), 126.90 (C-2), 126.74 (C-3),
is significant to unveil the biosensing capability of 1 and 2. DNA 125.03 (C-17), 123.4 (C-4),122.30 (C-12), 122.9 (C-5);
being an important cellular receptor is the focused target to in-
4.3. Mass fragmentation
vestigate antitumoral properties associated with DNA binding thus
varying its replication and disrupting cell growth [13]. Further-
Considering 1 a high intensity peak representing molecular ion
more, literature review found that fluoro chalcones show excellent
was found at m/z 320 (as base peak) and two prominent peaks
NBO, FMO and NLO responses [14].
were seen at m/z 291 and 275 by removal of C2 H5 radical and
The studies of chalcones and their derivatives revealed that
OC2H5 radical respectively. Moreover, some other peaks formed by
such type of compounds are significant candidates for the syn-
fragmentation are shown in scheme 2.
thesis of functional heterocyclic molecules. In this context, chal-
In compound 2 the high intensity peak (base peak) representing
cones owing to reactive site (α , β -unsaturated carbonyl moiety)
molecular ion appeared at m/z 325, whereas the peak at m/z 305.2
are synthetic intermediates for a variety of medicinally important
appeared by removal of a neutral molecule of HF from molecular
compounds i.e., pyrimidines, triazole, pyrazole, epoxide, benzofu-
ion. Similarly, fragment ion peaks at m/z 181and 256 were formed
ranones, isoxazoles, quinolinones and flavones. Herein, we present
due to loss of trifluoro methyl benzene and trifluoromethyl rad-
the synthesis, spectroscopic characterization, mass fragmentation
icals respectively. However, other peaks formed by fragmentation
pattern, molecular docking, DNA binding and theoretical studies of
are shown in Scheme 3.
fluorinated chalcones and ADME properties.
Following schemes were proposed for the fragmentation of 1
and 2 by using electron impact data.
2. Experimental procedure
4.4. Single crystal X-Ray crystallographic analysis
Determination of melting was accomplished using GallenKamp
apparatus. TLC was used to check the completion of reaction using Single crystal X-ray diffraction data of compound 1 was ob-
medium of ethyl acetate and petroleum ether (1:6). UV–VIS spec- tained at 285 K using a Bruker D8 Venture diffractometer equipped
tra were recorded by Shimadzu-1800 and IR was taken using FTIR- with Photon-100 CMOS detector. The Copper Kα (λ = 1.54178 Å)
ATR. The solvent CD3 OD was used to record 1 H NMR in a Bruker radiations were used as X-ray source. Crystal data were obtained
(300 MHz) spectrometer and TMS (reference). The JEOL MS route by mounting a tiny crystal on goniometer of X-ray diffractometer.
spectrometer was used to record mass spectra through EI (electron The collected data were further reduced and integrated by Bruker
impact) mode. SAINT Software [15]. Structure solution and structure refinement
were carried out by SHELX 97 [16]. All non-hydrogen atoms were
3. General synthetic protocol refined anisotropically while hydrogen atoms were fixed geomet-
rically for C–H atoms. PLATON program was used to determine
2-Trifluoromethyl acetophenone (1 mmol) was dissolved in inter-molecular hydrogen bond geometries [17]. Graphical repre-
C2 H5 OH with NaOH solutions (4 M), stirred at 15 °C for half an sentation were carried out by ORTEP3 [18].
hour and then continued for 4 h on stirring after the addition of
substituted aryl aldehyde (1 mmol). TLC was used to monitor the 4.5. Structural features
completion of reaction. The filtration was done and recrystalliza-
tion of product was carried out by Ethanol (See Scheme 1). The crystal data of title compound (1) has monoclinic symme-
try with C2/c space group. The molecular structure contain central
4. Results and discussion enone moiety (C7-C9/O2) bound with two phenyl substituents i.e.,.
ring A (C1-C6), and ring B (C10-C15). Ring A have an ethoxy sub-
4.1. Spectroscopic characterization of compound 1 stituent (O1/C17/C18) at C-6 while ring B binds with CF3 group at
C-15 atom. Due to stearic repulsion of ortho and para substituents
IR ῡ(cm−1 ): 1699 (C = O), 1667, 1643, 1524 (C = C), 772, 664 of both rings, the torsion angles between O2-C9-C10-C11 and O2-
(C-F). 1 HNMR (δ ppm) at 300 MHz: δ at 1.33–1.40 ppm, (t, 3H, C7-C8-C9 atoms are 97.2 (3) ° and 176.8 (3) ° , respectively. How-
J = 6 Hz), δ at 4.04–4.09 ppm, (q, 2H, J = 3, 9 Hz), δ at 6.94– ever, the dihedral angle between both phenyl groups is 81.23° in-
6.98 ppm, (d, 1H, J = 12 Hz), δ 7.22–7.26 ppm, (d, 1H, J = 12 Hz), dicated arrangement of rings is nearly orthogonal. The carbonyl

2
F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

Scheme 2. Proposed MS fragmentation pattern of 1.

Scheme 3. Proposed MS fragmentation pattern of 2.

3
F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

4.8. Antioxidant activity

Anti-oxidant activity was conducted by using procedure as

mentioned in literature [23]. Herein for compounds 1 and 2 the
calculated IC50 values were found >100 while, for reference BHA
it is found as 44.2 which showed that the title compounds are not
good antioxidants.

4.9. Molecular docking

Herein, the interactions of compounds 1 and 2 were inves-

tigated with the receptor DNA and Urease using Autodok and
Autodock Vina [24]. The protein data bank (http://www.rcsb.org/
Fig. 1. Ortep view of compound 1 drawn at 30% probability level. pdb) was used to obtain structures of H. Pylori Urease and B-
DNA dodecamer with PDB ID as 1E9Y and 1BNA respectively. The
whole water molecules were eliminated before docking and by
group (C9/O2) is anti to C = C bond while the molecule have over using UCSF Chimera Gasteiger charges were allotted to the com-
all E configuration. The CF3 substituent at C-6 appeared to have pounds [25]. However, structures of molecules were drawn on Mar-
positional disorder due to real dynamic motion in solid state with vin sketch, cleaned on 2D and 3D prior to structural optimization
splitting occupancy of 33%. through UCSF Chimera. Docked images were obtained by using Vi-
The molecular conformation inside the crystal is stabilized via sualizer of Discovery Studio [26].
pair vise C17-H17A-O2 and C18-H18C-F2C hydrogen bonds respon- The binding of B-DNA dodecamer with 1 and 2 was estimated
sible to linked the molecules in an infinite chain running along a- with the help of blind docking on DNA (double standard). The
axis. grid box and grid spacing used for docking against DNA were as
40 × 40 × 40 A◦ and 0.375A◦ respectively, whereas the grid box
used for docking against active residue of Urease was as 32 × 32
4.6. DNA interaction study by UV–Visible spectroscopy × 32 A◦ . Hence, docking results showed that molecules bind with
DNA through H-bonding and hydrophobic interactions. The binding
UV–Visible spectrum was primarily used to investigate the in- ability of 1 was calculated as −6.7 Kcal/mol. It was observed that
teraction between synthesized compounds and salmon sperm DNA. compound 1 showed one Hydrogen bonding interaction with the
The whole experiment was carried out using Tris-hydrochloride residue DG14 (B) of DNA. In addition to that, some Vander Waals
buffer medium to maintain pH at 7.2. Absorbance ratio of wave- and Pi-alkyl interactions were observed in {DC 15 (B), DG16 (B)}
length at 260/280 that was found in range of 1.8–1.9 confirm DNA and {DA17 9 (B)}. Additionally, a pool of hydrophobic interactions
free from protein [19]. Absorption titration was carried out by fix- was seen among ligand atoms and base pairs of DNA including
ing the concentrations of tested compounds and increasing the DA18 (B), DG10 (A), DC11 (A), and DG12 (A) (as shown in Fig. 3).
concentration of SS-DNA. The compound 2 with binding interaction of −6.6 Kcal/mol showed
For compound 1, the absorption region was observed in range conventional hydrogen bonding with B-DNA residue DG14 (B) as
of 325–343 nm and λmax was observed at 335 nm. However, well as Vander Waals interactions with DC15 (B) respectively. Fur-
two absorption peaks for compound 2 were observed in range of thermore, a number of hydrophobic contacts with bases of DNA
311–327 nm and λmax was found at 319 nm (see in Fig. 2). By were observed as DG12 (A), DG10 (A), DC9 (A), DA18 (B) and DA17
adding SS-DNA in both compounds the bands showed significant (A) respectively (as shown in Fig. 3). Herein it has been observed
hypochromic shifts. This effect leads to hypochromism which is that binding constant data obtained from experimental calculations
due to intercalative mode of binding. The π -stacking interlinkage for 1 and 2 (8.6 × 104 and 8.8 × 103 M − 1 ) were found in excel-
between SS-DNA and title compounds caused hypochromism [20]. lent concurrence with docked data as −6.7 and −6.6 Kcal/mol re-
The hypochromic shifts reflected non-covalent intercalative bind- spectively. Furthermore, DNA binding interactions in 3D for com-
ing mode of synthesized compounds [21]. For 1 and 2 the values pounds 1 and 2 are shown in Figs. 3 whereas Fig. 4 reflects the
of binding constant were calculated as 8.6 × 104 and 8.8 × 103 presence of biding molecules within the binding site of DNA. In
M − 1 respectively. The Gibbs’s free energy (G) values were calcu- addition to that, IC50 values for enzyme inhibition obtained from
lated by using equation as: experimental data found as 45 ± 0.56 (1) and 46 ± 0.76 (2) and
calculated data obtained from docking as −6.6 (1) and −6.5 (2)
G = −RT ln K kcal/mol were in good agreement. Furthermore, docked view of
1 and 2 in the active site of Urease, 2D and 3D interactions are
Here R reflects ideal gas constant with value 8.314 J /K mol and
shown in Figs. 6, 7 and 8 respectively.
T denotes the temperature (298 K). For 1 and 2 the Gibb’s free
energy (G) values were determined as −28.150 and −22.491 kJ
/mol respectively (as shown in Fig. 1). Moreover, the interaction of 4.10. Drug likeness
these compounds with SS-DNA is a spontaneous process as shown
by the negative values of G. Molecular properties as well as drug likeness of molecules can
be analyzed with the help of RO5 (Lipinski’s Rule of Five). The
drug likeliness of 1 and 2 was checked and results were tabu-
4.7. Enzyme inhibitory activity lated in Table 1. This rule states that ideal drug candidates have
no or only one violation. The parameters of RO5 include MW
The Urease inhibitory activity of prepared compounds was con- (molecular weight) ≤ 500 g/mol, partition coefficient of octanol-
ducted using procedure as reported in literature [22]. The calcu- water logp ≤ 5, H-bond donor ≤ 5 and hydrogen bond acceptor
lated percentage inhibition (IC50 ) was found as 45 and 46 for 1 ≤ 10 [27,28,29,30]. Conclusively, no violation was seen in 1 but 2
and 2 respectively while, 21.5 for reference Thiourea. show only one violation, hence both compounds follow RO5.

4
F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

Fig. 2. Absorption spectra 1(a), 2(a) and graph 1(b), 2(b) between A0 /A-A0 vs 1/DNA showing binding constant by interaction between SS-DNA and compound 1 and 2.

Fig. 3. Docking results reflecting 3D interactions of compounds 1 and 2 with B-DNA dodecamer.

4.11. Pharmacokinetic properties non-inhibitors of renal organic cation transporter which reflects no
accumulation of compounds 1 and 2 in renal tubules. Moreover,
The pharmacokinetic properties of 1 and 2 were predicted CYP 450 values showed that both compounds were substrate for
by using database of admetSAR i.e., (http://www.admetexp.org). CYP isoenzymes, but inhibit CYP 2C9 and CYP 1A2 that may cause
The calculated data predict that title compounds are sufficient slight adverse drug-drug interactions. The toxicity data showed
lipophilic for penetration through blood brain barrier and have ca- that 1 and 2 are non carcinogenous but compound 2 showed AMES
pacity to diffuse human intestinal Caco-2 cells. Furthermore, the toxicity as presented in Table 3.
entitled compounds are considered as promising candidates of
future drugs due to absorption in human intestine. The behav-
ior of aforementioned compounds toward P-glycoprotein substrate 4.12. Computational procedure for DFT studies
showed that they possess descent level of bioavailability. Addition-
ally, it has been noted that 2 plays pivotal role in resistance of The entire computational findings for (1) and (2) were ob-
multidrugs which reflects that it has excellent inhibition toward P- tained through Gaussian 09 package [31] using B3LYP level and
glycoprotein. The Table 2, it is obvious that compounds 1 and 2 are 6–311 G (d,p) basis set of DFT [32]. The frequency analysis was
performed at same level for confirmation of nature of station-

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F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

Fig. 4. 2D Images of 1 and 2 showing Vander waals, H-bonding, conventional hydrogen bonding interactions with different base pairs of DNA.

Fig. 5. Compounds 1 and 2 within the strands of DNA.

ary point on potential energy surface. Furthermore, NBOs, FMOs Generally, four kinds of interactions like σ → σ ∗ , n→σ ∗ , π →π ∗
and NLO were worked out at B3LYP/6–311 G(d,p) level. Never- and n→π ∗ have been found but in our studied compounds
theless, UV–Vis study was furnished at TDDFT/B3LYP/6–311G(d,p) only three types of interactions were observed. In 1, significant
level for photophysical properties of 1 and 2. Moreover, softwares π →π ∗ transitions have observed as π (C3-C4) → π ∗ (C1-C2) and
like Chemcraft [33], Avogadro [34], Gauss Sum [35] and Gauss view π (C19-C23) → π ∗ (C16-C17) with highest stabilization energies
5.0 [36] were used to interpret data. of 22.71 and 23.6 kcal/mol, respectively. Whereas, the transition
like π (C11-O34) → π ∗ (C1-C2) were characterized with least sta-
bilization energy of 0.78 kcal/mol. Likewise, some other impor-
4.13. Natural bonding orbital (NBO) and UV/Visible analysis
tant π →π ∗ transitions were observed indicating the existence
of conjugation as π (C1-C2)→π ∗ (C5-C6), π (C5-C6) →π ∗ (C3-C4),
NBO analysis is helpful to investigate atomic charge, hybridiza-
π (C16-C17)→π ∗ (C18-C21), π (C18-C21)→π ∗ (C19-C23) and π (C12-
tion, intra and intermolecular charge interactions, bond type like
H14)→π ∗ (C11-O34) affording the stabilization energies as 21.13,
covalent vs. co-ordinate covalent; covalent vs. ionic; σ vs. π , etc.
20.25, 20.33, 21.81, and 22.48 kcal/mol, respectively. Furthermore,
[37]. The stabilization energy of compounds in relation with sec-
interaction like π (C1-C2) → σ ∗ (C35-F36) was observed with sta-
ond order perturbation is shown in Eq. (1) [38–41].
bilization energy of 6.86 k kcal/mol as presented Table S1. In
 2 2, the most prominent π →π ∗ transitions were found i.e., π (C3-
Fi,j
E (2 ) = qi (1) C4) → π ∗ (C1-C2) and π (C12-C14) → π ∗ (C11-O33) which lead to
εj − εi highest energies of stabilization of 22.71 and 21.56 kcal/mol, re-
spectively. Whereas, interaction from π (C11-O33) →π ∗ (C12-C14)
Here; E(2) denotes stabilization energy wheras, qi = occupancy of
yields smallest value of energy as 6.18 kcal/mol. Additionally,
donor, εj and εi = diagonal elements and NBO Fock matrix ele-
some important transitions were seen as π (C1-C2) →π ∗ (C5-C6),
ments F(i.j) = off- diagonal respectively [42,43]. The representative
hyper conjugative interactions of 1 and 2 are shown in (Tables S1
π (C5-C6) →π ∗ (C3-C4), π (C5-C6)→π ∗ (C1-C2), π (C3-C4)→π ∗ (C5-
C6), π (C19-C24)→π ∗ (C16-C17) and π (C1–C2)→π ∗ (C3–C4) afford-
and S2).

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F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

Fig. 6. Docked views of compounds 1 and 2 in the active site of Urease.

Fig. 7. 2D Images of 1 and 2 showing Vander waals, H-bonding, conventional hydrogen bonding, pi-donor H-bond, pi-alkyl interactions with Urease.

Fig. 8. 3D Images showing interactions of H. Pylori Urease with 1 and 2.

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F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

Table 1 Table 2
Experimental crystallographic data target compound 1. Description of RO5 parameters in 1
and 2.
Properties Compound 1
Ligand 1 2
Molecular Formula C18 H15 F3 O2
Formula weight 320.30 Mol.wt 320.31 326.31
Temperature 285 (2) K logP 4.76 4.9
Wavelength 1.54178 A H-donor 0 0
Crystal system Monoclinic H-acceptor 5 4
Space group C 2/c Violation No logp > 5
Unit cell dimensions a = 24.5916(7) α =90°
b = 9.6499(3) β = 115.3920° (10)
c = 14.5968(4) γ = 90°
Volume 3129.28(16) Å3
Z 8 as 4.8, 4.85, 4.97, 5.13, 5.36 and 6.08 kcal/mol, respectively. More-
Density (calculated) 1.360 g/cm3 over, some other σ →σ ∗ were also seen σ (C21-H25)→σ ∗ (C16-C18),
0.954 mm−1
Absorption coefficient
σ (C19-C23) →σ ∗ (C21-C23), σ (C17-H20)→σ ∗ (C16-C18), σ (C17-
F(000) 1328
Crystal size 0.430 × 0.210 × 0.120 mm
C19)→σ ∗ (C23-O26) and σ (C2-C3) →σ ∗ (C1-C2) with energies of
Theta range for data collection 3.980 to 68.183° stabilization as 4.3, 4.37, 4.45, 4.68 and 4.73 kcal/mol respectively.
Index ranges −29<=h<=29 Herein, σ →σ ∗ hyper-conjugative interactions in 2 were
−11<=k<=11 seen as σ (C1-C6)→σ ∗ (C1-C2), σ (C1-C2)→σ ∗ (C1-C6), σ (C14-
−16<=l<=17
H15)→σ ∗ (C12-H13), σ (C6-H10)→σ ∗ (C1-C2), σ (C3-H7)→σ ∗ (C1-
Reflections collected 20,150
Independent reflections 2858 C2) and σ (C12-H13)→ σ ∗ (C14-H15) with stabilization energies
Completeness to theta = 67.679° 99.8% of 6.07, 5.34, 5.13, 4.98, 4.88 and 4.81 kcal/mol respectively.
Refinement method Full-matrix least-squares on F2 In addition to these, other σ →σ ∗ transitions were also noted
Data / restraints / parameters 2858 / 0 / 234
as σ (C14-H15)→σ ∗ (C16-C18), σ (C2-C3)→σ ∗ (C1-C2), σ (C17-
Goodness-of-fit on F2 1.039
Final R indices [I>2sigma(I)] R1 = 0.0526
H20)→σ ∗ (C16-C18), σ (C28-H31)→σ ∗ (C19-C24) and σ (C23-
wR2 = 0.1403 H27)→σ ∗ (C19-C24) with energies of stabilization as 4.79,4.77,
R indices (all data) R1 = 0.0624 4.76, 4.73 and 4.66 kcal/mol, respectively.
wR2 = 0.1500 The most important interactions in 1 have been deter-
Extinction coefficient 0.0044 (4)
mined as n2(O26) →π ∗ (C19-C23) with highest stabilization en-
Largest diff. peak, and hole 0.500 and −0.263 e.Å-3
CCDC 2,124,551 ergy of 32.45 kcal/mol. On contrary the conjugative interac-
tions like n1(F36) →σ ∗ (C1-C35) yielded least stabilization en-
ergies of 0.51 kcal/mol. In addition to these, some prominent
n→σ ∗ transitions were found such as n2(O34) →σ ∗ (C11-C12),
ing the stabilization energies as 20.97, 20.24, 20.08, 19.84, 18.01, n3(F37) →σ ∗ (C35-F38), n3(F38)→σ ∗ (C35-F37), n3(F36)→σ ∗ (C35-
and 17.89 kcal/mol respectively. Hence π →π ∗ interaction in 1 F38) n3(F36)→ σ ∗ (C35-F37) and n3(F37)→ σ ∗ (C35-F37) with
(23.6 kcal/mol) affords higher stabilization energy as compared to stabilization energies of 16.62, 12.24, 10.61, 10.34, 9.69 and
2 (22.71 kcal/mol) as shown (Tables S1 and S2). 8.65 kcal/mol, respectively as shown in Table S1.
In compound 1 the σ →σ ∗ transitions arise from weak donor- In compound 2 some interactions like n(O33)→σ ∗ (C2-C11),
acceptor interactions yielding small amount of stabilization energy n(O33)→σ ∗ (C11-C12), n(F36)→σ ∗ (C34-F37), n(F37)→σ ∗ (C34-F36),
as compared to π →π ∗ hyper-conjugative interactions. The com- n(F35)→σ ∗ (C34-F37), n(F35)→σ ∗ (C34-F36) and n(F37)→σ ∗ (C34-
paratively smaller amount of stabilization energy (0.53 kcal/mol) F37) were seen with stabilization energies of 20.96, 16.82, 12.25,
was observed due to σ (C21–H25) →σ ∗ (C21–C23) conjugative in- 10.73, 10.29, 9.78 and 9.73 kcal/mol, respectively (Table S2). Here
teraction. Considering the σ →σ ∗ transitions have been observed it can be observed that 1 has greater stabilization energy than 2.
as σ (C12-H13)→σ ∗ (C14-H15), σ (C14-H15)→σ ∗ (C16-C18), σ (C6- The entire discussion leads to the conclusion that the entitled com-
H10)→ σ ∗ (C1-C2), σ (C14-H15)→σ ∗ (C12-H13), σ (C1-C2)→ σ ∗ (C1- pounds exhibit charge transfer, hyper-conjugative interaction and
C6) and σ (C1-C6)→ σ ∗ (C1-C2) affording energies of stabilization extended conjugations.

Table 3
Some Representative values of ADMET properties of 1 and 2.

Absorption

Human Renal Organic

Intestinal Blood-Brain Caco2 P-glycoprotein P-glycoprotein Cation
Compounds Absorption Barrier Permeability Substrate Inhibitor Transporter

1 HIA+ BBB+ Caco2+ Non-substrate Inhibitor Non-inhibitor

2 HIA+ BBB+ Caco2+ Non-substrate Non-inhibitor Non-inhibitor

Metabolism

CYP450 3A4 CYP450 2C9 CYP450 1A2 CYP450 2C9 CYP450 3A4 CYP450 2D6
Substrate Substrate Inhibitor Inhibitor Inhibitor Substrate

1 Non-substrate Non-substrate Inhibitor Inhibitor Non-inhibitor Non-substrate

2 Non-substrate Non-substrate Inhibitor Inhibitor Non-inhibitor Non-substrate

Toxicity

AMES Toxicity Carcinogens

1 Non AMES toxic Non-carcinogens

2 AMES toxic Non-carcinogens

8
F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

Fig. 9. Comparison UV-visible spectra DFT and experimental of 1 and 2.

The experimental UV–VIS spectral analysis of synthesized com- (࢞E = ELUMO -EHOMO ) clearly explained the chemical stability. The
pounds was performed in various organic solvents i.e., chloroform, FMO diagram was used to evaluate energies of HOMO and LUMO
DMSO, ethanol and methanol. While, the spectrum obtained from orbitals along with HOMO-LUMO energy gap, 1 and 2 as shown
TD-DFT (time dependent-DFT) calculations in gas phase and sol- (Table 4 & Fig. 12). The HOMO-LUMO energy gaps in 1 and 2 were
vent phase (ethanol, methanol, chloroform and DMSO). The exper- computed as 4.082 and 3.945 eV, respectively.
imentally determined wave lengths in methanol, ethanol, DMSO The maximum electronic density in HOMO of compound 1
and chloroform were found as 333, 333, 336, 335 nm (1) and 319, was concentrated on whole molecule and little bit on trifluoro
320, 323, 322 nm (2) while computed values were observed as methyl phenyl group. Contrarily, in LUMO the electronic den-
334, 335, 333, 334 nm (1) and 319, 318, 319, 320 nm (2) hence, sity was maximum whole molecule except trfluoro methyl phenyl
both simulated and experimental data showed good agreement as group. Similarly, in compound 2 the electronic density in HOMO
shown in (Fig. 9). and LUMO was found maximum on whole molecule except triflu-
oro methyl phenyl ring. Hence, the lower E revealed that the
4.14. Natural population analysis (NPA) 1 have somewhat greater potential for transferring electrons as
shown in (Fig. 12).
In 1 and 2 net atomic charges were obtained by Natural popu-
lation analysis and shown in (Fig. 10).
4.16. Global reactivity parameters
4.15. Frontier molecular orbitals analysis (FMOs)
The energy of HOMO-LUMO and Egap (࢞E) were effectively ap-
plied to envisage global reactivity descriptors [44,45,46,47] which
The calculation of HOMO-LUMO energies and energy gaps
are in turn related to ICT, stability and reactivity of 1 and 2. The
(Egap) of 1 and 2 were conducted at B3LYP level of DFT using
calculation of electron affinity (A) as well as ionization energy (I)
6–311G(d,p) basis set . The EHOMO -ELUMO and Egap are considered
is shown in Eqs. (2) and 3.
very useful parameters in the field of quantum chemistry. FMOs
information was used to evaluate different parameters like elec- I = −EHOMO (2)
tronegativity, chemical reactivity, chemical hardness, and softness.
The HOMO is designated as electron donor while LUMO was
nominated as electron acceptor. The HOMO-LUMO energy gap A = −ELUMO (3)

9
F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

Table 4
Energies (E) calculation of 1 and 2 by FMOs.

1 2

MO(s) Energy E(eV) MO(s) Energy E(eV)

HOMO −6.12 4.08 eV HOMO −6.28 3.94 eV
LUMO −2.04 LUMO −2.34

E denotes energy, whereas ࢞E(eV) denotes ELUMO -EHOMO ;.

Table 5
Computed values of Global reactivity parameters of 1 and 2.

1 2

I 6.12 6.28
A 2.04 2.34
X 4.08 4.31
H 2.04 1.97
μ −4.08 −4.31
4.08 4.71
 0.24 0.25

The global softness could be calculated by using equation 8.

1
σ= (8)
2η
The data obtained by using above mentioned equations is shown
in (Table 5)

4.17. Determination of energy band gap (Tauc‘s method)

The Eg (energy band gap) is a significant tool in the arena

of opto-electronic materials. The energy gap of compounds 1 and
2 was evatuated using Taucs plot through UV–VIS spectroscopy
[48,49] (see Fig. 13). The direct energy gap of title compounds was
determined by using relation as: (α hυ )^2 Vs E (energy) and extrap-
olating the linear part of the curve that cut the x-axis. The com-
pound 1 showed two band gaps (Eg ) which were observed at 3.0
and 5.4 eV (Methanol). While, for 2 three band gaps were found
at 3.4, 4.3 and 5.3 eV (Methanol) (see in Fig. 13). The above dis-
cussion leads to the conclusion that Eg values of 2 >1 in solvent
methanol. Hence compound 1 may be good organic material in
opto-electronics than 2 due to low energy band gap.

Fig. 10. Diagrams showing charge distributions on compounds 1 and 2 by NPA

analysis 4.18. FT-IR analysis
In compound 1, the overall charges of atoms were obtained by NPA as shown in
Fig. 10(a). It was observed that positive charge persisted on all H-atoms while, neg- FT-IR was used to investigate molecular vibrations in experi-
ative charge was concentrated on all carbon atoms excluding C11 and C35. Herein, mental as well as in theoretical ways. For compounds 1 and 2
the atom containing highest negative charge is O34 (−0.53636 e) whereas, the high-
experimentally determined FT-IR spectra are shown in Figure S2
est positive charge carrying atom is C35 (1.11e). Moreover, for compound 2 O33
(−0.53 e) containing highest negative charge whereas, C35 (1) and C34 (2) carry- (supplementary information) while, computed as well as experi-
ing same charges as (1.11e). However, negative charges were localized on all carbon mental absorption frequencies are tabulated in (Tables 6 and 7) re-
atoms apart from C11 and C34 due to linkage with oxygen and Fluorine atoms {see spectively.
Fig. 10(b)}.

Global hardness (η) as well as electronegativity (X) was deter- 4.19. C–H bands
mined with the help of Eqs. (4) and 5.
I−A The computed C–H (symmetric frequencies) in benzene for
η= Equation (4) compound 1 was found as 3208, 3205, 3198 and 3193 cm−1 re-
2
spectively. Whereas, simulated C–H symmetric vibrations for 2
I+A were located at 3205, 3195, 3194 and 3185 cm−1 respectively. Sim-
X= (5)
2 ilarly, C–H vibrations (asymmetric) in 1 were found at 3193, 3184
The chemical potential (μ) was calculated by using equation 6. and 3171 cm−1 whereas the same for compound 2 were observed
at 3194, 3185, 3178, 3172 and 3166 cm−1 respectively. In addition
EHOMO + ELUMO
μ= (6) to that, the calculated C–H asymmetric stretching vibrations (2) in
2 ethoxy group were observed at 3116, 3109, 3041, 3039 and 3002
The electrophilicity can be calculated with the help of Eq. (7) cm−1 respectively. Additionally, some bending vibrations (C–H) in
μ2 1 and 2 were also calculated as 1546 cm− (rocking), 1522 cm−
ω= (7) (scissoring), 1430 cm− (wagging), 975 cm− (twisting) and 1518
2η

10
F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

Fig. 11. Optimized geometry of 1 and 2.

Fig. 14. MEPs and color scheme of the studied compounds 1 and 2.

4.21. C = O vibrations
Fig. 12. FMO analysis of 1 and 2.

The computed stretching frequencies of C = O were present at

1718 (1) and 1723 (2) cm−1 while, experimental results were lo-
cm− (rocking), 1471 cm− (scissoring) these values have good con- cated at 1699.9 (1) and 1699.7 (2) cm−1 respectively.
currence with experimental results as 1549, 1524, 1426, 982 and
1524,1462 cm−1 respectively as presented in (Tables 6 and 7). 4.22. C-F vibration

In 1 and 2 C-F symmetric stretching bands were observed at

736 and 794 cm−1 (DFT), which were found in agreement to ex-
perimental results as 772 and 773 cm−1 respectively. Besides these,
4.20. C = C vibrations in C-F the calculated scissoring vibrational bands for 1 and 2 were
also appeared at 664 and 662 cm−1 respectively.
The computed stretching vibrations of C = C in 1 were located
at 1643, 1600 cm−1 were in good synchroneity with experimen- 4.23. Non-linear optical property
tally determined values as 1642.32, 1550.3 cm−1 respectively. Con-
sidering 2 a good agreement was found between experimental as Organic compounds owing to structural diversity act as poten-
well as computed data in C = C stretching vibrations as 1524.7 tial candidates in the arena of photonics, optoelectronics, commu-
cm−1 and 1518 cm−1 respectively. nication technology, signal processing and nonlinear optics [50]. In

Fig. 13. The Taucs plots of 1 and 2 as (α hυ )2 vs E (in methanol) showing variation in energy band gap.

11
F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

Table 6
Computed and experimental vibrational frequencies of 1. Table 7
Computed and experimental vibrational frequencies of 2.
Vibrational
assignments Vibrational
Exp.Frequency Frequency Intensity v(cm−1 ) Scaled Intensity assignments
Exp. Frequency Frequency (km/mol) v(cm−1 )
3208 12 υ s (C–HBen )
3205 6 υ s (C–HBen ) 3205 5 υ s (C–HBen )
3198 7 υ s (C–HBen ) 3195 10 υ s (C–HBen ), υ
3193 12 υ s, υ as (C–H)
(C–HBen ) 3194 11 υ s, υ as
3184 7 υ as (C–HBen ) (C–HBen ),
3183 3 υ as (C–HBen ), 3185 7 υ s, υ as
(C = C) (C–HBen )
3171 2 υ as (C–HBen ) 3178 26 υ s, υ as
3171 12 υ as (C–HBen ) (C–HBen )
3166 9 υ as (C–HBen ), 3176 6 υ s (C–HBen ),
υ s (C–HC=C ) υ as (C–HC=C )
3152 3 υ s (C–HC=C ), 3172 2 υ as (C–HBen )
υ as (C–HBen ) 3166 2 υ as (C–HBen ), υ
3116 24 υ as (C–HCH3 ) (C–H)
3109 24 υ s , υ as (C–HCH3 ) 3164 9 υ s, υ as
3041 23 υ s (C–HCH3 ) (C–HBen ), υ as
3039 28 υ as (C–HCH2 ) (C–H)
3002 31 υ s (C–HCH2 ) 3161 11 υ s, υ as
1699 1718 315 υ (C = O) (C–HBen ), υ s
1673 78 υ (C = C), (C–HC=C )
(C=CBen ) 3160 2 υ as (C–HBen ),
1686 1646 393 υ (C = C, υ s (C–HC=C )
C–CBen ) 3155 1 υ as (C–HBen ),
1643 1643 66 υ (C = C, υ s (C–HC=C )
C–CBen ) 1686 1723 363 υ s (C = O)
1615 6 υ (C = C), 1667 1673 140 υ s (C=CBen )
(C–CBen ) (C = C)
1587 1600 84 υ as (C = C, 1663 134 υ s (C=CBen )
C–CBen ) (C = C)
1549 1546 95 ρ (C–HBen ) 1643 1643 10 υ (C–C)
1524 1522 64 δ (C–HCH2 ) 1640 7 υ (C–C)
1517 3 υ (C = C)
(C = C,C–CBen ) 1607 3 υ (C–C)
1503 5 δ s (C–HCH2, CH3 ) (C = C)
1484 8 δ (C–HCH3 ) 1524 1518 3 υ (C–C)
1462 1459 46 υ st (C = C, (C = C), ρ
C–CBen ) (C–HBen )
1426 1430 51 δ s (C–H CH2,CH3 ) 1549 1502 6 ρ (C–HBen )
982 975 4 δ as (C–H) 1462 1471 4 δ (C–HBen )
789 21 δ s (C–H) 1426 1414 1 ρ (C–HBen ), υ
772 736 5 υ s (C-F) (C–C) (C = C)
644 664 15 δ s (C-F) 1167 1181 172 δ (C–HBen )
1125 1120 164 ρ (C–HBen )
773 794 7 υ (C-F)
599 2 δ (C-F)
this context, the linear and hyperpolarizabilities of the compounds δ = Scissoring, υ s= symmetric, ρ rocking, δ s = wagging, Frequency =v(cm−1 ),
are the key indicator for the compound’s capability to behave as δ as= twisting, υ = stretching vibration, υ as = asymmetric, (Ben) = benzene and
NLO material. NLO properties of 1 and 2 compounds were studied Intensity = (km/mol).
at B3LYP/6–311G(d,p) level of DFT. The linear and hyper polariz-
ability results of 1 and 2 are shown in (Tables 8 and 10) whereas,
Table 8
dipole moment data is shown in Table 9.
The computed 1st order polarizability of 1 and 2.
Considering 1st order polarizability in 1 along three axis (x, y
and z) were computed as 332.6, 180.5, and 163.7 a.u. respectively 1st order
Polarizability 1 2
leading to α total as 225.6 a.u. The linear polarizability for 2 along
x, y and z axis was 361.3, 227.9 and 142.7 a.u. respectively leading α xx 332.6 361.3
to α total as 243.9 a.u. (Table 8). Similarly β total values of 1 and 2 α yy 180.5 227.9
α zz 163.7 142.8
were calculated as 3920.9 and 3018.6 a.u. respectively as shown in α total(a.u) 225.6 a.u. 243.9 a.u.
(Table 10). The commonly applied as standard molecule for com-
paring the NLO behavior of compounds is Urea [51]. The resultant
β tot value for 1 (3920.9 a.u.) were found greater than 2 (3018.6 Table 9
a.u.) and also greater in magnitude than the Urea molecule (β tot The calculated dipole moment of 1 and 2.
=43) [52]. The dipole moment of 1 (6.3) was found larger in value
Dipolemoment
than 2 (4.7) as shown (Table 9).
(Debye) 1 2

μx 3.7 −2.6
4.24. Molecular electrostatic potential (MEP) calculation μy −2.5 −3.1
μz 4.4 −2.4
The physical and chemical features i.e., electronic density, elec- μtotal 6.3 4.7

tron distribution, electrophilic and nucleophilic positions of any

12
F. Rasool, A. Hussain, K. Ayub et al. Journal of Molecular Structure 1253 (2022) 132194

Table 10 Mehreen Lateef: Biological activities

The computed 2nd order polarizability of 1 and 2.
Abdul Malik: Overall supervision
2nd order
Polarizability 1 2 Declaration of Competing Interest
β xxx −3959.7 2919.5
β xxy 554.1 −438.1 The authors declare that they have no known competing finan-
β xyy 2.7 22.7 cial interests or personal relationships that could have appeared to
β yyy −76.7 88.6
influence the work reported in this paper.
β xxz 26.2 229.5
β yyz 70.8 29.3
β xzz 69.1 35.5 Supplementary materials
β yzz −20.9 4.6
β zzz 124.2 96.7
Supplementary material associated with this article can be
β total(a.u.) 3920.9 a.u. 3018.6 a.u.
found, in the online version, at doi:10.1016/j.molstruc.2021.132194.

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