Highly efficient one pot palladium-catalyzed synthesis of 3,5-bis (arylated) pyridines: Comparative experimental and DFT studies

Article abstract of DOI:10.1016/j.molstruc.2020.128131

Many different alkyl and aryl substituted pyridine based organic derivatives have been synthesized due to its uniqueness pyridine core. However, the transition metal catalyzed Suzuki cross coupling reaction has provided an easy route to the synthesis of a

Full text of DOI:10.1016/j.molstruc.2020.128131

Journal Pre-proof
Highly efficient one pot palladium-catalyzed synthesis of 3,5-bis (arylated) pyridines:
Comparative experimental and DFT studies
Muhammad Akram, Muhammad Adeel, Muhammad Khalid, Muhammad Nawaz Tahir,
Hossein Asghar Rahnamaye Aliabad, Malik Aman Ullah, Javed Iqbal, Ataualpa A.C.
Braga
PII:
S0022-2860(20)30456-7
DOI:
https://doi.org/10.1016/j.molstruc.2020.128131
MOLSTR 128131
Reference:
To appear in: Journal of Molecular Structure
Received Date: 15 October 2019
Revised Date: 23 March 2020
Accepted Date: 23 March 2020
Please cite this article as: M. Akram, M. Adeel, M. Khalid, M.N. Tahir, H.A.R. Aliabad, M.A. Ullah,
J. Iqbal, A.A.C. Braga, Highly efficient one pot palladium-catalyzed synthesis of 3,5-bis (arylated)
pyridines: Comparative experimental and DFT studies, Journal of Molecular Structure (2020), doi:
https://doi.org/10.1016/j.molstruc.2020.128131.
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Highly Efficient one Pot Palladium-Catalyzed Synthesis of 3,5-bis (arylated)
pyridines: Comparative Experimental and DFT Studies
Muhammad Akramb,c, Muhammad Adeel*a, Muhammad Khalid*d, Muhammad Nawaz Tahire,
Hossein Asghar Rahnamaye Aliabadf, Malik Aman Ullaha, Javed Iqbalg, Ataualpa A. C.Bragah
a Institute of Chemical Sciences, Gomal University, Dera Ismail Khan, Khyber Pukhtoonkhwa, Pakistan
b Medicinal Botanic Centre, PCSIR Laboratories Complex Peshawar, Khyber Pukhtoonkhwa, Pakistan
c Institute of Chemical Sciences, University of Peshawar, Peshawar, Khyber Pukhtoonkhwa, Pakistan
d Department of Chemistry, Khwaja Fareed University of Engineering & Information Technology, Rahim
Yar Khan-64200, Pakistan
e Department of Physics, University of Sargodha, Sargodha, Punjab, Pakistan
fDepartment of Physics, Hakim Sabzevari University, Sabzevar, 96179-76487, Iran
gDepartment of Chemistry, University of Agriculture, Faisalabad-38000, Pakistan
hDepartamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof.
Lineu Prestes, 748, São Paulo, 05508-000,Brazil.
* Corresponding authors E-mail addresses:
(Dr. Muhammad Adeel) madeel@gu.edu.pk
.
(Dr. Muhammad Khalid) khalid@iq.usp.br; muhammad.khalid@kfueit.edu.pk
Abstract
Many different alkyl and aryl substituted pyridine based organic derivatives have been
synthesized due to its uniqueness pyridine core. However, the transition metal catalyzed Suzuki
cross coupling reaction has provided an easy route to the synthesis of alkyl and aryl substituted
pyridine based organic compounds. Herein, we reported the arylated pyridines derivatives: 3, 5-
bis (4-(trifluoromethoxy) phenyl) pyridine (BTFMP), 3,5-bis(4-bromophenyl)pyridine(BBPP),
3,5-bis(4-phenoxyphenyl)pyridine (BPPP) and 3,5-bis(2,5-dimethoxyphenyl)pyridine (BDMPP)
by cross coupling Suzuki methodology for the first time. All derivatives have been characterized
through 1H NMR, 13CNMR, 19F NMR and FT-IR spectroscopic techniques. Two compounds
(BPPP) and (BDMPP) exist in the form of crystals among studied compounds. Therefore, SC-
XRD has been performed for BPPP and BDMPP. In addition, computational studies using
density functional theory (DFT) have been carried out in order to compare the DFT based data
with the experimental findings. The optimization, FT-IR, natural bond orbitals (NBOs), frontier

molecular orbitals (FMOs) and nonlinear optical (NLO) calculations of all derivatives have been
performed using B3LYP/6-311G(d,p) level. The simulated HOMO-LUMO energy difference is
observed to be large which shows the kinetic stability of the molecules. The molecular stability
also originating from charge delocalization and hyper conjugative interactions has been
elucidated by NBOanalysis. MEP surfaces are also developed of entitled molecules. The NLO
data pointed out that the first order hyperpolarizability for BTFMP, BBPP and BPPP is greater
among studied molecules than the standard molecule.
Introduction:
Diversified biological activities and electronic properties make pyridine ring as unique
structural motif. Due to its uniqueness pyridine core has found numerous applications in
pharmaceutical science[1], agriculture[2], material science[3], catalysis[4] and organometallic
chemistry[5].Arylated pyridines have found multiple applications as building blocks for
numerous pharmaceuticals, ligands for organic synthesis and in material science as organic
materials[6].Starting with 2-chloro-3hydroxypyridine, Schmitt and co-workers for the first time
had synthesized pentaarylpyridine having five different aryl groups[7]. Use of zinc metal in
cross-coupling Suzuki reaction resulting in structural variations regarding alkyl, aryl and alkynyl
groups in substituted pyridines have been achieved by treating respective halides with boronic
acids [8]. Easily achievable reaction conditions and availability of modern spectroscopic
methods of structure elucidation has made preparation of these compounds viva C-C bond
formation very easy route to increase data base of organic compounds. Riser reaction is other
synthetically useful process which has employed for the synthesis of sulfur containing pyridine
derivatives [9].
The preparation and microtube destabiling properties of pyridine chalcone derivatives have
been designed and biological studies performed[10]. Palladium having the property of being
easily oxidized and reduced has found most frequent use of palladium (II) complexes as catalysts
in the preparation of compounds extending C-C bonds formation [11]. A high regioselectivity
control has been observed in preparing pyridine derivatives applying Suzuki-Moriyama synthesis
[12]. Moreover, pyridine has been widely used in Knoevenagel in the extension of carbon-carbon
bonds in many reactions [13]. Brominated bishamides contain both electrons donating and
withdrawing groups have been prepared and used in Suzuki coupling to obtain in excellent
yield[14]. Asako et al. (2017) has reported the preparation of multiply-arylated pyridines by

cross-coupling reaction of hydroxylaryl pyridines with bromine containing compounds [15].
Valuable novel Pyridines containing dihydroferrocenyl group have been reported [16]. Many
differently substituted pyridines deravatives have been prepared. Their photophysical properties
have been investigated and DFT studies of the complexes prepared from prepared pyridines
containing intermediates as a function of different substituent have reported [17]. Transition
metal catalyzed Suzuki cross coupling reaction has provided an easy route to the synthesis of
alkyl and aryl substituted pyridine based organic compounds. The Palladium (Pd) metal being
easily oxidized and reduced is most commonly used metal for cross coupling Suzuki reaction to
synthesize many compounds of medicinal interest [18]. We have already reported some studies
on arylated pyridines [19]. Nowin order to expand our knowledge on arylated pyridines, herein
we report synthesis, single crystal XRD and DFT of studies of novel arylated pyridines; which
are never reported in literature to the best of our knowledge.
Experimental
Material and method
IR spectra were recorded from Bruker Alpha FT-IR spectrometer. Melting points were
recorded on Fisher-John melting point apparatus. Bruker NMR spectrometers were used to
getNMRspectra working on 500 MHz and 400 MHz, 125 MHz and 75 MHz and 470 MHz for
1HNMR, 13C NMR and 19F NMR respectively, using TMS as internal standard.
Synthetic procedure and characterization
3, 5-bis (4-(trifluoromethoxy) phenyl) pyridine (BTFMP)
To a 38ml screw capped ace pressure tube were added 3,5-dibromopyridne (0.1g, 0.422 mmol),
and trifluoromethoxyphenyl boronic acid (0.104g, 0.506 mmol), K3PO4(0.134g, 0.632 mmol) in
distilled water and dioxane (1ml, 3ml), and Pd(PPh3)4 (1.5mol%). After adding all materialsthe
ace pressure tube was sealed with screw-cap, placed in the aluminum metal block and heated up
to 100 °C for a period of 8 hours. Completion of reaction was confirmed with help of TLC and
the reaction mixture were extracted three times with ethyl acetate (3×20 mL), the solvent was
evaporated on rotary evaporator at reduced pressure and the crude obtained was re-dissolved in
CHCl3(5 mL) and contents were taken 250ml round bottom flask andthe crude from reaction
mixture was adsorbed on silica to make slurry and was loaded on 50 Cm long Silica-Gel column
and eluted with n-hexane: ethyl acetate (98: 2 → 97: 3 → 95: 5). The fractions containing the
major compound were combined together and evaporated on Rotavap to get major compoundas

white amorphous solid. Melting Point = 172-174 °C, Yield 87%;
1H NMR (500 MHz,
Chloroform-d) δ: 8.82 (s, 2H, H-2,6), 7.99(s, 1H, H-4), 7.67-7.65 (d, J=2Hz, 4H, H-2′,2′′,6′,6′′),
7.37-7.36 (d, J=2Hz, 4H, H-3′,3′′,5′,5′′);13CNMR (125 MHz, Chloroform-d) δ: 149.49 (C-2,6),
147.28 (C-4), 136.27 (C-1', 1''), 135.53 (C-3,5), 132.86 (C-4), 128.75 (C-2', 2'', C-6', 6''), 121.67
(C-3', 5', 3'', 5'');19F NMR (470 MHz, Chloroform-d): δ = -57.80 (s, 6F).
3,5-bis(4-bromophenyl)pyridine (BBPP)
To the 3,5-dibromopyridine (0.1g, 0.422 mmol) and 4-bromophenyl boronic acid (0.19g,
0.97 mmol) in distilled water and dioxane (1ml, 3ml) and K3PO4 (0.268g, 1.26 mmol) added
Pd(PPh3)4 (3.0eq) at 100 °C in dried pressure tube. Product was white amorphous solid. Melting
Point =199-201 °C; Yield 85%;1H-NMR (400 MHz, CDCl3) δ: 8.83-8.82 (d, J=1Hz, H-2,6)
8.00-7.98 (t, J=1Hz , H-4), 7.68-7.64 (m, J = 4Hz, H-2',2'',6',6''), 7.38-7.35 (d, J= 3Hz, H-
3',3'',5',5''); 13C-NMR (75 MHz, CDCl3) δ: 149.25 (C-2,6), 133.57 (C-4), 134.72 (C-3,5), 135.83
(C-1', 1''),128.65 (C-2', 2'', C-6', 6''), 122.48 (C-3', 5', 3'', 5''), 124.51 (C-4',4'').
3,5-bis(4-phenoxyphenyl)pyridine (BPPP)
To the 3,5-dibromopyridine (0.1g, 0.422 mmol) and 4-phenoxyphenyl boronic acid
(0.198g, 0.928 mmol) in distilled water and dioxane (1ml, 3ml) and K3PO4 (0.134g, 0.632 mmol)
added Pd(PPh3)4 (1.5eq) at 100 °C in dried pressure tube. Product was white crystalline solid.
Melting Point = 209-210 °C; Yield 85%;1H-NMR (400 MHz, CDCl3) δ: 8.93 (H-2,6) 7.88 (H-
4), 7.75 (H-2', 2'',6',6''), 7.08 (H-3', 3'',5',5''), 7.02 (H-2''', 2'''',6''',6''''), 7.37 (H-3''', 3'''',5''',5''''),
7.01 (H-4''', 4''''); 13C-NMR (75 MHz, CDCl3) δ: 148.21 (C-2,6), 132.83 (C-4), 133.75 ( C-3,5),
130.32 ( C-1',1''), 128.74 (C-2',2'',6',6''), 117.91 (C-3', 5', 3'', 5''), 156.25 (C-4',4''), 156.34 (C-
1''',1''''), 119.53 (C-2''',2'''',6''',6''''), 127.72 (C-3''', 3''''',5''',5''''), 121.23 (C-4''',4'''').
3,5-bis(2,5-dimethoxyphenyl)pyridine(BDMPP)
To the 3,5-dibromopyridine (0.1g, 0.422 mmol) and 2,5-dimethoxyphenyl boronic acid
(0.169g, 0.928 mmol) in distilled water and dioxane (1ml, 3ml) and K3PO4 (0.134g, 0.632 mmol)
added Pd(PPh3)4 (1.5eq) at 100 °C in dried pressure tube. Product was white crystalline solid.
Melting Point =226-228 °C; Yield 92%;1H-NMR (400 MHz, CDCl3) δ: 8.91 (H-2,6), 7.86 (H-
4), 6.88 (H-2',2'',6',6''), 6.76 (H-4',4''), 3.78 (4×O-Me); 13C-NMR (75 MHz, CDCl3) δ: 148.24 (C-
2,6), 132.82 (C-4), 133.71 (C-3,5), 126.93 (C-1',1''), 148.8 (C-2',2''), 112.20 (C-3',3''), 116.21 (C-
4',4''), 154.14 (C-5',5''), 111.90 (C-6',6''), 55.8 (4×OMe).

Herein we showplausible mechanism for synthesis of novel arylated pyridines (BTFMP,
BBPP, BPPP and BDMPP).
Product
Ar1-4-B(OH)2
Yield %
87%
3a-BTFMP
85%
85%
92%
3b-BBPP
3c-BPPP
3d-BDMPP

Br
Br
Ar
Ar
Starting material
N
N
LnPd(0)
Pallidium catalyzed
1. Oxidative addition
3. Reductive elimination
Ar-(ii)Pd
Pd(ii)-Ar
OH
Br-(ii)Pd
Pd(ii)-Br
base HO
OH
HO
OR
B
B
Ar
1a-20a
Ar
N
N
M-OR'
2.Transmetallation
R'O-(ii)Pd
Pd(ii)-OR'
M-Br
N
OH
R'O
OR
B
Ar
Scheme 1:
Synthesis of derivatives of arylated pyridines.
Computational Procedure
The quantum chemical calculations for four phenyl pyridine derivatives: 3,5-bis(4-
(trifluoromethoxy)phenyl)pyridine (BTFMP), 3,5-bis(4-bromophenyl)pyridine (BBPP), 3,5-
bis(4-phenoxyphenyl)pyridine (BPPP) and 3,5-bis(2,5-dimethoxyphenyl)pyridine (BDMPP),
were accomplished with the assistance of DFT using Gaussian 09 program package [20-23]. The
SC-XRD driven crystal structures were used as the initial geometry for DFT study. Complete
geometrical optimization was done without symmetry restrictions by applying B3LYP level of
DFT and 6-311G(d,p) basis set. The DFT/B3LYP/6-311G(d,p) level of theory was used for
frequency analysis to obtain additional confirmation of stability related to optimized geometries.
NBO analysis was additionally administered at same level of theory and basis set using NBO 3.1
program package [24]. FMOs and NLO analysis was conducted at B3LYP level of DFT with 6-
311G(d,p) basis set. The input files were organized with the assistance of Gaussview 5.0. [25]
Avogadro [26], Gauss Sum [27] and Chemcraft programs [28] were used for deciphering output
files.We used Koopman's theorem [29]to calculate the electronegativity, chemical potential,
electrophilicity index and global hardness by using following equations.

Global hardness
Electronegativity
Global softness
Equation 1
Equation 2
Equation 3
I-A
2
η=
I+A
2
X=
1
σ
=
2η
We used Parr et al. [30-37] concept to obtain the electrophilicity index considered as a reactivity
index was calculated by following equation.
μ2
Electrophilicity Index
Equation 4
ω=
2η
η= global hardness, I= ionization energy, A= electron affinity, X= electro negativity, σ = global
softness, μ = chemical potential
Results and discussion
The molecules of 3,5-bis(4-phenoxyphenyl)pyridine(BPPP) [Figure 1] are symmetric w. r. t.
mirror plane passing through N and C-atoms in the pyridine ring. In this molecule, the phenoxy
group A (C1-C6/O1), benzene ring B (C7-C12) and pyridine ring (C13-C15/C14i/C15i/N1 i = x,
-y+1/2, z) are planar with r. m.s. deviation of 0.0299, 0.0020 and 0.0015 Å, respectively. The
dihedral angle between A/B, A/C and B/C is 63.87 (5)°, 37.22 (8)° and 32.77 (6)°,
respectively[Table 1]. There are no classical H-bonds. There are C-H…π and π…π interaction
which stabilize the molecules. The packing diagram is shown in Figure 2.
Figure1: ORTEP diagram of 3,5-bis(4-phenoxyphenyl)pyridine (BPPP) is drawn with thermal
ellipsoids at 50 % probability level with H-atoms as small circles of arbitrary radii. The labeling
of symmetry related atoms has been shortened.

Figure2: The packing diagram of BPPP.
In the molecule of 3,5-bis(2,5-dimethoxyphenyl)pyridine (BDMPP) [Figure 3] , the phenyl
groups A (C2-C7) and B (C14-C19) of 2,5-dimethoxyphenyl groups are planar with r. m.s.
deviation of 0.0065 and 0.0044 Å, respectively. The pyridine ring C (C9-C13//N1) is also planar
with r. m.s. deviation of 0.0033 Å. The dihedral angle between A/B, A/C and B/C is 89.67 (5)°,
53.80 (5)° and 53.70 (5)°, respectively [Table 1]. There are no classical H-bonds in BDMPP.
There is a C-H…O bonding in BDMPP which stabilize the molecules.The weak non classical
hydrogen bonding in BDMPP is C(21)–H(21)...O(3) with bond distance of 0.96 Å for C(21)–
H21, bond length of 2.59 Å for H(21)–O3 is and total distance of 3.325 Å for C21····O3. The
bond angle due to ∠(C(21)–H(21)...O(3)) is 134°. The H-bonding is shown in Figure 4.
Figure3: ORTEP diagram of 3,5-bis(2,5-dimethoxyphenyl)pyridine (BDMPP) is drawn with
thermal ellipsoids at 50 % probability level with H-atoms as small circles of arbitrary radii.
CIF= ORTEP ; N5= N1, C16= C10, C17= C9, C19= C6, C20=

Figure4:The C-H…O bonding in BDMPP.
Table 1: X-ray crystallographic data of BPPP and BDMPP.
Crystal parameters
BPPP
BDMPP
CCDC #
1947662
C29H21NO2
415.47
1947663
Chemical formula
C21H21NO4
351.39
Mr
Crystal system, space Orthorhombic, Pnma
Monoclinic, P21/n
group
Temperature (K)
296
296
a, b, c (Å)
6.4236 (5), 45.035 (3), 7.3855 (5)
13.0552 (11), 8.8528 (7), 16.3557
(14)
103.646 (2)
1837.0 (3)
4
β (°)
V (Å3)
2136.5 (3)
Z
4
Radiation type
µ (mm-1)
Mo Kα
Mo Kα
0.08
0.09
Crystal size (mm)
Data collection
0.35 × 0.30 × 0.22
0.40 × 0.32 × 0.30

Diffractometer
Absorption correction Multi-scan
(SADABS; Bruker, 2005)
0.973, 0.982
Bruker Kappa APEXII CCD
Bruker Kappa APEXII CCD
Multi-scan
(SADABS; Bruker, 2005)
Tmin, Tmax
0.966, 0.974
No. of measured,
independent and
observed [I> 2σ(I)]
reflections
17906, 2367, 1779
15389, 4006, 3040
Rint
0.034
0.639
0.024
0.639
(sin θ/λ)max (Å-1)
Refinement
R[F2> 2σ(F2)], wR(F2),
0.052, 0.131, 1.09
0.041, 0.115, 1.02
S
No. of reflections
No. of parameters
H-atom treatment
∆ρmax, ∆ρmin (e Å-3)
2367
4006
148
239
H-atom parameters constrained
0.23, -0.20
H-atom parameters constrained
0.18, -0.16
Computer programs: APEX2 (Bruker, 2007), SAINT (Bruker, 2007), SHELXS97 (Sheldrick, 2008), SHELXL2014/6
(Sheldrick, 2015), ORTEP-3 for Windows (Farrugia, 1997) and PLATON (Spek, 2009), WinGX (Farrugia, 1999) and
PLATON (Spek, 2009).
Molecular geometric parameters
As we have discussed already the compounds (BPPP) and (BDMPP)exist in the form of
crystals among studied compounds. Therefore, SC-XRD has been performed just for BPPP and
BDMPP. Herein, we will compare SC-XRD based parameters of BPPP and BDMPPwith DFT
based structural parameters.The obtained parameters were tabulated in Table S1 and S2
(Supplementary Information) for BPPP and BDMPP respectively. The comparative study was
done between DFT computed and experimentally determined parameters.
The exact same DFT and XRD determined values of bond lengths in BPPP has been found
to be 1.333Åfor both N1-C13a and N1-C13 while that for BDMPP was found to be 1.37Å for
O2-C5. Whilethe minimum deviation between DFT and XRD determined values of bond lengths
in BPPP has been found to be 0.001Å for O1a-C1a, C10a-C14a, O1-C1 and C10-C14. In the
same way, the minimum deviation of 0.001Å was found in BDMPP for O4-C18.Moreover, the
maximum deviation between DFT and XRD determined values of bond lengths in BPPP has
been found to be 0.025Å for C4a-C5a and C4-C5 and 0.024Å for C3a-C4a and C3-C4. While
that of BDMPP were found to be 0.018Å for C12-C11, 0.017Å for C18-C17 and 0.016Å for
C10-C9.

The exact same DFT and XRD determined values of bond angles in BPPP has been found
to be 120.8°, 119.6° and 121.6°for C1a-O1a-C7a, C3a-C4a-C5aand C8a-C9a-C10a respectively
while that for BDMPP was found to be 119.2° and119.7° for C19-C18-C17 and C6-C5-C4
respectively. The minimum deviation between DFT and XRD determined values of bond angles
in BPPP has been found to be 0.1° for O1a-C1a-C2a, C2a-C1a-C6a and C2a-C3a-C4a.
Similarly, in BDMPP has found to be 0.1° for C21-O4-C18, C15-O3-C20 and C11-C12-C13.
Moreover, the maximum deviation between DFT and XRD determined values of bond angles in
BPPPhas been found to be 1.7° for C13a-N1-C13 while that of BDMPP was found to be 1° for
C11-N1-C10, C15-C14-C12 and C14-C12-C11.
Overall, bond lengths and bond angles in both derivatives are deviated in the ambient
range of 0.025-0.0Å and 0.0-1.7° respectively.The comparative analysis revealed that DFT
values of bond angles and bond lengths were higher than XRD values. However, in a few cases
the opposite happened as the DFT values of bond angles and bond lengths were smaller than the
XRD values. The dissimilarity between DFT and experimental findings could be because of the
medium effect[38].
FT-IR Analysis
DFT studies were conducted to have a clear understanding of vibration modes of entitled
compounds in solvent free conditions. The animation option available in Avogadro software was
used for assigning vibration modes related to the specific structural features of entitled
compounds. The quantity of atoms in BTFMP, BBPP, BPPP and BDMPP are 39, 31, 53 and 47
atoms respectively with symmetry point group C1. Their experimental spectra can be seen in
Figures S1-S4.
C-H stretching vibration
In BTFMP, the aromatic ring carbon-hydrogen (C-H) stretching frequencies are found in
the range of 3206-3153 cm-1 (DFT) and 2922 cm-1 (EXP) (Figure S1). For BBPP, carbon-
hydrogen (C-H) stretching frequencies of the aromatic ring are located in the span of 3204-3152
cm-1. In BPPP, the aromatic ring (C-H) stretching frequencies are appeared at 3199-3151 cm-1
range (DFT) and 3066-2922 cm-1 (EXP) in Figure S2. Further, in BDMPP, the aromatic ring (C-
H) stretching modes are occurred at 3225-3000 cm-1 range (DFT) and 2951.09-2900 cm-1 range
(EXP) in Figure S3.
C-C stretching vibrations

The C-C stretching vibrations are appeared in the range of 1645-1538, 1628-1339, 1649-
1518 and 1643-1535 cm-1 for BTFMP, BBPP, BPPP and BDMPP respectively which are found
in correspondence to experimental values:1509-1499 cm-1 (Figures S1-S4)
C-N stretching vibrations
The C-N stretching modes are observed at 3206, 1618, 1038 and 664 cm-1 in BTFMP.
Similar modes are observed at 1626, 1304 and 653 cm-1 in BBPP. Likewise, FTIR bands are
found at 1625,1259 and 634 cm-1 in BPPP. The C-N modes of BDMPP are appeared at 1628,
1264, 1044 and 660 cm-1. The experimental modes are found as 1506.45 for BTFMP and
1585.49 cm-1 for BBPP and BDMPP in Figures S1-S4.
Natural Bond Orbital (NBO) Analysis
Inspection of inter and intramolecular interactions can be adequately accomplished using
natural bond orbital (NBO)[39] analysis, which contributes promising facts for exploring charge
transfer or hyper-conjugative synergy. The software named NBO 3.1 is utilized to perform
hybridization, intramolecular charge delocalization, and electron density in molecules simulated
by Gaussian 09 package.NBO approach can be used to analyses bonding and anti-bonding
interactions due to second-order perturbation theory [40]. Second-order stabilization energies E
(2) have been acquired using equation 5:
ꢇ
ꢂꢃ
ꢆ
ꢄ,ꢅ
( )
ꢀ
E
= qꢁ
Equation 5
ꢈ -ꢈ
ꢅ
ꢄ
Where qi is the ith donor orbital occupancy, Ej, Ei the diagonal elements (orbital energies)
and (j, i) the off diagonal NBO Fock Matrix elements [41].
The natural bond orbital (NBO) analysis has been completed for four compounds, i.e.,
BTFMP, BBPP, BPPP andBDFMP.The natural bond orbital (NBO) analyses for BTFMP,
BBPP, BPPP and BDFMP have been elaborated in Tables S3-S6. While some selected values
are given Table 2. The NBO numbering scheme for title compounds are represented in Figure 5.

BTFMP
BBPP
BPPP

BDMPP
Figure 5: NBO numbering scheme of entitled derivatives
Table 2: Natural bond orbital (NBO) analysis for BTFMP, BBPP, BPPP and BDMPP (Representative
Values)
Donor(i)
Type
Acceptor
(j)
Type
E(2)a
E(j)_E(i)b
[a.u.]
0.27
0.32
0.27
0.32
0.57
0.57
0.66
0.27
0.32
0.28
0.28
0.88
0.88
0.86
0.85
0.86
0.85
0.25
0.28
4.89
4.98
0.35
0.89
0.31
0.09
0.76
0.28
0.01
F(i; j)c
[a.u.]
Derivative
ꢉ∗
ꢉ∗
ꢉ∗
ꢊ∗
ꢉ∗
ꢉ∗
ꢊ∗
C15 - C16
N2 - C13
C29 - C31
N2 - C13
O1
π
π
π
N2 - C13
C29 - C31
N2 - C13
C15 - C16
C32 - F36
C33 - F39
C32 - F36
N1-C12
C27-C29
C14 -C15
C27-C29
C12-C14
C27-C29
C17-C18
C17-C25
C2-C3
26.58
25.43
18.46
14.19
14.88
14.88
7.14
26.56
25.28
9.28
0.076
0.082
0.063
0.061
0.083
0.082
0.062
σ
BTFMP
LP2
LP2
LP2
π
π
π
O18
F35
C14-C15
N1-C12
C5-C7
C20-C22
N1
N1
Br30
Br30
Br31
π
*
0.075
0.082
0.046
0.045
0.085
0.085
0.048
0.048
0.048
0.048
0.074
0.071
0.166
0.159
0.077
0.082
0.807
0.406
0.110
0.066
0.067
ꢊ∗
π*
*
π
π
9.01
ꢊ∗
ꢊ∗
ꢊ∗
ꢊ∗
ꢊ∗
ꢊ∗
ꢉ∗
ꢉ∗
σ∗
σ∗
LP
LP
LP
LP
LP
LP
ꢉ
ꢉ
σ
10.10
10.10
3.41
3.41
3.41
BBPP
Br31
C2-C10
3.41
C27 - C53
C4 - C6
N2 - C51
N2 - C51
O1
N2 - C51
C3 - C12
C47 - C49
C51 - H52
C14 - C15
C51 - C53
C44 - H45
C15 - C17
C15 - C17
C10 - C11
C40 - H41
27.21
22.04
7.10
6.37
18.77
9.38
2651.48
2363.37
19.86
19.33
519.47
BPPP
σ
LP2
LP1
σ
σ
σ
π*
N2
σ
*
σ∗
σ∗
σ∗
ꢉ∗
σ∗
C44 - H47
C44 - H47
O4 - C37
C13 - C14
O2
BDMPP
ꢉ
LP2

ꢉ∗
O1
LP1
C23 - C29
10.06
0.34
0.056
b
aE(2)means energy of hyper conjugative interaction (stabilization energyin kcal/mol), Energydifference
c
between donor and acceptor iand j NBO orbitals, F(i;j) is the Fock matrix element between iand j NBO
orbitals.
Tables S3-S6 contain NBO orbitals which show mostly efficient interactions between
Lewis type -(bonding) and non-Lewis (anti-bonding) for the BTFMP, BBPP, BPPP and
BDMPP. The enhanced stabilization energy E(2) values are obtained due to the existence of
strong interactions between donor and acceptor moieties.
Herein, NBO analysis revealed that the ꢉ(C15-C16)→ꢉ*(N2-C13) and ꢉ(N2-C13) →
ꢉ*(C29-C31) transitions provide strongest stabilization energy values as 26.58 and 25.43
kcal/mol respectively to the compound (BTFMP). Further, the stabilization energy values found
to be 18.46 and 14.19 kcal/mol for transitions as ꢉ(C29-C31)→ꢉ*(N2-C13) and ꢊ(N2-
C13)→ꢊ*(C15-C16). The transitions (σ→σ*) originated due to weak interactions which offer
small stabilization energy values to the BTFMP as can be seen in Table 2. The similar trend of
interaction was also observed in reference to resonance in the BTFMP as LP2(O1)→ꢉ*(C32-
F36) and LP2(O18)→ꢉ*(C33-F39) produced14.88 kcal/moleach respectively with peak values.
While LP2(F35)→ꢊ*(C32-F36) produced 7.14 kcal/mol which is least value for BTFMP.
For BBPP, the stabilization energies also obtained to be 26.56 and 25.28 kcal/mol owing
to ꢉ(C14-C15)→ ꢉ*(N1-C12) and ꢉ(N1-C12)→ ꢊ*(C27-C29) transitions respectively (Table 2).
NBO analysis revealed that the ꢉ(C5-C7)→ꢉ*(C14-C15) and ꢉ(C20-C22)→ꢉ*(C27-C29)
transitions also give stabilization to the BBPP with energy values 9.28 and 9.01 kcal/mol
respectively. The identical trend of interaction was also noticed in relation to resonance in the
BBPP as both LP(N1)→ꢊ*(C12-C14) and LP(N1)→ꢊ*(C27-C29) produced 10.10kcal/mol
which was the highest value. While all transitions: LP(Br30)→ꢊ*(C17-C18),
LP(Br30)→ꢊ*(C17-C25), LP(Br31)→ꢊ*(C2-C3) and LP(Br31)→ꢊ*(C2-C10) produced same
3.41kcal/mol interaction energy. For BPPP, the stabilization energy values obtained to be 27.21
and 22.04 kcal/mol for transitions as ꢉ(C27-C53)→ꢉ*(N2-C51) and ꢉ(C4-C6)→ꢉ*(C3-C12)
respectively (Table2). While transitions as ꢊ(N2-C51)→ꢊ*(C47-C49) and ꢊ(N2-
C51)→ꢊ*(C51-H52) exposed 7.10 and 6.37 kcal/mol respectively.These transitions originated
due to weak interactions between the donor ꢉ/σ and acceptor ꢉ*/σ* and offer small stabilization
to BPPP (Table 2). The same tendency of interaction was also noted regarding to resonance in

BPPP as LP2(O1)→ꢉ*(C14-C15) and LP1(N2)→ꢊ*(C51-C53) produced 18.77 and 9.38
kcal/mol respectively which are highest values.
The highest interactions in BDMPP have ꢊ(C44-H47)→ꢊ*(C44-H45) and ꢊ(C44-
H47)→ꢊ*(C15-C17) leads to the stabilization energy of 2651.48 and 2363.37kcal/mol
respectively (Table 2). These values were found the enormous values among all the stabilization
energies. Moreover, other representative interactions are observed as ꢊ(O4-C37)→ꢊ*(C15-C17)
andꢉ(C13-C14)→ꢉ*(C10-C11) with stabilization energy values like 19.86 and 19.33 kcal/mol
respectively.TheLP2(O2)→ꢊ*(C40-H41) transition shows the stabilization energy of
519.47kcal/molwhichwas the highest value. While LP1(O1)→ꢉ*(C23-C29) shows 10.06
kcal/mol which was exhibited a very low interaction energy (Table 2). A bunch of stabilization
energy values were shown in Tables S3-S6 despite of representative NBO values of BTFMP,
BBPP, BPPP and BDMPP.It might be deduced from NBO results that the strong intra-
molecular hyper conjugation interactions are the crucial for the stability of these compounds.
Natural Population Analysis (NPA)
The Mulliken atomic charges of the BTFMP, BBPP, BPPP and BDMPP were determined
and presented in Figure 6. The phenomenon associating the electronegativity equalization can be
explained through Mulliken population examination and atomic charge transformation process
takes place in reactions and to obtain the electrostatic potential on external surfaces of systems
[42]. The electronic charges of atoms play a significant functionformolecular conformation as
well as bonding capability [43]. The data of Mulliken population disclose that more
electronegative atoms as O and N in title compounds make unequal redistribution of the electron
density over the benzene rings [44]. Our concern is to illustrate the electron distribution over the
title compounds and also to explore their reactive sites.Moreover, Mulliken population analysis
displays that no discrepancy is observed regarding charge distribution over all the hydrogen
atoms. The positive charges over the hydrogen atoms are found as a result of the negative
charges of carbon atoms.Thefluoro and bromo atoms are presented in BTFMP and BBPP
contain high negative charges. Mostly carbon, all oxygen and nitrogen atoms with negative
charges are found in BTFMP, BBPP, BPPP and BDMPP (see Figure 6).

BTFMP
BBPP
BPPP
BDMPP
Figure 6. Natural population analysis of entitled derivatives
Frontier molecular orbitals (FMOs)
The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital
(LUMO) are collectively known frontier molecular orbitals (FMOs) which are valuable
descriptors for predicting kinetic stability and chemical reactivity of the chemical
system[45].The energy values of HOMO/LUMO are calculated to be -6.454/-2.230, -6.302/-
0.910, -6.017/-1.235 and -5.650/-1.132 eV for BTFMP, BBPP, BPPP and BDMPP respectively
(Table 3). These molecular orbitals are formedbecause of the combination of atomic π-electron
orbitals. Thus,π-electrons can bereadilydistorted, that’s why the nonlinear optical responsibility
is held by FMOs of the investigated compounds. The HOMO and LUMO plots of all derivatives
are displayed in Figure7.

For BTFMP, in HOMO, the charge density is accumulated on the 3,5-dimethylpyridine; while,
in reference to LUMO, the charge density moves to the (trifluoromethoxy) benzene too. For
BBPP in case of both HOMO and LUMO the charge density is mainly accumulated on the
whole structure of BBPP. For BPPP, in case of HOMO, the charge density is mainly
accumulated on the 3,5-bis(4-phenoxyphenyl)pyridine (BPPP), whereas, in case of LUMO, the
charge density moves to the 3,5-bis(4-phenoxyphenyl)pyridine (BPPP) with the exception of
both attached side phenoxy groups. For BDMPP, in case of HOMO, the charge density is mainly
accumulated on the 3,5-bis(2,5-dimethoxyphenyl)pyridine (BDMPP), whereas, in case of
LUMO, the charge density moves to the 3,5-diphenylpridine.
The HOMO-LUMO energy gaps 4.224, 4.290, 4.782 and 4.518eV (Table 2) for BTFMP,
BBPP, BPPP and BDMPP respectively is comparatively small, whichpoints out that the kinetic
stability isfragilebut the chemical reactivity of the molecule is forcible in terms of strengthens.
Density of States (DOS) of the BTFMP, BBPP, BPPP and BDMPP was determined using the
GaussSum software which is shown in Figure 7.
Table 3: Frontier Molecular Orbitals Energy calculated for BTFMP, BBPP, BPPP and BDMPP.
Articles
BTFMP
Energy
BBPP
BPPP
BDMPP
Energy
(eV)
∆
E
Energy
(eV)
Energy
(eV)
MO(s)
∆
E (eV)
∆E (eV)
∆E (eV)
(eV)
(eV)
HOMO
LUMO
HOMO-1 -6.595
LUMO+1 -1.753
HOMO-2 -7.128
LUMO+2 -1.032
-6.454
-2.230
-6.302
-0.910
-6.662
-1.990
-7.427
-2.012
-6.017
-1.235
-6.194
-1.188
-6.836
-0.747
-5.650
-1.132
-5.701
-1.022
-6.621
-0.304
4.224
4.290
4.672
6.517
4.782
4.518
4.679
6.317
4.842
6.096
5.006
6.089
HOMO = Highest Occupied Molecular Orbital, LUMO = Lowest Unoccupied Molecular Orbital
BTFMP

BBPP
BPPP
BDMPP
Figure 7: Two levels below & up of HOMO & LUMO orbitals of entitled derivatives and units in eV.

Global Reactivity Parameters
Energies of HOMO, LUMO and their energy gaps are thereforeemployed to indicate the
stability and reactivity of BTFMP, BBPP, BPPP andBDMPPby predicting global reactivity
descriptors. The popular Koopmans’ theorem [29] explains electron affinity (EA) and ionization
potential (IP)by the negative of energy eigen values of LUMO and HOMO respectively.
EA = −ꢋꢌꢍꢎꢏ
IP = −ꢋꢐꢏꢎꢏ
Equation 6
Equation 7
Equations 6 and 7 defined asEA= Electron affinity, IP= Ionization potential;
Those compounds are known electron acceptors which contain positive electron affinity
valuesand could be participated in charge transfer processes. In our investigation, BTFMP,
BBPP, BPPP and BDMPP also consisting of positive electron affinity values as 2.23, 0.91,
1.235 and 1.132 eV respectively. Therefore, it is also known electron acceptors by nature and
may be involved to charge transfer processes.Whereas, BTFMP, BBPP, BPPP and BDMPP
contain highly positive ionization potential values as 6.454, 6.302, 6.017 and 5.65 respectively.
These high values of IP point out the high reactivity of entitled molecules. IP and EA are
frequently utilized as electronic descriptors;alsohave the positive point that they are conveniently
accessible from theory point of view and experimental aspects. IP is a scale for degree of the
nucleophilicity of a compound. EA is a scale for degree of the effectiveness of the chemical
system to afford the corresponding negative ion.
The reactivity assessment of compound is one of the most significantaims of computational
analysis and many reportsareavailablerelatedtothis topic in the literature. DFT is one of the most
successful theories in contributing theoretical accomplishments of trustworthy qualitative
chemicalideas[30].In
current
study,
various
reactivity
descriptors
arepredictedwhichareutilizedtostudythesite selectivity as well as chemical reactivity. Theglobal
softness, electronegativity, global hardness, electrophilicity index and chemical potential are
frequentlyadopted global reactivity parameterswhich are used to comprehend the global nature of
chemical speciesin reference to their reactivity and stability.
Table 4: The calculated global reactivity parameters of studied compounds.
Compounds
I
A
X
η
μ
ω
σ

6.454
6.302
6.017
5.65
2.23
0.91
2.112
2.696
2.391
2.259
4.342
3.606
3.626
3.391
-4.342
-3.606
-3.626
-3.391
4.463
2.412
2.750
2.545
0.237
0.186
BTFMP
BBPP
1.235
1.132
0.209
BPPP
0.221
BDMPP
Ionization potential (I), electron affinity (A), electronegativity (X), global hardness (
), global electrophilicity ( ) and global softness ( ).
η
), chemical potential
(
μ
ω
σ
The calculated results of BTFMP, BBPP, BPPP and BDMPP are shown in Table 4. The
electronegativity illustrates the tendency of attraction of electron might in the direction of
functional moiety, which is known a chemical property. The entitled molecules: BTFMP,
BBPP, BPPP and BDMPP contain 4.342, 3.606, 3.626 and 3.391 eV electronegativity values
respectively (Table 4). The BTFMP contains high electronegativity value as compared to other
derivatives due to the presence of fluoro group. The BTFMP, BBPP, BPPP and BDMPP
contain the negative values to the chemical potential (μ) like -4.342, -3.606, -3.626 and -3.391 eV
respectively(Table 4). These values explain that the all derivatives are favorably stable and such
molecules could not be decomposed by spontaneous way into their fundamental elements.
However, the compounds contain positive chemical potential are really unstable and are found
challenging to synthesize as well as conserve.
Chemical hardness figures out the shieldthealterationfor the electronic distribution framework as
in acollection of electrons and nuclei. The chemical compound with a large HOMO-LUMO
energy differenceisassimilatedas hardchemicalspecie,contrarily, the chemical compound with
having a small HOMO-LUMO energy gap is assimilated as chemical specie. The
softchemicalspecieshave more capacity to polarizein the comparison of the hard ones because
theexcitation of such molecules requiresless amount of energy.
The global hardness values are observed as 2.112, 2.696, 2.391 and 2.259 eV for BTFMP,
BBPP, BPPP and BDMPP respectively, contrary, the softness values are observed as 0.237,
0.186, 0.209 and 0.221 eV for BTFMP, BBPP, BPPP and BDMPP respectively (Table 4). These
values highlighted that the title molecules are relatively hard so they do not tend to go through in
to reactions or changes conveniently.
The global electrophilicity index defines the stabilization energy when the compound obtains an

extra charge from the surroundings. It indicates the stabilization energy of the compounds when
they become full with electrons arriving from the environment. In the entitled molecules they are
calculated to be 4.463, 2.412, 2.750 and 2.545 eV for BTFMP, BBPP, BPPP and BDMPP
respectively (Table 4). The electrophilicity values contain insights regarding reactivity, structural
and selectivity factors of ground and excited electronic states of molecules.
BBPP
BTFMP
BPPP
BDMPP
Figure 8: Density of states for entitled derivatives.
Non-Linear Optical (NLO) Properties
In recent years, chemist community is performing extensive investigation and successive
improvement in the nonlinear optics (NLO) field[46-47]. Inorganic and organic materials due to
their significance in giving the key role of frequency shifting, optical switching, optical
modulation, optical memory and optical logic for the modern sophisticated technologies in fields

like telecommunications, optical interconnections and signal processing[48-52]. Many classes of
inorganic and organic NLO compounds were analyzed for their promisingelectro-optical (EO)
functions. Among these classes, organic compounds are considered as effective electro-optical
(EO) materials due to their particular and unique structural parameters, which normally
consisting of the donor-
π,
π-acceptor and donor-
π-acceptor (D-
π-A) configurations[53].The basic
concept of utilizing electron-acceptor and electron-donor groups is to polarize the
π-electronic
organic compounds. This fundamental concept may become the solid reason for growing the
NLO chromophores containing greater improved solubility, molecular nonlinearity,
processability and good thermal stability. From the aspect of promisingapplications to optical
devices, we calculated the linear response (polarizability,
(hyperpolarizabilities, ) of BTFMP, BBPP, BPPP and BDMPP. The <
calculated and results were tabulated in Table 5.
α
) and nonlinear responses
β
α>values were
Table 5: Dipole polarizabilities with major contributing tensors (a.u.) anddipolemomentsof the studied
compounds
Polarizability
BTFMP
356.805
214.377
119.755
230.312
BBPP
BPPP
BDMPP
365.463
232.736
202.300
266.833
392.940
216.854
118.144
242.646
597.894
283.147
197.499
359.513
αxx
αyy
αzz
<α>
Dipole
moments
BTFMP
0.0001
-0.1464
-0.9299
0.9413
BBPP
BPPP
BDMPP
-0.0011
-2.6456
0.1043
0.0000
-0.5796
-0.1262
0.5931
0.0000
-0.5320
0.3268
0.6244
X
Y
Z
2.6477
total
BTFMP,BBPP, BPPPand BDMPP are polar molecules comprising non-zero dipole
moments as0.9413, 0.5931, 0.6244 and 2.6477 respectively. The averagepolarizability < >of
α
BTFMP,BBPP, BPPPand BDMPPcontain values 230.312, 242.646, 359.513 and 266.833
respectively. Among studied molecules, BPPP contains maximum average polarizability,
whereas, BTFMP consisting of minimumaverage polarizability as can be seen in Table 5.
Table 6: The computed second-order polarizabilities (βtot) and major contributing tensors (a.u) of the
studied compounds
Polarizability
BTFMP
BBPP
BPPP
BDMPP
0.018
-0.001
-0.004
-0.301
βxxx

149.230
0.007
1.416
-28.922
-9.882
0.003
21.273
19.462
173.004
420.404
-0.000
97.824
27.117
23.335
-0.000
8.660
1003.489
-0.000
4.540
-123.430
17.347
0.000
-25.946
-0.040
-21.691
1.715
βxxy
βxyy
βyyy
βxxz
βyyz
βxzz
βyzz
βzzz
30.101
-0.985
-0.543
-1.704
22.844
2.873
0.002
529.298
987.800
31.284
βtotal
The computed second-order polarizabilities (βtot) of BTFMP,BBPP, BPPPand BDMPP contain
values 173.004, 529.298, 987.800 and 31.284 respectively. Among studied molecules, BPPP
contains maximum second-order polarizabilities (βtot), contrarily, BDMPPconsisting of
minimum second-order polarizabilities (βtot) as can be seen in Table 5. Urea is one of the
prototypical compounds utilized in the investigation of the NLO properties of chemical systems
and mostly utilized considering a threshold value for comparative purpose. The first
hyperpolarizability (βtot) of BTFMP,BBPPandBPPPis4.0, 12.0 and 23.0times larger respectively
but BDMPP is 0.7 times less that of urea (
β= 43)[54]. Hence, it is concluded that BPPP may be
effective in NLO related device applications.
Molecular Electrostatic Potential (MEP) plots
Usually, the plot for total electron density in 3-D is termed molecular electrostatic potential
(MEP) surface[55-56].The MEP could be noteworthy descriptor for understanding the non-
covalent interactions (NCIs) and reaction mechanism and MEP surface activity for both
crystals.The relative reactivity of any compound in the context of electrophilic as well as
nucleophilic attack can bean explained by using different colors of anelectrostatic potential
plot[57-59].The color scheme of any MEPmap could becommenced from deep red to deep blue,
in which blue color indicates positive potential whereas, redcolor indicates negative potential,
so,the charge contribution could be systematic decreased order asred > orange > yellow >green >
blue[60].Consequently, it can be concluded that the red and yellowcolored are bestpositions
overMEP surfacefor attacking of electrophilicspecieswhile the bluecolored are best positions
over MEP surface for attacking of nucleophilic species. We displayed herein just MEP of BPPP
and BDMPP as representative surfaces.

BPPP
BDMPP
Figure 9: Molecular electrostatic potential surfaces for entitled derivatives.
Figure 9 pointed out that negative potential is disseminated over the oxygen atoms of phenoxy
and methoxy moieties of BPPP and BDMPPrespectively and nitrogen atoms of pyridine of both
molecules. However, positive potential can be seen around the hydrogen atoms for BPPP and
BDMPP as well as methyl group of methoxy moiety.
Conclusion

We synthesized four arylated pyridines derivatives with good yields by cross coupling
Suzuki methodology for the first time.The structures of derivatives have been confirmed through
1H NMR, 13CNMR, 19F NMR and FT-IR spectroscopic techniques. In addition, SC-XRD
technique has been performed for BPPP and BDMPP which are confirmed asOrthorhombic,
Pnma and Monoclinic, P21/n crystal systems with space groups respectively. The ground state
geometric structures of BTFMP, BBPP, BPPP and BDMPPwith spectroscopic FT-IR, FMOs,
NBOs, MEP and NLO properties have been studied utilizing quantum chemical calculations.
The DFT based geometric parameters are found in excellent concurrence to SC-XRD obtained
data. NBO and FMO analysis provide a proof for the charge transfer interactions with in the
entitled molecules lead to nonlinear behaviour. Moreover, the hyperconjugative interactions
affording stabilization to the chemical structures have been explained through second order
perturbation energy analysis.The energy gap between HOMO and LUMO indicated that the
structures of BTFMP, BBPP, BPPP and BDMPPcan be efficiently polarized and appropriate to
show NLO properties.Terefore, the values of the first hyperpolarizability of BTFMP,
BBPPandBPPPare greater as compared to standard molecule. Due to unique electronic
properties might open the method for BTFMP, BBPP and BPPP materials to be effective in
NLO device applications. MEP surfaces explain the attacking of electrophilic and nucleophilic
species on suitable positions of entitled molecules.
Conflict of interest
No conflicts declared.
Acknowledgments
Ataualpa A. C. Braga, (grants # 2011/07895-8, 2015/01491-3 and 2014/25770-6) is thankful to
Fundação de Amparo à Pesquisa do Estado de São Paulo for financial support. AACB (grant
309715/2017-2) also thanks the Brazilian National Research Council (CNPq) for financial
support and fellowships. This study was financed in part by the Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
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