Synthesis, crystal structure, DFT and antibacterial activity studies of (E)-2-benzyl-3-(furan-3-yl)-6,7-dimethoxy-4-(2-phenyl-1H-inden-1-ylidene)-1,2,3,4-tetrahydroisoquinoline

Article abstract of DOI:10.4067/S0717-97072015000300008

The title compound (I), (E)-2-benzyl-3-(furan-3-yl)-6,7-dimethoxy-4-(2-phenyl-1H-inden-1-ylidene)-1,2,3,4-tetrahydroisoquinoline (C₃₇H₃₁NO₃), was synthesized and structurally characterized by elemental analysis, 1H NMR and 13C NMR and single crystal X-ray diffraction. In the compound, the N-containing six-membered ring of the tetrahydroisoquinoline unit adopts a distorted half-chair conformation. In the crystal structure, supramolecular chains mediated by C-H...O contacts along the b-axis are linked into a double layer via C-H...π hydrogen bonds. The resulting double layer stacks along the c-axis without any specific interactions. The molecular geometry was also optimized using density functional theory using (DFT/B3LYP) method with the 6-311G(d,p) basis set and compared with the experimental data. In addition to the optimized geometrical structure, molecular orbital, molecular electrostatic potential (MEP) and chemical reactivity studies of the compound have been investigated by using DFT. The antibacterial activity of the compound for various concentrations were determined against eight test pathogens Bacillus cerus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Acinetobacter baumannii, Staphylococcus epidermidis, Klebsiella pneumoniae and Proteus vulgaris. The results revealed that the compound exhibited good to moderate antibacterial activity.

Full text of DOI:10.4067/S0717-97072015000300008

J. Chil. Chem. Soc., 60, Nº 3 (2015)
SYNTHESIS, CRYSTAL STRUCTURE, DFT AND ANTIBACTERIALACTIVITY STUDIES OF (E)-2-BENZYL-3-
FURAN-3-YL)-6,7-DIMETHOXY-4-(2-PHENYL-1H-INDEN-1-YLIDENE)-1,2,3,4-TETRAHYDROISOQUINOLINE
(
1
2
3
4
S. MURUGAVEL *, N. MANIKANDAN , D. LAKSHMANAN , KANAGARAJ NAVEEN ,
4
PARAMASIVAN THIRUMALAI PERUMAL
1
*
Department of Physics, Thanthai Periyar Government Institute of Technology, Vellore-632 002, Tamilnadu, India
Department of Physics, Bharathidasan Engineering college, Nattrampallii , Vellore - 635 854, Tamilnadu, India
2
3
Department of Physics, C. Abdul Hakeem College of Engineering & Technology, Melvisharam, Vellore-632 509, Tamilnadu, India
4
Organic Chemistry Division, CSIR – Central Leather Research Institute, Adyar, Chennai 600020, India, Tamilnadu, India
ABSTRACT
The title compound (I), (E)-2-benzyl-3-(furan-3-yl)-6,7-dimethoxy-4-(2-phenyl-1H-inden-1-ylidene)-1,2,3,4-tetrahydroisoquinoline (C H NO ), was
3
7
31
3
1
13
synthesized and structurally characterized by elemental analysis, H NMR and C NMR and single crystal X-ray diffraction. In the compound, the N-containing
six-membered ring of the tetrahydroisoquinoline unit adopts a distorted half-chair conformation. In the crystal structure, supramolecular chains mediated by
C–H…O contacts along the b-axis are linked into a double layer via C–H…π hydrogen bonds. The resulting double layer stacks along the c-axis without any
specific interactions. The molecular geometry was also optimized using density functional theory using (DFT/B3LYP) method with the 6-311G(d,p) basis set and
compared with the experimental data. In addition to the optimized geometrical structure, molecular orbital, molecular electrostatic potential (MEP) and chemical
reactivity studies of the compound have been investigated by using DFT. The antibacterial activity of the compound for various concentrations were determined
against eight test pathogens Bacillus cerus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Acinetobacter baumannii, Staphylococcus
epidermidis, Klebsiella pneumoniae and Proteus vulgaris. The results revealed that the compound exhibited good to moderate antibacterial activity.
Key Words: X-ray structure determination; Hydrogen bonds; DFT calculations;MEP; antibacterial activity.
1
. INTRODUCTION
2. Experimental and Computational Methods
.1 Synthesis of (I)
2
Compounds containing tetrahydroisoquinoline fragment in their structure
display a broad spectrum of biological activities. In particular, derivatives
of this type have been recently recognized as being G-protein-coupled
1
receptor 40 (GPR40) antagonists . The tetrahydroisoquinoline derivatives
2, 3
have attracted great attention in recent years due to their neurotoxicity
4, 5
6, 7
antitumor activities , and antimicrobial activity . The title compound has
been synthesized by our co-authors . Here we present the crystal structure of
8
(
1
E)-2-benzyl-3-(furan-3-yl)-6,7-dimethoxy-4-(2-phenyl-1H-inden-1-ylidene)-
,2,3,4-tetrahydroisoquinoline (I), C H NO . Literature survey reveals that so
3
7
31
3
for there is no experimental, theoretical and antibacterial studies for the title
compound. In recent years, density functional theory (DFT) has become an
increasingly useful tool for theoretical studies. The success of DFT is mainly
due to the fact that it describes small molecules more reliably than Hartree-
Fock theory. It is also computationally less demanding than wave function
Scheme1 : Reaction scheme and chemical diagram of the title compound
The title compound (I) was obtained according to the reaction scheme-I.
(I)
9
, 10
based methods with inclusion of electron correlation
. Thus, in order to
characterize the correlation between molecular structure and macroscopic
properties in the studied compound, it seems to be essential to undertake a
detailed comparative study of the isolated molecule and the solid state unit. In
this paper, a concerted approach by X-ray crystallography and DFT calculation
was used, which takes advantage of both the high interpretative power of the
theoretical studies and the precision and reliability of the experimental method.
Also, DFT is a powerful mathematical algorithm which is a useful tool to
provide sets of quantum chemical descriptors that helps for finding suitable
correlations for biological activities of various classes of organic compounds
and their derivatives.
A solution of (E)-N-benzyl-N-(2-bromo-4,5-dimethoxybenzyl)-1-(furan-3-yl)-
3-(2-styrylphenyl)prop-2-yn-1-amine (0.3 mmol) in 1,4-dioxane (4 mL) was
added to a mixture of Pd(PPh ) (0.03 mmol, 10 mol-%) and K CO (0.15 mmol)
3
4
2
3
in a clean, dry, two-necked round-bottomed flask under a N atmosphere. The
2
reaction mixture was stirred at 100 °C for 3 h. Then, the reaction mixture was
cooled to room temperature and ethyl acetate (15 mL) and water (3 - 15 mL)
were added. The organic layer was separated, dried with anhydrous Na SO ,
2
4
and concentrated under reduced pressure. The crude material was purified by
column chromatography (silica gel, 5-40% petroleum ether/ethyl acetate) to
afford the title compound. Single crystals of the title compound (I), suitable
for single crystal X-ray diffraction studies have been grown in an ethanolic
solution by slow evaporation of the solvent at room temperature and collected
(yield (88 %) , m.p. 176 - 178 ˚C).
In this paper, we report the synthesis, crystal structure and antibacterial
activity
of
(E)-2-benzyl-3-(furan-3-yl)-6,7-dimethoxy-4-(2-phenyl-1H-
inden-1-ylidene)-1,2,3,4-tetrahydroisoquinoline (C H NO ), as well as
3
7
31
3
1
13
theoretical studies using the DFT(B3LYP) method and 6-311G(d,p) basis set.
The aim of the present work was to describe and characterize the molecular
structure and some electronic structure properties of the title compound,
both experimentally and theoretically. We also make comparisons between
experimental and calculated values. Further the title compound has been
screened for antibacterial activity against Bacillus cerus, Escherichia coli,
Pseudomonas aeruginosa, Staphylococcus aureus, Acinetobacter baumannii,
Staphylococcus epidermidis, Klebsiella pneumoniae and Proteus vulgaris at
three different concentrations 25, 50 and 75 µg/ml. The results were evaluated
by measuring the inhibition zones diameter in millimeters and were compared
with the standard antibiotic ciprofloxacin (25µg/ml).
The Nuclear magnetic resonance spectra ( H NMR and C NMR)
were recorded in CDCl on Bruker NMR 400 MHz spectrometer and the
3
chemical shifts are reported as δ values in parts per million (ppm) relative to
1
tetramethylsilane, with J values in Hertz. The splitting patterns in H NMR
spectra are reported as follows: s = singlet; d = doublet; br s = broad singlet; br
1
3
d = broad doublet; m = multiplet. C NMR data are reported with the solvent
peak (CDCl = 100.0 MHz) as the internal standard.
3
o
1
Yellow solid; m.p.: 176 - 178 C; Yield: 88 %; H NMR (400 MHz,
CDCl ): δ = 7.39 – 7.33 (m, 5H, Ar-H), 7.29 – 7.23 (m, 5H, Ar-H), 7.18 (t, J
3
= 8.00 Hz, 1H, Ar-H), 7.09 – 7.00 (m, 6H, Ar-H), 6.43 (s, 1H, Ar-H), 6.42 (s,
1H, Ar-H), 6.28 (s, 1H, Ar-H), 5.81 (s, 1H, -CH), 4.10 (d, J = 12.00 Hz, 1H,
-
–
CH ), 4.00 (d, J = 12.00 Hz, 1H, -CH ), 3.83 (d, J = 16.00 Hz, 1H, -CH ), 3.76
2
2
2
1
3
3.72 (m, 4H, -CH -OCH ), 3.42 (s, 3H, -OCH ) ppm; C NMR (100 MHz,
2
,
3
3
email: smurugavel27@gmail.com
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J. Chil. Chem. Soc., 60, Nº 3 (2015)
CDCl ): δ = 150.19, 146.29, 143.04, 142.97, 142.89, 141.69, 141.66, 139.01,
3
1
1
38.74, 137.29, 133.97, 133.45, 128.88, 128.86, 128.71, 128.35, 127.65,
27.19, 126.77, 126.21, 125.29, 125.06, 123.40, 122.04, 120.97, 116.90,
1
10.88, 107.55, 59.63, 58.59, 55.69, 55.36, 48.91 ppm.
.2 X-ray Crystallography
2
Crystal of the title compound having approximate dimension
3
0
.30×0.26×0.20 mm was mounted on a glass fiber using cyanoacrylate
adhesive. All measurement were made on a BrukerAXSKapppa Apex II
single crystal X-ray diffractometer using graphite mono-chromated MoKα (λ
=
0.71073 Å) radiation and CCD detector. Diffraction data were collected at
room temperature by the ω-scan technique. Accurate unit cell parameters and
orientation matrix were obtained by a least-squares fit of several high angle
o
o
reflections in the ranges 2.12 < θ < 28.16 for the title compound. The unit cell
o
parameters were determined for 36 frames measured (0.5 phi-scan) from three
different crystallographic zones and using the method of difference vectors.
The intensity data were collected with an average four-fold redundancy per
reflection and optimum resolution (0.75 Å). The intensity data collection,
frames integration, Lorentz-polarization correction and decay correction
were done using SAINT-NT (version 7.06a) software. Empirical absorption
Figure 1: (a) View of title compound showing the atom-numbering
scheme. Displacement ellipsoids for the non-H atoms are drawn at the 20%
probability level. The H atoms are presented with spheres with arbitrary radii.
(b) The theoretical geometric structure of the title compound (B3LYP/6-
11
correction (multi-scan) was performed using SADABS program. The
1
2
structure was solved by direct methods using SHELXS-97 implemented in
13
WinGX program suit. The refinement was carried out by full-matrix least-
3
11G(d,p) level).
square method on the positional and anisotropic temperature parameters of the
1
4
non-hydrogen atoms, using SHELXL-97 . All the H atoms were positioned
The N-containing six-membered ring of the tetrahydroisoquinoline unit
adopts a distorted half-chair confirmation, with the local two-fold axis passing
geometrically and constrained to ride on their parent atom with C—H =
0
.93–0.97 Å and with U (H) = 1.5 U for methyl H atoms and 1.2U (C) for
i
s
o
e
q
e
q
through the midpoint of the (C2-C7) and (C9-N1) bonds. The asymmetry
other H atoms. Owing to poor agreement, the reflection [0 0 2], was omitted
from the final cycles of refinement. The general-purpose crystallography tool
2
4
25
parameter ΔC [C2-C7] is 12.35(16)˚ and the puckering parameters Q, θ and
2
15
16
17
φ are 0.4840(13) Å, 128.18(17)˚ and 135.6(2)˚, respectively. The essentially
planar furan ring (O3/C34-C37) [maximum deviation = -0.006(1) Å for the
C36 atom] is equatorially attached to the tetrahydroisoquinoline unit. The
indene ring (C12-C20) is essentially planar [maximum deviation = 0.051(1) Å
for the C13 atom] and is oriented at a dihedral angle of 44.9 (1)˚ with respect
to tetrahydroisoquinoline unit.
PLATON , ORTEP and MERCURY were used for structure analysis and
presentation of the results.
2
.3 Computational Details
The molecular structure of the compound in ground state (in vacuo) was
1
8, 19
optimized using density functional theory DFT (B3LYP)
method with
20
the 6-311G (d, p) basis sets. All the calculations were performed without
specifying any symmetry for the title molecule by using GaussView molecular
21
22
The hydrogen bond geometry for compound (I) is presented in Table 2.
In the crystal structure, intermolecular C36-H36…O2 contacts lead to the
formation of C(10) supramolecular chain along b axis. These chains are linked
visualization program and Gaussian 03 program package . The optimized
geometrical parameters were calculated using Gaussian 03W package and
GaussView 03 program has been used to construct optimized molecular
geometry.
ii
into a double layer via intermolecular C19-H19…Cg1 (symmetry code: (ii)
iii
1
1
-x, 1/2+y, 1/2-z) and C21-H21A…Cg2 (symmetry code: (iii) 1-x, -1/2+y,
/2-z) hydrogen bonds [Fig. 2. and Table-2; Cg1 and Cg2 are the centroids
2
.4 Antibacterial test
Antibacterial susceptibility test was carried out using Kirby-bauer disk
2
3
of the (C22-C27) and (C28-C33) benzene rings, respectively]. The resulting
double layer stacks along the c axis without any specific interactions (Fig. 3).
diffusion method as per CLSI M38-A guidelines . The synthesized compound
was dissolved in DMSO at various concentrations (25, 50 and 75 µg/ml) and
tested against selected bacterial pathogens. Suspension of bacterial isolates
was adjusted to 0.5 McFarland standards in 0.85% saline (suspension will
8
contain approximately 4 x 10 CFU/ml) and lawn culture was spread using
sterile swabs on Muller Hinton agar media (Hi-media, Mumbai). Wells (6 mm/
dm, 2 cm apart) were bored upon the lawn culture of the agar media using a
sterile borer. Test compound (25, 50 and 75µg/ml) were loaded to the wells
under aseptic conditions and the plates were incubated at 37°C for 24 hours.
Presence of inhibition zones surrounding each well evidenced antimicrobial
activity. The antimicrobial activity was evaluated by measuring the inhibition
zones diameter in millimeters. Each experiment was repeated three times and
the mean of inhibitory zones were recorded.
Tests strains were procured from MTCC, INTECH, Chandigarh, India.
They include Bacillus cerus (MTCC 430), Escherichia coli (MTCC 443),
Pseudomonas aeruginosa (MTCC 1435), Staphylococcus aureus (MTCC
1
0623), Acinetobacter baumannii (MTCC 1425), Staphylococcus epidermidis
(MTCC 10623), Klebsiella pneumoniae (MTCC 432) and Proteus vulgaris
(MTCC 742). Standard antibiotic ciprofloxacin (25 µg) was used as positive
control to perform the test.
3
. RESULTS AND DISCUSSION
3
.1 Description of Crystal structure
The displacement ellipsoid plot and theoretical geometry structure with the
atom-numbering scheme for compound (I) is shown in Fig. 1. The compound
crystallizes in the monoclinic system, space group P21/c with cell constants:
Figure 2:A view of the crystal packing showing supramolecular double
layer along the b axis, mediated by C-H…O and C-H…π interaction.[ Cg1
and Cg2 are the centroids of the (C22-C27) and (C28-C33) rings, respectively,
symmetry codes (i) x, -1+y, z (ii) 1-x, 1/2+y, 1/2-z (iii) 1-x,-1/2+y,1/2-z ].
a = 11.2121(4) Å, b = 10.4797(3) Å, c = 24.4375(9) Å, α = γ = 90.0˚, β =
3
9
8.174(2)˚, V = 2842.22(17) Å , Z = 4. Details of the data collection, crystal
parameters and refinement process of compound (I) are given in Table 1.
3
016

J. Chil. Chem. Soc., 60, Nº 3 (2015)
Independent reflections
Completeness to theta = 28.16°
Absorption correction
6950 [R(int) = 0.0285]
99.7 %
Semi-empirical from equivalents
0.984 and 0.977
Max. and min. transmission
Refinement method
2
Full-matrix least-squares on F
Data / restraints / parameters
6950 / 0 / 372
2
Goodness-of-fit on F
1.018
Final R indices [I > 2σ(I)]
R indices (all data)
R1 = 0.0434, wR2 = 0.1053
R1 = 0.0666, wR2 = 0.1217
0.183 and -0.222
-3
Largest diff. peak and hole (e.Å
)
TABLE 2. Hydrogen bonding geometry for the compound (I) (Å, °).
D–H...A
D–H
0.93
0.93
0.97
d(H...A)
2.52
d(D...A)
3.064(2)
3.631(2)
3.717(2)
<(DHA)
117.8
164
i
C36–H36A...O2
Figure 3: A view of the overall crystal packing highlighting the stacking
of double layers along the c axis without any specific interactions
ii
C19–H19...Cg1
2.73
iii
C21–H21A...Cg2
2.87
146
3
.2 DFT Calculations
The first task of the computational work is to determine the optimized
geometry of the title compound. The starting coordinates were obtained from
X-ray structure determination. The optimized parameters (bond lengths, bond
angles) of the compound (I) were obtained using (DFT/B3LYP) method with
the 6-311G(d,p) basis set. The results are listed in Table-3 and compared with
the experimental data for the title compound. As seen from the Table-3, the
agreement between the theoretically calculated and the experimentally obtained
structure parameters for the title compound are very good. In view of the bond
lengths in Table 3, most predicted values are longer than experimental ones.
We note that the experimental results are for the solid phase and the theoretical
calculations are for the gas phase. In the solid state, the existence of a crystal
field along with the intermolecular interactions connect the molecules together,
which results in the difference in bond parameters between the calculated and
Cg1 is the centroid of the C22–C27 ring,
Cg2 is the centroid of the C28–C33 ring.
Symmetry codes : (i) x,-1+y,z; (ii) 1-x,1/2+y,1/2-z ; (iii) 1-x,-1/2+y,1/2-z .
TABLE 3. Selected structural parameters by X-ray Diffraction and DFT
calculations for compound (I).
Parameters
X-ray
Bond lengths (Å)
1.454(2)
DFT
N1-C1
C9-C34
C8-C9
C8-C12
C4-O1
C10-O2
C11-O1
C4-C5
C5-C6
C3-C4
1.460
1.508
1.534
1.374
1.355
1.421
1.421
1.421
1.382
1.388
1.495(2)
26
experimental values .
1.519(2)
1.362(2)
TABLE 1. Crystal and experimental data for the compound (I).
1.361(2)
Empirical formula
C37 H31 NO3
537.63
1.413(2)
Formula weight
1.411(2)
Temperature (K)
293(2)
1.407(2)
Wavelength (Å)
0.71073
Monoclinic
P 21/c
1.365(2)
Crystal system
1.370(2)
Space group
Bond angles (°)
105.97(1)
109.03(1)
111.67(1)
115.06(1)
117.86(1)
122.90(1)
126.99(1)
121.51(1)
120.39(1)
Torsion angles (°)
146.68(2)
-36.10(2)
Unit cell dimensions(Å, ˚)
C36-O3-C35
N1-C9-C34
106.773
110.446
112.807
113.916
118.116
120.914
129.800
119.682
122.328
a
b
c
β
11.2121(4)
10.4797(3)
24.4375(9)
98.174 (2)
2842.22(2)
4
N1-C21-C22
N1-C1-C21
3
C5-O2-C10
Volume (Å )
C19-C20-C28
C28-C20-C12
C33-C28-C20
C29-C28-C20
Z
3
Calculated density (Mg/m )
1.256
-1
Absorption coefficient (mm
F(000)
)
0.079
1136
3
Crystal size (mm )
0.30 x 0.26 x 0.20
2.12 to 28.16.
N1-C21-C22-C23
N1-C21-C22-C27
C7-C8-C12-C13
139.176
-43.033
157.471
Theta range for data collection (°)
Index ranges
-
-
14<=h<=14, -13<=k<=13,
32<=l<=32
151.91(1)
Reflections collected
51656
3
017

J. Chil. Chem. Soc., 60, Nº 3 (2015)
change in the electron distribution or charge transfer. On the basis of frontier
molecular orbitals, chemical hardness corresponds to the gap between the
Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied
Molecular Orbital (LUMO). Chemical hardness is approximated using
equation η = (ELUMO− EHOMO)/2, where ELUMO and EHOMO are the LUMO and
HOMO energies, respectively. The larger the HOMO–LUMO energy gap, the
molecule will be harder, more stable and less reactive. Table 4 (row 4) contains
the computed chemical hardness value for title compound.
N1-C9-C34-C35
C8-C9-C34-C35
-119.18(2)
3.60(2)
129.426
-5.346
When the X-ray structure of the title compound was compared with
its optimized counterpart (see Fig. 1), conformational discrepancies were
observed. The orientation of the phenyl ring, furan ring attached to the
tetrahydroisoquinoline of compound (I) proved the most notable discrepancy,
and is defined with torsion angle N1–C21–C22–C27 = 146.7 (2)° and N1–C9–
C34–C37 = 59.5 (2)°, which is calculated at 139.2° and 53.2°, respectively, for
B3LYP/6-311G(d,p) level.
As seen from Table 3, the difference between the X-ray and calculated
values for the bond lengths C8–C9 and C10–O2 are 0.015 Å and 0.008 Å,
respectively. Similarly, the difference for bond angles C28-C20-C12, C19–
C20–C28 and N1–C21–C22 are 2.81°, 1.99° and 1.14°, respectively. This
difference is more due to intermolecular C36–H36…O2 hydrogen bond.
According to experimental and calculated values, the dihedral angle between
indene ring and phenyl ring attached to the tetrahydroisoquinoline is 58.7 (1)º
and 55.6°, respectively.
A global comparison was performed by superimposing the molecular
skeletons obtained from X-ray diffraction and the theoretical calculations atom
by atom (Fig.4.), obtaining RMSE’s values of 2.684 Å for DFT/B3LYP) method
with the 6-311G(d,p) basis set. This magnitude of RMSE can be explained
by the fact that the intermolecular columbic interaction with the neighboring
molecules are absent in gas phase, whereas the experimental result corresponds
to interacting molecules in the crystal lattice.
Figure 5: The molecular orbital and energies for the HOMO and LUMO
of compound (I).
3
0
The concept of electronegativity put forward by Pauling is defined as
‘
‘the power of an atom in a molecule to attract electrons towards itself’’. Higher
is the electronegativity of the species, greater is its electron accepting power
or rather the electrophilicity. Electronegativity is determined using equation χ
=
- (EHOMO + ELUMO) /2, Table 4 (row 6) contains the computed electronegativity
values for the title compound.
Electronic chemical potential is defined as the negative of electronegativity
3
1
of a molecule and determined using equation μ = (EHOMO + ELUMO)/2.
Physically, μ describes the escaping tendency of electrons from an equilibrium
3
2
system . The value of μ for the title compound is presented in Table 4 (row 5).
Global electrophilicity index (ω), introduced by Parr, is calculated using the
electronic chemical potential and chemical hardness as shown in equation ω =
2
μ /2η. Electrophilicity index measures the propensity or capacity of a species to
Figure 4: Atom-by-atom superimposition of the calculated structure (red)
on the X-ray structure (blue) for compound
3
3,34
accept electrons . It is a measure of the stabilization in energy after a system
3
5,36
accepts additional amount of electronic charge from the environment . The
electrophilicity values of the title compound is presented in (Table 4, row 7).
The HOMO and LUMO orbital energies are related to gas phase ionization
energies (I) and electron affinities (A) of the isomers according to the Koopmans’
theorem through equations A = − ELUMO, I = − EHOMO. Electron affinity refers to
the capability of a ligand to accept precisely one electron from a donor.
3
.3 Molecular orbital studies
The most widely used theory by chemists is the molecular orbital (MO)
theory. The frontier molecular orbitals play an important role in the electronic
2
7
and optical properties, as well as in UV-VIS spectra and chemical reactions .
The DFT calculated electronic absorption spectra, the maximum absorption
wavelength corresponding to the electronic transition is from the highest
occupied molecular orbital (HOMO) to the lowest unoccupied molecular
orbital (LUMO). The frontier molecular orbital energies of the title compound
are shown in Fig 5.
TABLE 4. Calculated energy values of compound (1) by B3LYP/6-
3
11G(d,p).
Basis set
B3LYP/6-311G(d,p)
-5.3572
EHOMO (eV)
The energy gap between HOMO and LUMO is a critical parameter
2
8,29
in determining molecular electrical transport properties.
The lowest
ELUMO (eV)
-2.0515
unoccupied molecular orbital (LUMO) energy is -2.0515 eV and the highest
occupied molecular orbital (HOMO) energy is -5.3572 eV. The energy gap of
HOMO–LUMO explains the ultimate charge transfer interaction within the
molecule, and the frontier orbital energy gap of title compound is found to
be -3.3057 eV obtained at DFT method using 6-311G(d,p) basis set. Lower
the HOMO–LUMO gap explains the eventual charge transfer interactions
taking place within the molecule, which influences the biological activity of
the molecule.
EHOMO - ELUMO gap (eV)
Chemical hardness (η)
Chemical potential (µ)
Electronegativity (χ)
Electrophilicity index (ω)
-3.3057
1.6528
-3.7043
3.7043
4.1511
3
.4 Chemical reactivity
Chemical reactivity indices like chemical hardness (η), electronegativity
χ), electronic chemical potential (μ), and electrophilicity Index (ω), are
calculated using DFT. Chemical hardness is associated with the stability and
3.5 Molecular Electrostatic Potential
The Molecular Electrostatic Potential (MEP) is a plot of electrostatic
potential mapped onto the constant electron density surface. The MEP has
(
reactivity of a chemical system. In a molecule, it measures the resistance to
been used primarily for predicting sites and relative reactivity towards
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018

J. Chil. Chem. Soc., 60, Nº 3 (2015)
electrophilic attack, in studies of biological recognition and hydrogen
bonding interactions . The negative electrostatic potential corresponds to an
attraction of the proton by the concentrated electron density in the molecule
potential corresponds to repulsion of the proton by atomic nuclei in regions
where low electron density exists and the nuclear charge is incompletely
shielded (and is coloured in shades of blue). Potential increases in the order red
< orange < yellow < green < blue.
37,38
(and is coloured in shades of red on the EPS surface), the positive electrostatic
Figure 6: Molecular electrostatic potential map calculated using B3LYP/6-311G(d, p) level.
Figure 6 shows the molecular electrostatic potential (MEP), was
(-3.3057 eV) depicts the chemically reactivity of the title compound (I) and
hence it is highly suitable for biological studies. Hence, the title compound was
tested for in vitro antibacterial activity studies.
determined using B3LYP/6-311G(d, p) method. The different values of the
electrostatic potential at the surface are represented by different colours. As
can be seen in Fig. 6, the negative (red) region is localized on the unprotonated
atom of O2 with a minimum value of -0.0441a.u. However, positive (blue)
region is localized on atom C36 probably due to hydrogen, with a value of
Each zone size is interpreted by reference to the Table 2G (Zone Diameter
Interpretative Standards and equivalent Minimum Inhibitory Concentration
Breakpoints) of the NCCLS M100-S12: Performance Standards for
3
9
0
.042 a.u. Therefore, Fig. 6 confirms the existence of an intermolecular C36—
H36A…O2 interaction.
Antimicrobial Susceptibility Testing: Twelfth Informational Supplement .
Results indicated that target compound exhibited significant antimicrobial
activity against selected pathogens, Bacillus cerus , Escherichia coli,
Pseudomonas aeruginosa, Staphylococcus aureus, Acinetobacter baumann,
Staphylococcus epidermidis, Klebsiella pneumoniae and Proteus vulgaris
when compared with the standard antibiotic ciprofloxacin (25 µg).
3
.6 Interpretation of antibacterial activity
Generally, a molecule with small Homo-Lumo energy gap is considered as
a chemically reactive. The chemically reactive compounds are highly suitable
for biological studies. From the DFT studies, a small Homo-Lumo energy gap
TABLE 5. Antibacterial Activity of Compound at Different Concentrations against Bacterial Pathogens.
Zone of inhibition (mm)
Microorganisms
Compound Concentration
Positive control
CIPX (25 µg)
(
25 µg/ml)
(50 µg/ml)
(75 µg/ml)
Bacillus cereus (MTCC 430)
18
8
22
12
22
8
25
18
28
8
38
30
36
16
18
24
35
30
Escherichia coli (MTCC 443)
Pseudomonas aeruginosa (MTCC 1435)
Staphylococcus aureus (MTCC 10623)
Acinetobacterbaumannii (MTCC 1425)
Staphylococcus epidermidis (MTCC 10623)
Klebsiella pneumonia (MTCC 432)
Proteus vulgaris (MTCC 742)
18
NI
NI
22
20
18
8
8
25
22
22
25
26
27
NI : No Inhibition, CIPX: Ciprofloxacin. Values are mean of three independent experiments
The most susceptible pathogens were Bacillus cereus, Pseudomonas
aeruginosa (28 mm), Proteus vulgaris (27 mm), Klebsiella pneumoniae (26
mm) and Staphylococcus epidermidis (25 mm) at concentration 75 µg/ml of the
compound, exhibiting good antibacterial activity against these pathogens when
compared to other pathogens studied, while 50 and 25 µg/ml concentrations of
the compound exhibited moderate activity ranging from 18-25 mm in diameter
for almost all pathogens as shown in Table 5. Figure 7 explains a bar diagram
for the antibacterial activity. The present study concludes that the compound
exhibited good to moderate antibacterial activity against all tested pathogens.
3
019

J. Chil. Chem. Soc., 60, Nº 3 (2015)
9
1
.
W. Koch and M.C.A. Holthausen, AChemistry Guide to Density Functional
Theory, Wiley-VCH, Weinheim, New York, Chichester, (2000).
0. R.G. Parr and R.G. Yang, Density Functional Theory of Atoms and
Molecules, Oxford University Press, New York, USA, (1989).
11. Bruker, APEX-II, SAINT-Plus (Version 7.06a), BrukerAXS Inc. Madion,
Wisconsin, USA, (2004).
1
2. G.M. Sheldrick, SHELXS97, A Program for Crystal Structure Solution,
University of Göttingen: Germany (1997).
1
1
3. LJ. Farrugia, J. Appl. Cryst., 32, 837 (1999)
4. G.M. Sheldrick, SHELXL97,AProgram for Crystal Structure Refinement,
University of Göttingen: Germany (1997).
1
1
1
5. A.L. Spek, J. Appl. Cryst., 36, 7 (2003)
6. L.J. Farrugia, J. Appl. Cryst., 30, 565 (1997)
7. I.J. Bruno, J.C. Cole, P.R. Edgington, M.K. Kessler, C.F. Macrae, P.
McCabe, J. Pearson and R. Taylor, Acta.Cryst., B58, 389 (2002)
8. A.D. Becke, J. Chem. Phys., 98, 5648 (1993)
9. C.T. Lee, W.T. Yang and R.G. Parr, Phys. Rev. B., 37, 785 (1988)
0. R. Ditchfield, W.J. Hehre and J.A. Pople, J. Chem. Phys., 54, 724 (1971)
1. R. Dennington II, T. Keith and J. Millam, Gauss View Version 4.1.2,
Semichem Inc., Shawnee Mission, KS, (2007)
1
1
2
2
Figure 7: A bar diagram for the antibacterial activity for compound (I).
CONCLUSION
2
2. M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R.
Cheeseman, J.A. Montgomery, T. Vreven Jr, K.N. Kudin, J.C. Burant, J.M.
Millam, S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G.
Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, M. Klene, X. Li, J.E. Knox, H.P Hratchian, J.B. Cross,
C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J.
Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y Ayala, K. Morokuma,
G.A. Voth, P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S. Dapprich,
A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck,
K. Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S.
Clifford, J. Cioslowski, B.B. Tefanov, G. Liu, A. Liashenko, P. Piskorz, I.
Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng,
A. Nanayakkara, M. Challacombe, P.M. W. Gill, B. Johnson, W. Chen,
M.W. Wong, C. Gonzalez and J.A. Pople, Gaussian03, Gaussian Inc,
Wallingford, CT, USA, (2004)
The title compound was synthesized and structurally characterized by
1
13
elemental analysis, H NMR and C NMR and single crystal X-ray diffraction.
In the crystal structure, supramolecular chains mediated by C–H…O contacts
along the b-axis are linked into a double layer via C–H…π hydrogen bonds. The
resulting double layer stacks along the c axis without any specific interactions.
To support the solid state structure, the geometric parameters of the title
compound have been calculated using density functional theory DFT (B3LYP)
method with the 6-311G (d,p) basis sets, and compared with the experimental
findings. It was noted here that the experimental results belong to solid phase
and theoretical calculations belong to gaseous phase. In the solid state, the
existence of the crystal field along with the intermolecular interactions have
connected the molecules together, which result in the differences of bond
parameters between the calculated and experimental values. The MEP map
confirms the existence of intermolecular C–H…O interactions. The small
HOMO-LUMO gap value shows that the molecule is biologically active. The
obtained antibacterial activity results indicate that the compound exhibits good
to moderate activity against all tested pathogens.
2
3. A. W. Bauer, W. M. M. Kirby, J. C. Sherris and M. Turck, Antibiotic
susceptibility testing by a standardized single disk method. Am. J. Clin
Pathol., 45, 493 (1966)
2
4. W. L. Duax, C. M. Weeks and D.C. Rohrer, Topics in Stereochemistry,
Vol. 9, edited by E. L. Elliel & N. Allinger, pp. 271-383. New York: John
Wiley. (1976).
Supplementary Materials
CCDC 1021077contains the supplementary crystallographic data for this
paper. This data can be obtained free of charge at http://www.ccdc.cam.ac.uk/
data_request/cif, by e-mailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK; fax: +44(0)1223-336033.
2
2
2
5. D. Cremer and J. A. Pople, J. Am. Chem. Soc., 97, 1354 (1975).
6. F.F. Jian, P.S. Zhao and Z.S. Bai, I. Zhang, Struct. Chem., 16, 635 (2005)
7. I. Fleming, Frontier orbitals and organic chemical reactions, London:Wiley,
(1976)
2
2
8. K. Fukui, Science. 218, 747–754, (1982)
9. P. Udhayakala, T. V. Rajendiran, S. Seshadri, S. Gunasekaran, J. Chem.
Pharm. Res.(3), 610-625, (2011)
ACKNOWLEDGEMENTS
The authors thank Dr Babu Vargheese, SAIF, IIT, Madras, India, for his
help with the data collection.
3
0. L. Pauling, The nature of chemical bond, Cornell University Press, Ithaca,
(1960)
3
3
3
3
3
3
3
1. R. G. Parr, R. G. Pearson, J. Am. Chem. Soc. 105, 7512, (1983)
2. P. K. Chattaraj, B. Maiti, J. Am. Chem. Soc. 125, 2705, (2003)
3. A. Vektariene, G. Vektaris, J. Svoboda, ARKIVOC. 7, 311, (2009)
4. R. G. Parr, L. Szentpaly, S. Liu, J. Am. Chem Soc. 121, 1922, (1999)
5. T. Koopmans, Physica. 1, 104, (1933)
6. S. Liu, J. Chem. Sci. 117, 477, (2005)
7. J. S. Murray, K. Sen, Molecular Electrostatic Potentials, Concepts and
Applications, Elsevier, Amsterdam, pp 7–624, (1996)
8. E. Scrocco, J. Tomasi, Adv. Quant. Chem. 11, 115, (1978)
9. National Committee for Clinical Laboratory Standards (NCCLS),
Performance standards for antimicrobial susceptibility testing; Twelfth
informational supplement, Wayne, PA, M100-S12 (2002).
REFERENCES
1
.
P. S. Humphries, J. W. Benbow, P. D. Bonin, D. Boyer, S. D. Doran, R.
K. Frisbie,
D. W. Piotrowski, G. Balan, B. M. Bechle, E. L. Conn, K. J. Dirico, R. M.
Oliver, W. C. Soeller, J. A. Southers and X. Yang, Bioorg. Med. Chem.
Lett., 19, 2400 (2009.)
2
.
K. Abe, T. Saitoh, Y. Horiguchi, I. Utsunomiya and K. Taguchi, Biol.
Pharm. Bull., 28, 1355 (2005).
A. Storch, S. Ott, Y. I. Hwang, R. Ortmann, A. Hein, S. Frenzel, K.
Matsubara, S. Ohta, H. U. Wolf and J. Schwarz, Biochem. Pharmacol.,
3
3
3
.
6
3, 909 (2002).
4.
5.
6.
7.
8.
J. W. Lane, A. Estevez, K. Mortara, O. Callan, J. R. Spencer and R. M.
Williams, Bioorg. Med. Chem. Lett., 16, 3180 (2006).
A. E. Wright, D. A. Forleo, G. P. Gunawardana, S. P. Gunasekera, F. E.
Koehn and O. J. McConnell, J. Org. Chem., 55, 4508 (1990).
A. M. Kamal, S. M. Radwan and R. M. Zaki, Eur. J. Med. Chem., 46, 567
(2011).
X. H. Liu, J. Zhu, A. N. Zhou, B.A. Song, H.L. Zhu, L.S. Bai, P.S. Bhadury
and C. X. Pan, Bioorg. Med. Chem., 17, 1207 (2009).
K. Naveen, D. Muralidharan and P. T. Perumal, Eur. J. Org. Chem., 1172
(2014).
3
020