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DFT Based Characterization of Some Heterocyclic Compounds
and Their Biological Studies
Jayaraman Jayabharathi
a,*
, Manoharan Padmavathy
a
, Natesan Srinivasan
a

a
Department of Chemistry, Annamalai University, Annamalainagar 608 002, India
*
Correspondence e-mail: jtchalam2005@yahoo.co.in
Conformation and orientation of hydroxy group in isomeric alcohols were characterized by NMR, analysis of coupling
constant reveal that they exist in normal chair conformation with equatorial orientation of substituents. Both spectral and
theoretical (B3LYP/6-31G (d,p) studies confirmed that the hydroxy group in isomeric alcohols oriented towards the sterically
free side, i. e. gauche to C(5). The shortening of C-H bond length, blue shifting of the C-H stretching wave number, blue
shifted abs and flu proved the existence of improper weak C-H

O intramolecular hydrogen bonding which is also confirmed

by the natural bond orbital analysis (NBO). Theoretical analysis was carried out for NBO, NLO and for HOMO-LUMO energies.
The antimicrobial activities of these synthesized compounds were evaluated.
Received: 7 August 2010 Published: 22 September 2010 Structural Chemistry Communications, 2010, Vol. 1, No. 1, pp. 15-24
Introduction
The relative chemical shift order of equatorial and axial
protons in the normal chair conformation of cyclohexane
and its derivatives (oeq>oax) is attributed to the magnetic
anisotropic effect of the CC single bonds. The influence of
substituents on the chemical shift of protons attached to
the adjacent carbon has been studied in detail [13]. In
normal chair conformation, it has been reported [4] that
the equatorial substituent at | or -position cannot affect
the oeqoax significantly. However, a -axial substituent or
|-axial substituent can decrease oeqoax value
significantly. The negative value [4] is even reported in t(4)-
hydroxy-3,3-dimethyl-r(2), c(6)-phenylpiperidinewhereaxial
hydrogen at C5 experiences severe 1,3-diaxial interaction
with axial methyl group at the -position (C(3)) and
deshielding magnetic anisotropic effect of axial hydroxy
group at the |-position (C(4)).
Quantum mechanical computations are the newly emerging
technique in resolving the structural chemical behaviour of
the bio-chemicals [5]. Density functional theory (DFT)
computation, which incorporate the electron correlation,
have recently become an efficient tool in the prediction of
molecular structure, harmonic frequencies, IR and Raman
activities of biological compounds [6-8]. The vibrational
spectroscopy has proved to be a powerful tool for probing
the occurrence of the hydrogen bonds. C-H

O hydrogen
bonds are currently one of the main field of hydrogen
bonding research both experimentally and theoretically [9]
and these type of hydrogen bonds are taken as the key
interaction in structure and activity of the biological
systems [10].
The present work deals with conformational analysis of 3,3-
dimethyl-2,6-di-p-chlorophenyl-piperidin-4-one (1), 3,3-
dimethyl-2,6-di-p-tolyl- piperidin-4-one (2) and their
isomeric alcohols 3-6 by NMR studies. The orientation of
hydroxy group in isomeric alcohols 3-6 were studied by
chemical shift and confirmed by Density Functional Theory
[11, 12] and theoretically computed wave numbers are
compared with experimental values. The redistribution of
electron density (ED) in various bonding and anti-bonding
orbitals and their E2 energies have been calculated by
Natural Bond Orbital (NBO) analysis by using DFT method
to give clear evidence for stabilization of molecules
originating from various intramolecular interactions. The
HOMO-LUMO analysis has been used to elucidate
information regarding charge transfer within the
molecule.The absorption and emission spectroscopic
studies along with NLO analysis have also been carried out.
Experimental Section
Spectral Measurements and Composition Analysis
NMR spectra were recorded for 1-6 on a Bruker 400 MHz.
The ultravioletvisible (UVVis) spectra were measured on
UVVis spectrophotometer (Perkin Elmer, Lambda 35) and
corrected for background due to solvent absorption.
Photoluminescence (PL) spectra were recorded on a
(Perkin Elmer LS55) fluorescence spectrometer. MS
spectra were recorded on a Varian Saturn 2200 GCMS
spectrometer.
Non-linear Optical Measurements
Its second harmonic generation efficiency was assessed by
Kurtz powder technique [13] at IISc., Bangalore, India. It is
a well established tool to evaluate the conversion efficiency
of nonlinear optical materials. A Q-switched Nd:YAG laser
operating at the fundamental wavelength of 1064 nm,
16 STRUCTURAL CHEMISTRY COMMUNICATIONS, 2010, Vol. 1, No. 1, pp. 15-24

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generating about 4.1 mJ and pulse width of 8 ns was used
for the present experimental study. The input laser beam
was passed through an IR reflector and then incident on
the powder form of the specimen, which was packed in a
glass capillary tube. The output energy was detected by a
photodiode detector integrated with oscilloscope assembly.
Computational Details
Quantum mechanical calculations were used to carry out
the optimized geometry, NLO, PES, HOMO-LUMO energies
and excited state parameters by CIS method with Guassian-
03 program using the Becke3-Lee-Yang-Parr (B3LYP)
functional supplemented with the standard 6-31G(d,p)
basis set[11]. As the first step of our DFT calculation, the
geometry taken from the starting structure was optimized
andfor NLO analysis, the electric dipole moment and |
tensor components of the compounds 1-6 were calculated.
The total first hyperpolarisability (|tot) for the compounds 1-
6 and the components of the first hyperpolarisability can
be calculated using the following equation:

+ 1/3 (

(1)
Using the x, y and z components, the magnitude of the first
hyperpolarisability tensor can be calculated by

= (

2
+

2
+

2
)
1/2
(2)
The complete equation for calculating the magnitude of
first hyperpolarisability from Gaussian-03 output is given as
follows

= [(

)
2
+
+(

)
2
+ (

)
2
]
1/2
(3)
All the electric dipole moment and the first
hyperpolarisability [14] were calculated by taking the
Cartesian coordinate system (x, y, z) = (0, 0, 0) at own
center of mass of the compounds 1-6.
Synthesis of 3,3-dimethylpiperidones (1 and 2) and 4-
hydroxypiperidines (3-6)
The 4-hydroxy piperidines 3-6 were prepared from the
corresponding piperidin-4-ones 1 and 2 by adopting the
general procedure described by Balasubramanian and
Padma [15]. Reaction progress was monitored by thin layer
chromatography while the isomeric alcohols were
separated by neutral alumina (60-325 mesh) column
chromatography.
3,3-Dimethyl-r(2),c(6)-bis(4-chlorophenyl)- piperidin-4-one
(1). Yield: 75%. mp 82C, Anal. calcd. for C19H19Cl2NO: C,
65.53; H, 5.50; N, 4.02. Found: C, 64.25; H, 4.89; N, 3.86,
1
H NMR (400 MHz, CDCl3): oH(6) (J6a,5a = 12.00 Hz, J6a,5e =
2.97 Hz),3.80 H(2), 4.03 2.85 (H5a), 2.44 (H5e) (J5a,5e =
13.75 Hz), 1.86 (NH), 1.17 CH3(eq), 0.94 CH3(ax),
7.277.45 (aromatic protons);
13
C NMR (100 MHz, CDCl3):
o211.86 C(4), 68.72 C(2), 60.84 C(6), 49.66 C(3), 47.04
C(5), 20.29 CH3(eq), 19.82 CH3(ax), 141.34, 137.45 (ipso
carbons), 133.60, 133.49,130.00, 128.86, 128.00,
127.85 (aromatic carbons).MS: m/z 347.98, calcd 348.27.
3,3-Dimethyl-r(2),c(6)-bis(4-methylphenyl) piperidin-4-one
(2). Yield: 65%. mp 84C, Anal. calcd. for C21H25NO: C,
82.03; H, 8.20; N, 4.56. Found: C, 81.90; H, 7.89; N, 3.86,
1
H NMR (400 MHz, CDCl3): o 4.03 H(6) (J6a,5a = 12.00 Hz, J6a,5e
= 2.97 Hz),3.80 H(2), 2.93 (H5a), 2.46 (H5e) (J5a,5e = 13.75
Hz), 1.93 (NH), 1.21 CH3(eq), 0.96 CH3(ax), 7.187.39
(aromatic protons);
13
C NMR (100 MHz, CDCl3): o213.17
C(4), 69.28 C(2), 61.32 C(6), 49.91 C(3), 47.25 C(5),
21.07(4-methylphenyl), 20.41 CH3(eq), 19.98
CH3(ax),140.24, 137.43 (ipso carbons), 137.32, 136.27,
129.28, 128.69, 128.41, 126.42 (aromatic carbons).
MS: m/z 307.43,calcd 307.00.
3,3-Dimethyl-t(4)-hydroxy-r(2),c(6)-bis(4-chlorophenyl)
piperidine (3).Yield: 15%. mp 71C, Anal. calcd. for
C19H21Cl2NO: C, 65.15; H, 6.04; N, 4.00. Found: C, 63.85;
H, 5.08; N, 3.23.
1
H NMR (400 MHz, CDCl3): o 4.27 H(6)
(J6a,5a = 11.90 Hz, J6a,5e = 2.18 Hz), 4.13 H(2), 3.88 (H5e)
(J5a,5e = 11.40 Hz), 3.69 (H5a), 3.58 H(4), 1.42 (NH), 1.01
CH3(eq), 0.86 CH3(ax), 7. 267.45 (aromatic protons);
13
C
NMR (100 MHz, CDCl3): o75.29 C(4), 68.36 C(2), 62.64
C(6), 55.32 C(3), 37.45 C(5), 24.43 CH3(eq), 19.50
CH3(ax), 143.39, 149.68 (ipso carbons), 142.58,
138.70,129.74, 128.13, 127.82, 127.28 (aromatic
carbons).MS: m/z 349.10, calcd 349.00.
3,3-Dimethyl-c(4)-hydroxy-r(2),c(6)-bis(4-chlorophenyl)
piperidine (4). Yield: 65%. mp 72C, Anal. calcd. for
C19H21Cl2NO: C, 65.15; H, 6.04; N, 4.00. Found: C, 64.85;
H, 4.92; N, 3.20.
1
H NMR (400 MHz, CDCl3): o 3.82 H(6)
(J6a,5a = 11.40 Hz, J6a,5e = 2.76 Hz), 3.48 H(2),3.55 H(4),
1.91 (H5a), 1.74 (H5e), 1.48 (NH), 0.90 CH3(eq), 0.87
CH3(ax), 7. 277.41 (aromatic protons);
13
C NMR (100 MHz,
CDCl3): o76.70 C(4), 68.80 C(2), 59.79 C(6), 39.71
C(3), 37.89 C(5), 23.89 CH3(eq), 12.76 CH3(ax), 142.60,
139.03 (ipso carbons), 132.92, 130.11, 128.53,
128.33, 128.07, 127.73, (aromatic carbons).MS: m/z
349.10, calcd 349.00.
3,3-Dimethyl-t(4)-hydroxy-r(2),c(6)-bis(4-methylphenyl)
piperidine (5). Yield: 20%. mp 72C, Anal. calcd. for
C21H27NO: C, 81.51; H, 8.79; N, 4.53. Found: C, 81.50; H,
8.00; N, 4.53.
1
H NMR (400 MHz, CDCl3): o 4.27 H(6)
(J6a,5a = 11.90 Hz, J6a,5e = 2.18 Hz), 4.13 H(2), 3.88 (H5e)
(J5a,5e = 11.40 Hz), 3.69 (H5a), 3.58 H(4), 1.42 (NH), 1.01
CH3(eq), 0.86 CH3(ax), 7.407.32, 7.107.12 (aromatic
protons);
13
C NMR (100 MHz, CDCl3): o69.29 C(4), 61.32
C(2), 59.92 C(6), 49.90 C(3), 47.25 C(5), 21.01 (4-
methylphenyl), 20.38 CH3(eq), 19.96 CH3(ax), 140.25,
137.39 (ipso carbons), 137.29,136.29, 129.26, 128.66,
128.39, 126.36 (aromatic carbons).MS: m/z 309.45,
calcd 309.00.
3,3-Dimethyl-c(4)-hydroxy-r(2),c(6)-bis(4-methylphenyl)
piperidine (6). Yield: 72%. mp 68C, Anal. calcd. for
C21H27NO: C, 81.51; H, 8.79; N, 4.53. Found: C, 81. 01; H,
STRUCTURAL CHEMISTRY COMMUNICATIONS, 2010, Vol. 1, No. 1, pp. 15-24 17

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7.92; N, 3.82.
1
H NMR (400 MHz, CDCl3): o 3.87 H(6)
(J6a,5a = 11.40 Hz, J6a,5e = 2.76 Hz), 3.55 H(2), 2.34 (H5e),
1.91 (H5a), 1.66 H(4), 1.42 (NH), 0.94 CH3(eq), 0.88
CH3(ax), 7.107.36 (aromatic protons);
13
C NMR (100 MHz,
CDCl3): o77.74 C(4), 69.24 C(2), 60.10 C(6), 39.65 C(3),
39.48 C(5), 23.97 (4-methylphenyl), 21.02 CH3(eq),
12.82 CH3(ax), 141.65, 137.74 (ipso carbons), 136.75,
136.62, 129.00, 128.78, 128.10, 126.57 (aromatic
carbons). MS: m/z 309.45, calcd 309.00.
In vitro Antibacterial and Antifungal Activity
The in vitro activities of the compounds were tested in
Sabourauds dextrose broth (SDB; Hi-media, Mumbai) for
bacteria by the twofold serial dilution method. The test
compounds were dissolved in dimethylsulfoxide (DMSO) to
obtain 1 mg/ml stock solutions. Seeded broth (broth
containing microbial spores) was prepared in NB from 24-h-
old bacterial cultures were suspended in SDB. The colony
forming units (cfu) of the seeded broth were determined by
plating technique and adjusted in the range of 10
4
-10
5

cfu/ml. The final inoculum size was 10
5
cfu/ml for
antibacterial assay and 1.1-1.5 X 10
2
cfu/ml for antifungal
assay and testing was performed at pH 7.4 0.2. Exactly
0.2 ml of the solution of each test compound was added to
1.8 ml of seeded broth to form the first dilution. One ml of
this was diluted with a further 1 ml of the seeded broth
give the second dilution and so on till six such dilutions
were obtained. A set of assay tubes containing only seeded
broth was kept as control and likewise solvent controls
were also run simultaneously. The tubes were incubated in
BOD incubators at 37 1 C for bacteria and 28 1C for
fungi. The minimum inhibitory concentrations (MICs) were
recorded by visual observations after 24 hr (for bacteria)
and 72-96 hr (for fungi) of incubation; streptomycin50
(antibacterial) and Amphotericin B25 (antifungal) were
used as standards.
Results and Discussion
Conformational Analysis of 1-6
The observation of one large (~11.98 Hz) and one small
coupling (3.03 Hz) about C(5)C(6) bond in 3,3-
dimethylpiperidin-4-ones (1,2) and their isomeric alcohols
namely 3,3-dimethyl axial alcohol(3, 5)and 3,3-dimethyl
equatorial alcohol (4, 6)reveal that these compounds
exist in normal chair conformation with equatorial
orientation of substituted phenyl rings at C(2) and C(6)
carbons and one of the methyl group at (C3) carbon is in
equatorial and another methyl group at (C3) carbon is in
axial (Fig. 1). The J6a,5e value observed for 3,3-dimethyl
equatorial alcohol 4 (2.76 Hz) is higher than that of 3,3-
dimethyl axial alcohol 3 (2.18 Hz). This suggest that the
piperidine ring is highly flattened about C(5)C(6) bond
in 3,3-dimethyl axial alcohol 3 relative to equatorial
alcohol 4. Whereas the J6a,5e value observed for 3,3-
dimethyl axial alcohol 5 (3.03 Hz) is higher than that of 3,3-
dimethyl equatorial alcohol 3 (2.55 Hz). This suggest that
the piperidine ring is highly flattened about C(5)-C(6) bond
in 3,3-dimethyl equatorial alcohol 3 relative to 3,3-dimethyl
axial alcohol 6.

Figure 1. Chair conformations of 1-6
In order to find out quantitatively the magnitude of
flattening, torsional angle calculations have been made by
DAERM method [16] and the calculated torsional angles
are displayed in Table 1. The observed torsional angle also
supports the flattened nature of C(5)C(6) bond in 3,3-
dimethyl axial alcohol 3 relative to 3,3-dimethyl equatorial
alcohol 4 and flattened nature of C(5)C(6) bond in 3,3-
dimethyl equatorial alcohol 6 relative to 3,3-dimethyl axial
alcohol 5.The torsional angle between vicinal protons
about C(5)C(6) bond were determined using Haasnoot
equation 4 for trisubstituted ethane system.

HH
= 13.22 cos
2
0.99 cos +
+

[0.87 2.46 cos

2
(19.91|

)] (4)

Table 1.Calculation of Coupling constant (Hz), Karplus constant and torsional angle
of1-6
Compound Karplus constant Torsional angle ()
*

J6a,5a J6a,5e k1 k2 |6a,5a |6a,5e
1 12.00 2.97 11.07 12.30 177.1 57.1 (43.7)
3 11.90 2.18 10.98 12.20 181.63 61.68 (46.8)
4 11.40 2.76 10.53 11.70 177.4 57.4 (44.1)
5 11.98 3.03 11.05 12.28 176.7 56.7(45.57)
6 11.04 2.55 10.20 11.34 168.61 58.1(47.87)
*
Torsional angle values in the parentheses are calculated by Haasnoot method

Analysis of Chemical Shifts
1
H spectral analysis.The high resolution
1
H NMR spectra
were recorded for 1-6and the signals were assigned based
on their positions, multiplicities and integrals. In all these
compounds the aromatic protons absorb around 7.1-7.4
ppm. From the
1
H chemical shift values of the 3,3-dimethyl-
4-hydroxy piperidines (3, 4) it was observed that the
protons at C(2) and C(6) of axial alcohols 3 and 5 (+0.18-
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0.26ppm H(2); +0.15 ppm H(6) (3)) are deshielded when
compared to equatorial alcohols 4 and 6 [(+0.58 ppm)
H(2), (+0.40 ppm) H(6)]. The H(2) and H(6) protons of the
axial alcohols 3 and 5 deshielded by the axial hydroxy
group at C(4) carbon due to syn-1,3-diaxial interaction. In
3,3-dimethyl axial alcohols 3 and 5, the hydroxy group
causes polarization of the CH bond so that the hydrogen
gets positive charge and the carbon gets negative charge.
Thus, hydrogen is deshielded and the carbon is shielded.
Comparison of chemical shift of methylene protons (H5e
and H5a) of 3,3-dimethyl axial alcohols 3 and 5 with those
in equatorial alcohols 4 and 6 reveal that axial hydroxy
group deshields the H5a proton chemical shift but shields
the chemical shift of H5e. The deshielding chemical shift of
H5a may be due to the magnetic anisotropic effect of the
hydroxy substituent at C(4). The C(4) proton resonate at
downfield (3.58 ppm) in axial alcohol 3 than the
corresponding equatorial (3.30 ppm) alcohol 4. This is in
accordance with that of the expectation because C(4)
proton is axial in equatorial alcohol 4 and equatorial in axial
alcohol 3 and this may be due to the magnetic anisotropic
effect of the hydroxy substituent.
13
C NMR spectral analysis. The high resolution
13
C NMR
spectra were recorded for 1-6and the signals were
assigned based on their positions, multiplicities and
integrals. The aromatic carbons could be readily
distinguished by their characteristic absorption around 120
ppm. The ipso carbons should absorb at downfield around
140 ppm compared to the other aromatic carbons.
Assignments for the heterocyclic ring carbons and alkyl
carbons have been made on the basis of known effect of
alkyl substituents in six membered ring compounds. The
upfield signal in 1-6 assigned to axial and equatorial methyl
carbons at C(3). Assignment for heterocyclic ring carbons in
16 have been made on the basis of known effect of the
substituents in six-membered ring and the relative signal
intensities.
In the 3,3-dimethylpiperidone 1, the signals for the
heterocyclic ring carbons and methyl carbons appeared at
68.72, 49.66, 211.86, 47.04, 60.84, 20.29 and 19.82
ppm. The upfield signals at 20.29 and 19.82 ppm are due
to equatorial and axial methyl groups at C(3). Among the
two signals at 68.72 and 60.84 ppm, the downfield signal
at 68.72 ppm is assigned to C(2) based on the known
deshielding |-effect of the methyl groups. Obviously, the
other signal at 60.84 ppm is assigned to C(6) carbon. The
signal at 49.66 ppm is assigned to C(3) based on the
known o-effect of two methyl groups at C3. Obviously the
remaining signal at 47.04 ppm is due to C(5). The most
downfield signal at 211.86 ppm is due to the carbonyl
carbon at C4. In a similar manner the
13
C chemical
shift for 2is assigned.
In t(3,3)-dimethyl-c(4)-hydroxy-r(2),c(6)-di-p-chlorophenyl-
piperidine(4),signals for heterocyclic ring carbons appeared
at 68.80, 39.71, 76.70, 37.89, 59.79, 23.89 and 12.76
ppm. The C(4) signal in the equatorial alcohol appeared at
downfield relative to axial alcohol, since the effect of
o-substituent parameter for the equatorial hydroxy group is
greater than axial hydroxy group [17]. Therefore the most
downfield signal at 76.70 ppm is assigned to C(4) carbon.
Among the two signals 68.80 and 59.79 ppm, the signal at
68.80 ppm is assigned to C(2) based on the
|-effect of the two methyl groups at C(3) carbon and
obviously the other signal at 59.79 ppm is assigned to C(6)
carbon. The downfield signal at 39.71 ppm is assigned to
C(3) based on the o-effect of the two methyl groups at C(3)
and the other signal at 37.89 ppm is assigned to the
methylene carbon C(5). The upfield signals at 24.43 and
19.50 ppm are due to equatorial and axial methyl groups at
C(3) carbon. In a similar manner the assignments were
made for 3,3-dimethyl axial alcohols (3, 5) and 3,3-dimethyl
equatorial alcohol 6.
Optimized Geometry.Conformation of HydroxyGroup in 3,3-
dimethyl-4-hydroxy piperidines 3 6.
Generally there are three possible rotamers (A,B and C) for
axial and equatorial hydroxy group in 3-6, in rotamer (A) the
hydroxy group is gauche to C(3) where as in rotamer (B) the
hydroxy group is gauche to C(5). These two rotamers are
equivalent in symmetrical compounds. In rotamer (C) the
hydroxy group is inside the ring exclusively. In order to find
out the more stable conformer, theoretical calculations
were carried out and the results are displayed in Table 2.

Table 2 Relative heat of formation (kJ/mol) for orientation of hydroxyl group in 3-6 by
DFT method
Compound Rotamers Relative heat of
formation (kJ/mol)
3,3-Dimethyl axial alcohol 3 A 2.98
B 0.00
C 11.08
3,3-Dimethyl equatorial alcohol 4 A 1.90
B 0.00
C 8.80
3,3-Dimethyl axial alcohol 5 A 1.31
B 0.00
C 14.70
3,3-Dimethyl equatorial alcohol 6 A 1.79
B 0.00
C 3.93

The optimized structures reveal that these molecules 1-6
exist in normal chair conformation with equatorial
orientation of substituents at C(2), C(6) carbons and one
methyl group at C(3) carbon (one methyl group at C(3) is
axial) and the orientation of OH group in axial and
equatorial secondary alcohols 3-6 is towards sterically less
hindered side i. e., gauche to C(5) [rotamer (B)]. The
minimized energy molecular modeling structures of
secondary alcohols 3, 4 and 5, 6 by DFT calculation are
shown in Figs. 2 and 3, respectively. These observations
are in good agreement with the same observed from
coupling constant and chemical shift analysis and
optimized geometric parameters (bond length, bond angles
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and torsional angles are in good agreement with X-ray data
[18,19] ) of 1-6 are displayed in Table S1.

Figure 2. Energy-minimized molecular modeling structures of 3 and 4


Figure 3.Energy-minimized molecular modeling structures of 5 and 6
The Newman-projection of axial and equatorial alcohols 3
and 4 about C3-C4 bond is shown in Figs. 4a and 4b,
respectively. In axial alcohol 3, there are two severe gauche
interactions exist between OH [(C4)] and C2(H)(NH)(C6H5Cl)
and -OH [(C4)] and -CH3 (C3) and in equatorial alcohol also,
two severe gauche interactions exist between -OH [(C4)]
with axial and equatorial methyl groups at (C3) separately.
In order to reduce these interactions, these bonds may be
elongated from other C-C bonds and the bond lengths
calculated from the optimized structures are (C2)-(C3) 1.57
; (C3)-(C4) 1.58 (2); (C3)-(C4) 1.58 (3).


Figure 4. Gauche interactions of 3 (4a) and 4 (4b)

Potential Energy Surface (PES) Scan Studies for
Conformation of Hydroxy Group in 3 and 4
The potential energy surface studies have been carried out
to show the orientation of -OH group (3 and 4) in sterically
free side i.e., gauche to (C5). The potential energy surface
scan of 3,3-dimethyl axial alcohol 3 about C5-C33-O42-
H43 is performed for OH bond using B3LYP/6-31G(d,p)
level. During the calculation all the geometrical parameters
were simultaneously relaxed while the C5-C33-O42-H43
torsional angles are varied in steps of 0, 10, 20,
30

360. The potential energy surface diagram clearly

reveals that the minimum energy conformation
corresponds to rotomer B for both 3 and 4 i. e., OH group
is gauche to C5 which formed by the rotation of 170(3)
(Fig. S1) and 190(4) (Fig. S2). Similar observations were
found for secondary alcohols 5 and 6.
Second Harmonic Generation (SHG) Studies of 1-6
Second harmonic signal of 2 mV, 2.5 mV, 1.6mV, 1.7mV,
5.7 mV and 9.0 mV were obtained for 1-6 by an input
energy of 4.1mJ/pulse. But the standard KDP crystal gave
a SHG signal of 110mV/pulse for the same input energy.
The second order nonlinear efficiency will vary with the
particle size of the powder ample [20]. Higher efficiencies
are expected to be achieved by optimizing the phase
matching [21]. On a molecular scale, the extent of charge
transfer (CT) across the NLO chromophore determines the
level of SHG output, the greater the CT, the larger the SHG
output.
Hyperpolarizability of 1-6 by DFT Calculation
In addition to well known empirical rules to estimate
qualitatively the microscopic nonlinear response in 1-6,
DFT calculation is a more accurate prediction of the NLO
activity [22, 23]. From Tables S2S4, it was suggested that
these compounds 1-6 are polar having non-zero dipole
moment, hyperpolarizabilities and hence have well
microscopic NLO behaviour [24, 25].
Natural Bond Orbital (NBO) Analysis
The NBO analysis was performed by DFT/B3LYP/6-31G(d,p)
level to identify and confirm the possible intra- and
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intermolecular interactions between the units that would
form the hydrogen bonding, hyperconjugate interaction and
electron transfer in the investigated molecule. The
importance of hyperconjugative interaction and electron
density transfer (EDT) from lone pair electrons of the Y-
atom to the X-H antibonding orbital in the X-H

Y system
have been analyzed for 1-6 and the results of 3,3-dimethyl
piperidone 1 and its isomeric alcohols 3 and 4 are
presented in the Tables S4 and S5.
The second order Fock matrix was carried out to evaluate
the donor-acceptor interactions in the NBO analysis [26,
27].For each donor(i)and acceptor (j), the stabilization
energy E(2) associated with the delocalization i j is
estimated as
(2) =

2
(,)

(5)
Where qi is the donor orbital occupancy, i and j are
diagonal elements and F(i,j) is the off diagonal NBO Fock
matrix element. The larger the E(2)value, the more
intensive is the interaction between electron donors and
electron acceptors.
The important contribution to the delocalization
corresponding to donor-acceptor interactions in all the
three compounds are C20C21 C19C20, LpN5
C4H26, LpN5 C6H28, LpCl15 C10C11 and
C10C11 C9C12, C10C11 C13C14, C19C20
C16C17, and C19C20 C18C21. NBO analysis
clearly manifests the evidence of the intramolecular charge
transfer from LpO23 to antibonding orbital of C5-C6 shows
that the hydroxy group is inclined towards the sterically less
hindered side, i. e. C5 side (3 and 4).
A molecular charge distribution and bond states are
changed, due to the substitution of hydrogen by the 15Cl
and 22Cl. As electronegativity of chlorine is significantly
higher than that of hydrogen, the electronic cloud is shifted
to the substituent side (negative inductive effect), on the
other hand the opposite displacement of electrons along
axis of t-cloud takes place due to participation of chlorine
lone pair of electrons in the conjugation (positive mesmeric
effect) [28]. The negative inductive effect is stronger than
that of positive mesomeric effect and this result in
displacement of electron density from the rest part of the
molecules to the chloride atom. Quantum mechanical
calculations revealed a partial negative charge on Cl
atoms, around 0.06 on 15Cl and 0.04 on 22Cl. The
conversion of O
C H3
C H3
group (1) into CHOH (3 and 4),
increases the electronegativity on oxygen in the alcohols
from 0.64 (1) to 0.80 (3 and 4) and lowered the
electronegativity of corresponding carbon C(2) from
0.69 to 0.08. The charge distribution shows that the
more negative charge is concentrated on chlorine and
oxygen whereas the partial positive charge resides at
hydrogens. These results suggest that the carbon atom
bear oxygen atoms are electron acceptor and also indicates
that the charge transfer from hydrogen to oxygen (3 and 4).
Table S3 shows the charge distributions are calculated by
the NBO and Mulliken methods. These two methods predict
the same tendencies, i.e. the hydrogen atoms bonded to
N5 and O23 are acidic and that hydrogen is easily
extracted. The concept of the global electrophilicity is a
good indicator of the chemical reactivity. When a molecule
is involved in an electrophilic substitution reaction it is
possible to use the global electrophilicity descriptor to
characterize the nucleophilic trend, low value indicates
high nucleophilicity.
The percentage of p-character [29] in each NBO natural
atomic hybrid orbital is presented in Table S5. The
C13C14 bond of equatorial alcohol 4 the carbon hybrids
p character reduced to around 64% however in the case
of the compounds 1 and 3 the carbon hybrids has almost
100% p character. Similarly, in C16C19 bond the
percentage of p character of the carbon hybrids reduced
to 65% for compounds 1 and 4 and 100% for axial alcohol
3. Around 65% of p character was observed for C2C3
and C18C21 bond whereas 100% p character was
observed for 3,3-dimethylpiperidone 1 and similar
observations are observed for 2, 5 and 6.
HOMO-LUMO Energies of 1-6 by DFT Method
Molecular orbital and their properties, like energy are very
useful for physicists and chemists and their frontier
electron density used for predicting the most reactive
position in -electron systems and also explained several
types of reaction in conjugated system [30]. Moreover,
eigen values of LUMO and HOMO and their energy gap
reflect the chemical activity of the molecule. Recently the
energy gap between highest occupied molecular orbital
(HOMO) and the lowest unoccupied molecular orbital
(LUMO) have been used to prove the bioactivity from
intramolecular charge transfer (ICT) [31, 32]. The HOMO-
LUMO energy gap for 1-6 were calculated by B3LYP/6-
31G(d,p) and the HOMO-LUMO orbital picture of 1-6
given in Fig. 5. The filled orbital (HOMO) is mostly
located on the phenyl ring, OH and NH moieties and the
unfilled orbital (LUMO) on the piperidine ring. The HOMO-
LUMO transition (Table 3) implies an electron density
transfer to piperidine ring from phenyl ring. Therefore,
introduction of an electron-donating substituent into the
piperidine ring raises the energy of the LUMO whereas the
introduction of an electron donating substituent into the
phenyl ring raises the energy of the HOMO.
Intramolecular Hydrogen Bonding (C-H

O) in 1-6
Generally a hydrogen bond is formed when the hydrogen
atom of a covalent bond of a proton donor molecule
interacts with a lone pair electron of an atom of a proton
acceptor. Recently, it has been established that a C-H group
can be a hydrogen bond donor and although the C-H

O
interactions are considered weak, they form 20-25% of the
total number of hydrogen bonds constituting the second
most important group [33]. These interactions have been
shown to be of greater importance in biological
STRUCTURAL CHEMISTRY COMMUNICATIONS, 2010, Vol. 1, No. 1, pp. 15-24 21

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Figure 5.HOMO-LUMO orbitals of 1-6.
systems in order to elucidate the structure-activity
relationship [34]. The C-H

O interaction have been

identified from DFT calculation, in which the C-H donor
group is strengthened, shortened and blue shifted in the
stretching vibrational wave number [35]. The
intramolecular H

O distances of H16-O23 and H31-O23 is

found to be 2.25and 2.252 respectively. The
intramolecular C-H

O distance of C3-H24

O23 is found to
be 2.53 (1), C3-H24

O23 is found to be 2.61 (4), and C3-

H24

O23, C3-H25

O23 is found to be 2.58 and 2.07

(3) respectively. These distances are significantly shorter
than that of the van der Waals separation between the O
atom and the H-atom (2.72 ) [36] indicating the existence
of the C-H

O interaction in 1-6. The calculated C-H

O angle
nearly equal to 103.6 is within the angle limit, as the
interaction path is not necessarily be linear as several C-
H

O hydrogen bonding have a bend structure.

Table 3. HOMO-LUMO energies (eV) of 1-6
Compound HOMO LUMO Energy gap (E)
1 -9.26 -2.83 6.43
2 -8.52 -1.76 6.76
3 -9.09 -2.94 6.15
4 -6.48 -0.52 5.96
5 -7.89 -1.82 6.07
6 -6.02 -0.48 5.54
Vibrational Assignments
OH and NH vibrations. In the case of alcohols a very
sharp line like band appears in the neighbourhood of 3600
cm

1
in very dilute solution prepared using non-polar
solvents if intramolecular hydrogen bonding is absent [37].
In bonded form, a broad and intense band appears in the
region 32003550 cm

1
. In the present work the medium
intensity broadband centered at 3427 and 3442 cm

1
is
assigned to OH and NH stretching modes for 3 and 4,
3376 and 3425 is assigned to OH and NH stretching
modes for 5 and 6 respectively. However, the theoretical
calculation by B3LYP method for NH vibration for these
compounds deviates enormously even after scaling
around 100 cm

1
. But, theoretical OH vibrations are in
good agreement with experimental vibrations (Table S6).
CH vibrations. Presence of stretching vibrations in the
region 31003000 cm

1
is the characteristic region for
ready identification of CH stretching vibrations [38]. In
this region the bands are slightly affected by the nature of
the substituents. The scaled vibrations are around 3000
cm

1
for 1 and 2, around 3176 cm

1
for 3 and 5 around
2900 cm

1
for 4and 6. The experimental observations are
around 2970 (1), 2974 (2), 2964 (3 and 5), 2923 and
2853 cm

1
(4), 2924 and 2860 cm

1
(6). From Table S6 it
22 STRUCTURAL CHEMISTRY COMMUNICATIONS, 2010, Vol. 1, No. 1, pp. 15-24

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is concluded that CH vibrations calculated theoretically
are in good agreement with experimental vibrations.
CN vibrations.The identification of the CN vibration is a
very difficult task since mixing of several bands is possible
in this region. Silverstein et al. [39] assigned the CN
stretching absorption in the region 13821266 cm

1
for
aromatic amines. The CN stretching mode is reported at
1368 cm

1
for benzamide [40], at 1382 and 1307 cm

1
for
benzotriazole [41], at 1335, 1331 cm

1
for 2,4-
dinitrophenylhydrazine [42] and at 1316, 1213 cm

1
for
morpholine-4-ylmethylthiourea [43]. In the present study, a
weak band is observed in the spectra around 1080 (1-3, 5)
around 1000 cm

1
(4 and 6) and these frequencies are in
good agreement with theoretically computed values of
1076 (1 and 3), 1074 (2 and 5), 1014 (4) and 1017cm

1

(6), respectively.
C=C vibrations. The benzene ring possesses six stretching
vibrations, of which the four with the highest wave numbers
occurring near 1600, 1580, 1490 and 1440 cm

1
are good
group vibrations [44]. With heavy substituents, the bands
tend to shift to somewhat lower wave numbers and
greater the number of substituents on the ring, broader
the absorption regions. In the present paper, the strong
band recorded around 1440 cm

1
(1-6) is assigned to
C=C stretching mode. The calculated wave number for
this fundamental mode is around 1400 cm

1
by B3LYP
method.
Methyl group vibrations.For the assignments of CH3 group
frequencies one can expect nine fundamentals to be
associated with each CH3 group, viz., the symmetrical
stretching in CH3 (CH3 sym. stretching), asymmetrical
stretching (i. e. in-plane hydrogen stretching mode), the
symmetrical (CH3 sym. deformation) and asymmetrical (CH3
asy. deformation) deformation modes, the in-plane
rocking (CH3ipr) and twisting t(CH3) modes. In addition to
that CH3 ops, out-of-plane stretch and CH3 opb, out-of-plane
bending modes of the CH3 group would be expected to be
depolarized for asymmetry species.
The C-H stretching in methyl group occurs at lower
frequencies than use of the aromatic ring (3100
3000 cm

1
). The asymmetric and symmetric stretching are
observed around 2900 cm

1
are attributed to CH3
asymmetric stretching modes, theoretically scaled values
by B3LYP method around 3000 cm

1
assigned to
asymmetric stretching vibration. The scale down values
2900 cm

1
by B3LYP method for methyl symmetric
stretching vibration shows good agreement with the
recorded FT-IR spectra. Very strong band around 1440
cm

1
have assigned to CH3 asymmetric and symmetric
deformations which are in satisfactory agreement with the
theoretical values. Goodgraphic correlation (Figs. 6a and
6b) exists between experimental and calculated wave
numbers obtained by DFT/B3LYP/6-31G (d, p) method for
the isomeric alcohols 3-6.
C-Cl vibrations. Vibrations belonging to the bond between
the ring and the halogen atoms are worth to discuss here,
since mixing of vibrations are possible due to the lowering
the molecular symmetry and the presence of heavy atoms
on the periphery of molecules [45]. The assignments of C-
Cl stretching and deformation vibrations have been made
by comparision with similar molecules, p-bromophenol [46]
and the halogen-substituted benzene derivatives [47].
Moorey [48, 49] assigned vibrations of C-X group (X = Cl,
Br, I) in the frequency range of 1129-480 cm
-1
. Compounds
with more than one chlorine atom exhibit very strong bands
due to asymmetric and symmetric stretching mode. In FT-
Raman spectrum of 2,4-dichloro-6-nitrobenzene the very
strong band at 777 cm
-1
is assigned to C-Cl stretching
vibration. The theoretical wave number of C-Cl stretching
vibration coupled with C-C-C in-plane bending vibration
mode, 765 cm
-1
coincides very well with the experimental
value. The in-plane bending and out-of-plane bending
vibrations are assigned to the Raman bands at 345 and
170 cm
-1
, respectively. This is in agreement with the
literature data [45-48]. In the present study, a strong band
is observed around 720 cm
-1
which is in good agreement
with theoretically computed wave numbers.
Photophysical Studies of 1-6
The absorption and emission spectra were recorded (Fig.
7) for 1-6 in methanol medium, the isomeric alcohols 3-6
are largely blue shifted when compared with its parent
ketones 1 and 2 in both absorption and emission. This may
be strong evidence for the presence of intramolecular weak
hydrogen bond in isomeric alcohols 3-6. Time-dependent
(TD) DFT/B3LYP was also used to calculate the low lying
excited states of 1-6. According to Franck-Condon principle,
the maximum absorption peak corresponds in an UV-Visible
spectrum to vertical excitation. The calculated max values
are in good agreement with the experimental max values
are shown in Table 4.

Table 4.Absorption (abs), emission (flu) and Stokes shift of 1-6
Compound abs(nm)(cal) abs
(nm)(exp)
flu
(nm)(exp)
Stokes shift
(cm
-1
)
1 329.78 298.50 412.5 9258
260.85 265.86
250.88 258.70
2 360.0 358.0 460.8 6231
312.5 306.8
290.6 282.0
3 239.33 276.68 341.5 8042
236.34 267.92
234.03 258.23
4 237.50 275.64 342.5 8287
235.53 266.78 308.05(sh)
233.19 259.21
5 287.2 280.5 378.2 9209
280.6 273.1
6 282.5 280.0 370.6 8731
278.0 275.2
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Figure 6.Graphical correlation between experimental and theoretical absorption frequencies of 3 (a) and 4(b)


Figure 7. Absorption and emission spectra of 1 and 3.

Structural Activity
Antibacterial activity. The synthesized compounds 1-6were
tested for antibacterial activity invitro against Steptococcus
Aureus, Escherichia Coli, Pseudomonan Aeruginosa and
Klebsielra Pneumoniae using Streptomycin as the standard
drug (Table 5). The antibacterial screening reveal that all
the synthesized 3,3-dimethylpiperidone (1,2) and their
isomeric alcohols (3-6) exhibited a wide spectrua of
antibacterial profile in vitro against the tested organisms.
Chloro substituted 3,3-dimethyl- piperidone (1) and their
derivatives (3, 4) shows good antibacterial activity against
all the tested strains (6.25-100 g/ml) but 3,3-dimethyl-
piperidone (2) and their derivatives (5, 6) shows moderate
antibacterial activity against all the tested strains.
Table 5. In vitro antibacterial activity of compounds 1-6
Compound Minimum inhibitory concentration (MIC) in g/ml
S. aureus E. coli P. aeruginosa K. pneumoniae
1 12.5 6.25 6.25 12.5
2 6.25 12.5 6.25 6.25
3 50 25 25 100
4 25 12.5 25 50
5 50 12.5 25 50
6 25 12.5 12.5 25
Streptomycin 50 25 12.5 12.5 12.5

Antifungal activity. The in vitro antifungal activity of
compounds (1-6) were examined against the fungal strains
viz., AspergillusNiger, AspergillusFlavus, Rhizopus, Candida
6 using Amphotericin B as the standard drug (Table 6).The
antifungal spectra of 3,3-dimethylpiperidone (1) and their
24 STRUCTURAL CHEMISTRY COMMUNICATIONS, 2010, Vol. 1, No. 1, pp. 15-24

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isomeric alcohols 3-6falls in the region of 6.25-100 g/ml.
From Table 6, it was exploited that chloro substituted
heterocyclic compounds (1, 3, 4) shows good antifungal
activity when compared to 3,3-dimethyl piperidone (2) and
their derivatives (5, 6).
Table 6.In vitro antifungal activity of compounds 1-6
Compound Minimum inhibitory concentration (MIC) in g/ml
Rhizopus Candida-6 A. Niger A. Flavus
1 12.5 6.25 25 12.5
2 6.25 12.5 12.5 6.25
3 50 50 100 100
4 25 25 50 50
5 25 50 50 50
6 12.5 25 25 12.5
Amphotericin 25 50 25 50 50

The more sterically crowded Chloro substituted axial
alcohol (3) exhibits higher antimicrobial activities against
all the tested strains than other compounds [50-53].
Conclusion
The results of the present investigation show that all the
heterocyclic molecules adopt chair conformation with
equatorial orientation of substituents. In isomeric alcohols,
OH group is oriented towards the sterically free side i. e.
gauche to C(5). NBO analysis indicates the presence of
donor-acceptor centers in the investigated molecules.
Observation of blue shifts in absorption and emission
spectral studies of isomeric alcohols support the presence of
C-H

O intramolecular hydrogen bond. The experimental and

theoretical first hyperpolarizability values show that all these
synthesized compounds might have microscopic NLO
behaviour. The HOMO-LUMO interactions were determined.
All the results derived from experimental are in good
agreement with DFT calculation.
Acknowledgments
One of the author Dr. J. Jayabharathi, Reader in Chemistry,
Annamalai University is thankful to University Grants
Commission (F. No. 30-71/2004(SR) for providing fund to
this research work.
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