Synthesis, characterization, computational calculation and biological studies of some 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oxime derivatives

Article abstract of DOI:10.1016/j.saa.2014.12.014

A new series of 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes (17-24) were designed and synthesized from 2,6-diarylpiperidin-4-one oximes (9-16) with propargyl bromide. Unambiguous structural elucidation has been carried out by investigating IR, NMR (¹H, ¹³C, ¹H-¹H COSY and HSQC), mass spectral techniques and theoretical (DFT) calculations. Further, crystal structure of compound 17 was evaluated by single crystal X-ray diffraction analysis. Single crystal X-ray structural analysis of compound 17 evidenced that the configuration about CN double bond is syn to C-5 carbon (E-form). The existence of chair conformation was further confirmed by theoretical DFT calculation. All the synthesized compounds were screened for in vitro antimicrobial activity against a panel of selected bacterial and fungal strains using Ciprofloxacin and Ketoconazole as standards. The minimum inhibition concentration (MIC) results revealed that most of the 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes (17, 19, 20 and 23) exhibited better activity against the selected bacterial and fungal strains.

Full text of DOI:10.1016/j.saa.2014.12.014

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
Synthesis, characterization, computational calculation and biological
studies of some 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oxime
derivatives
G. Sundararajan a, D. Rajaraman a, T. Srinivasan b, D. Velmurugan b, K. Krishnasamy a,
⇑
a Department of Chemistry, Annamalai University, Annamalainagar 608002, Tamil Nadu, India
b CAS in Crystallography and Biophysics, University of Madras, Chennai 600025, Tamil Nadu, India
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
ꢀ
Series of 2,6-diaryl-1-(prop-2-yn-1-
yl)piperidin-4-one oxime derivatives
were synthesized and characterized.
2,6-Diaryl-1-(prop-2-yn-1-
ꢀ
yl)piperidin-4-one oxime compounds
were confirmed by IR, NMR and Mass
spectroscopy.
ꢀ
ꢀ
Compound 17 structure is elucidated
by single crystal XRD analysis.
Better antimicrobial activities are
observed.
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes (17–24) were designed and synthe-
sized from 2,6-diarylpiperidin-4-one oximes (9–16) with propargyl bromide. Unambiguous structural
Received 29 September 2014
Received in revised form 29 November 2014
Accepted 10 December 2014
Available online 19 December 2014
1
elucidation has been carried out by investigating IR, NMR (1H, 13C, 1Hꢁ H COSY and HSQC), mass spectral
techniques and theoretical (DFT) calculations. Further, crystal structure of compound 17 was evaluated
by single crystal X-ray diffraction analysis. Single crystal X-ray structural analysis of compound 17 evi-
denced that the configuration about C@N double bond is syn to C-5 carbon (E-form). The existence of
chair conformation was further confirmed by theoretical DFT calculation. All the synthesized compounds
were screened for in vitro antimicrobial activity against a panel of selected bacterial and fungal strains
using Ciprofloxacin and Ketoconazole as standards. The minimum inhibition concentration (MIC) results
revealed that most of the 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes (17, 19, 20 and 23) exhib-
ited better activity against the selected bacterial and fungal strains.
Keywords:
1D-NMR
2D-NMR spectroscopy
Single crystal-XRD
DFT calculations
Antimicrobial activities
Ó 2014 Elsevier B.V. All rights reserved.
Introduction
prop-2-nylamines are used as drugs, pesticides [5], anticancer [6]
and antibacterial agents [7]. Activation of a terminal alkyne CAH
Heterocyclic acetylenic amines are very important class of com-
pounds due to their pharmacological properties such as activity,
low toxicity and more easily absorbed into the body than
their olefinic and saturated analogues [1–4]. Moreover various
bond by transition metal catalysts is a reaction of fundamental
interest in organic synthesis [8,9]. It has also been claimed that
the acetylenic bond is not considered essential for activity but
favours entry in the central nervous system (CNS) by reducing
the base strength [10]. Some of the N-substituted piperidone deriv-
atives have demonstrated fascinating potential applications
⇑
Corresponding author.
E-mail address: krishnasamybala56@gmail.com (K. Krishnasamy).
including anti-HIV, cytotoxins, 5a-reductase inhibitors, CARM1
http://dx.doi.org/10.1016/j.saa.2014.12.014
1386-1425/Ó 2014 Elsevier B.V. All rights reserved.

G. Sundararajan et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
109
inhibitors, anti-proliferative, antioxidant and antimicrobial activi-
ties [11–16]. In addition piperidone oximes were also reported to
exhibit nerve-agent anti-dote [17] analgesic, local anaesthetic
and antifungal activities [18]. Recently the synthesis of 2,6-diary-
lpiperidin-4-one oxime derivatives and their biological importance
are discussed elaborately [19–26]. Aiming at extending our knowl-
edge in structure–activity relationship, we considered that it is
valuable to synthesis a system that unites biolabile functional
groups like prop-2-yn-1-yl with piperidin-4-one oximes. In this
work the biologically active 3-alkyl-2,6-diaryl-1-(prop-2-yn-1-
yl)piperidin-4-one oximes (17–24) were synthesized and charac-
terized by IR, NMR (1H, 13C, 1H–1H COSY and HSQC) Mass spectra
and DFT analysis. Further crystal structure of compound 17 was
evaluated by single crystal X-ray diffraction technique. The X-ray
diffraction analysis is used to predict the location of N-Alkylated
propargyl group. The reaction sequence involves successive
N-alkylation of the corresponding hydantoin, followed by second-
ary amine. The synthetic procedure was optimized for all steps
and could easily be carried out on a multigram scale. All the synthe-
sized compounds were screened for in vitro antimicrobial activities.
ac.uk/conts/retrieving.html, or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: (+44) 1223 336 033: or e-mail: deposit@ccdc.cam.ac.uk.
General procedure for synthesis of compounds
Synthesis of 3-alkyl-2,6-diarylpiperidin-4-ones (1–8)
The all parent 2,6-diarylpiperidin-4-ones were synthesized by
adopting the literature procedure of Noller and Baliah [29] with
the condensation of respective ketones, aldehydes and ammonium
acetate in warm ethanol in 1:2:1 ratio.
Synthesis of 3-alkyl-2,6-diarylpiperidin-4-one oximes (9–16)
To the stirred solution of 3-methyl-2,6-diphenylpiperidin-4-
one (1 mmol) in ethanol, sodium acetate (1.5 mmol) and hydroxyl-
amine hydrochloride (1.5 mmol) were added. The reaction mixture
was refluxed for 2 h and monitored by thin layer chromatography.
After completion of reaction, the reaction mixture was slowly
poured into ice-cold water and after cooling to room temperature,
the crude product was obtained. Then it was subjected to recrystal-
lization from ethanol to get pure oxime 9 with excellent yield. The
same procedure was followed for the other piperidones to get their
corresponding oximes (10–16).
Experimental
General characterization techniques
Synthesis of 3-alkyl-2,6-diaryl-1-(prop-2-yn-1-yl piperidin-4-one
oximes (17–24)
TLC was carried out to monitor the course of the reaction and
the purity of the product. Melting points were recorded in open
capillaries and were uncorrected. IR spectra were recorded on
AVATAR 330 FT-IR spectrometer KBr pellets. 1H NMR spectra were
recorded at 400 MHz on BRUKER AMX spectrophotometer using
CDCl3 and TMS as internal standard. 13C NMR spectra were
recorded at 100 MHz on BRUKER AMX 400 MHz spectrometer
using CDCl3 and the 1H–1H COSY, 1H–13C COSY correlation spectra
were recorded on BRUKER AMX 400 MHz NMR spectrometer using
standard parameters. Mass spectra were recorded with JEOL
GCMATE II instrument. All the chromatographic purifications were
performed with silica gel (100–200 mesh) whereas all TLC (silica
gel) was performed on silica gel coated (Merk Kiesel 60 GF-254,
0.2 mm thickness) sheets. All reagents and solvents are commer-
cially obtained (Alfa AeSar, Himedia) and used directly without
any further purification.
To a stirred solution of 3-alkyl-2,6-diphenylpiperidin-4-one
oxime (1 mmol) in dry DMF (10 mL) and potassium carbonate
(1.4 mmol) was added. After stirring for 10 min, propargyl bromide
(1.4 mmol) was added drop wise to the reaction mixture in a per-
iod of 15 min. It was stirred at (40 °C) for 2 h and the progress of
the reaction was monitored by thin layer chromatography. After
completion of the reaction, the mixture was diluted with water
(20 mL) and extracted with ethyl acetate (2 ꢂ 20 mL). The com-
bined organic layer was washed with water (2 ꢂ 20 mL), dried over
anhydrous sodium sulphate (5 g), filtered and concentrated under
reduced pressure to get the crude product. It was further recrystal-
lized with chloroform. The physical data of compounds (17–24) is
shown in Table 1.
(E)-3-methyl-2,6-diphenyl-1-(prop-2-yn-1-yl)piperidin-4-one oxime
(17). Yield: 88%, White Solid: IR (KBr, cmꢁ1)
; mmas 3286 (OH),
3147 (C„CH), 1601 (C@N); 1H NMR (400 MHz, CDCl3); d (ppm)
0.82 (d, J = 6.0 Hz, 3H, CH3); 2.70 (m, 1H, H-3a); 3.59 (d,
J = 13.6 Hz, 1H, H-5e); 3.46 (d, J = 10.4 Hz, 1H, H-2a); 3.79 (d,
J = 11.6 Hz, 1H, H-6a); 2.94, 2.83 (AB quartet, J = 17.6, 18.0 Hz,
2H, H-7a, H7b); 2.22 (d, 2H, H-5a); 2.16 (s, 1H, H-9, acetylene pro-
ton); 7.29–7.48, (m, 10H, aromatic protons); 9.04 (s, 1H, oxime
OH); 13C NMR (100 MHz, CDCl3); d (ppm) 12.7 (CH3); 71.8 (C-2);
43.0 (C-3); 159.5 (C-4); 33.8 (C-5); 63.8 (C-6); 40.0 (C-7); 77.6
(C-8); 73.9 (C-9); 141.8, 142.8 (Aromatic ipso carbon).
X-ray crystallography
Crystal was grown by slow evaporation technique using chloro-
form as solvent. X-ray diffraction intensity data was collected on
Bruker AXS SMART APEXII single crystal X-ray diffractometer
equipped with graphite monochromated MoKa (k = 0.7103 Å) radi-
ation and CCD detector. Crystals were cut to suitable size and
mounted on a glass fibre using cyanoacrylate adhesive. The unit
cell parameters were determined from 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 fourfold redundancy per reflection and optimum
resolution (0.75 Å). The intensity data collection, frames integra-
tion, Lorentz and polarization correction and decay correction were
done using SAINT-NT (version 7.06a) software. Empirical absorp-
tion correction (multi-scan) was performed using SADABS [27] pro-
gramme. Crystal structure was solved by direct methods using
SHELXS-97 [28]. The structure was then refined by the full-matrix
least-squares method using SHELXL-97. The refinement converged
to a final R-factor of 0.047. Crystallographic data have been depos-
ited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 985707 for 17. Copies of the
data can be obtained free of charge via http://www.ccdc.cam.
(E)-2,6-bis(4-methoxyphenyl)-3-methyl-1-(prop-2-yn-1-yl)piperidin-
4-one oxime (18). Yield: 85%, White Solid: IR (KBr, cmꢁ1)
; mmas 3279
Table 1
Physical data of compounds 17–24.
Compound
R1
R2
X
Melting point (°C)
Mass (m/z)
1, 9, 17
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH3
H
H
H
H
H
H
H
CH03
H
OMe
Cl
Br
Me
H
158–160
157–159
189–191
190–192
190–192
150–152
158–160
180–182
317.62
2, 10, 18
3, 11, 19
4, 12, 20
5, 13, 21
6, 14, 22
7, 15, 23
8, 16, 24
–
–
–
–
–
–
–
F
H
CH3

110
G. Sundararajan et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
(OH), 3167 (C„CH), 1610 (C@N); 1H NMR (400 MHz, CDCl3); d
(ppm) 0.80 (d, J = 5.6 Hz, 3H CH3); 2.63 (m, 1H, H-3a); 3.54 (d,
J = 13.6 Hz, 1H, H-5e); 3.37 (d, J = 10.4 Hz, 1H, H-2a); 3.71 (d,
J = 10.8 Hz, 1H, H-6a); 2.91, 2.84 (AB quartet, J = 17.6, 18.0 Hz,
2H, H-7a, H7b); 2.23 (d, 1H, H-5a); 2.15(s, 1H, H-9, acetylene pro-
ton); 3.81 (s, 6H, p-OCH3); 6.87–7.39, (m, 8H aromatic protons);
7.75 (s, 1H, oxime OH); 13C NMR (100 MHz, CDCl3); d (ppm) 12.7
(CH3); 71.1 (C-2); 43.0 (C-3); 159.1 (C-4); 33.7 (C-5); 63.1 (C-6);
39.8 (C-7); 77.8 (C-8); 73.7 (C-9); 55.27, 55.30 (OCH3 at p);
133.6, 134.9 (Aromatic ipso carbon).
(E)-2,6-bis(4-methylphenyl)-3-methyl-1-(prop-2-yn-1-yl)piperidin-
4-one oxime (21). Yield: 83%, White Solid: IR (KBr, cmꢁ1)
mas 3279
;
m
(OH), 3163 (C„CH), 1674 (C@N); 1H NMR (400 MHz, CDCl3); d
(ppm) 0.80 (d, J = 4.8 Hz, 3H CH3); 2.65 (m, 1H, H-3a); 3.54 (d,
J = 13.6 Hz, 1H, H-5e); 3.39 (d, J = 9.6 Hz, 1H, H-2a); 3.72 (d,
J = 12.4 Hz, 1H, H-6a); 2.93, 2.84 (AB quartet, J = 17.6, 17.6 Hz,
2H, H-7a, H-7b); 2.18 (d, 1H, H-5a); 2.14(s, 1H, H-9, acetylene pro-
ton); 2.34 (s, 6H, p-CH3); 7.14–7.36, (m, 8H aromatic protons); 7.84
(s, 1H, oxime OH); 13C NMR (100 MHz, CDCl3); d (ppm) 12.7 (CH3);
71.5 (C-2); 42.9 (C-3); 160.1 (C-4); 33.7 (C-5); 63.5 (C-6); 39.9 (C-
7); 77.8 (C-8); 73.6 (C-9); 21.18, 21.21 (CH3 at p); 137.3, 138.5
(Aromatic ipso carbons).
(E)-2,6-bis(4-chlorophenyl)-3-methyl-1-(prop-2-yn-1-yl)piperidin-4-
one oxime (19). Yield: 77%, White Solid: IR (KBr, cmꢁ1)
; mmas 3285
(OH), 3157 (C„CH), 1594 (C@N); 1H NMR (400 MHz, CDCl3); d
(ppm) 0.80 (d, J = 5.6 Hz, 3H CH3); 2.62 (m, 1H, H-3a); 3.54 (d,
J = 13.6 Hz, 1H, H-5e); 3.43 (d, J = 10.0 Hz, 1H, H-2a); 3.75 (d,
J = 11.2 Hz, 1H, H-6a); 2.89, 2.80 (AB quartet, J = 18.4, 18.0 Hz,
2H, H-7a, H7b); 2.08 (d, 1H, H-5a); 2.17(s, 1H, H-9, acetylene pro-
ton); 7.26–7.40, (m, 8H–aromatic protons); 8.27 (s, 1H, oxime OH);
13C NMR (100 MHz, CDCl3); d (ppm) 12.6 (CH3); 71.1 (C-2); 42.8 (C-
3); 158.8 (C-4); 33.5 (C-5); 63.1 (C-6); 40.0 (C-7); 77.3 (C-8); 74.3
(C-9); 133.5, 133.6 (Aromatic ipso carbon).
(E)-3-ethyl-2,6-diphenyl-1-(prop-2-yn-1-yl)piperidin-4-one
oxime
(22). Yield: 85%, White Solid: IR (KBr, cmꢁ1)
;
mmas 3280 (OH),
3161 (C„CH), 1669 (C@N); 1H NMR (400 MHz, CDCl3); d (ppm)
0.82 (d, 3H, CH3); 1.50, 1.15 (m, 2H, CH2 CH3- at C-3 methylene
protons); 2.55 (m, 1H, H-3a); 3.55–3.60, (m, 2H, H-5e,with merged
H2a); 3.79, (d, J = 11.6 Hz, 1H, H-6a); 2.92, 2.77, (AB quartet,
J = 17.6, 18.0 Hz, 2H, H-7a, H-7b); 2.21 (resolved 1H, H-5a); 2.17
(s, H-9, acetylene proton); 7.26–7.46, (m, 10H aromatic protons);
9.04 (s, 1H, oxime OH); 13C NMR (100 MHz, CDCl3); d (ppm) 11.9
(CH3); 19.7 (CH2CH3 at C-3 methylene carbon); 70.0 (C-2); 49.7
(C-3); 158.1 (C-4); 34.0 (C-5); 63.8 (C-6); 40.0 (C-7); 77.8 (C-8);
73.8 (C-9); 141.5, 142.8 (Aromatic ipso carbon).
(E)-2,6-bis(4-bromophenyl)-3-methyl-1-(prop-2-yn-1-yl)piperidin-4-
one oxime (20). Yield: 75%, White Solid: IR (KBr, cmꢁ1)
; mmas 3285
(OH), 3167 (C„CH), 1603 (C@N); 1H NMR (400 MHz, CDCl3); d
(ppm) 0.80 (s, J = 6.0 Hz, 3H CH3); 2.61 (m, 1H, H-3a); 3.54 (d,
J = 14.0 Hz, 1H, H-5e); 3.41 (d, J = 10.4 Hz, 1H, H-2a); 3.73 (d,
J = 11.6 Hz, 1H, H-6a); 2.89, 2.80 (AB quartet, J = 17.6, 17.6 Hz,
2H, H-7a, H7b); 2.08 (d, 1H, H-5a); 2.17(s, 1H, H-9, acetylene pro-
ton); 7.30–7.48, (m, 8H aromatic protons); 8.19 (s, 1H, oxime OH);
13C NMR (100 MHz, CDCl3); d (ppm) 12.6 (CH3); 71.1 (C-2); 42.8 (C-
3); 158.8 (C-4); 33.5 (C-5); 63.1 (C-6); 40.0 (C-7); 77.4 (C-8); 74.3
(C-9); 131.9, 132.0 (Aromatic ipso carbon).
(E)-2,6-bis(4-fluorophenyl)-3-methyl-1-(prop-2-yn-1-yl)piperidin-4-
one oxime (23). Yield: 78%, White Solid: IR (KBr, cmꢁ1)
; mmas 3285
(OH), 3157 (C„CH), 1603 (C@N); 1H NMR (400 MHz, CDCl3); d
(ppm) 0.80 (d, J = 5.6 Hz, 3H CH3); 2.63 (m, 1H, H-3a); 3.55 (d,
J = 14.0 Hz,1H, H-5e); 3.43 (d, J = 10.0 Hz, 1H, H-2a); 3.76 (d,
J = 12.0 Hz,1H, H-6a); 2.89, 2.80 (AB quartet, J = 17.6, 17.6 Hz, 2H,
H-7a, H-7b); 2.12 (d, 1H, H-5a); 2.17 (s, 1H, H-9, acetylene proton);
7.04–7.41, (m, 8H, aromatic protons); 8.21 (s, 1H, oxime OH); 13C
Scheme 1. Synthetic scheme of 3-alkyl-2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes 17–24. Reagents and conditions: 3-alkyl-2,6-diphenylpiperidin-4-one oxime
(1 mmol), DMF, K2CO3 with propargyl bromide(1.4 mmol) stirring 2 h and ambient temperature.

G. Sundararajan et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
111
Fig. 1. 1H NMR spectrum of compound 17.
NMR (100 MHz, CDCl3); d (ppm) 12.6 (CH3); 71.0 (C-2); 43.00 (C-
3); 159.2 (C-4); 33.7 (C-5); 63.0 (C-6); 39.8 (C-7); 77.3 (C-8);
74.1 (C-9); 137.1, 138.3 (Aromatic ipso carbon).
[30]. The test compounds were dissolved in 1 mL of chloroform.
The different concentrations test compounds were prepared with
the range of 200–3.125
twofolds. Where in 100
l
g/mL. It was then serially diluted into
l
L of sterile Mueller Hinton Broth for bac-
teria and Sabouraud Dextrose broth for fungus was decanted into
each well of a sterile 96-well micro plate. Highest concentration
(E)-3,3-dimethyl-2,6-diphenyl-1-(prop-2-yn-1-yl)piperidin-4-one
oxime (24). Yield: 83%, White Solid: IR (KBr, cmꢁ1)
; mmas 3307 (OH),
3143 (C„CH), 1599 (C@N); 1H NMR (400 MHz, CDCl3); d (ppm)
0.93 (d, 3H CH3); 1.28 (s, 3H, CH03); 3.62 (d, J = 14.0 Hz, 1H, H-
5e); 3.51 (d, 1H, H-2a); 3.79 (d, J = 12.0 Hz, 1H, H-6a); 3.05, 3.00
(AB quartet, J = 18.4, 18.0 Hz, 2H, H-7a, H7-b); 2.36 (d, 1H, H-5a);
2.10 (s, 1H, H-9, acetylene proton); 7.26–7.52, (m, 10H, aromatic
protons); 8.68 (s, 1H, oxime OH); 13C NMR (100 MHz, CDCl3); d
(ppm) 22.2, 23.2 (CH3, CH03); 73.9 (C-2); 41.3 (C-3); 163.2 (C-4);
30.0 (C-5); 64.0 (C-6); 40.6 (C-7); 77.3 (C-8); 73.9 (C-9); 138.1,
143.3 (Aromatic ipso carbon).
of the test compounds added at 100
ing of the above 100 L of the same was transferred to the second
well and in this way of the dilution procedure was continued as a
lL to the first well. After mix-
l
series of dilution of 200–3.125 lg/mL respectively. The final inocu-
lums size was 105 cfu/mL and antibacterial 1.1–1.5 ꢂ 102 cfu/mL
for antifungal assay at 50 lL was added to every well. The microti-
tre plates were incubated at 24 h for 37 °C bacteria, yeast at 28 °C
for 24–48 h and 30 °C at 72–96 h for Aspergillus of incubation. The
tubes were monitored for turbidity growth and non turbidity as no
growth. The MIC values were interpreted as the highest dilution
(lowest concentration) of the sample, which showed clear fluid
with no development of turbidity. Ciprofloxacin and Ketoconazole
were used as standards for bacterial and fungal study, respectively.
All the tests were carried out in triplicate. Bacterial and fungal
growth was indicated by the measure of a white pellet on well
bottom.
Antimicrobial activities
The clinical isolates of bacterial strains viz., Staphylococcus
aureus, Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae and
Pseudomonas aeruginosa. Fungal strains viz., Candida albicans,
Candida glabrata, Candida tropicalis, Aspergillus niger and Aspergillus
flavus. These strains were obtained from the Department of Micro-
biology, Rajah Muthiah Medical College and Hospital, Annamalai
University, Annamalainagar, Tamil Nadu, India. The strains were
inoculated on a sterile medium and sub-cultured on to Mueller
Hinton Agar plates, these strains are maintained on agar slant at 4°.
Results and discussion
Experimental results
In the present study, oximes were subjected to react with prop-
argyl bromide in the presence of K2CO3 to prepare the correspond-
ing compounds (17–24) (Scheme 1). Representative compound 17
was characterized by IR, 1H and 13C NMR, 2D NMR (COSY, HSQC)
Mass spectra analyses were consistent with the assigned
structures. Compound 17 was successfully crystallized and its
Determination of minimum inhibitory concentration (MIC)
The in vitro antimicrobial activities of the compounds were
tested in dilution susceptibility testing method and the MIC deter-
minations are reproduced with reference to the cited literature

112
G. Sundararajan et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
3-CH3
H-9
H-5(a)
H-3(a)
H-7(a,b)
H-2(a)
H-5(e)
H-6(a)
HO
N
R2
4
R1
5
3
2
6''
2''
6
1
6'
2'
6'''
6''''
2'''
N
Ha
Hb
2''''
7
8
OH
H
H
H
9
Fig. 2. 1H–1H COSY spectrum of compound 17.
structure was determined by single-crystal X-ray diffraction
analysis.
at 3.59 ppm (J25e,5a = 13.6 Hz) as doublet are assigned to H-5e. 1H
NMR signal appeared as multiplet at 2.70 ppm is assigned to H-3a
while the singlet at 2.16 ppm with one proton integral value is
assigned to H-9 proton. Moreover, the observed vicinal coupling con-
stants of J36a,5a and J23a,3a are 11.6 and 10.4 Hz and the geminal cou-
pling constant of J25e,5a is 13.6 Hz. These coupling constant values
show that compound 17 exists in a normal chair conformation as
shown in Fig. 5. In the other oximes also H-5e has a higher chemical
shift than H-5a and C-5 has a lower chemical shift than C-3. Hence,
in all the oximes (17–24) the configuration about the C@N bond
should be E and six membered heterocyclic ring adopts chair confor-
mation with the orientation of oxime moiety syn to the C-5 carbon
Fig. 5. Methylene protons signal at C-7 appeared as an AB quartet
centred at 2.88 ppm. The exact chemical shifts of these diastereotop-
ic proton are found at 2.94 ppm (J H7a = 17.6 Hz) and 2.83 ppm (J
NMR spectral analysis of compound 17
The spectroscopic numbering of carbon atoms in (17–24) is
shown in Scheme 1. Protons are numbered accordingly and thus
the proton at C-2 is denoted as H-2. Compound 17 was considered
as a representative compound and their signals were assigned
based on their position, integrals and multiplicities and confirmed
by the correlations observed in the COSY spectra. The observed 1
H
and 13C chemical shifts were given in Tables S1 and S3 respectively.
The 1H–1H coupling constant (J) and 2D spectral correlations were
given in Tables S2 and S4 respectively (Supplementary). The 1D
and 2D NMR spectra of compound 17 were shown in Figs. 1–4.
In 1H NMR spectrum of compound 17 the signals appeared in
the range 7.29–7.48 ppm corresponding to ten protons integral
which are due to the aromatic protons of the two phenyl groups
in piperidine ring at C-2 and C-6 positions. There is a sharp singlet
peak at 9.04 ppm corresponding to one proton. This is due to the
hydroxyl proton of the oxime group. Methyl protons appeared as
a doublet at 0.82 ppm with a coupling constant of 6.0 Hz. In the
higher frequency region, there are three doublets were observed
H7b = 18 Hz) respectively. These are due to the H7a and H7b protons
each corresponding to one proton. 1H–1H connectivity of the repre-
sentative compound 17 is explained by 1H–1H COSY spectrum Fig. 2.
The signal which is observed at 0.82 ppm has only one correlation
with H-3a proton observed at 2.70 ppm. Therefore, it is confirmed
that the signal appeared at 0.82 ppm corresponds to methyl protons.
In the 13C NMR spectrum of compound 17 quaternary carbons are
easily distinguished from other carbons based on small intensities.
Assignments of the aromatic ring carbons and side chain carbons
are confirmed on the basis of cross peaks observed in 1H–13C COSY
spectra. Two weak signals observed at 141.8 and 142.8 ppm were
at 3.79 (J36a 5a = 11.6 Hz), 3.59 ppm (J52e,5a = 13.6 Hz) and 3.46 ppm
,
(J32a,3a = 10.4 Hz). The signals appeared at 3.46 and 3.79 ppm as dou-
blet are assigned to H-2 and H-6 protons respectively and the signal

G. Sundararajan et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
113
Fig. 3. 13C NMR spectrum of compound 17.
due to ipso carbons of the aryl ring at C-20 and C-60 carbons. The sig-
nals observed in the region 127.5–128.8 ppm were assigned to aro-
matic carbons. There was a weak signal at 159.5 ppm is due to the
oximino carbon. Eight signals were appeared in the aliphatic region.
Signals at 71.8 and 63.8 ppm are assigned to C-2 and C-6 carbons
among them C-6 was observed slightly upfield region compared C-
2 carbon due to the extended c0–syn effect. Further the signals
appeared at 43.0 and 33.8 ppm is assigned to C-3 and C-5 carbons
of the piperidine ring system. Among the carbons, C-5 carbon is
shielded due to c0–syn effect (the CAH bond is polarized and the car-
bon C-5 acquired slightly negative charge) [31] as shown in Fig. 5.
The remaining signals appeared at 40.0, 77.6 and 73.9 ppm were
assigned to C-7, C-8 and C-9 carbons. Further C-2 and C-6 carbons
were observed in the downfield region compared to C-3 and C-5. It
is known that introduction of a methyl group at an equatorial posi-
tion on the six membered ring makes the nearby carbon shifted to
down field region, due to the b-effect. The alkyl substituent carbon
C-3 was appeared at 12.6 ppm. 13C NMR spectral study supported
the proposed chair conformation of the synthesized compounds
with the equatorial orientation of the aryl groups. Moreover, the car-
bon signal at 40.00 ppm has HSQC cross peak with methylene proton
signals at 2.94 and 2.83 ppm respectively confirmed that the carbon
observed at 40.00 ppm was methylenic carbon C-7. Consequently
the acetylenic proton signal at 2.16 ppm has correlation with
73.9 ppm is due to the terminal carbon C-9.
a = 36.3216(1) Å, b = 6.0829(2) Å, c = 21.6691(6) Å. The ORTEP of
compound 17 is given in Fig. 6. The refinement converged to a final
R-factor of 0.047. The crystallographic data for the compound 17 is
given in Table 2. The hydrogen bond geometry is given in Table 3.
The ORTEP plot of the compound 17 with the atom numbering
scheme, the displacement ellipsoids are drawn at 30% probability
level. The compound crystallizes with chloroform in the solvated
form. The piperidine ring (N1/C1–C5) adopts a chair conformation
with the puckering parameters q2,
placement asymmetric parameters
u
[32] and the smallest dis-
D
s [33] as follows q2 = 0.5762
(2) Å,
u = 10.28 (2)° and Ds(N1) = 9.5 (1)°. The piperidine ring
makes a dihedral angle of 88.85 (1)° with the phenyl ring (C6–
C11) which shows that they are almost orthogonal to each other.
The piperidine ring makes a dihedral angle of 74.89 (1)° with the
phenyl ring (C12–C17). The dihedral angle between the two phenyl
rings is 57.90 (1)°. The methyl carbon atom C21 is attached with
the phenyl ring deviates by ꢁ0.3444 (2) Å. The crystal packing is
stabilized by O1AH1aꢃ ꢃ ꢃN2 hydrogen bond forming R22 (6) ring
motif is shown in Fig. 7. It also features intramolecular CAHꢃ ꢃ ꢃO
interaction Table 3.
Computational studies
Molecular modelling was carried out by Gaussian-03 package
using DFT method at B3LYP/6-31G/(d,p) level. In order to supple-
ment the XRD data the theoretical parameters were compared with
the XRD data and are displayed in Tables S5 and 6. The bond
length, bond angle and Torsion angle were extracted from the opti-
mized structure of 17. The theoretical parameters are higher than
that of XRD parameters because the theoretical calculations were
X-ray crystal structure of compound (17)
The compound crystallized in monoclinic C2/c space group with
four molecules in the asymmetric unit. The cell dimensions are

114
G. Sundararajan et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
Fig. 4. HSQC spectrum of compound 17.
X
orbital is mostly located on C2–N1–C6 atoms of the piperidine ring
and the propargyl group connected with nitrogen atom of the
piperidine ring. Whereas LUMO located at oxime as well as piper-
idine connected phenyl groups Pz orbital electron density of atoms
N1, C18, C19 and C20 are transferred into LUMO orbital. Propargyl
group are not participate in LUMO orbital. The HOMO–LUMO
energy gap (5.5661 eV) have been calculated by B3LYP/6-
31G(d,p) method as shown in Fig. 9. The charge transfer from lone
pair of atom to its antibonding orbital is more. The HOMO ? LUMO
transition implies that intramolecular charge transfer takes place
within the molecule [34].
H
R1
H
N
2
3
9
HO
4
δ−
5
1
6
N
8
7
H
R2
Hb
H
δ+
Ha
X
Fig. 5. Chair conformation of compound 17.
Molecular electrostatic potential map (MEP)
MEP surface diagram is used to understand the reactive behav-
iour of a molecule. The negative regions can be regarded as nucle-
ophilic centres whereas the positive regions are potential
electrophilic sites. The MEP diagram of compound 17 is show in
Fig. 10. This diagram shows that oxygen and nitrogen atoms repre-
sent the most negative potential region (dark red). The nitrogen
atom seems to exert small negative potential compare to oxygen
atom. The hydrogen atoms bear the maximum brunt of positive
charge. The predominance of green region in the MEP surface cor-
responds to a potential halfway between the two extremes red and
dark blue colour.
made for molecules in gaseous state. The representative molecular
modelling of compound 17 is shown in Fig. 8. The chair conforma-
tion of compound 17 was confirmed by XRD data which is further
evidenced from the molecular modelling studies.
HOMO–LUMO energies of 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-
one oxime by DFT method
The energy gap between highest occupied molecular orbital
(HOMO) and the lowest unoccupied molecular orbital (LUMO)
are the main orbital take part in chemical stability. The HOMO

G. Sundararajan et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
115
Fig. 6. ORTEP of the compound 17.
Table 2
Crystal data of compound 17.
Table 3
Hydrogen bond geometry for the compound [Å and °] 17.
Parameters
Compound
Distance (Å)
Angle (°)
Empirical formula
Formula weight
Temperature (K)
C43H45Cl3N4O2
756.18
293(2)
0.71073
DAH. . .A
DAH
H. . .A
D. . .A
DAH. . .A
O1AH1A. . .N2i
C2AH2A. . .O1
0.82
0.97
2.08
2.27
2.789(2)
2.702(3)
145
106
Wavelength (Å)
Crystal system, space group
Unit cell dimensions
Monoclinic, C2/c
a = 36.3216(1) Å
b = 6.0829(2) Å
c = 21.6691(6) Å
b = 123.3300(1)°
V = 4000.1(2)
4, 1.256
0.270
1592
Symmetry code: (i) ꢁx, ꢁy, ꢁz.
Volume (Å3)
Z, Calculated density (Mg/m3)
Absorption coefficient (mmꢁ1
F(000)
)
Crystal size (mm3)
0.30 ꢂ 0.25 ꢂ 0.20
Theta range for data collection
Limiting indices
Reflections collected/unique
Completeness to theta (%)
Refinement method
1.34–28.25°
ꢁ48 6 h 6 47, ꢁ7 6 k 6 8, ꢁ28 6 l 6 28
18,938/4889 [R(int) = 0.0219]
98.8
Full-matrix least-squares on F2
4889/3/255
Data/restraints/parameters
Goodness-of-fit on F2
1.022
Final R indices [I > 2
R indices (all data)
r
(I)]
R1 = 0.0478, wR2 = 0.1228
R1 = 0.0698, wR2 = 0.1450
0.321 and ꢁ0.356
Largest diff. peak and hole (e Åꢁ3
)
Fig. 7. The molecular packing of the compound forming R22 (6) ring motif 17.
Charge distribution
The charge distribution of the molecule has been calculated on
the basis of Mulliken method using B3LYP/6-31G(d, p) level calcu-
lation [35]. The calculation depicts the charge of the every atom in
the molecule. Distributions of positive or negative charges are vital
to increasing or decreasing of bond length between the atoms. The
survey of literature reveals that effective atomic calculations are
given an important role in the application of chemical calculation

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G. Sundararajan et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
to molecular system because of atomic charges, dipole moment,
molecular polarizability, electronic structure, acidity–basicity
behaviour and more lot of properties of molecular system [35].
Mulliken atomic charges and plot are shown in Table S7. In Mullik-
en scheme, the negative charge more or less evenly on N1, C20, O1
and C21 atoms and splits the positive charge with C19, C3 and H38
atoms. Mulliken population analysis revealed that C-20 and N-1
atoms have maximum negative charge (ꢁ0.5253 and ꢁ0.51539)
carbon atom has maximum negative charge than the rest of the
atoms. Some of the carbon and hydrogen atoms C19 (0.30169),
C3 (0.263015) and H38 (0.3351) bearing maximum positive
charge.
NBO analyses
In natural bond orbital (NBO) analyses several donor–acceptor
interactions are observed in compound (17) and among the
strongly occupied NBOs, the most important delocalization sites
are in the p system and in the lone pairs (n) of the oxygen and
nitrogen present on the oxime moiety. The
r system shows some
contribution to the delocalization and almost the donor–acceptor
interactions are same in these compound. The important contribu-
tion to the delocalization corresponds to the donor–acceptor inter-
actions are C7–C8 (2) ? C6–C11 (2), C12–C17 (2) ? C16–C15 (2)
and lone pair O10 ? N2–C3. The charge distribution shows that
the more negative charge is concentrated on hetero atoms whereas
the partial positive charge resides at hydrogens are given in
Table S8.
Hyperpolarizability
The first hyperpolarizabilities (b,
calculated using B3LYP/6-31G(d, p) level of theory based on the
finite-field approach. This study reveals that the
p⁄ interaction
a and l) of compound 17 is
p–
Fig. 8. Optimized molecular structure of compound 17.
can make larger intra-molecular interaction and hence the polariz-
ability of the molecule increases. It is evident from Table 4 that the
molecular dipole moment (l), molecular hyperpolarizability and
polarizability are calculated about 0.246 (D), 1.626 ꢂ 10ꢁ30 and
133.6412 ꢂ 10ꢁ25 esu, respectively. The b value of the title com-
pound is ꢄ4.5 times greater than that of urea.
0.1701 eV
Antibacterial activity (17–24)
The antibacterial activity of the synthesized compounds were
screened against Gram positive strains S. aureus, B. subtilis and K.
pneumoniae and Gram negative strains E. coli, P. aeruginosa by com-
paring their minimum inhibitory concentration values with Cipro-
floxacin standard drug. All the MIC values obtained for compounds
(17–24) are given in Table 5. Compound 17, without any substitu-
ent at para position of phenyl ring at C-2 and C-6 positions of the
six membered heterocyclic rings and with methyl group attached
at C-3 position exhibited equal activity against S. aureus, B. subtilis,
P. aeruginosa, E. coli and K. pneumonia. Similarly, compound 23 pos-
sessing electronegative of fluorine atom in the para position
showed equal activity against S. aureus, B. subtilis, P. aeruginosa,
E. coli and K. pneumonia which is comparable with the standard
drug (Ciprofloxacin).
5.5661 eV
Compound 18, para position of the aryl moieties at C-2 and C-6
by possessing electron donating methoxy analogue exhibited min-
imum antibacterial activity against S. aureus, P. aeruginosa. While
the replacement of methoxy analogue by methyl analogue com-
pound 21 twofold decreased against S. aureus, P. aeruginosa (25–
5.7362 eV
100 lg/mL) is observed.
The introduction of chloro and bromo analogues compound 19
Fig. 9. HOMO–LUMO orbital picture of compound 17.
and 20 exhibited moderate antibacterial activity against S. aureus,

G. Sundararajan et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
117
Fig. 10. Molecular electrostatic potential surface (MEP) of compound 17.
(12.5–100 lg/mL). These results revealed that substitution at C-3
carbon playing an important role on the antibacterial activity.
Table 4
The molecular electric dipole moment
l
(Debye), hyperpolarizability (b0) and
polarizability (a) values of compound 17.
Antifungal activity of compounds (17–24)
Parameters
B3LYP/6-31G(d,p)
Dipole moment
The results of the present study provide an evidence for the
antifungal effects of an array of 2,6-diaryl-1-(prop-2-yn-1-
yl)piperidin-4-one oximes (17–24) were also screened for in vitro
antifungal activity with five fungal strains viz. C. albicans,
C. tropicalis, C. glabrata, A. niger and A. flavus. Here, Ketoconazole
was used as the standard drug. MIC values ranging from (6.25–
200 lg/mL) are listed in Table 6. Compound 9, which lacks any
substituents at the aryl groups, showed better antifungal activity
than Ketoconazole against C. albicans, C. tropicalis, C. glabrata, A.
niger, and A. flavus (6.25–25 lg/mL). Compounds 19 and 20 exerted
lx
ly
lz
l
0.1779858
ꢁ0.0968163
ꢁ0.1410821
0.246893702
Hyper polarizability
bxxx
bxxy
bxyy
byyy
bxxz
bxyz
byyz
bxzz
byzz
bzzz
b0
20.2153838
9.4764916
31.8478213
ꢁ19.7056055
ꢁ92.8879426
ꢁ4.8395937
ꢁ3.4137651
4.6872113
ꢁ56.7663001
ꢁ70.2040875
1.626 ꢂ 10ꢁ30 esu
twofold decreased activity against C. tropicalis and C. glabrata fun-
gal species. Among them compound 19 and 20 showed maximum
activity against A. niger, C. glabrata and A. flavus at a MIC value of
(6.25–25 lg/mL). Similarly 23 showed better activity against all
the fungal strains screened. This effect introduces halogen substit-
uents at the para position of aryl groups compounds of 19, 20, and
23 due to the chloro, bromo and fluoro substituents. Moreover,
compounds 18 and 21 possessing electron-donating methoxy and
methyl groups substitutions at the para position of phenyl ring
shows moderate activity against the entire tested fungal strains
Polarizability
axx
axy
ayy
axz
ayz
azz
a
276.9087367
5.1082602
171.7391684
ꢁ1.1875073
8.8930945
224.7977984
133.6412 ꢂ 10ꢁ25 esu
except A. niger (MIC at 12.5 lg/mL) it is maximum activity against
compared with other strains. Further the unsubstituents in the
phenyl group compounds 22 and 24 showed minimum antifungal
activity against all fugal strains. At the outset, the trend of the
antifungal activity of all the compounds is as follows: 17 > 19 >
23 > 20 > 18 > 21 > 22 > 23.
In noticed substitution at the para position of the phenyl rings
and alkyl substitution at C-3 position are more important to
antimicrobial assay. Further substitution on the phenyl ring by
P. aeruginosa, E. coli, and K. pneumoniae (6.25–50 lg/mL).
Compounds 22 and 24 at C-3 position attached ethyl and two
methyl groups without substituents in the aryl ring showed
minimum activity against S. aureus, P. aeruginosa and B. subtilis
Table 5
In vitro antibacterial activity of compounds 17–24.
Compounds
Entry
R1
Minimum inhibitory concentration (MIC) in lg/mL
R2
X
S. aureus
B. subtilis
P. aeruginosa
E. coli
K. pneumoniae
17
18
19
20
21
22
23
24
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH3
H
H
H
H
H
H
H
CH3
H
MeO
Cl
Br
Me
H
6.25
12.5
12.5
6.25
25
6.25
25
25
12.5
25
25
6.25
25
6.25
12.5
25
25
25
50
50
12.5
25
12.5
50
25
25
50
100
12.5
25
25
50
25
50
100
100
25
50
12.5
25
F
H
6.25
12.5
6.25
CH3
Ciprofloxacin
12.5
12.5

118
G. Sundararajan et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 139 (2015) 108–118
Table 6
In vitro antifungal activity of compounds 17–24.
Compounds
Entry
R1
Minimum inhibitory concentration (MIC) in lg/mL
R2
X
C. albicans
C. tropicalis
C. glabrata
A. niger
A. flavus
17
18
19
20
21
22
23
24
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH3
H
H
H
H
H
H
H
CH3
H
MeO
Cl
Br
Me
H
12.5
25
12.5
12.5
25
25
12.5
25
12.5
50
25
25
25
50
12.5
50
25
50
25
25
50
100
25
100
25
6.25
12.5
6.25
12.5
12.5
12.5
12.5
25
12.5
25
12.5
25
50
50
25
50
25
F
H
CH3
Ketoconazole
12.5
12.5
12.5
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results indicated that representative compound 17 exhibits in
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One of the authors Dr. K. Krishnasamy is grateful to University
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the form of the Major Research project (F.No. 42-342/2013).
Authors are thankful to Dr. D. Velmurugan, CAS in Crystallography
and Biophysics, University of Madras, Chennai for his help in the
Crystallographic study.
Appendix A. Supplementary data
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