Synthesis, spectral, stereochemical, single crystal XRD and biological studies of 3t-pentyl-2r,6c-diarylpiperidin-4-one picrate derivatives

Article abstract of DOI:10.1016/j.molstruc.2014.06.096

Various substituted 3t-pentyl-2r,6c-diphenylpiperidin-4-one picrates (1-7) were synthesised and characterised by elemental analysis, FT-IR and NMR spectral studies. NMR spectral assignments were made unambiguously by their one dimensional (¹H N

Full text of DOI:10.1016/j.molstruc.2014.06.096

Journal of Molecular Structure 1075 (2014) 430–441
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, spectral, stereochemical, single crystal XRD and biological
studies of 3t-pentyl-2r,6c-diarylpiperidin-4-one picrate derivatives
⇑
S. Savithiri, M. Arockia doss, G. Rajarajan , V. Thanikachalam
Department of Chemistry, Annamalai University, Annamalainagar 608002, Tamil Nadu, India
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
ꢀ
The main advantages are time saving,
easy workup and high yield of the
product.
ꢀ
Spectral and stereochemical analyses
by means of 1D and 2D NMR, Mass
spectral techniques and single crystal
XRD.
ꢀ
ꢀ
Piperidone ring protons are
influenced by picrate anion.
Picrate derivatives have good
antimicrobial activities compared to
standard drugs.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2014
Received in revised form 30 June 2014
Accepted 30 June 2014
Available online 9 July 2014
Various substituted 3t-pentyl-2r,6c-diphenylpiperidin-4-one picrates (1–7) were synthesised and char-
acterised by elemental analysis, FT-IR and NMR spectral studies. NMR spectral assignments were made
unambiguously by their one dimensional (1H NMR and 13C NMR) and two dimensional (1H–1H COSY,
HSQC, HMBC, NOESY, DEPT) NMR spectra. Single crystal XRD analysis of the compound (1) has confirmed
that the complex crystallized in monoclinic system with P21/n space group. The difference in the chem-
ical shifts between equatorial methylene proton and axial proton at C(5) [
D
= deq ꢁ dax] is highly negative
Keywords:
Picrates
FT-IR
NMR
Single crystal XRD
Biological activity
in compounds 1–7 in contrast to the value observed for the corresponding parent piperidine-4-one and is
indicative of the 1,3-diaxial interaction between the axial NH bond and axial hydrogen at C(5). The chem-
ical shifts of the heterocyclic ring protons are influenced by the picrate anion. All the synthesised com-
pounds exhibited good activity against S. aureus-Staphylococcus aureus bacterial strains and C. albicans
fungal strains.
Ó 2014 Elsevier B.V. All rights reserved.
Introduction
on the 1H and 13C chemical shifts of 2r,6c-diarylpiperidin-4-ones
and their derivatives has also been studied widely [4–9].
Piperidine heterocycles play an important role in the field of
medicinal chemistry. The relative chemical shift order of equatorial
and axial protons in the normal chair conformation of cyclohexane
and its derivatives (deq > dax) are considered as caused by magnetic
anisotropic effect of the CAC single bonds. The influence of substit-
uents on the chemical shifts of protons attached to the adjacent
carbons has been studied in detail [1–3]. The effect of protonation
Arumugam et al [10] have investigated the effects of protonation
on 1H chemical shifts in 2r,6c-diarylpiperidin-4-ones and 2r,6c-
diphenylpiperidines by comparing their chemical shifts with those
of their hydrochlorides. Manimekalai and Jayabharathi [11] have
studied the effect of protonation on the 1H and 13C chemical shifts
in 2r,6c-diphenylpiperidin-4-one by examining carefully their
picrates. By investigating one picrate with the corresponding
hydrochloride [12], they have shown that anions also could influ-
ence 1H chemical shifts. However, the chemical shifts of the
picrates have been determined in CDCl3 and there could be a
⇑
Corresponding author. Mobile: +91 9444147388.
E-mail address: rajarajang70@gmiail.com (G. Rajarajan).
http://dx.doi.org/10.1016/j.molstruc.2014.06.096
0022-2860/Ó 2014 Elsevier B.V. All rights reserved.

S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
431
solvent effect. Vimalraj and Pandiarajan [12] have studied the
effect of protonation and co-anion on the 1H and 13C chemical
shifts of diphenylpiperidin-4-one (NMR, antimicrobial, XRD and
theoretical studies have been made on 3t-pentyl-2r,6c-diphenylpi-
peridin-4-ones and their oximes) [13–15]. Several 2,6-disubsti-
tuted derivatives of this class have been found to possess useful
biological activities such as herbicidal, insecticidal, fungicidal, bac-
tericidal, anti-inflammatory, antihistaminic, hypertensive, antican-
cer, CNS stimulant, depressant and nerved activities [16–25]. The
present study, the syntheses of picrates characterized by spectral
techniques and screens its antimicrobial activities.
(C@C stretching), 1433 (CAO stretching), 1562, 1513, 1488 (NO2
asymmetric stretching), 1364, 1335, 1271 (NO2 symmetric stretch-
ing), 1078 (CAN stretching), 749–710 (aromatic CAH out of plane
bending vibration); 1H NMR (400 MHz, DMSO-d6, d, ppm): 9.41 (s,
1H, Ax-NH), 9.97 (s, 1H, Eq-NH), 8.60 (s, 2H, picryl ring), 7.30-7.37,
7.59–7.66 (m, Ar-H), 4.98 (t, 1H, H(6), J6a5a = 10 Hz), 4.75 (t, 1H,
H(2), J2a3a = 9.2 Hz), 3.19 (m, 1H, H(3a)), 3.38 (d, 1H, H(5a)
,
J5a5e = 14.4 Hz), 2.75 (d, 1H, H(5e)), 1.04–1.39 (m, 8H, CH2), 0.75 (t,
3H, CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 202.91 (C@O),
115.43–141.76, 161.27–163.78 (Ar-C), 160.79 (CAO), 61.98 C(2),
57.79 C(6), 50.31 C(3), 44.14 C(5), 21.60–31.16 (CH2), 13.63 (CH3).
3t-Pentyl-2r, 6c–di (4-chlorophenyl) piperidin-4-one picrate (3)
Yield 82%; m.p.: 152–154 (°C); MF: C28H28Cl2N4O8; IR (KBr)
(cmꢁ1): 3433 (NAH stretching), 3131 (aromatic CAH stretching),
2929 (aliphatic CAH stretching), 1713 (C@O stretching), 1628
(C@C stretching), 1433 (CAO stretching), 1560, 1490, 1463 (NO2
asymmetric stretching), 1363, 1337, 1272 (NO2 symmetric stretch-
ing), 1086 (CAN stretching), 791–710 (aromatic CAH out of plane
bending vibration); 1H NMR (400 MHz, DMSO-d6, d, ppm): 9.50 (d,
1H, Ax-NH), 10.0 (d, 1H, Eq-NH), 8.59 (s, 2H, picryl ring), 7.56–7.60
(m, Ar-H), 4.96 (d, 1H, H(6), J6a5a = 12 Hz), 4.72 (d, 1H, H(2),
J2a3a = 12 Hz), 3.19 (d, 1H, H(3a)), 3.33 (t, 1H, H(5a), J5a5e = 14.4 Hz),
2.75 (d, 1H, H(5e)), 1.03–1.38 (m, 8H, CH2), 0.74 (t, 3H, CH3); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 202.78 (C@O), 124.46–141.71
(Ar-C), 160.82 (CAO), 62.11 C(2), 57.89 C(6), 50.21 C(3), 44.04
C(5), 21.58-31.13 (CH2), 13.61 (CH3); Mass (m/e): 618 (M+),
Experimental
Materials and methods
All the solvents used were of spectral grade. The melting points
of the compounds were measured in open capillaries and are
uncorrected. IR spectra were recorded on an AVATAR-330 FT-IR
spectrometer (Thermo Nicolet) using KBr (pellet form). 1H NMR
spectra were recorded at 400 MHz and 13C NMR spectra at
100 MHz on a BRUKER model using DMSO-d6 as solvent for all
the compounds. Tetramethylsilane (TMS) was used as internal ref-
erence for all NMR spectra, with chemical shifts reported in d units
(parts per million) relative to the standard. 1H NMR splitting pat-
terns are designated as singlet (s), doublet (d), doublet of doublet
(dd), triplet (t), quartet (q) and multiplet (m). Coupling constants
are expressed in Hertz (Hz). Mass spectra were recorded in VAR-
IAN-SASTURAN 2200 GC–MS spectrometry using electron impact
technique. The sample was prepared by dissolving about 1 mg in
5 ml of methanol. Microanalyses were performed on VarioMicro
V2.2.0 CHN analyser. Microbial screening studies were made at
Centre for biological sciences in Pondicherry.
3t-Pentyl-2r, 6c–di (4-bromophenyl) piperidin-4-one picrate (4)
Yield 70%; m.p.: 158–160 (°C); MF: C28H28Br2N4O8; IR (KBr)
(cmꢁ1): 3427 (NAH stretching), 3128 (aromatic CAH stretching),
2929 (aliphatic CAH stretching), 1715 (C@O stretching), 1625
(C@C stretching), 1432 (CAO stretching), 1559, 1487, 1432 (NO2
asymmetric stretching), 1395, 1335, 1271 (NO2 symmetric stretch-
ing), 1076 (CAN stretching), 740–711 (aromatic CAH out of plane
bending vibration); 1H NMR (400 MHz, DMSO-d6, d, ppm): 9.45 (s,
1H, Ax-NH), 9.99 (s, 1H, Eq-NH), 8.60 (s, 2H, picryl ring), 7.50–7.56,
7.68–7.74 (m, Ar-H), 4.96 (d, 1H, H(6), J6a5a = 9.6 Hz), 4.72 (d, 1H,
General procedure for the synthesis of 3t-pentyl-2r,6c-diarylpiperidin-
4-one picrates (1–7)
The piperidinium picrates (1–7) were prepared by mixing equi-
molar solutions of the corresponding 3t-pentyl-2r,6c-diphenylpi-
peridin-4-one [14] with picric acid in ethanol and stirring the
solution for 30 min. The yellowish crystals formed were filtered.
The yield of the product was found to be 95%. The harvested crys-
tals were recrystallized repeatly to get excellent quality crystals.
H(2), J2a3a = 10.4 Hz), 3.18 (q, 1H, H(3a)), 3.33 (t, 1H, H(5a)
,
J5a5e = 14), 2.75 (d, 1H, H(5e)), 1.04–1.38 (m, 8H, CH2), 0.75 (t, 3H,
CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 202.67 (C@O),
122.79–141.73 (Ar-C), 160.69 (CAO), 62.09 C(2), 57.90 C(6),
50.06 C(3), 43.91 C(5), 21.62–31.16 (CH2), 13.64 (CH3).
3t-Pentyl-2r, 6c-di (4-methoxyphenyl) piperidin-4-one picrate (5)
Yield 78%; m.p.: 154–156 (°C); MF: C30H34N4O10; IR (KBr)
(cmꢁ1): 3433 (NAH stretching), 3112 (aromatic CAH stretching),
2931 (aliphatic CAH stretching), 1712 (C@O stretching), 1627
(C@C stretching), 1437 (CAO stretching), 1561, 1516, 1484 (NO2
asymmetric stretching), 1364, 1335, 1269 (NO2 symmetric stretch-
ing), 1078 (CAN stretching), 745–709 (aromatic CAH out of plane
bending vibration); 1H NMR (400 MHz, DMSO-d6, d, ppm): 9.19 (d,
1H, Ax-NH), 9.84 (d, 1H, Eq-NH), 8.59 (s, 2H, picryl ring), 7.01–7.06,
7.47–7.51 (m, Ar-H), 4.89 (t, 1H, H(6), J6a5a = 11.6 Hz), 4.63 (t, 1H,
3t-Pentyl-2r,6c-diphenylpiperidin-4-one picrate (1)
Yield 80%; m.p.: 150–152 (°C); MF: C28H30N4O8; IR (KBr)
(cmꢁ1): 3422 (NAH stretching), 3084 (aromatic CAH stretching),
2925 (aliphatic CAH stretching), 1716 (C@O stretching), 1629
(C@C stretching), 1430 (CAO stretching), 1562, 1489, 1461 (NO2
asymmetric stretching), 1364, 1335, 1271 (NO2 symmetric stretch-
ing), 1077 (CAN stretching), 750–702 (aromatic CAH out of plane
bending vibration); 1H NMR (400 MHz, DMSO-d6, d, ppm): 9.41 (d,
1H, Ax-NH) 10.1 (d, 1H, Eq-NH), 8.61 (s, 2H, picryl ring), 7.43–7.52,
7.57–7.62 (m, Ar-H), 5.01 (t, 1H, H(6), J6a5a = 10.8 Hz), 4.74 (t, 1H,
H(2), J2a3a = 11.2 Hz), 3.15 (q, 1H, H(3a)), 3.34 (d, 1H, H(5a)
,
H(2), J2a3a = 10.8 Hz), 3.23 (m, 1H, H(3a)), 3.39 (d, 1H, H(5a)
,
J5a5e = 14.4 Hz), 2.67 (d, 1H, H(5e)), 1.04–1.38 (m, 8H, CH2), 0.76 (t,
3H, CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 203.43 (C@O),
113.90–141.74, 159.93–159.95 (Ar-C), 160.81 (CAO), 62.34 C(2),
57.99 C(6), 50.44 C(3), 44.34 C(5), 21.64–31.20 (CH2), 13.65 (CH3).
J5a5e = 14.4 Hz), 2.75 (d, 1H, H(5e)), 1.07–1.40 (m, 8H, CH2), 0.74 (t,
3H, CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 203.14 (C@O),
124.41–141.76 (Ar-C), 160.83 (CAO), 63.01 C(2), 58.65 C(6),
50.38 C(3), 44.28 C(5), 21.59–31.16 (CH2), 13.62 (CH3); Mass (m/
e): 550 (M+),
3t-Pentyl-2r, 6c-di (3, 4-dimethoxyphenyl) piperidin-4-one picrate (6)
Yield 83%; m.p.: 135–137 (°C); MF: C32H38N4O12; IR (KBr)
(cmꢁ1): 3448 (NAH stretching), 3139 (aromatic CAH stretching),
2997 (aliphatic CAH stretching), 1715 (C@O stretching), 1632
(C@C stretching), 1437 (CAO stretching), 1562, 1528, 1487 (NO2
asymmetric stretching), 1368, 1335, 1273 (NO2 symmetric
3t-Pentyl-2r, 6c– di (4-fluorophenyl) piperidin-4-one picrate (2)
Yield 75%; m.p.: 143-145 (°C); MF: C28H28F2N4O8; IR (KBr)
(cmꢁ1): 3425 (NAH stretching), 3085 (aromatic CAH stretching),
2928 (aliphatic CAH stretching), 1715 (C@O stretching), 1629

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S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
stretching), 1081 (CAN stretching), 793–742 (aromatic CAH out of
plane bending vibration); 1H NMR (400 MHz, DMSO-d6, d, ppm):
9.31 (d, 1H, Ax-NH), 9.87 (d, 1H, Eq-NH), 8.59 (s, 2H, picryl ring),
7.02–7.22 (m, Ar-H), 4.87 (t, 1H, H(6), J6a5a = 10 Hz), 4.61 (t, 1H,
H(2), J2a3a = 10 Hz), 3.19 (t, 1H, H(3a)), 3.41 (q, 1H, H(5a), J5a5e = 14.8 -
Hz), 2.72 (d, 1H, H(5e)), 1.04–1.42 (m, 8H, CH2), 0.76 (t, 3H, CH3);
13C NMR (100 MHz, DMSO-d6, d, ppm): 203.40 (C@O), 111.42-
141.63, 148.45-149.46 (Ar-C), 160.27 (CAO) 62.93 C(2), 58.34
C(6), 50.47 C(3), 44.23 C(5), 21.62–31.11 (CH2), 13.61 (CH3).
carried out by the same procedure used in antibacterial studies
except the temperature, which was maintained at 28 1 °C for
about 72 h. Similarly for disc diffusion method, the petridishes
were incubated at 28 1 °C for about 72 h. The same concentration
of the test compound, solvent (DMSO) and Cetramazole (standard)
prepared previously were used for the antifungal studies.
Minimum inhibitory concentration (MIC)
The lowest concentration of the test compounds which caused
apparently the inhibition of growth of organism, was taken as
the minimum inhibitory concentration. The MIC was recorded by
visual observation after 24 h (bacteria) and 72–96 h (fungi) of incu-
bation. The sterile distilled water and DMSO did not show any
inhibition.
3t-Pentyl-2r, 6c-di (4-methylphenyl) piperidin-4-one picrate (7)
Yield 70%; m.p.: 144–146 (°C); MF: C30H34N4O8; IR (KBr)
(cmꢁ1): 3436 (NAH stretching), 3079 (aromatic CAH stretching),
2925 (aliphatic CAH stretching), 1712 (C@O stretching), 1629
(C@C stretching), 1436 (CAO stretching), 1560, 1490, 1487 (NO2
asymmetric stretching), 1365, 1335, 1272 (NO2 symmetric stretch-
ing), 1078 (CAN stretching), 815-744 (aromatic CAH out of plane
bending vibration); 1H NMR (400 MHz, DMSO-d6, d, ppm): 9.32
(d, 1H, Ax-NH), 9.96 (d, 1H, Eq-NH), 8.60 (s, 2H, picryl ring),
7.24-7.29, 7.43-7.48 (m, Ar-H), 4.92 (t, 1H, H(6), J6a5a = 11.2 Hz),
4.66 (t, 1H, H(2), J2a3a = 10.8 Hz), 3.19 (t, 1H, H(3a)), 3.36 (t, 1H,
Results and discussion
The general schematic representation describing the routes of
synthesis is furnished in Scheme 1. The 3t-pentyl-2r,6c-diph-
enylpiperidin-4-ones were obtained by the condensation of appro-
priate benzaldehyde, 2-octanone and ammonium acetate in the
ratio 2:1:1. The piperidinium picrates (1–7) were prepared by mix-
ing equimolar solutions of 3t-pentyl-2r,6c-diphenylpiperidin-4-
one and picric acid in ethanol and stirring the solution for
30 min. The reaction yields, physical constant and elemental anal-
ysis of compounds (1–7) are given in Table 1. The structures of all
the synthesised compounds (1–7) are established on the basis of
FT-IR, 1H and 13C NMR spectroscopies. For compound 1, in addition
to the 1D NMR (1H and 13C NMR), 2D NMR (1H–1H COSY, HSQC,
HMBC, NOESY, DEPT) and single crystal XRD studies were per-
formed to make unambiguous configurational and conformational
characterisations.
In general, IR spectra of piperidone picrates showed C@O peaks
at 1700 cmꢁ1 and the NH2 stretching vibrations at 3400 cmꢁ1. Nor-
mally, the CAO stretching vibration of piperidone picrates is found
around 1400 cmꢁ1. FT-IR spectral data are summarized in Table 2.
The signals in the 1H NMR spectra were assigned based on their
positions, integrals and multiplicities. The observation of large
J = ꢃ11 Hz and small J = ꢃ3 Hz coupling about C(5)AC(6) bond
and one large coupling J = ꢃ10 Hz about C(2)AC(3) bond in 1–7,
confirm equatorial orientation of alkyl group at C(3) and aryl group
at C(2) and C(6). Hence, all the compounds 1–7 exist in normal
chair conformation with equatorial orientation of all the substitu-
ents similar to their corresponding parent ketones. In compounds
1–7 the coupling constants about C(2)AC(3) bond are considerably
lower than that of trans coupling about C(5)AC(6) bond. This is due
severe gauche interaction between alkyl group at C(3) and the aryl
groups C(2) and C(6) and in order to avoid this gauche interaction
the ring is flattened about C(2)AC(3) bond. The flattening is
H
(5a), J5a5e = 14.4 Hz), 2.69 (d, 1H, H(5e)), 1.04-1.36 (m, 8H, CH2),
0.74 (t, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 203.28
(C@O), 124.49–141.72 (Ar-C), 160.70 (CAO), 62.74 C(2), 58.37
C(6), 50.38 C(3), 44.37 C(5), 20.65–25.40 (CH2), 13.62 (CH3).
X-ray crystallography
The crystal was grown by the slow evaporation technique in
ethanol solvent. Diffraction data were collected on a Bruker SMART
APEX CCD difractometer using graphite-monochromated Mo K
a
radiation (K = 0.71073 Å) at 298 (2) with crystal size of
K
0.35 ꢂ 0.30 ꢂ 0.25 mm. the structure was solved by direct methods
and successive Fourier difference synthesis (SHELXS-97) and
refined by full matrix least square procedure on F2 with anisotropic
thermal parameters. All non-hydrogen atoms were refined (SHEL-
XL-97) and placed at chemically acceptable positions. A total of
361 parameters were refined with 5028 unique reflections which
covered the residuals to R1 = 0.0722. Crystallographic data have
been deposited with the Cambridge Crystallographic data centre
as supplementary publication number CCDC 1002105 for 1. Copies
of the data can be obtained free of charge via http://www.ccdc.ca-
m.ac.uk or from the Cambridge Crystallographic data centre, 12
union road, Cambridge CB2 1EZ, UK; fax: +44 1223 336 033: or
e-mail: deposit@ccdc.cam.ac.uk.
Antibacterial activity by disc diffusion method
Nutrient agar plates were prepared under sterile conditions and
incubated overnight to detect contamination. About 0.2 ml of
working stock culture was transferred into separate nutrient agar
plates and spread thoroughly using a glass spreader. Whatmann
No. 1 discs (6 mm in diameter) were impregnated with the test
compounds dissolved in DMSO (200 mg/ml) for about half an hour.
responsible for the lower magnitude of J2a3a compared to J6a5a
,
increasing bulkiness of substituent at C(3) decreases J2a,3a to a
greater extent.
The coupling of NH proton with the benzylic protons was
observed for 1–7 in DMSO-d6. This is due to a slow exchange of
NH protons between one molecule and another due to hydrogen
bonding. In the salts for the benzylic protons only the couplings
with the axial NH proton and the adjacent axial CAH protons were
observed. Hence, the benzylic protons appeared as triplets. In
many cases, the lines were broad with poor resolution. Hence,
the coupling constants could not be determined with great accu-
racy. In many cases, small coupling constants involving adjacent
axial and equatorial protons could not be determined. In the case
of large vicinal coupling constants J6a5a and J6a5e, NH could not be
determined due to lake of data. The 1H chemical shifts values are
given in Table 3.
Commercially available drug disc (Ciprofloxacin 10 lg/disc) was
used as positive reference standard. Negative controls were also
prepared by impregnating the disc of same size in DMSO solvent.
The discs were placed on the inoculated agar plates and incubated
at 37 1 °C for about 18–24 h. Antibacterial activity was evaluated
by measuring the zone of inhibition against the test organism.
Antifungal activity by disc diffusion method
Sabouraud’s dextrose agar (SDA) medium was used for the
growth of fungi and testing was done in Sabouraud’s dextrose
broth (SDB) medium. The subculture and the viable count were

S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
433
Scheme 1. Synthetic route for 3t-pentyl-2r,6c-diarylpiperidin-4-one picrate derivatives.
It is seen from Table 3 that the chemical shifts of H(2) are con-
siderably lower than that of H(6) in compounds 1–7. This also sup-
ports the equatorial orientation of alkyl group at C(3) in 1–7. The
1H spectrum of 1 is shown in Fig. 1. The lower magnitude is
observed for H(2) compared to H(6) in all the compounds due to
the magnetic anisotropic effect. Similar upfield shift has been
reported on the nearby axial proton by the introduction of equato-
rial substituent [3].
tons acquired partial positive charges. It is also interesting to note
that the chemical shifts of H(5a) are considerably higher when com-
pared to H(5e), i.e. deq ꢁ dax is negative in these cases. In the proton-
ated piperidine derivatives, the axial NH bond experiences severe
syn 1,3-diaxial interaction with axial hydrogens at C(5), H(5a) and
C(3), H(3a) and due to these interactions the protons are deshielded
to a greater extent and the corresponding carbons are shielded
Fig. 2.
It is clearly showed that all the protons of the piperidine ring
are remarkably deshielded by protonation, whereas all carbons of
the piperidine ring are markedly shielded. The shieldings on C(2),
C(3), C(5) and C(6) can be attributed to the polarisation of the
CAH bonds that carbons acquired partial negative charges and pro-
The benzylic protons are deshielded to a greater extent than the
protons at C(3) and C(5). However, the benzylic carbons are less
shielded than C(3) and C(5). Deshielding magnitude observed on
these protons may be due to the change in the electronegativity
of nitrogen and the magnetic anisotropic effect of the additional

434
S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
Table 1
Elemental analysis of compounds (1–7).
Compound
M.p. (°C)
Yield (%)
Molecular formula
C28H30N4O8
Elemental analysis (%)
C
H
N
Found
(Calcd)
Found
(Calcd)
Found
(Calcd)
1
2
3
4
5
6
7
150–152
143–145
152–154
158–160
154–156
135–137
144–146
80
75
82
70
78
83
70
60.62
(61.08)
5.51
9.99
(5.49)
(10.18)
C
28H28F2N4O8
58.76
(57.34)
4.97
8.96
(4.81)
(9.55)
C28H28Cl2N4O8
C28H28Br2N4O8
54.69
(54.29)
4.66
8.98
(4.56)
(9.04)
47.72
(47.48)
4.02
7.75
(3.98)
(7.91)
C
C
30H34N4O10
32H38N4O12
58.65
(59.01)
5.59
9.37
(5.61)
(9.18)
54.46
(57.31)
5.72
8.47
(5.71)
(8.35)
C30H34N4O8
56.91
5.10
(5.92)
11.24
(9.68)
(62.27)
Table 2
IR spectral data (cmꢁ1) of compounds (1-7).
1
2
3
4
5
6
7
Assignment
3422
3084
2925
1716
1077
1629
750
3425
3085
2928
1715
1078
1629
749
3433
3131
2929
1713
1086
1628
791
3427
3128
2929
1715
1076
1625
740
3433
3112
2931
1712
1078
1627
745
3448
3139
2997
1715
1081
1632
793
3436
3079
2925
1712
1078
1629
815
NH
CAH
C@O
CAN
C@C
Aromatic CAH Out Of Plane Bending Vibrations
702
710
710
711
709
742
744
679
624
678
658
657
705
707
Aromatic CAC out of plane bending vibrations
1430
1562
1489
1461
1364
1335
1271
1433
1562
1513
1488
1364
1335
1271
1433
1560
1490
1463
1363
1337
1272
1432
1559
1487
1432
1395
1335
1271
1437
1561
1516
1484
1364
1335
1269
1437
1562
1528
1487
1368
1335
1273
1436
1560
1490
1487
1365
1335
1272
CAO
NO2 asymmetric stretching
NO2 symmetric stretching
Table 3
1H chemical shifts (ppm) of compounds (1–7).
Compound
H(6)
H(2)
H(5a)
H(3a)
H(5e)
Ax-NH
Eq-NH
10.1
9.97
10.0
9.99
9.84
9.87
9.96
CH2
CH3
OCH3
CH3
Picryl ring
Aromatic protons
1
2
3
4
5
6
7
5.01
4.98
4.96
4.96
4.89
4.87
4.92
4.74
4.75
4.72
4.72
4.63
4.61
4.66
3.39
3.38
3.33
3.33
3.34
3.41
3.36
3.23
3.19
3.19
3.18
3.15
3.19
3.19
2.75
2.75
2.75
2.75
2.67
2.72
2.69
9.41
9.41
9.50
9.45
9.19
9.31
9.32
1.07–1.40
1.04–1.39
1.03–1.38
1.04–1.38
1.04–1.38
1.04–1.42
1.04–1.36
0.74
0.75
0.74
0.75
0.76
0.76
0.74
–
–
–
–
3.78
3.78
–
–
–
–
–
–
–
2.31
8.61
8.60
8.59
8.60
8.59
8.59
8.60
7.43–7.52, 7.57–7.62
7.30–7.37, 7.59–7.66
7.56–7.60,
7.50–7.56, 7.68–7.74
7.01–7.06, 7.47–7.51
7.02–7.22
7.24–7.29, 7.43–7.48
axial NAH bond present in the protonated derivatives. The order of
the chemical shifts of the methine protons at C(2) and C(6) are not
reversed deq ꢁ dax rather than the magnetic anisotropic effect.
In order to determine the effect of protonation on chemical
shifts, the chemical shifts of picrates 1–7 were compared with
the corresponding piperidin-4-ones. Data in Table 4 reveal that
picrate formation deshields H(2) and H(6) to a greater extent. In
the picrate derivatives the two protons at nitrogen occupy axial
and equatorial orientations. The magnetic anisotropic effect of
the axial NAH bond is responsible for the greater downfield shift
observed on H(6) and H(2) in 1–7. It is also seen that axial methy-
lene proton H(5a) is deshielded to a greater extent and it can be
explained by syn 1,3-diaxial interaction. Picrate formation
deshields the alkyl protons at C(3) also.
It is seen that protonation shields carbonyl carbon by about
200 ppm. This is due to a decrease in the polarity of the C@O bond
due to the electrostatic effect of the positive charge on the nitrogen
atom. The decrease in the polarity of the C@O bond should
decrease the positive charge on the carbonyl carbon causing a
shielding on it. The 13C spectrum of 1 is shown in Fig. 3.
The 13C NMR spectra have been recorded for 1–7 and the chem-
ical shifts values are reproduced in Table 5. It is clearly indicated
that protonation shields all carbons. The shielding magnitude
observed on C(3) and C(5) carbons is more that of C(2) and C(6)
carbons. Due to protonation, the axial NAH bond experiences
severe syn 1,3-diaxial interaction with axial hydrogens at C(3)
and C(5) and due to these interactions pentyl protons at C(3) and
H(5a) proton are shielded and the corresponding carbons are

S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
435
Fig. 1. 1H NMR Spectrum of compound 1.
The NOESY spectrum of 1 is shown in Fig. 4. It is seen that NOE
between H(2) and H(3a) and that between H(6) and H(5) (i.e. H(5a)
and H(5e)) are strong. The aromatic proton at 7.43 ppm should
show strong NOE with H(3a) and H(5a). Obviously, these protons
must be the ortho protons of the phenyl ring group at C(2) and
C(6). Thus, the observed NOE of 1 supports the determined vicinal
coupling constant. For 1 these assignments were confirmed by
HSQC and HMBC spectra. The observed correlations in the HOMO-
COSY, HSQC, HMBC and NOESY spectra are given in Table 7.
Single crystal X-ray diffraction method
Fig. 2. Schematic representation of syn 1,3-diaxial interactions.
Single crystal measurement was made at 298 (2) K using the
stable crystal for data collection. Accurate lattice parameters were
determined from least square refinements of well centered reflec-
tions in the range 0.0722–0.02385.
Table 4
1H Chemical shift difference between piperidonesa and picrates (1–7).
The complex, 3t-pentyl-2r,6c-diphenylpiperidin-4one picrate
belongs to the monoclinic crystal system with space group P21/n.
The lattice parameters obtained are a = 15.343(4) Å, b = 11.926(3)
Compound
H(6)
H(2)
H(5a)
H(3a)
H(5e)
CH3
0.04
0.01
ꢁ0.12
ꢁ0.04
0.03
1
2
3
4
5
6
ꢁ0.95
ꢁ0.03
ꢁ0.03
ꢁ1.02
ꢁ0.89
ꢁ0.85
ꢁ1.04
ꢁ0.02
ꢁ0.02
ꢁ1.14
ꢁ1.00
ꢁ0.96
ꢁ0.66
0.27
0.18
ꢁ1.38
ꢁ0.64
ꢁ1.68
ꢁ0.62
ꢁ0.49
0.19
ꢁ0.71
ꢁ0.77
ꢁ0.54
ꢁ0.14
ꢁ0.24
ꢁ0.06
ꢁ0.18
ꢁ0.58
0.85
Å, c = 15.617(4) Å,
a = 90°, b = 92.870(5)°, c = 90° and the unit cell
volume is 2854.2 Å3. The crystallographic data and structure
refinements of 3t-pentyl-2r,6c-diphenylpiperidin-4one picrate
complex are given in Table 8.
0.03
a
Taken from Ref. [15].
The 3t-pentyl-2r,6c-diphenylpiperidin-4-one ion and picrate
ion appeared in crystalline lattice as protonated cation and depro-
tonated anion, respectively. Single crystal XRD structure reveals
that phenolic proton is transferred to the piperidine nitrogen atom
of 3t-pentyl-2r,6c-diphenylpiperidin-4-one. 3t-pentyl-2r,6c-diphe-
nylpiperidinium cation gives intermolecular hydrogen bonding
association with deprotonated picarte anions. The ORTEP diagram
of 3t-pentyl-2r,6c-diphenylpiperidin-4-one picrate is depicted in
Fig. 5.
The selected bond lengths, bond and dihedral angles are given
in Table 9. In the picrate anion, the CAO bond distance of the anion
shows characteristic value with O(2)AC(23) (1.243(3) Å) which is
intermediate between single and double bond lengths. The loss
of a proton from picric acid is confirmed by the lengthening of
the CAC bond. The C(23)AC(24) and C(23)AC(28) bond lengths
are 1.441(4) Å and 1.431(4) Å, respectively which are deviated
shielded. The 13C chemical shifts of picrates 1–7 were compared
with the corresponding piperidin-4-ones (Table 6).
For 3t-pentyl-2r,6c-diphenylpiperidin-4-one picrate 1, 1H-1H
COSY spectrum was also recorded to confirm the assignments.
The COSY spectrum reveals that the downfield signal at 3.39 ppm
is unambiguously assigned at H(5a) and it shows cross peak with
the doublet at 5.01 ppm. Therefore, the signal at 5.01 ppm is obvi-
ously due to the H(6) only. The upfield signal at 2.75 ppm H(5e)
shows cross peak with the doublet at 5.01 ppm. And also confirm
the signal at 5.01 ppm as due to H(6). The signal at 3.23 ppm
H(3a) shows cross peak with the doublet at 4.74 ppm and this con-
firms the assignment of the signal at 4.74 ppm for H(2).

436
S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
Fig. 3. 13C NMR Spectrum of compound 1.
Table 5
13C chemical shifts (ppm) of compounds (1–7).
Compound
C(2)
C(3)
C(5)
C(6)
CH2
CH3
C@O
CH3
OCH3
CAO
Aromatic Carbons
1
2
3
4
5
6
63.01
61.98
62.11
62.09
62.34
62.93
50.38
50.31
50.21
50.06
50.44
50.47
44.28
44.14
44.04
43.91
44.34
44.23
58.65
57.79
57.89
57.90
57.99
58.34
21.59–31.16
21.60–31.16
21.58–31.13
21.62–31.16
21.64–31.20
21.62–31.11
13.62
13.63
13.61
13.64
13.65
13.61
203.14
202.91
202.78
202.67
203.43
203.40
–
–
–
–
–
–
–
–
–
–
160.83
160.79
160.82
160.69
160.81
160.27
124.41–141.76
115.43–141.76, 161.27–163.78
124.46–141.71
122.79–141.73
113.90–141.74, 159.93–159.95
111.42–141.63, 148.45–149.46
55.20
55.04
56.04
–
7
62.74
50.38
44.37
58.37
21.62–31.18
13.62
203.28
20.65
160.70
124.49–141.72
Table 6
13C Chemical shift difference between piperidonesa and picrates (1–7).
111.7(3)° angles joining the deprotonated hydroxyl group is signif-
icantly smaller than the expected angle (120°) for sp2 hybridised
carbon. On comparison of bond lengths of C(23)AC(24) 1.441(4)
Å, C(23)AC(28) 1.441(4) Å, C(24)AC(25) 1.369(5) Å, C(27)AC(28)
1.373(4) Å and CAO, 1.243(3) Å with normal bond lengths of
CAC, C@C and CAO, it is found that the C(23)AC(24),
C(23)AC(28) (1.4 Å) have single bond character and C(24)AC(25),
C(27)AC(28) (1.39 Å) have double bond character. The CAO
(1.21 Å) also carries double bond character. This indicates that
the complex possesses more quinonoid character than benzenoid
character.
Compound
C(2)
C(3)
C(4)
C(5)
C(6)
CH3
1
2
3
4
5
6
4.23
0.49
0.45
4.3
4.26
4.08
6.72
ꢁ5.55
0.3
6.89
6.86
5.56
6.19
0.38
0.30
5.61
6.30
5.16
7.31
ꢁ13.05
0.62
7.5
7.43
7.31
3.23
0.59
0.61
3.25
3.26
3.28
0.33
0.00
0.03
0.38
0.37
0.37
a
Taken from Ref. [15].
The twist angles of the three nitro groups attached to the ben-
zene ring are [O(3)AN(2)AO(4) = 118.7(5)°, O(5)AN(3)AO(6) =
123.3(4)° and O(7)AN(4)AO(8) = 121.3(3)°. The twisting nature of
the nitro groups in picrate ion shows that the ortho nitro groups
are deviate away from the plane of the benzene ring, possibly as
a result of steric interaction with the phenloic group at C(23). It
is found that this deviation facilitates at O(3) in this nitro group
taking part in NAHꢄ ꢄ ꢄO hydrogen bond formation with the cations.
However, the para nitro group lies the plane of the benzene ring.
To confirm the above ascertained stereochemistry of 1 by 1D
and 2D NMR studies, single crystal XRD analysis has been per-
formed and as a result, the following information about the
puckering in the piperidone ring N(1)AC(7)AC(8)AC(9)A
C(10)AC(11) has been acquired. An equatorial orientation of the
phenyl group is witnessed by its torsional angles 173.9(2)°
from the standard aromatic CAC bond lengths (1.40 Å). These dif-
ferences are attributed to the loss of a hydroxyl proton of picric
acid, leading to conversion from the neutral to the anionic state
where the negative charge is constrained to lie in the ring. The
crystal packing diagram of 3t-pentyl-2r,6c-diphenylpiperidin-4-
one picrate is shown in Fig. 6.
The repulsive interactions of the deprotaneted oxygen atom O
with the electron withdrawing NO2 groups attached in the ortho
positions in relation to the O are responsible for the shortening
of the C(24)AC(25), 1.369(5) Å and C(27)AC(28), 1.373(4) Å bonds
as well as for the significant difference between the internal
CACAC angles within the ring. Both CACAC angles joining the
NO2 groups C(23)AC(24)AC(25), 124.7(3)° and C(23)AC(27)A
C(28), 123.8(3)° are significantly greater and C(24)AC(23)AC(28),

S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
437
Fig. 4. NOESY spectrum of compound 1.
Table 7
Correlation in HOMOCOSY, NOESY, HSQC and HMBC spectra of compound 2 (d, ppm).
1H NMR signal
5.01 (H(6))
Correlation in HOMOCOSY
Correlation in NOESY
Correlation in HSQC
58.65 (C(6))
Correlation in HMBC
–
3.39(H(5a)), 2.75(H(5e)), 9.41
(axial NH)
3.39(H(5a)), 2.75(H(5e)), 7.43–7.62
Aromatic proton
4.74 (H(2))
3.23(H(3a)), 9.41 (axial NH)
2.75(H(5e)), 5.01(H(6))
3.39(H(3a)), 7.43–7.62 Aromatic proton 63.01 (C(2))
127.07–141.76, (Aromatic Carbon),
3.39 (H(5a)
3.23 (H(3a)
2.75 (H(5e)
)
)
)
2.75(H(5e)), 5.01 (H(6)), 4.74 (H(2)),
7.43–7.62 Aromatic proton
44.28 (C(5))
58.65 (C(6), ), 127.07–
141.76, (Aromatic
63.01 (C(2), ), 203.14 (C(4), a),
a
), 203.14 (C(4),
a
1.07–1.40 (CH2), 4.74(H(2))
4.74 (H(2)), 1.07–1.40 (CH2), 7.43–7.62 50.38 (C(3))
Aromatic proton
a
3.39(H(5a)), 5.01(H(6))
0.74(CH3), 1.07–1.40 (CH2),
3.39(H(5a)), 5.01 (H(6))
1.07–1.40 (CH2)
0.74(CH3)
44.28 (C(5))
13.62 (CH3)
21.59–31.16 (CH2)
50.38 (C(3), b), 203.14 (C(4), b)
–
21.59–31.16 (CH2, a), 13.62 (CH3, a),
0.74 (CH3)
1.07–1.40 (CH2)
1.07–1.40 (CH2),3.23 (H(3a)
)
63.01 (C(2),
a)
9.41 (axial NH)
10.1 (equatorial NH),
5.01(H(6)), 4.74(H2)
10.1(equatorial NH), 3.39(H(5a)
)
–
–
10.1 (equatorial NH) 9.41(axial NH)
8.61 (pic)
9.41(axial NH), 3.39(H(5a)
–
)
–
–
–
127.07–141.76 (Aromatic
Carbon)
127.07–141.76, 160.83 (Aromatic Carbon)
7.43–7.62 (Aromatic –
Proton)
4.74 (H2), 3.23(H3a),
3.39(H5a), 5.01 (H6)
127.07–141.76, 160.83
(Aromatic Carbon)
58.65 (C6), 63.01 (C2)
[C(8)AC(9)AC(10)AC(18)]
and
ꢁ174.8(2)°
[N(1)AC(11)A
tertiary amino group along with an equatorial orientation of all
other substituents.
C(10)AC(18)]. The torsion angles of the phenyl groups on both
sides of the amino group are ꢁ173.8(2)° [C(6)AC(7)AC(8)AC(9)]
and ꢁ176.9(2)° [C(9)AC(10)AC(11)AC(12)] which support the
equatorial orientation of the phenyl groups on both sides of the
amino group. The N-atom of the piperidone molecule shows sp3
hybridization, which can be noticed from the angles around that
nitrogen. The NAH(1a) group also adopts an equatorial disposition
to the best plane of the piperdone ring, which is evidenced from
the torsion angles H(1b)AN(1)AC(7)AC(8) = 176.4° and H(1b)A
N(1)AC(11)AC(10) = 176.9° and H(1a)AN(1)AC(7)AC(8) = ꢁ66.6°
and H(1a)AN(1)AC(11)AC(10) = 59.9°. Overall, the detailed crys-
tallographic studies such as asymmetry parameters, ring puckering
parameters and torsion angles calculated for 1 proved that the pip-
eridone ring exists in a slightly distorted chair conformation with
equatorial orientation of the phenyl rings on both sides of the
Antimicrobial activity
All the synthesized compounds were screened for in vitro anti-
bacterial activity. The antibacterial activity was evaluated against
different bacterial strains such as B. subtilis-Bacillus subtilis, S. aur-
eus, E. coli-Escherichia coli and V. cholerae-Vibrio cholerae. Minimum
inhibitory concentration (MIC) values were determined using
standard agar method. Ciprofloxacin is used as a standard for the
comparison of antibacterial activity. DMSO is used as solvent con-
trol. MIC values of the tested compounds are presented in Table 10.
The unsubstituted phenyl groups at C(2) and C(6) of 3t-pentyl-
2r,6c-diphenylpiperidin-4-one picrates 1 showed excellent activity
against B. subtilis and S. aureus whereas against E. coli and

438
S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
Table 8
Crystal data and structure refinement for 1.
Compound
1
Empirical formula
Formula weight (Mr)
Temperature (K)
Wavelength (Å)
Crystal system
C
28H30N4O8
550.56
298(2)
0.71073
Monoclinic
Space group
P21/n
Unit cell dimensions (Å)
a = 15.343(4)
b = 11.926(3)
c = 15.617(4)
2854.2(13)
a
= 90
b = 92.870(5)
= 90
c
Volume (Å3)
Z
4
Density (calculated) (Mg/m3)
1.281
0.095
1160
Absorption coefficient (mmꢁ1
F(000)
)
Crystal size (mm)
Theta range for data collection (°)
Index ranges
0.35 ꢂ 0.30 ꢂ 0.25
1.82–25.00
ꢁ18 6 h 6 18, ꢁ14 6 k 6 14, ꢁ18 6 l 6 18
26863
Reflections collected
Independent reflections
Completeness to theta = 25.00° (%)
Refinement method
5028 [R(int) = 0.0368]
100.00
Full-matrix least-squares on F2
5028/0/361
Data/restraints/parameters
Goodness-of-fit on F2
1.059
R1, wR2 [I > 2
r
(I)]
0.0722, 0.2143
R1, wR2 (all data)
0.1026, 0.2385
0.571 and ꢁ0.305
Largest diff. peak and hole (e Åꢁ3
)
Fig. 5. The ORTEP diagram of compound 1.
V. cholerae had no effect even at 200
on 1 i.e. compound 2 had no improvement against all the tested
bacterial strains, but against B. subtilis had no effect even at
200 lg/mL. Also, the chloro substituent on 1, that is, compound 3
showed an appreciable improvement against E. coli and V. cholerae
and avtivity was noted against B. subtilis and S. aureus. Introduction
of p-methoxy phenyl group at C(2) and C(6) position of 1 (com-
pound 5) exhibited similar activity against B. subtilis and S. aureus
except E. coli and V. cholerae. Substitution of p-methylphenyl
l
g/mL. The fluoro-substituent
groups in place of phenyl groups at C(2) and C(6) positions in 1
(compound 7) has shown activity against E. coli, B. subtilis and S.
aureus while against V. cholerae has improved activity. The incor-
poration of bromo functionality at the para position of phenyl
group in 1 (compound 4) showed excellent activity against B. sub-
tilis and S. aureus whereas poor activity was noted against E. coli
and V. cholerae. Replacement of methoxy group and 3,4-dimethoxy
in 5 (compound 6) retained the same activity towards S. aureus,
while for the E. coli and V. cholerae increased activity was noted

S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
439
Table 9
Bond lengths (Å), Bond angles (°) and Torsional angles (°) for 1.
Bond length
Bond angle
Torsional angle
O(1)AC(9)
O(7)AN(4)
N(1)AC(7)
N(1)AC(11)
C(23)AO(2)
O(8)AN(4)
C(7)AC(6)
1.212(3)
1.187(4)
1.503(3)
1.504(3)
1.243(3)
1.198(3)
1.511(4)
1.524(4)
1.515(4)
1.551(4)
1.451(4)
1.486(4)
1.378(4)
1.394(4)
1.381(4)
1.385(4)
1.431(4)
1.441(4)
1.508(4)
1.521(4)
1.365(4)
1.376(4)
1.375(4)
1.215(5)
1.218(5)
1.449(5)
1.145(5)
1.234(5)
1.441(5)
1.373(4)
1.386(4)
1.372(5)
1.520(5)
1.380(5)
1.356(5)
1.369(5)
1.470(6)
1.507(7)
1.565(10)
C(7)AN(1)AC(11)
N(1)AC(7)AC(6)
N(1)AC(7)AC(8)
114.04(19)
110.7(2)
109.1(2)
113.8(2)
110.3(2)
108.1(2)
114.2(2)
121.3(3)
118.0(3)
120.7(3)
111.9(2)
119.9(3)
118.4(3)
119.3(3)
122.2(3)
126.7(3)
121.6(3)
111.7(3)
112.9(2)
105.9(2)
114.6(2)
120.9(3)
118.8(2)
119.5(2)
121.7(2)
120.9(3)
123.3(4)
117.8(4)
118.7(4)
118.7(5)
121.5(4)
119.1(4)
123.8(3)
116.2(3)
120.1(3)
122.0(3)
123.5(3)
114.5(2)
124.7(3)
C(6)AC(1)AC(2)AC(3)
C(1)AC(2)AC(3)AC(4)
C(2)AC(3)AC(4)AC(5)
C(11)AN(1)AC(7)AC(6)
C(11)AN(1)AC(7)AC(8)
C(7)AC(6)AC(1)AC(2)
N(1)AC(7)AC(8)AC(9)
N(1)AC(7)AC(6)AC(1)
N(1)AC(7)AC(6)AC(5)
N(1)AC(11)AC(10)AC(9)
N(1)AC(11)AC(10)AC(18)
N(1)AC(11)AC(12)AC(17)
N(1)AC(11)AC(12)AC(13)
C(7)AN(1)AC(11)AC(10)
C(7)AN(1)AC(11)AC(12)
C(8)AC(9)AC(10)AC(18)
C(8)AC(7)AC(6)AC(1)
0.3(5)
1.2(6)
ꢁ1.8(6)
C(6)AC(7)AC(8)
ꢁ179.1(2)
54.9(3)
N(1)AC(11)AC(12)
N(1)AC(11)AC(10)
C(12)AC(11)AC(10)
O(7)AN(4)AO(8)
O(7)AN(4)AC(28)
O(8)AN(4)AC(28)
C(9)AC(8)AC(7)
C(16)AC(17)AC(12)
C(1)AC(6)AC(5)
C(1)AC(6)AC(7)
176.5(3)
ꢁ49.5(3)
82.8(3)
C(7)AC(8)
C(11)AC(12)
C(11)AC(10)
N(4)AC(28)
C(8)AC(9)
C(17)AC(16)
C(17)AC(12)
C(6)AC(1)
ꢁ99.4(3
60.0(2)
ꢁ174.8(2)
50.7(3)
ꢁ130.2(2)
ꢁ61.6(2)
172.9(2)
173.9(2)
ꢁ153.8(2)
23.9(4)
ꢁ173.8(2)
ꢁ176.9(2)
ꢁ51.7(3)
ꢁ71.2(3)
107.9(3)
ꢁ122.7(3
55.8(3)
C(5)AC(6)AC(7)
C(6)AC(5)
O(2)AC(23)AC(28)
O(2)AC(23)AC(24)
C(24)AC(23)AC(28)
C(9)AC(10)AC(18)
C(9)AC(10)AC(11)
C(18)AC(10)AC(11)
C(2)AC(1)AC(6)
C(13)AC(12)AC(17)
C(13)AC(12)AC(11)
C(17)AC(12)AC(11)
C(15)AC(16)AC(17)
O(5)AN(3)AO(6)
O(6)AN(3)AC(26)
O(5)AN(3)AC(26)
O(3)AN(2)AO(4)
O(3)AN(2)AC(24)
O(4)AN(2)AC(24)
C(23)AC(28)AC(27)
C(27)AC(28)AN(4)
C(23)AC(28)AN(4)
O(1)AC(9)AC(8)
C(23)AC(28)
C(23)AC(24)
C(10)AC(9)
C(10)AC(18)
C(1)AC(2)
C(8)AC(7)AC(6)AC(5)
C(6)AC(7)AC(8)AC(9)
C(9)AC(10)AC(11)AC(12)
C(12)AC(11)AC(10)AC18
C(10)AC(11)AC(12)AC(17)
C(10)AC(11)AC(12)AC(13)
C(7)AC(8)AC(9)AO(1)
C(7)AC(8)AC(9)AC(10)
C(16)AC(17)AC(12)AC(11)
C(16)AC(17)AC(12)AC(13)
C(12)AC(17)AC(16)AC(15)
C(7)AC(6)AC(5)AC(4)
C(12)AC(13)
C(16)AC(15)
N(3)AO(6)
N(3)AO(5)
N(3)AC(26)
N(2)AO(3)
N(2)AO(4)
N(2)AC(24)
C(27)AC(28)
C(13)AC(14)
C(14)AC(15)
C(18)AC(19)
C(26)AC(27)
C(25)AC(26)
C(24)AC(24)
C(19)AC(20)
C(20)AC(21)
C(21)AC(22)
ꢁ179.9(3)
1.0(4)
ꢁ0.9(5)
ꢁ177.0(3)
0.8(5)
118.7(3)
ꢁ59.8(3)
170.2(3)
ꢁ68.4(3)
ꢁ179.6(3)
176.4
C(1)AC(6)AC(5)AC(4)
C(11)AC(10)AC(9)AO(1)
C(11)AC(10)AC(9)AC(8)
C(11)AC(10)AC(18)AC(19)
C(9)AC(10)AC(18)AC(19)
C(11)AC(12)AC(13)AC(14)
H(1b)AN(1)AC(7)AC(8)
H(1b)AN(1)AC(11)AC(10)
H(1a)AN(1)AC(11)AC(10)
H(1a)AN(1)AC(7)AC(8)
O(1)AC(9)AC(10)
C(8)AC(9)AC(10)
C(23)AC(24)AC(25)
176.9
59.9
ꢁ66.6
and for B. subtilis decreased activity was noted. Comparison of anti-
bacterial potency of compounds (1–7) is shown in Fig. 7.
MIC ð
l
g=mLÞ of refernce compound
Antimicrobial potency ð%Þ ¼
MIC ð
lg=mLÞ of tested compound
ꢂ 100
All the synthesized compounds were screened for in vitro anti-
fungal activity. The antifungal activity was evaluated against dif-
ferent fungal strains such as A. niger, C. albicans, A. flavus and T.
mentagraphytes. Minimum inhibitory concentration values were
determined using standard agar method. Cetramazole used as a
standard for the comparison of antibacterial activity. DMSO is used
as solvent control. MIC values of the tested compounds are pre-
sented in Table 10.
All the synthesized compounds were found to show good anti-
fungal activity. From the antifungal activity data shown Table 10, it
is observed that compounds 2, 3, 4 and 7 have good activity against
C. albicans and T. mentagrophytes-Trichophyton mentagrophytes
whereas there was no effect against A. niger-Aspergillus niger and
A. flavus. Compound 1 showed excellent activity against C. albicans
and good activity against T. mentagraphytes while against A. niger
and A. flavus poor activity was noted.
Introduction of methoxy group on 4-phenyl group at C(2) and
C(6) positions of piperidine ring 1 (compound 5) exhibited excel-
lent activity against C. albicans, A. flavus and T. mentagraphytes
whereas against A. niger poor activity was noted.
Fig. 6. Packing diagram of compound 1.
Substitution of another methoxy group on phenyl group at C(2)
and C(6) positions of piperidine ring 5 (compound 6) exhibited
excellent activity against C. albicans-Candida albicans whereas poor
activity was noted against A. flavus-Aspergillus flavus and T. menta-
graphytes and there was no effect against A. niger. Comparison of
antifungal potency of compounds (1–7) is shown in Fig. 8.

440
S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
Table 10
Antibacterial and Antifungal activities of compounds (1–7).
Compound
Minimum inhibitory concentration in
Antibacterial
lg/mL
Antifungal
E. coli
B. subtilis
S. aureus
V. cholerae
A. niger
C. albicans
A. flavus
T. mentagraphytes
1
2
3
4
5
6
7
200
200
100
200
50
6.25
200
6.25
6.25
12.5
50
6.25
6.25
–
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
–
200
200
100
100
200
25
100
6.25
–
200
200
200
200
200
200
100
–
6.25
6.25
6.25
6.25
6.25
6.25
6.25
–
100
200
50
100
12.5
25
100
–
6.25
25
6.25
6.25
6.25
6.25
100
6.25
–
25
200
6.25
–
Ciprofloxacin
Cetramazole
6.25
6.25
6.25
chair conformation with equatorial orientation of all the substitu-
ents. Due to protonation, the axial NAH bond experiences severe
syn 1,3-diaxial interaction with axial hydrogens at C(3) and C(5)
and due to these interactions the protons H(3a) and H(5a) are
deshielded and corresponding carbons C(3) and C(5) shielded.
The chemical shifts of the heterocyclic ring protons are influenced
by the picrate anion. All the piperdone ring protons are deshielded
whereas carbons are shielded. All the newly synthesized com-
pounds were screened for their antibacterial and antifungal activ-
ities. Most of the compounds showed good antibacterial and
antifungal activities. However, the antibacterial and antifungal
activities are significantly influenced by the aromatic substituents.
E. coli
B. subtilis
S. aureus
V. cholerae
100
80
60
40
20
0
Acknowledgment
The authors would like to acknowledge University Grant Com-
mission of India for providing Major research project No: 42-343/
2013(SR) and Annamalai University for providing necessary
facilities.
1
2
3
4
5
6
7
Compound
Fig. 7. Comparison of antibacterial potency of compounds (1–7).
Appendix A. Supplementary material
A. niger
C. albicans
A. Flavus
T. Mentagraphytes
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2014.
06.096.
100
References
80
60
40
20
0
[1] E.L. Eliel, M.H. Gianni, T.N.H. Williams, Tetrahedron Lett. 17 (1962) 741–747.
[2] N.S. Bhacca, D.H. Williams, Applications of NMR Spectroscopy in Organic
Chemistry, Holden-Day.inc., 1964. p. 184.
[3] H. Booth, J.H. Little, Tetrahedron 23 (1967) 291–297.
[4] J.L. Sudmeier, C.N. Reilley, Anal. Chem. 36 (1964) 1698–1706.
[5] J.L. Sudmeier, C.N. Reilley, Anal. Chem. 36 (1964) 1707–1712.
[6] I. Morishima, K. Yoshikawa, K. Okada, K. Goto, J. Am. Chem. Soc. 95 (1973) 165–
171.
[7] J.E. Sarneski, H.L. Suprement, F.K. Molen, C.N. Reilley, Anal. Chem. 47 (1975)
2116–2124.
[8] M.U. Hasan, Mohammed Arab, K. Pandiarajan, R. Sekar, Magn. Reson. Chem. 23
(1985) 292–295.
1
2
3
4
5
6
7
Compound
[9] K. Pandiarajan, R.T. Sabapathymohan, M.U. Hasan, Magn. Reson. Chem. 24
(1986) 312–316.
Fig. 8. Comparison of antifungal potency of compounds (1–7).
[10] N. Arumugam, M. Sundharavadivelu, S. Sivasubramanian, D.A. Wilson, Magn.
Reson. Chem. 25 (1987) 869–871.
[11] A. Manimekalai, J. Jayabharathi, Indian J. Chem. 45B (2006) 1686–1691.
[12] V. Vimalraj, K. Pandiarajan, Magn. Reson. Chem. 49 (2011) 682–687.
[13] P. Gayathri, J. Jayabharathi, G. Rajarajan, A. Thiruvalluvar, R.J. Butcher, Acta
Cryst. E 65 (2009) o3083.
[14] S. Subashchandrabose, H. Saleem, Y. Erdogdu, G. Rajarajan, V. Thanikachalam,
Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 82 (2011) 260–269.
[15] S. Savithiri, G. Rajarajan, V. Srividhya, J. Jijesh, V. Thanikachalam, J.
Jayabharathi, M. Arockia doss, Can. Chem. Trans. 21 (2014) 201–220.
[16] M. Rubiralta, E. Giralt, A. Diel, Elsevier, Amsterdam, 1991. pp. 225–312.
[17] E.I. Subbagh, S.M. Abu-Zaid, M.A. Mahran, F.A. Badria, A.M. Ai-obaid, J. Med.
Chem. 43 (2000) 2915–2921.
Our studied compounds have good antimicrobial activities
compared to standard drugs as well as p-phenyledediame [26]
and 2,6-diaminopyridine picrates [27].
Conclusions
The NMR spectral and XRD data of bond length, bond and tor-
sional angles suggest that the title compounds exist in normal
[18] R.V. Perumal, M. Adiraj, P. Shanmugapandiyan, Indian Drugs 38 (2001) 156–
159.

S. Savithiri et al. / Journal of Molecular Structure 1075 (2014) 430–441
441
[19] C. Ramalingam, Y.T. Park, S. Kabilan, Eur. J. Med. Chem. 41 (2006) 683–696.
[20] S. Balasubramanian, G. Aridoss, P. Parthiban, Biol. Pharm. Bull. 29 (2006) 125–
130.
[21] S. Murugesan, S. Perumal, S. Selvaraj, Chem. Pharm. Bull. (Tokyo) 54 (2006)
795–801.
[24] J. Jayabharathi, A. Manimekalai, T. Consalata vani, M. Padmavathy, Eur. J. Med.
Chem. 42 (2007) 593–605.
[25] J. Jayabharathi, A. Manimekalai, R. Selvaraj, A. Praveena, Med. Chem. Res. 15
(2007) 452–462.
[26] I.M. Khan, Afaq Ahmed, M. Oves, Spectrochim. Acta Part A Mol. Biomol.
Spectrosc. 77 (2010) 1059–1064.
[27] I.M. Khan, A. Ahmad, M.F. Ullah, J. Photochem. Photobiol., B 103 (2011) 42–49.
[22] A. Manimekalai, J. Jayabharathi, L. Rufina, R. Mahendhiran, Indian J. Chem. 42B
(2003) 2074–2079.
[23] Sameer Rastogi, Harshita Rastogi, Indian J. Chem. 49B (2010) 547–553.