Conformational analysis of 2,6-diarylpiperidin-4-one hydrazones by X-ray diffraction and NMR spectroscopy

Article abstract of DOI:10.1016/j.molstruc.2014.10.015

A new series of 3t-alkyl-2r,6c-diarylpiperidin-4-one N-isonicotinoylhydrazones (12-22) derived from the condensation of 3t-alkyl-2r,6c-diarylpiperidin-4-ones with isoniazid (INH) is reported. Newly synthesized compounds have been characterized by using el

Full text of DOI:10.1016/j.molstruc.2014.10.015

Journal of Molecular Structure 1083 (2015) 27–38
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Conformational analysis of 2,6-diarylpiperidin-4-one hydrazones
by X-ray diffraction and NMR spectroscopy
c
a,
C. Sankar a,b, , S. Umamatheswari , K. Pandiarajan
⇑
⇑
a Department of Chemistry, Annamalai University, Annamalainagar 608 002, India
b Department of Chemistry, TRP Engineering College, Irungalur, Tiruchirappalli 626 126, India
c Department of Chemistry, Govt. Arts College for Women, Pudukkottai, 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
A series of 3t-alkyl-2r,6c-diarylpiperidin-4-one N-isonicotinoylhydrazone (11–22) derivatives have been
synthesized.
ꢀ
Conformational analysis study of 3t-
alkyl-2r,6c-diarylpiperidin-4-one N-
isonicotinoyl hydrazone.
ꢀ
ꢀ
ꢀ
In solution compounds exist in two
forms, there are the E and Z forms.
Single crystal X-ray diffraction
analysis.
In solid state the compound have E
configuration about the C@N bond.
N
R
O
O
H
R
C
N
H3C
R1
+
N
a
R1
H
O
H
O
b
N
H
R1
R1
R1
R1
11-22
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 3t-alkyl-2r,6c-diarylpiperidin-4-one N-isonicotinoylhydrazones (12–22) derived from the
condensation of 3t-alkyl-2r,6c-diarylpiperidin-4-ones with isoniazid (INH) is reported. Newly synthe-
sized compounds have been characterized by using elemental analysis, IR, 1H, 13C and 2D NMR spectral
analysis. Moreover, representative crystal structure of 3,3-dimethyl-2r,6c-diarylpiperidin-4-one N-ison-
icotinoylhydrazone has been determined by X-ray diffraction analysis.
Received 28 February 2014
Received in revised form 9 October 2014
Accepted 9 October 2014
Available online 29 October 2014
NMR data revealed that two geometrical isomers (E and Z) are formed in all cases, and the piperidine
ring adopts chair conformation. Whereas in solid state the compounds have E configuration about the
C@N bond. These conclusions have also been confirmed by X-ray data of compound 16.
Ó 2014 Elsevier B.V. All rights reserved.
Keywords:
Piperdin-4-ones
Isoniazid
Hydrazones
NMR
Conformation
Single crystal
Introduction
⇑
Corresponding authors at: Department of Chemistry, TRP Engineering College,
Irungalur, Tiruchirappalli 626 126, Tamil Nadu, India. Tel.: +91 9944585257 (C.
Sankar).
The NMR techniques are useful for the conformational analysis
too. 1H and 13C NMR techniques have been extensively applied in
deriving stereodynamical information about a wide variety of sys-
tems. These techniques gives information about the influence of
E-mail addresses: sankschem@gmail.com (C. Sankar), prof.kprajan@yahoo.com
(K. Pandiarajan).
http://dx.doi.org/10.1016/j.molstruc.2014.10.015
0022-2860/Ó 2014 Elsevier B.V. All rights reserved.

28
C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
electronic and conformational effects on chemical shifts [1,2]. Cou-
pling constants can be used for conformational analysis since they
depend on the torsional angle between two protons in adjacent
carbons [3].
Continuing our studies on the synthesis of heterocyclic com-
pounds with potential therapeutic activity, we report in this paper
the synthesis and the structural study of a series of isoniazide
hydrazones (12–22) derived from 3t-alkyl-2r,6c-diarylpiperidin-
4-ones (1–11) characterized by IR and NMR spectroscopy. The
unambiguous assignment of all proton and carbon resonances
was achieved by double resonance experiments. The structure of
3,3-dimethyl-2r,6c-diarylpiperidin-4-one N-isonicotinoylhydraz-
one (16) in the solid state was determined by X-ray diffraction.
with ethanol–ether (1:5) mixture. The hydrochloride was sus-
pended in acetone, and made alkaline using strong ammonia solu-
tion. On dilution with excess of water, the base was precipitated
which was filtered, vacuum dried and recrystallized from absolute
alcohol.
Synthesis of 2r,6c-diarylpiperidin-4-one N-isonicotinoylhydrazones
(12–22)
A
mixture of 3t-alkyl-2r,6c-diarylpiperidin-4-ones (1–11)
(1.0 mmol), isoniazid (1.5 mmol) in methanol and few drops of
acetic acid was added and refluxed for 1–2 h. On the completion
of reaction a solid mass was formed. After cooling to room temper-
ature the precipitate was filtered and washed with cold mixture of
ethanol and water. The crude product was recrystallized from eth-
anol. The results of elemental analysis and IR data are given in
Tables 1 and 2. Elemental analysis shows excellent agreement
between calculated and experimental values. Spectroscopic data
for compounds 12–22 are presented below.
Experimental
Purchasing materials and recording spectra
All the solvents and chemicals (INH) were purchased from
Sigma–Aldrich and were used as received and the purity of the
compounds was checked by TLC. The melting points were recorded
in open capillaries and are uncorrected. IR spectra were recorded in
KBr (pellet forms) on AVATAR-330 FT-IR spectrophotometer
(Thermo Nicolet) and noteworthy absorption levels (reciprocal
centimeters) alone are listed. 1H and 13C NMR spectra of 12–22
have been recorded on a BRUKER DRX 500 NMR spectrometer
operating at 500.03 MHz for 1H and 125.75 MHz for 13C, in
DMSO-d6. The following spectral parameters were used 1H; acqui-
sition time = around 3.0 s, number of scans = around 100 s, number
of data points = 32 K and special with = 5000 Hz. 13C; acquisition
time = around 0.5 s, number of scans = around 1000, number of
data points = 32 K and special with = 30,000 Hz. 1H–1H COSY,
HSQC, HMBC spectra were recorded on a BRUKER DRX 500 MHz
NMR spectrometer using standard parameters. All NMR measure-
ments were made on 5 mm NMR tubes. The solutions were pre-
pared by dissolving about 10 mg of the compound in 0.5 mL of
DMSO-d6.
2r,6c-Diphenylpiperidin-4-one
isonicotinylhydrazone
(12). Pale
yellow powder, yield 95%, mp: 172–173 °C; 1H NMR: d = 3.93 (d,
J2a,3a = 11.0 Hz; 1H, H-2a), 3.85 (d, J5a,6a = 12.3 Hz; 1H, H-6a), 2.42
(t, 1H, H-3a), 2.58 (d, J3a,3e = 12.8 Hz, 1H, H-3e), 2.04 (t, 1H,
H-5a), 3.14 (d, 1H, H-5e), 2.88 (bs, 1H, NH), 11.04 (s, 1H, ACOANHA),
8.71 (d, 2H, pyridine a), 7.72 (d, 2H, pyridine b), 7.73 (d, 4H, H-o,
H-o0), 7.35-7.48 (dd, 4H, H-m, H-m0), 7.27 (m, 2H, H-p, H-p0) ppm;
13C NMR: d = 60.84 (C-2), 59.62 (C-6), 43.25 (C-3), 36.80 (C-5),
163.33 (C@O), 161.98 (C@N), 149.94 (pyridine a), 121.59 (pyridine
b), 141.02 (pyridine ipso carbon), 143.89 (C-20, C-60), 126.71,
126.51 (C-o, C-o0), 128.12 (C-m, C-m0), 127.03 (C-p, C-p0) ppm.
3t-Methyl-2r,6c-diphenylpiperidin-4-one isonicotinylhydrazone (13). White
powder, yield 94%, mp: 209–210 °C; 1H NMR: d = 3.53 (d, J2a,3a = 9.8 Hz,
1H, H-2a), 3.87 (d, J5a,6a = 11.5,Hz, 1H, H-6a), 2.62 (sextet, 1H, H-3a), 2.16
(t, 1H, H-5a), 3.16 (d, J5a,5e = 12.8 Hz, 1H, H-5e), 2.71 (s, 1H, NH), 11.06 (s,
Table 2
Characteristic IR stretching frequencies (cmꢁ1) of compounds 12–22.
Compound
C@O
C@N
NAH (ring)
NH (amide)
Material synthesis
12
13
14
15
16
17
18
19
20
21
22
1661
1651
1644
1649
1650
1649
1652
1650
1652
1650
1651
1511
1546
1524
1510
1545
1546
1548
1545
1544
1547
1549
3303
3311
3239
3309
3311
3292
3287
3287
3309
3326
3258
3167
3183
3189
3173
3183
3189
3186
3178
3204
3181
3188
Synthesis of 2r,6c-diarylpiperidin-4-ones (1–11)
The parent 2r,6c-diarylpiperidin-4-one (1–11) were synthe-
sized through Mannich reaction by adopting literature methods
[4]. A mixture of ketone (0.1 mol), dried ammonium acetate
(0.1 mol), appropriate benzaldehyde (0.2 mol) in ethanol (30 ml)
and heated to simmering carefully. It was kept at room tempera-
ture for 12 h. Dry ether (50 ml) was added followed by concen-
trated hydrochloric acid (30 ml) and cooled in ice water. The
precipitated hydrochloride was filtered and washed repeatedly
Table 1
Physical data and analytical data of compounds 12-22.
Compounds
Yield (%)
mp (°C)
Calculated
% C
Experimental
% C
% H
% N
% H
% N
12
13
14
15
16
17
18
19
20
21
22
90
91
90
85
89
75
72
94
85
65
62
172–173
209–210
210–212
184–185
216–217
206–207
180–182
210–211
196–197
165–166
185–187
75.50
74.91
63.52
68.49
75.28
75.95
70.66
64.19
69.05
–
5.94
6.24
4.85
5.23
6.52
7.03
6.54
5.13
5.52
–
15.12
14.57
12.35
13.32
14.05
13.13
12.21
11.98
12.89
–
74.55
73.86
63.53
67.40
75.24
77.90
70.62
64.21
69.08
–
5.88
6.20
4.80
5.21
6.55
7.01
6.57
5.09
5.47
–
15.07
14.54
12.30
13.36
13.09
13.15
12.26
11.96
12.76
–
–
–
–
–
–
–

C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
29
1H, COANHA), 0.84 (d, J3a,Me = 6.4 Hz, 3H, ACH3 at C-3), 8.71 (d, 2H, pyr-
α
idine a
), 7.72 (d, 2H, pyridine b), 7.49 (d, 4H, H-o, H-o0), 7.23-7.37 (m, 6H,
H-m, H-m0, H-p, H-p0); 13C NMR: d = 69.39 (C-2), 60.92 (C-6), 45.54 (C-3),
37.61 (C-5), 12.18 (CH3 at C-3), 168.80 (C@O), 156.84 (C@N), 149.49
N
β
γ
(pyridine
a
), 123.82 (pyridine b), 140.88 (pyridine ipso carbon), 142.35,
O
H
143.00 (C-20, C-60), 127.59, 127.84 (C-o, C-o0), 128.68, 128.489 (C-m,
C-m0), 126.68 (C-p, C-p0) ppm.
N
N
3t-Methyl-2r,6c-bis(p-chlorophenyl)piperidin-4-one isonicotinylhyd-
razone (14). White powder, yield 90%, mp: 210–212 °C; 1H NMR:
d = 3.54 (d, J2a,3a = 9.53 Hz, 1H, H-2a), 3.89 (d, J6a,5a = 10.9 Hz; 1H,
H-6a), 2.58 (sextet, 1H, H-3a), 2.10 (1H, H-5a), 3.15 (d,
J5a,5e = 12.87 Hz; 1H, H-5e), 2.93 (bs, 1H, NH), 11.06 (s, 1H,
ACOANHA), 0.84 (d, J = 6.3 Hz, 3H, ACH3 at C-3), 8.72 (d, 2H, pyr-
R1
R2
4
5
3
o'
o
2
6
6'
1
2'
m
p
m'
p'
N
H
idine
a
), 7.73 (d, 2H, pyridine b), 7.51 (t, 4H, H-o, H-o0), 7.41 (dd,
4H, H-m, H-m0); 13C NMR: d = 67.52 (C-2), 58.95 (C-6), 44.66
(C-3), 37.19 (C-5), 12.22 (ACH3 at C-3), 165.90 (C@O), 161.82
(C@N), 149.98 (pyridine
a), 121.60 (pyridine b), 141.15 (pyridine
ipso carbon), 142.76 (C-60), 141.91 (C-20), 129.7 (C-o, C-o0), 128.57
(C-m, C-m0), 131.49, 131.72 (C-p, C-p0) ppm.
Fig. 1. Numbering and designation of carbon atoms in 12–22.
141.15 (C-60), 139.87 (C-20), 129.47 (C- C-o, C-o0), 114.69 (C-m, C-
m0), 162.35 (JCAF = C-p, C-p0) ppm.
3t-Methyl-2r,6c-bis(p-flurophenyl)piperidin-4-one isonicotinylhydraz-
one (15). White powder, yield 85%, mp: 184–185 °C; 1H NMR:
d = 3.55 (d, J2a,3a = 9.59 Hz, 1H, H-2a), 3.88 (d, J6a,5a = 11.5 Hz; 1H, H-
6a), 2.57 (sextet, 1H, H-3a), 2.12 (t, 1H, H-5a), 3.15 (d, J5a,5e = 13.0 Hz;
1H, H-5e), 2.81 (bs, 1H, NH), 11.06 (s, 1H, ACOANHA), 0.84 (d, 3H,
3,3-Dimethyl-2r,6c-diphenylpiperidin-4-one
isonicotinylhydrazone
(16). White powder, yield 89%, mp: 216–217 °C; 1H NMR:
d = 3.76 (s, 1H, H-2a), 3.85 (d, J6a,5a = 11.6 Hz, 1H, H-6a), 2.28 (t,
1H, H-5a), 3.01 (d, J5e,5a = 13.11 Hz, 1H, H-5e), 2.67 (bs, 1H, NH),
11.03 (s, 1H, ACOANHA), 1.03, 1.14 (s, 6H, ACH3(a), CH3(e) at
ACH3 at C-3), 8.72 (d, 2H, pyridine a), 7.73 (d, 2H, pyridine b), 7.51
(t, 4H, H-o, H-o0), 7.41 (dd, 4H, H-m, H-m0); 13C NMR: d = 67.46
(C-2), 58.85 (C-6), 44.65 (C-3), 37.15 (C-5), 165.90 (C@O), 161.82
(C@N), 12.04 (ACH3 at C-3), 166.23 (C@O), 160.05 (C@N), 149.84
C-3), 8.71 (d, 2H, pyridine
a), 7.73 (d, 2H, pyridine b), 7.55 (d,
(pyridine
a), 121.45 (pyridine b), 139.05 (pyridine ipso carbon),
2H, H-200), 7.46 (d, 2H, H-600), 7.28–7.39 (m, 6H, H-m, H-m0, H-p,
O
R1
H3C
O
R2
R1
EtOH / warm
O
H
H
+
O
R2
NH4OAc
N
H
R
R
1-11
R
R
MeOH / INH /
3 h reflux
0.5 mL AcOH
R1
H
R2
H
R
H
N
1,12
2,13 CH3
3,14 CH3
4,15 CH3
5,16 CH3
6,17 CH3
7,18 CH3
8,19 CH3
9,20 CH3
H
H
H
CH3
CH3
CH3
CH3
CH3
H
H
Cl
F
H
CH3
OCH3
Cl
F
H
O
C
N
H
N
R1
R2
N
H
10,21 CH2CH3
11,22 CH(CH3)2 H
H
R
R
12-22
Scheme 1. Schematic diagram showing the synthesis of title compounds 12–22.

30
C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
H-p0); 13C NMR: d = 69.61 (C-2), 60.04 (C-6), 42.97 (C-3), 33.79
(C-5), 22.77, 21.22 (ACH3(e,a) at C-3), 170.37 (C@O), 161.69
Table 3
Crystal data and structure refinement of compound 16.
(C@N), 149.98 (pyridine
a), 121.58 (pyridine b), 140.36 (pyridine
Empirical formula
Formula weight
Temperature
C25H26N4O
398.5
293(2) K
ipso carbon), 144.10, 141.12 (C-60, C-20), 128.95, 128.16 (C-o,
C-o0), 126.76 (C-2000, C-6000, 127.31, 127.16 (C-p, C-p0) ppm.
Wavelength
0.71073 Å
Crystal system, space group
Unit cell dimension
Triclinic, Pꢁ1
a = 6.21280(10) Å,
a
= 65.29(10)°
3,3-Dimethyl-2r,6c-bis(p-methylphenyl)piperidin-4-one isonicotinylhyd-
razone (17). White powder, yield 75%, mp: 206–207 °C; 1H NMR:
d = 3.72 (s, 1H, H-2a), 3.80 (d, J6a,5a = 11.64 Hz, 1H, 6a), 2.28 (t, 1H,
H-5a), 2.95 (d, J5a,5e = 13.50 Hz, 1H, H-5e), 11.03 (s, 1H, ACOANHA),
b = 12.8346(3), Å, b = 78.82(10)°
c = 15.0022(3), Å,
1065.62(4) Å3
2, 1.242 Mg/m3
0.078 mmꢁ1
424
c = 86.94(10)°
Volume
Z, density
Absorption coefficient
F(000)
Crystal size
1.02, 1.13 (s, 6H, ACH3(a), CH3(e) at C-3), 8.72 (d, 2H, pyridine
a),
7.73 (d, 2H, pyridine b), 7.42 (d, 2H, H-m), 7.34 (d, 2H, H-m0); 13C
NMR: d = 69.35 (C-2), 59.78 (C-6), 42.99 (C-3), 33.85 (C-5), 21.18,
20.58 (CH3(a,e) at C-3), 22.69 (CH3 at C-20000 and C-60000), 170.81 (C@O),
0.22 ꢂ 0.18 ꢂ 0.16 mm
Theta range for data collection
Limiting indices
1.78–28.61°
ꢁ8 6 h 6 8, ꢁ17 6 k 6 17, ꢁ20 6 l 6 20
25,613/5420 [R(int) = 0.0232]
25 99.8%
Semi-empirical from equivalents
Full-materix least square on F2
5420/0/271
161.55 (C@N), 149.95 (pyridine a), 121.51 (pyridine b), 136.14 (pyri-
Reflections collected
Completeness to theta
Absorption correction
Refinement method on
Data/restraints/parameter s
Goodness-of-fit on F2
Final R Indices [I > 2sigma(I)]
CCDC No
dine ipso carbon), 141.11, 137.35 (C-60, C-20), 126.58 (C-o, C-o0), 127.89
(C-m, C-m0), 128.68 (C-p, C-p0) ppm.
3,3-Dimethyl-2r,6c-bis(p-methoxyphenyl)piperidin-4-one isonicotinylhyd-
razone (18). White powder, yield 72%, mp: 180–182 °C; 1H NMR:
d = 3.72 (s, 1H, H-2a), 3.80 (1H, 6a), 2.28 (t, 1H, H-5a), 2.95 (d,
J5e,5a = 14.5, J5e,6a = 3.0 Hz, 1H, H-5e), 11.03 (s, 1H, ACOANHA), 1.02,
1.041
[I > 2sigma(I) R1 = 0.0505, wR2 = 0.1406
653067
1.13 (s, 6H, ACH3(a), CH3(e) at C-3), 8.72 (d, 2H, pyridine
a), 7.73 (d,
C-3), 8.71 (d, 2H, pyridine
a
), 7.73 (d, 2H, pyridine b), 7.55 (d, 2H, H-
2H, pyridine b), 7.42 (d, 2H, H-o), 7.34 (d, 2H H-o0), 7.16 (m, 6H, H-m,
H-m0); 13C NMR: d = 69.02 (C-2), 59.49 (C-6), 43.10 (C-3), 33.92 (C-5),
22.73, 21.17 (CH3(a,e) at C-3), 55.01 (OCH3 at C-20000, C-60000)ppm, 170.83
o), 7.46 (d, 2H, H-o0), 7.28-7.39 (m, 4H, H-m, H-m0); 13C NMR:
d = 69.61 (C-2), 60.04 (C-6), 42.97 (C-3), 33.79 (C-5), 22.77, 21.22
(ACH3(e,a) at C-3), 169.65 (C@O), 161.67 (C@N), 149.95 (pyridine a),
(C@O), 161.62 (C@N), 149.99 (pyridine
a), 121.56 (pyridine b),
121.53 (pyridine b), 139.21 (pyridine ipso carbon), 142.97, 141.07
(C-60, C-20), 128.95, 128.16 (C-o, C-o0), 126.76 (C-m, C-m0), 127.31,
127.16 (C-p, C-p0) ppm.
136.21 (pyridine ipso carbon), 141.13, 136.19 (C-60, C-20), 129.84,
127.80 (C-o, C-o0), 113.56, 112.75 (C C-m, C-m0), 158.41(C-p, C-p0).
3,3-Dimethyl-2r,6c-bis(p-chlorophenyl)piperidin-4-one isonicotinylhyd-
razone (19). White powder, yield 94%, mp: 210–211 °C; 1H NMR:
d = 3.76 (s, 1H, H-2a), 3.85 (d, J6a,5a = 11.4 Hz, 1H, H-6a), 2.28 (t, 1H,
H-5a), 3.01 (d, J5e,5a = 13.4 Hz, 1H, H-5e), 2.67 (bs, 1H, NH), 11.03 (s,
3,3-Dimethyl-2r,6c-bis(p-flurophenyl)piperidin-4-one isonicotinylhyd-
razone (20). White powder, yield 85%, mp: 196–197 °C; 1H NMR:
d = 3.75 (s, 1H, H-2a), 3.84 (d, J6a,5e = 11.68 Hz, 1H, H-6a) 2.23 (t,
1H, H-5a), 2.99 (d, J5a,5e = 12.96 Hz, 1H, H-5e), 2.77 (bs, 1H, NH),
1H, ACOANHA), 1.03, 1.14 (s, 6H, ACH3(a)
,
CH3(e) at
Fig. 2. ORTEP diagram of compound 16.

C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
31
Table 4
Selected Bond lengths, Bond angles and Torsional angles for 16.
N
Bond lengths [A]
Torsional angles [°]
C(7)AN(1)
C(7)AC(8)
C(7)AH(7A)
C(8)AC(9)
1.4600(17) C(4)AC(5)AC(6)AC(7)
176.04(16)
ꢁ175.73(15)
ꢁ138.40(15)
37.83(19)
O
1.555(2)
0.98
1.524(2)
1.530(2)
1.530(2)
C(2)AC(1)AC(6)AC(7)
C(5)AC(6)AC(7)AN(1)
C(1)AC(6)AC(7)AN(1)
C(5)AC(6)AC(7)AC(8)
C(1)AC(6)AC(7)AC(8)
C
N
C(8)AC(25)
C(8)AC(24)
C(9)AN(2)
C(9)AC(10)
C(10)AC(11)
C(11)AN(1)
C(18)AO(1)
C(18)AN(3)
C(18)AC(19)
N(1)AH(1B)
N(2)AN(3)
N(3)AH(3B)
97.18(17)
ꢁ86.59(17)
H
N
1.2752(19) N(1)AC(7)AC(8)AC(9)
56.96(15)
1.506(2)
1.531(2)
C(6)AC(7)AC(8)AC(9)
N(1)AC(7)AC(8)AC(25)
ꢁ178.86(11)
ꢁ62.36(16)
61.82(17)
176.34(12)
ꢁ59.48(17)
ꢁ115.11(16)
124.08(15)
66.94(18)
ꢁ171.70(14)
ꢁ53.86(17)
ꢁ124.05(17)
53.63(18)
1.4564(19) C(6)AC(7)AC(8)AC(25)
1.2266(19) N(1)AC(7)AC(8)AC(24)
1.3429(19) C(6)AC(7)AC(8)AC(24)
O
1.498(2)
0.86
C(25)AC(8)AC(9)AN(2)
C(7)AC(8)AC(9)AN(2)
N
H
1.3886(17) C(25)AC(8)AC(9)AC(10)
0.86
C(24)AC(8)AC(9)AC(10)
Fig. 3. Conformation of isatin-3-isonicotinoylhydrazone.
Bond angles [°]
C(7)AC(8)AC(9)AC(10)
N(2)AC(9)AC(10)AC(11)
C(8)AC(9)AC(10)AC(11)
C(9)AC(10)AC(11)AN(1)
C(9)AC(10)AC(11)AC(12)
N(1)AC(11)AC(12)AC(17)
C(5)AC(6)AC(7)
N(1)AC(7)AC(6)
N(1)AC(7)AC(8)
C(6)AC(7)AC(8)
C(9)AC(8)AC(25)
C(9)AC(8)AC(24)
N(2)AC(9)AC(10)
N(2)AC(9)AC(8)
C(10)AC(9)AC(8)
C(9)AC(10)AC(11)
N(1)AC(11)AC(12) 110.57(12)
N(1)AC(11)AC(10) 108.68(12)
O(1)AC(18)AN(3)
O(1)AC(18)AC(19) 119.62(13)
N(3)AC(18)AC(19) 120.01(13)
C(11)AN(1)AC(7)
C(9)AN(2)AN(3)
C(18)AN(3)AN(2)
120.10(14)
109.42(11)
109.88(12)
115.27(12)
109.77(13)
111.20(12)
127.76(14)
116.54(13)
115.66(12)
109.85(13)
H-p0) ppm; 13C NMR: d = 67.22 (C-2), 60.42 (C-6), 51.89 (C-
3), 38.17 (C-5), 19.38 (ACH2ACH3) 12.47 (ACH2ACH3), 165.92
ꢁ53.48(16)
ꢁ175.89(12)
146.91(15)
(C@O), 162.34 (C@N), 150.60 (pyridine
a), 122.23 (pyridine
C(10)AC(11)AC(12)AC(17) ꢁ91.77(18)
b), 141.73 (pyridine ipso carbon), 144.36, 143.47 (C-20, C-60),
127.14, 127.33 (C-o, C-o0), 128.52, 128.70 (C-m, C-m0), 127.68
(C-p, C-p000) ppm.
N(1)AC(11)AC(12)AC(13)
ꢁ33.1(2)
C(10)AC(11)AC(12)AC(13) 88.2(2)
C(11)AC(12)AC(13)AC(14) 179.40(19)
O(1)AC(18)AC(19)AC(23)
N(3)AC(18)AC(19)AC(23)
O(1)AC(18)AC(19)AC(20)
N(3)AC(18)AC(19)AC(20)
32.7(2)
ꢁ148.77(16)
ꢁ143.86(18)
34.6(2)
3t-Isopropyl-2r,6c-diphenylpiperidin-4-one isonicotinylhydrazone (22). Faint
yellow solid, yield 62%, mp: 185–187 °C; 1H NMR: d = 3.99 (d, 2H, H-2a,
H-6a), 2.54 (1H, H-3a), 2.27 (d, J5a,6a = 11.3 Hz, 1H, H-5a), 3.07 (dd,
J5a,5e = 14.4 Hz, 1H, H-5e), 11.98 (s, 1H, ACOANHA), 8.71 (d, 2H, pyridine
120.36(14)
C(18)AC(19)AC(20)AC(21) 177.20(16)
C(12)AC(11)AN(1)AC(7)
C(10)AC(11)AN(1)AC(7)
C(6)AC(7)AN(1)AC(11)
C(8)AC(7)AN(1)AC(11)
C(10)AC(9)AN(2)AN(3)
C(8)AC(9)AN(2)AN(3)
O(1)AC(18)AN(3)AN(2)
C(19)AC(18)AN(3)AN(2)
C(9)AN(2)AN(3)AC(18)
ꢁ174.80(12)
61.97(15)
167.08(12)
ꢁ65.41(16)
0.3(2)
ꢁ177.35(13)
ꢁ166.94(16)
14.6(2)
a
), 7.72 (d, 2H, pyridine b), 1.81 (m, 2H, ACH(CH3)2), 1.09 (d, J = 6.7 Hz,
112.80(11)
119.05(13)
119.97(13)
3H, ACH3 at C-7); 0.93 (d, J = 6.7 Hz, 3H, -CH03 at C-7), 7.48 (m, 4H, H-o,
H-o0), 7.23–7.37 (m, 6H, H-m, H-m , H-p, H-p ) ppm; 13C NMR: d = 64.03
(C-2), 58.5074 (C-6), 54.96 (C-3), 37.31 (C-5), 27.89 [ACH(CH3ACH3)],
20.88 [ACH(CH3ACH3)], 18.44[ACH(CH3ACH3)], 165.07 (C@O), 161.65
0
0
C(18)AN(3)AH(3B) 120
N(2)AN(3)AH(3B) 120
(C@N), 149.96 (pyridine
a), 121.61 (pyridine b), 141.09 (pyridine ipso car-
ꢁ175.73(16)
bon), 144.16, 144.06 (C-20, C-60), 127.01, 126.62 (C-o, C-o0), 127.71, 128.09
0
0
(C-m, C-m ), 127.11 (C-p, C-p ) ppm.
Table 5
X-ray crystallographic analysis
CAN Bond lengths in 16.
Crystals were grown by slow evaporation technique using a
mixture of ethanol and ethyl acetate as solvent. Diffraction data
were collected on a Bruker, 2004 APEX 2 diffractometer using
Bond
Bond lengths [Å]
C(7)AN(1)
C(11)AN(1)
C(9)@N(2)
C(18)AN(3)a
1.460(17)
1.4564(19)
1.2752(19)
1.3429(19)
graphite-monochromated Mo
Ka radiation (K = 0.71073 Å) at
293 K with crystal size of 0.22 ꢂ 0.18 ꢂ 0.16 mm. The structure
was solved by direct methods and successive Fourier difference
syntheses (SHELXS-97) [5] and refined by full matrix least square
procedure on F2 with anisotropic thermal parameters. All non-
hydrogen atoms were refined (SHELXL-97) [6] and placed at chem-
ically acceptable positions. A total of 696 parameters were refined
with 25613 unique reflections which covered the residuals to
R1 = 0.0232. Crystallographic data for 16 have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 653067 for 16.
a
C(18)AN(3) bond is C(O)AN bond.
11.02 (s, 1H, ACOANHA), 1.10, 1.00 (s, 6H, ACH3(a), CH3(e) at C-3),
8.70 (d, 2H, pyridine a), 7.72 (d, 2H, pyridine b), 7.48 (m, 2H, H-o),
7.58 (m, 2H, H-o0), 7.28–7.39 (m, 4H, H-m, H-m0); 13C NMR:
d = 68.71 (C-2), 59.22 (C-6), 42.89 (C-3), 33.78 (C-5), 21.08, 22.69
(CH3(a,e) at C-3), 169.87 (C@O), 161.76 (C@N), 150.00 (pyridine
a),
121.61 (pyridine b), 136.47 (pyridine ipso carbon), 141.13, 140.26
(C-60, C-20), 130.66, 128.72 (C-o, C-o0), 114.4 (C-m, C-m0), 162.51
(C-p, C-p0) ppm.
Results and discussion
Numbering and designation of atoms
3t-Ethyl-2r,6c-diphenylpiperidin-4-one
isonicotinylhydrazone
(21). White solid, yield 65%, mp: 165–166 °C; 1H NMR:
d = 3.66 (d, J2a,3a = 8.08 Hz, 1H, H-2a), 3.89 (d, J6a,5a = 11.2 Hz,
1H, H-6a), 2.14 (t, 1H, H-5a), 3.16 (d, J5a,5e = 12.7 Hz, 1H, H-
5e), 1.62 (heptet, 1H, H of ACHH0 of C-7), 1.19 (m, H, H0 of
C-7), 0.81 (t, 3H, ACH3 at C-7), 2.62 (bs, 1H, NH), 11.07 (s,
The reported new hydrazones 12–22 were synthesized as
shown in Scheme 1 and their analytical data (Table 1) are fit well
with their proposed molecular formula.
The numbering of the carbons of the piperidine ring is shown in
Fig. 1. The ipso carbons of the aryl groups at C-2 and C-6 are desig-
nated as C-20 and C-60. The other carbons of the aryl group at C-2
are denoted as o, m and p-carbons and those of the aryl group at
1H, ACOANHA), 8.71 (d, 2H, pyridine
a), 7.73 (d, 2H, pyridine
b), 7.49 (m, 4H, H-o, H-o0), 7.23–7.37 (m, 6H, H-m, H-m0, H-p,

32
C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
Fig. 4. Packing diagram of compound 16.
IR spectral studies
The important IR stretching frequencies of 12–22 are given in
4
2
3
Table 2. In IR spectra, the presence of C@N stretching frequency
around 1540 cmꢁ1 confirm the hydrazone formation. The bands
observed in the region of 3160–3220 cmꢁ1 are due to NAH stretch-
ing frequency of hydrazone analogues and the piperidine NH
Py
1
H3C
H
H
O
C
18
N
stretching frequency are in the range 3230–3310 cmꢁ1
. The
3
N
2
(3)
N
absorption band in the region 3070–2800 cmꢁ1 are ascribed to aro-
matic and aliphatic CAH stretching frequencies. The band observed
in the region 1645–1660 cmꢁ1 are due to C@O stretching fre-
quency of amide carbonyl group.
3
2
N
H
(3)
1
O
C
CH3
18
H
Py
3
2
4
Crystal structure determination of 3,3-dimethyl-2r,6c-diphenylpiperidine-
4-one N-isonicotinoylhydrazone (16)
Fig. 5. Hydrogen bonding interactions of 16.
X-ray crystallographic study has been made for 3,3-dimethyl-
2r,6c-diphenylpiperidin-4-one N-isonicotinoylhydrazone (16).
The crystal is a triclinic system with Pꢁ1 symmetry. The molecular
structure of 16 is shown in Fig. 2 as the ORTEP diagram. The num-
bering of carbon atoms in the ORTEP diagram differs from that in
Fig. 1. Crystal data and structure refinement of compound 16 is
given in Table 3. The selected bond lengths, bond angles and tor-
sional angles, obtained from XRD-study, are given in Table 4.
From the geometrical parameters it is observed that the piper-
idine ring adopts chair conformation. The phenyl groups and one
C-4 are denoted as o0, m0 and p0-carbons. The carbons of the pyri-
dine ring are designated using Greek letters , b and . The protons
are denoted accordingly. For example, the benzylic proton at C-2 is
denoted as H-2, that at C- is denoted as H- and so on. The meth-
ylene protons at C-5 are denoted as H-5a and H-5e assuming chair
conformation for the piperidine ring.
a
c
a
a
Table 6
Hydrogen bond geometry (Å, °).
Compounds
DAHꢃ ꢃ ꢃA
d(DAH)
d(Hꢃ ꢃ ꢃA)
d(Dꢃ ꢃ ꢃA)
<(DAHꢃ ꢃ ꢃA)
16
N(3)AH(3B)...O(1)#1
0.86
2.22
2.9654(18)
144.6

C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
33
N
N
O
O
C
N
C
N
H
H
N
N
CH3
CH3
CH3
CH3
N
H
N
H
A
B
Fig. 6. Possible Tautomeric forms of hydrazone 16.
Fig. 7. 1H NMR spectrum of compound 16.
methyl group adopt equatorial orientations. The other methyl
group adopts axial orientation. The pyridine ring is tilted about
the C(c)@O plane by 32.7°. Also the molecule 16 has E configura-
tion about the C@N bond. The observed CAN bond distances in
16 are given in Table 5.
double bond character. In the solid state the configuration exists
in one tatutomeric form A with E orientation about the (O)CANH
bond Fig. 2. This contrasts with the observation that isatin-3-ison-
icotinoylhydrazone adopts Z configuration (Fig. 3) about the
(O)CANH bond in the solid state [7].
It is seen that (O)CAN bond length lies between those of typical
CAN and C@N bonds, suggesting that (O)CAN bond has partial
Compound 16 exist as dimers, which are stabilized by NHꢃ ꢃ ꢃO
intermolecular hydrogen bonds. The type of hydrogen bonding is

34
C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
Py
H
O
H
N
C
N
C
O
H
N
Py
H
H
H
N
H
H
Ph
CH3
Ph
N
CH3
H
Ph
H
N
H
Ph
CH3
H
CH3
16 Z
16
E
Fig. 8. E and Z forms (16 E) and 16 Z).
the 1H NMR spectrum of all compounds in DMSO-d6. This result
indicates that several interconverting forms of compounds exist
in solution.
Table 7
Proton chemical shifts of compound 16.
Protons
Chemical shifts (d, ppm)
In order to analyze the spectral assignments of synthesized
novel compounds 12–22, we have chosen compounds 16 as the
representative compound. The 1H and 13C signals for the remaining
compounds were assigned by comparison with 16 considering
known effects [8,9] of the Cl, CH3 and OCH3 substituents in the aryl
rings.
Major
Minor
amide NH
11.03
8.71
7.73
7.46
7.55
7.34
7.24
3.76
2.28
3.01
3.85
1.14
1.03
2.67
11.12
8.71
7.73
7.46
7.55
7.34
7.24
3.66
2.16
3.30a
3.85
1.03
0.69
2.67
H-a
H-b
o-H
o0-H
m-H, m0-H
p-H, p0-H
H-2a
H-5a
H-5e
H-6a
CH3 (a)
CH3 (e)
piperidine NH
In the 1H NMR spectrum of 16 two signals are attributed to the
NH proton of the amide group at 11.03 and 11.12 ppm Fig. 7. Three
signals are observed for the benzylic protons at 3.66, 3.77 and
3.85 ppm. Four signals are observed for the methyl protons at
1.03, 0.69 and 1.14 ppm. Two signals are observed for the methane
proton at 2.28 and 2.16 ppm.
These observations suggest that the compound exists in two
forms in solution. These are E and Z forms (16E) and 16Z) Shown
in Fig. 8. For the amide NH-proton, H-2a, H-5a and H-5e separate
signals are observed for the two isomers. For the minor isomer
the signal for H-5e has merged with the solvent signal. Three sig-
nals are observed at 1.14, 1.03 and 0.69 ppm for the methyl pro-
tons at C-3. The signal at 0.69 ppm corresponds to the E minor
isomer. This should be due to the signal for the equatorial methyl
protons to the minor E-isomer. Since the axial methyl protons
should have a higher chemical shift than the equatorial methyl
protons the signal at 1.14 ppm is assigned to the axial methyl pro-
tons of the major isomer. The integral value of the signal at
1.03 ppm is almost equal to the sum of the integral values for
the signals at 1.14 and 0.69 ppm. The signal at 1.03 ppm is due
to the equatorial methyl protons of the major isomer and axial
a
Merged with solvent signals and approximately taken.
shown in Fig. 4. These dimers are linked by CHꢃ ꢃ ꢃO hydrogen bonds
as shown in Fig. 5. The details about the geometries of the intermo-
lecular hydrogen bonds are given in Table 6.
1H NMR spectral analysis
It is very likely that the tautomeric form A (Fig. 6) observed in
crystal is stabilized due to the formation of intermolecular H-
bonds. However, the behavior of carbohydrazide in solution is
much more complex. Thus, two sets of signals were observed in
Table 8
Correlations for the Major isomer in the COSY and NOESY spectra 16.
Protons
Correlations in the COSY spectrum
Correlations in the NOESY spectrum
11.03 (amide NH)
–
7.73 (H-b), 3.01 (H-5e)
8.71 (H-
a)
7.73 (H-b)
11.03 (amide NH)
7.73 (H-b)
7.46 (o-H)
7.55 (o0-H)
8.71 (H-
a
)
11.03 (amide NH), 8.71 (H-a)
7.34 (m-H, m0-H)
7.34 (m-H, m0-H)
1.03 (CH3a), 1.14 (CH3a), 3.76 (H-2a), 2.67 (NH)
2.28 (H-5a), 3.85 (H-6a)
2.67 NH
7.34 (m-H, m0-H)
7.24 (p-H, p0-H)
3.76 (H-2a)
7.55 (o0-H), 7.46 (o-H), 7.24 (p-H, p0-H)
7.34 (m-H, m0-H)
–
7.55 (o0-H), 7.46 (o-H), 7.24 (p-H, p0-H)
7.34 (m-H, m0-H)
7.46 (o-H), 2.67 (NH), 1.03 (CH3e)
7.55 (o0-H), 3.01 (H-5e)
2.28 (H-5a)
3.85 (H-6a), 3.01 (H-5e)
1.14 (CH3a)
3.01 (H-5e)
3.85 (H-6a)
2.28 (H-5a)
2.28 (H-5a)
11.03 (amide NH), 2.28 (H-5a)
7.55 (o0-H), 3.01 (H-5e)
1.03 (CH3e)
1.14 (CH3a)
2.67 piperidine NH
–
–
–
7.46 (o-H), 3.76 (H-2a)
7.46 (o-H), 2.28 (H-5a)
7.46 (o-H), 7.55 (o0-H), 3.76 (H-2a)

C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
35
Table 9
Correlations for the major isomer in the HSQC and HMBC spectra 16.
13C Chemical shifts (d, ppm)
Correlations in the HSQC spectrum
Correlations in the HMBC spectrum
170.4
161.7
150.0
121.6
141.1
140.4
144.1
129.0
126.8
128.2
127.3, 127.2
69.6
–
–
11.03 (amide NH), 2.28 (H-5a) 1.14 (CH3a), 1.03 (CH3e)
11.03 (amide NH), 7.73 (H-b)
–
8.71 (H-
7.73 (H-b)
–
–
a)
8.71 (H-
8.71 (H-
a
a
)
)
7.34 (m-H, m0-H), 3.76 (H-2a)
7.34 (m-H, m0-H)
7.24 (p-H, p0-H)
–
7.46 (o-H)
7.55 (o0-H)
7.34 (m-H, m0-H)
7.24 (p-H, p0-H)
3.76 (H-2a)
7.24 (p-H, p0-H)
7.55 (o0-H)
7.46 (o-H), 7.55 (o0-H)
7.46 (o-H), 1.14 (CH3a)
1.03 (CH3e)
43.0
–
3.76 (H-2a), 1.14 (CH3a)
1.03 (CH3e)
33.8
60.0
21.2 (a)
22.8 (e)
2.28 (H-5a), 3.01 (H-5e)
3.85 (H-6a)
1.14 (CH3a)
–
7.55 (o0-H), 2.28 (H-5a), 3.76 (H-2a)
3.76 (H-2a), 1.03 (CH3e)
1.14 (CH3a)
1.03 (CH3e)
In the NOESY spectrum the signal for amide NH proton at
11.03 ppm has nOe with the pyridine H-b signal at 7.73 ppm. Such
a nOe is possible only in the Z form. Obviously, the signal due to
11.03 ppm is due to Z form. In other words the major form is Z
form (16Z) and the minor form is E form (16E).
In the NOESY spectrum the signal for H-2a of the major isomer
has nOe with the methyl protons at 1.03 ppm. Obviously, this sig-
nal should be due to the equatorial methyl protons, because only
the equatorial methyl protons can have nOe with the adjacent axial
proton H-2a.
If there is slow interconversion between the two isomers corre-
lations will be observed between the two exchanging nuclei in the
NOESY spectrum. Indeed correlation between the methyl signals at
1.03 ppm and 0.0.69 ppm is observed. Thus, it is obvious that there
is interconversion between the two isomers at room temperature.
However, the interconversion is slow on NMR time scale, so that
different signals are observed for the two isomers.
Table 10
Carbon chemical shifts of compound 16.
Carbons
Chemical shifts (d, ppm)
Major
Minor
C@O
C@N
161.7
170.4
160.0
170.04
149.2
123.1
141.1
140.4
144.1
129.0
126.8
128.2
127.3, 127.2
69.6
42.5
32.0
a-C
150.0
b-C
121.6
c
-C
141.1
140.4
144.1
C-20
C-60
o-C
129.0
126.8
128.2
127.3; 127.2
69.6
o0-C
m-C, m0-C
p-C, p0-C
C-2
C-3
43.0
C-5
33.8
C-6
60.0
60.0
Alkyl
21.2 (a), 22.8 (e)
20.7 (a), 22.8 (e)
In 12–15 and 17–22, individual assignments of the protons
were made based on their positions, multiplicities, integral values
of the signals and by comparison with 16. Normally, the ortho,
meta and para protons of phenyl group attached at C-2 and C-6 car-
bons of piperidine ring give separate signals. Ortho protons are
deshielded by the lone pair of electrons on the nitrogen while
the meta and para protons are shielded and resonate in the upfield
region. The 1H chemical shifts of major isomer of 12–15 and 7–22
are given in Tables 12 and 13.
Table 11
Relative population of Z and E isomers for compounds 13–22.a
Compounds
% Z isomer
% E isomer
13
14
15
16
17
18
19
20
21
22
78.23
71.49
75.09
80.63
80.57
81.23
80.67
77.30
77.89
80.27
21.77
28.51
24.91
19.37
19.43
18.77
19.33
22.70
22.11
19.63
13C NMR spectral analysis
In order to assign the signals unambiguously HSQC and HMBC
spectra have been recorded for 16. The observed correlations in
the HSQC and HMBC spectra are given in Table 9. The signals for
carbons linked to hydrogen are assigned based on the observed
correlations in the HSQC spectrum. Signals which do not show
any correlation in the HSQC spectrum are those that are not linked
to protons due to carbons containing no proton.
a
Relative population could not calculated for 12.
The 13C NMR spectrum shows weak signal at 170.4 ppm with no
correlation in the HSQC spectrum. In the HMBC spectrum, this sig-
nal shows correlation with the amide NH proton, H-5a and the
methyl protons. Hence, this signal must be due to C-4. There are
four weak signals at 161.7, 141.1, 144.1 and 140.4 ppm. These sig-
nals have no correlation in the HSQC spectrum. The signal at
161.7 ppm shows correlation with H-b and amide NH proton at
11.03 ppm. Hence, this signal should be due to the carbonyl carbon
methyl protons of the minor isomer. The 1H chemical shifts of the
both the isomers of 16 are given in Table 7.
In order to confirm the above assignments 1H–1H COSY and
NOESY spectra have been recorded. The observed correlations for
the major isomer in the 1H–1H COSY and NOESY spectra of 16
are given in Table 8. The observed 1H–1H COSY correlations con-
firm the assignments made.

36
C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
Table 12
Proton chemical shifts in major isomer of compounds.a
Protons
12b
(H)
14
15
17d
18
[(3-CH3)/p-Cl]
[(3-CH3)/p-F]
[(3,3-CH3)/p-CH3]
[(3,3-CH3)/p-OCH3]g
Amide NH
11.04
8.71
7.72
7.51
7.51
11.06 (11.23)
8.72 (8.65)
7.73 (7.60)
7.51
7.51
7.41
11.06 (11.23)
8.72 (8.64)
7.73
7.52
7.52
11.03 (11.10)
8.71
7.72
7.40
7.33
11.03 (11.08)
8.71 (8.67)
7.72 (7.60)
7.36
7.43
6.90
H-a
H-b
o-H,
o0-H
m-H, m0-H
7.35
7.26
7.16
–
7.14
–
p-H, p0-H
–
–
H-2a
H-3a
H-5a
H-5e
3.93
3.54 (3.43)
2.58
3.55 (3.42)
2.57 (2.41)
2.12 (1.98)
3.15
3.71 (3.61)
–
3.70 (3.62)
2.26 (2.13)
2.95 (3.2)
3.78
2.42 (2.27)
2.04 (1.96)
3.16
2.10c (1.96)
3.15
2.29e (2.12)
2.97
H-6a
3.85
–
–
2.88
3.89 (3.84)
–
0.84 (0.51)
2.93
3.88 (3.83)
–
0.84 (0.51)
2.81
3.80
1.13 (1.00)
1.12 (1.05)
1.00 (0.66) (e)
2.44
Alkyl proton at C-3 (ax)
Alkyl proton at C-3 (eq)
NH in piperidine ring
1.00 (0.67)
f
11.03 (11.08)
a
Wherever separate signals are observed for the two isomers the chemical shifts for the minor isomer are given in parenthesis. Otherwise both isomers have the chemical
shift.
b
The chemical shift same of H-3e is 2.58 ppm.
The signal for H-5a is merged with moisture peak and the chemical shift was approximately taken as 2.10 ppm.
The chemical shift of p-CH3 is 2.29 ppm.
The signal for H-5a is merged with p-CH3 and chemical shift was approximately taken as 2.29 ppm.
NH proton signal is merged with DMSO signal.
The chemical shift of p-OCH3 is 3.74 ppm.
c
d
e
f
g
Table 13
Proton chemical shifts in major isomer for compounds.a
Protons
19h
20i
21jh
22kh
[(3,3-CH3)/p-Cl]
[(3,3-CH3)/p-F]
(3-CH2CH3)
[3-CH(CH3)2]
amide NH
11.02 (11.14)
8.72 (8.78)
7.72 (7.65)
7.48
7.57
7.41
11.02 (11.12)
8.68 (8.66)
7.71
7.48
7.52
11.07 (11.22)
8.71 (8.60)
7.73 (7.54)
7.48
10.98 (11.08)
8.71 (8.62)
7.72
H-a
H-b
o-H
7.48
o0-H
m-H, m0-H
7.16
–
7.30
7.23
3.67 (3.53)
2.16 (2.01)
3.17 (3.42)
3.90 (3.82)
–
7.36
7.25
3.99i
2.27
3.07
3.99i
–
p-H, p0-H
–
H-2a
H-5a
H-5e
H-6a
3.76 (3.65)
2.23 (2.11)
3.00 (3.11)
3.85
1.10 (0.81)
1.01 (0.66) (e)
2.90
3.75 (3.64)
2.23 (2.14)
2.99 (3.29)
3.84 (3.79)
1.10
Alkyl proton at C-3 (ax)
Alkyl proton at C-3 (eq)
NH in piperidine ring
1.00 (0.66) (e)
2.77
1.19, 1.62 (CH2); 0.81 (CH3)
2.62
1.08 (CH3); 0.92 (CH3); 1.81 (CH)
f
a
Wherever separate signals are observed for the two isomers the chemical shifts for the minor isomer are given in parenthesis. Otherwise both isomers have the chemical
shift.
f
NH proton signal is merged with DMSO signal.
The signal for H-3a is merged with DMSO signal and the chemical shift was approximately taken as 2.50 ppm.
The signals for H-2a and H-6a have merged and the chemical shift was approximately taken as 3.99 ppm.
h
i
(C@O). In the HMBC spectrum the signal at 141.1 ppm has correla-
tion with H- . Hence, this signal should be due to C- . The signal at
the axial methyl carbon in the E-isomer has a slightly lower chem-
ical shift than that in the Z-isomer. The relative populations of the
Z and E isomers have been calculated from the observed integral
values and are given in Table 11.
a
c
140.4 ppm has correlation with the benzylic proton H-2a. There-
fore, this signal can be assigned to ipso-carbon C-20. Obviously,
the signal at 144.1 ppm can be assigned to C-60. The 13C signals
for the major isomer 16 Z are assigned based on the observed HSQC
and HMBC correlations. The 13C chemical shifts of the minor iso-
mer 16 E are assigned by comparison. The 13C chemical shifts are
given in Table 10. The equatorial methyl protons in the E-isomers
are shielded by 0.34 ppm relative to the Z-isomer. This shielding is
comparable to that (0.32 ppm) observed in 16. The axial methyl
protons in the E-isomer are shielded only by 0.11 ppm relative to
the Z-isomer. Thus, the shielding by the magnetic anisotropic
effects of the pyridine ring is considerably less on the axial methyl
protons than on the equatorial methyl protons. In both isomers the
equatorial methyl carbons have the same chemical shift. However,
The 13C signals for 12–15 and 17–22 were assigned based on
their positions, intensities and by comparison with those of 16.
The observed 13C chemical shifts of major isomer of 12–15 and
17–22 are given in Tables 14 and 15.
Analysis of coupling constants
In order to understand the conformation of piperidine ring, vic-
inal coupling constants are an important parameter. The observed
coupling constant for the major isomer (16Z) of the piperidine ring
could be determined for 16. These values are J5a,6a = 11.68 Hz and
J5a,5e = 13.12 Hz. The observed vicinal coupling constants suggest

C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
37
Table 14
Carbon chemical shifts in major isomer for compounds.a
Carbons
12a
(H)
14c
[(3-CH3)/p-Cl]
15d
[(3-CH3)/p-F]
17e
18f
[(3,3-CH3)/p-CH3]b
[3,3-CH3)/p-OCH3]c
C@O
C@N
162.0
163.3
150.0
121.6
141.0
143.9
161.8
165.9
150.0 (149.1)
121.6 (123.0)
141.9
141.2
142.8
129.6
128.6
166.2
171.3
149.8
121.5
139.9
139.0
141.2
129.5
128.5
114.5
162.0, 160.0
67.5
161.6
170.8
150.0 (149.5)
121.6 (123.0)
137.4
136.1
141.1
126.6
126.6
127.9
128.7
69.4
161.6
170.8
150.0 (149.2)
121.6 (123.0)
136.2
132.4
141.1
129.8
127.8
a-C
b-C
c
-C
C-20,C-60
o-C
o0-C
m-C, m0-C
p-C, p0-C
C-2
127.0
127.0
128.1
126.7, 126.5
60.8
128.0
131.7, 131.5
67.5
113.6, 112.8
158.4
69.0
C-3
43.3
44.7
44.7
43.0
43.1
C-5
C-6
36.8
59.6
37.2 (35.8)
59.0
37.2
58.9
33.9
59.8
33.9 (32.1)
59.5
CH3(ax) at C-3
CH3(eq) at C-3
–
–
–
12.2
–
12.0
20.6
21.8
21.2 (20.6)
22.7
a
Wherever separate signals are observed for the two isomers the chemical shifts for the minor isomers are given in parenthesis. Otherwise both isomers have the same
chemical shift.
b
The chemical shift of p-CH3 is 22.7 ppm.
The chemical shift of p-OCH3 is 54.9 ppm.
c
Table 15
Carbon chemical shifts in major isomer in compounds.
Carbons
19g
20h
21i
22j
[(3,3-CH3)/p-Cl]
[(3,3-CH3)/p-F]
(3-CH2CH3)
[3-CH(CH3)2]
C@O
C@N
161.7
169.7
162.5
169.9
161.8
165.4
161.7
165.0
a
b-C
-C
150.0 (149.1)
121.5 (123.0)
141.1
139.2, 143.0
130.7
150.0 (149.2)
121.6 (122.5)
140.3
136.5, 141.1,
130.7
150.0
121.6
142.9
141.2, 143.8,
128.0
127.8
126.7
127.2, 127.0
150.0 (149.2)
121.6 (122.1)
141.1
144.0, 144.1
128.1
127.1
127.7, 127.0
126.6
c
-C
C-20,C-60
o-C
o0-C
128.1
128.7
m-C, m0-C
128.6, 127.3
131.7, 131.6
68.7
114.8, 114.1
162.5, 160.1
68.7
p-C, p0-C
C-2
66.7
64.0
C-3
42.8
42.9
51.4 (51.1)
55.0 (54.3)
C-5
C-6
33.6
59.1
33.8 (31.5)
59.2
37.5 (36.2)
59.8
37.3 (36.3)
58.1
Alkyl (ax) at C-3
Alkyl (eq) at C-3
21.0
22.6
21.1 (19.6)
22.7
–
–
18.8 (CH2); 11.8 (11.4) (CH3)
27.9 (26.9) (CH); 20.9 (20.2)(CH3); 18.4 (17.8) (CH3)
that piperidine ring adopts chair conformation 16C on which equa-
torial orientations of the aryl groups and of one methyl group
should be equatorial and the other methyl group should be axial.
The parent piperidin-4-ones (1–11) should exist in chair confor-
mation. In these conformations the aryl groups are equatorial and
the alkyl group at C-3 is equatorial in the 3t-alkyl compounds. The
coupling constant values and position of the chemical shifts were
used to predict the conformation of the compounds. The observa-
tions of large vicinal coupling constant values between 9.53–11.0
(J32a,3a) and 10.90–11.60 Hz (J53a,6a) and of small value of the vicinal
coupling constants of 2.5– 3.2 Hz (J36a,5e) for the protons of C-6 and
C-2 of the synthesized compounds 12–22 indicate that the six-mem-
bered heterocyclic ring of compounds 12–22 adopts normal chair
conformation (Fig. 9) with equatorial orientation of phenyl groups
at C-2 and C-6, and equatorial orientation of methyl group at C-3.
However, compounds 17–22, which have two methyl groups at C-3
carbon and in these compounds one methyl group should have the
axial orientation and the remaining one is equatorially oriented
[10,11]. Furthermore, equatorial disposition of phenyl groups at C-2
and C-6 makes the chair conformation more rigid thereby preventing
inter-conversion from one chair into another. In the other compounds
12–22 the heterocyclic ring may be flattened or distorted about the
C2AC3 bond to decrease gauche interaction between the equatorial
phenyl group and the equatorial methyl groups at C-2 and C-3
respectively.
The vicinal coupling constant between the isopropyl methine
proton and H-3 is 2.3 Hz in 22 suggesting that in 22 also the isopro-
pyl group adopts a similar conformation. Hence, the CH bond of the
isopropyl group cannot interact with the nitrogen of the C@N
group in 22. In this compound there may be a shielding due to
the eclipsing of C@N bond with the C(3)-CHMe2 bond.
Configuration about C(4)@N bond
In all cases the chemical shift of H-5e is greater than that of H-
5a by about 0.73 ppm. Also, C-5 has a much lower chemical shift
than C-3. Those observations suggest that the configuration about
C(4)@N bond is E. In such a configuration the C(5)AH(5e) bond will
be polarized by gamma-syn effect, so that H-5e gets a partial posi-
tive charge and C-5 gets a partial negative charge. The partial posi-
tive charge on H-5e deshields it. The partial negative charge on C-5
shields it and H-5a. Indeed in this reaction two isomers should be

38
C. Sankar et al. / Journal of Molecular Structure 1083 (2015) 27–38
Conclusion
Py
H
A series of piperidin-4-one hydrazones have been synthesized
N
C
successfully in appreciable yields and were characterized by IR
and NMR. Single crystal XRD analysis was also performed for com-
pound 16. The observations suggest that the compound exists in
two forms in solution, the E and Z forms 16(E) and 16(Z). The
observed vicinal proton–proton coupling constants suggest that
in hydrazones 12–22, the piperidine ring adopts chair conforma-
tion with equatorial orientations of the aryl groups. The observed
chemical shifts of H-5e, H-5a and C-5 are in accord with E config-
uration about the C@N bond. In 12–22, the equatorial alkyl carbon
attached to C-3 is shielded by the nitrogen atom of the C@N bond
due to d-syn effect. However in the solid state the configuration
exist in tatutomeric form A with E orientation about the (O)CANH
bond.
O
H
N
H
H
Ph
CH3
N
H
Ph
H
CH3
16 C
Fig. 9. Chair conformation of 16C.
Acknowledgements
formed. However, only in this study we report the formation of two
isomers.
The authors are thankful to SIF, Indian Institute of Science, Ban-
galore and to SAIF IIT Chennai for recording NMR spectra. Thanks
are due to CECRI, Karaikudi for elemental analysis. One of the
authors (C. Sankar) is thankful to UGC for the award of a
fellowship.
Analysis of chemical shifts
In compounds 13–22 H-2a has a lower chemical shift than H-6a.
However, H-2a has a higher chemical shift in 16–22 than in 13–15.
These observations suggest that an equatorial methyl group shields
an adjacent axial proton but an axial methyl group deshields an
adjacent axial proton. These observations are consistent with those
made earlier [1,12]. Also C-2 has a higher chemical shift than in 9-
12. Moreover, C-2 in 17-22 has a higher chemical shift than in 13-
15. It has been observed that an equatorial for methyl group
deshields adjacent carbon [2].
Comparison of 16 and 19 suggest that the methyl group shields
the meta protons significantly. Also the ipso carbons and meta car-
bons are shielded. The methoxy group places significant negative
charges on the meta and ipso carbons due to mesomeric effect. This
results in a shielding of ortho protons, ortho and ipso carbons. The
shielding on ortho carbons is greater than those on the ipso carbon,
because meta carbons are subjected to additional shielding by ste-
ric interaction.
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