New Schiff bases derived from benzyl carbazate with alkyl and heteroaryl ketones: Isolation, structural characterization, thermal behavior and molecular docking studies

Article abstract of DOI:10.1007/s10973-017-6205-8

The condensation reaction of benzyl carbazate with the ketones, viz., dimethylketone, dipropylketone, cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone, 2-acetylpyridine, 3-acetylpyridine and 4-acetylpyridine, yielded the Schiff bases [benzyl 2

Full text of DOI:10.1007/s10973-017-6205-8

J Therm Anal Calorim
DOI 10.1007/s10973-017-6205-8
New Schiff bases derived from benzyl carbazate with alkyl
and heteroaryl ketones
Isolation, structural characterization, thermal behavior and molecular docking studies
Palanivelu Nithya1 Jim Simpson2 Sannasi Helena1 Ramar Rajamanikandan1
Subbiah Govindarajan1
•
•
•
•
Received: 20 June 2016 / Accepted: 15 February 2017
´
´
Ó Akademiai Kiado, Budapest, Hungary 2017
Abstract The condensation reaction of benzyl carbazate
with the ketones, viz., dimethylketone, dipropylketone,
cyclobutanone, cyclopentanone, cyclohexanone, cyclo-
heptanone, 2-acetylpyridine, 3-acetylpyridine and 4-acet-
ylpyridine, yielded the Schiff bases [benzyl 2-(propan-2-
ylidene)hydrazinecarboxylate (1), benzyl 2-(heptan-4-yli-
dene)hydrazinecarboxylate (2), benzyl 2-(cyclobutanyli-
dene)hydrazinecarboxylate (3), benzyl 2-(cyclopentnylidene)
hydrazinecarboxylate (4), benzyl 2-(cyclohexanylidene)
hydrazinecarboxylate (5), benzyl 2-(cycloheptanylidene)hy-
drazinecarboxylate (6), benzyl 2-(1-(pyridine-2-yl) ethyli-
dene)hydrazinecarboxylate (7), benzyl 2-(1-(pyridine-3-yl)
ethylidene)hydrazinecarboxylate (8) and benzyl 2-(1-(pyr-
idine-4-yl) ethylidene)hydrazinecarboxylate (9)], respec-
tively. These were all characterized by elemental analysis,
FT-IR and NMR (1H and 13C) spectroscopic methods, and in
addition, the structures of compounds 4, 8 and 9 have been
confirmed by single-crystal X-ray diffraction studies, and their
crystal structures are shown to be stabilized by hydrogen
bonding. The thermal properties of all the Schiff bases have been
studied in air and all of them underwent melting followed by
endo- and exothermic decomposition processes to yield an
ethanimine (CH3–CH=NH) intermediate which in turn decom-
poses exothermically to give gaseous products. In a nitrogen
atmosphere, these compounds also show similar thermal
behavior but with the absence of an intermediate. A docking
study of compounds 2, 4 and 9 with human BChE provides
useful structural information on their inhibition properties.
Keywords Schiff bases Á Benzyl carbazate Á Ketones Á
Crystal structures Á Thermal properties Á Docking studies
Introduction
In the recent past, the chemistry of hydrazine has been of
interest owing to the presence of two free electron pairs,
four substitutable hydrogen atoms and an N–N bond.
Hydrazine and its derivatives can act as a uni- or bidentate
(bridging) ligands due to the presence of two free electron
pairs [1]. Our research group has investigated the salt-
forming ability of hydrazine and its derivatives with dif-
ferent aliphatic- [2, 3], aromatic- [4, 5] and nitrogen-con-
taining heteroaromatic carboxylic acids [6–11] over a
period. Hydrazines not only form salts with carboxylic
acids, but also undergo condensation reactions with car-
bonyl compounds to form Schiff bases; their metal com-
plexes have also been studied [12, 13]. Among the
hydrazine derivatives, carbazates (esters of hydrazinecar-
boxylic acid, NH2–NH–COO–R, where R = CH3, C2H5 or
CH2C6H5) are interesting as ligands in view of the variety
of their potential donor atoms. The use of methyl carbazate
[14, 15] and ethyl carbazate [16] as ligands to transition
metal ions has been exploited by many researchers,
including our own reports [17–22]. Apart from their
coordination ability, carbazates can also undergo conden-
sation reactions; the hydrazinic part of the terminal amine
group reacts with a carbonyl group from aldehydes or
ketones to form Schiff bases.
Electronic supplementary material The online version of this
article (doi:10.1007/s10973-017-6205-8) contains supplementary
material, which is available to authorized users.
& Subbiah Govindarajan
drsgovind@yahoo.co.in
1
Department of Chemistry, Bharathiar University,
Coimbatore 641 046, Tamil Nadu, India
2
Department of Chemistry, University of Otago,
Dunedin 9054, New Zealand
123

P. Nithya et al.
The preparation and structures of Schiff bases derived
from methyl and ethyl carbazates with a variety of carbonyl
compounds has been reported previously [23–33] but to the
best of our knowledge, the chemistry of comparable Schiff
base derivatives, prepared from benzyl carbazate with
carbonyl compounds in general and ketones in particular,
has not been explored. Therefore, we present here a sys-
tematic study of the synthesis, structural characterization
and thermal reactivity of Schiff bases derived from benzyl
carbazate (bc) and the following ketones: dimethyl ketone
(dmk), dipropyl ketone (dpk), cyclobutanone (cb),
cyclopentanone (cp), cyclohexanone (ch), cycloheptanone
(chp), 2-acetylpyridine (2ap), 3-acetylpyridine (3ap) and
4-acetylpyridine (4ap). In addition, the ability of benzyl
carbazate Schiff bases to inhibit human butyryl-
cholinesterase (human BChE) receptor has been studied
using a molecular docking approach for the first time. The
binding of these Schiff bases to human BChE was therefore
evaluated in order to better understand the biological sig-
nificance of benzyl carbazate Schiff bases.
Experimental
Preparation of the Schiff bases
To a methanolic solution (20 mL) of benzyl carbazate
(0.166 g, 0.001 mol), 0.001 mol of a suitable ketone such
Scheme 1 Preparation of the
Schiff bases (1–9)
R1
R1
H2N
CH3OH
+
O C
C
N
HN
O
NH
R2
R2
O
O
O
R1, R2 = CH3 (1)
R1, R2 = n–C3H7 (2)
O
H2N
NH
O
CH3OH
+
N
HN
O
n
O
O
n = 1 (3), 2 (4), 3 (5), 4 (6)
N
H2N
NH
O
H3C
O
O
CH3OH–H2O
H3C
H3C
H3C
N NH
+
N
O
O
(7)
N
H2N
NH
O
H3C
O
O
O
CH3OH–H2O
H
+
N N
N
O
(8)
N
H2N
O
H3C
NH
O
CH3OH–H2O
N
+
O
O
H
O
N
N
(9)
123

New Schiff bases derived from benzyl carbazate with alkyl and heteroaryl ketones
X-ray structure determinations
as the simple ketones (dmk, 0.07 mL and dpk, 0.14 mL)
and the cyclic ketones (cb, 0.07 mL; cp, 0.09 mL; ch,
0.1 mL and chp, 0.12 mL) was added drop wise. The
resulting solution was covered with filter paper and kept at
room temperature for crystallization. The compounds
formed after a day were filtered off, washed with water and
air-dried. The same procedure was adopted with the
heteroaromatic ketones (2, 3 and 4 ap, 0.11 mL) using 1:1
methanol-H2O as the solvent. Details of the preparations of
the Schiff bases are shown in Scheme 1.
The X-ray measurements on single crystals of 4, 8 and 9
were taken on an Agilent Duo diffractometer using CuKa
˚
radiation (k = 1.5418 A) with data collection, reduction
(a)100
80
60
40
20
Materials and instrumentation
Benzyl carbazate and the ketones used in this study were
purchased from Sigma-Aldrich, USA, and methanol was
used as received without further purification. The hydra-
zine content of the carbazate moiety in all the ligands was
determined volumetrically using 0.025 M KIO3 solution
under Andrews’ conditions [34]. Elemental analyses for C,
H and N were performed on a Vario-ELIII elemental
analyzer. IR spectra were recorded on a JASCO- 4100
spectrophotometer as KBr pellets in the range of
0
4000 3500 3000 2500 2000 1500 1000 500
Wavenumber/cm–1
(b)
80
4000–400 cm-1 1H NMR and 13C NMR spectra were
.
recorded on a Bruker AV 400 (400 MHz (1H) and
100 MHz (13C)) spectrometers using tetramethylsilane
(TMS) as an internal reference. Chemical shifts are
expressed in parts per million (ppm). Coupling constants
(J) are reported in hertz (Hz). Simultaneous TG–DTA
studies were undertaken on a PerkinElmer SII thermal
analyzer, and the curves were obtained in air using plat-
inum cups as sample holders, each with 5–10 mg of sample
at a heating rate of 10 °C min-1. Thermal analysis curves
(TG and DTA) were obtained from a TA instrument, SDT
Q600 thermal analyzer in a flowing nitrogen atmosphere
60
40
20
4000 3500 3000 2500 2000 1500 1000 500
Wavenumber/cm–1
with a heating rate of 10 °C min-1
.
Fig. 1 FT-IR spectra of compound 2 (a) and 7 (b)
Table 1 Analytical data
Compound
m.pt./°Ca
N2H4/%
C/%
H/%
N/%
Yield/%
obsd.
calcd.
obsd.
calcd.
obsd.
calcd.
obsd.
calcd.
1
2
3
4
5
6
7
8
9
a
85
90
16.25
12.70
14.40
12.70
12.80
11.80
11.10
10.90
10.70
15.53
12.21
14.68
13.79
13.01
12.31
11.81
11.81
11.81
63.98
68.58
65.94
66.85
67.88
68.93
66.23
66.45
66.36
64.08
68.70
66.06
67.24
68.29
69.23
66.91
66.91
66.91
6.55
7.96
6.10
6.25
6.98
7.35
5.28
5.45
5.30
6.80
8.40
6.42
6.90
7.32
7.69
5.58
5.58
5.58
13.29
10.45
12.68
11.88
11.02
10.50
15.43
15.35
15.40
13.59
10.69
12.84
12.07
11.38
10.77
15.61
15.61
15.61
85
88
80
79
83
75
80
81
84
80
95
100
130
120
130
150
Values obtained from TG–DTA experiments in air
123

P. Nithya et al.
Table 2 1H NMR spectral data/ppm for DMSO-d6 solutions of the compounds (1–9)
Compound
CH2/CH3
OCH2
Phenyl ring
Pyridine ring
–
NH
1
1.815 (s, 3H)
5.136 (s, 2H)
7.362–7.395 (m, 5H)
9.786 (s, 1H)
1.883 (s, 3H)
2
0.879 (q, 6H, J = 7.2 Hz)
1.361–1.481 (m, 4H)
2.120 (t, 2H, J = 8 Hz)
2.218 (t, 2H, J = 8 Hz)
1.823–1.903 (m, 2H)
2.831 (t, 4H, J = 8 Hz)
1.613–1.727 (m, 4H)
2.212–2.288 (m, 4H)
1.514–1.592 (m, 6H)
2.187 (t, 2H, J = 5.6 Hz)
2.314 (t, 2H, J = 5.6 Hz)
1.481–1.591 (m, 8H)
2.346–2.500 (m, 4H)
2.313 (s, 3H)
5.115 (s, 2H)
7.320–7.387 (m, 5H)
–
9.893 (s, 1H)
3
4
5
5.106 (s, 2H)
5.122 (s, 2H)
5.115 (s, 2H)
7.311–7.384 (m, 5H)
7.303–7.400 (m, 5H)
7.309–7.401 (m, 5H)
–
–
–
10.027 (s, 1H)
9.693 (s, 1H)
9.939 (s, 1H)
6
7
5.122 (s, 2H)
5.229 (s, 2H)
7.320–7.385 (m, 5H)
7.337–7.455 (m, 5H)
–
9.643 (s, 1H)
10.451 (s, 1H)
7.801 (t, 1H, J = 7.6 Hz)
8.002 (d, 1H, J = 8 Hz)
8.561 (d, 1H, J = 3.6 Hz)
8.086 (d, 1H, J = 8 Hz)
8.556 (d, 1H, J = 4 Hz)
8.918 (S, 1H)
8
9
2.258 (s, 3H)
2.232 (s, 3H)
5.220 (s, 2H)
5.233 (s, 2H)
7.321–7.452 (m, 5H)
7.332–7.463 (m, 5H)
10.413 (s, 1H)
10.530 (s, 1H)
7.668 (d, 1H, J = 1.6 Hz)
7.68 (d, 1H, J = 1.6 Hz)
8.599 (d, 2H, J = 6 Hz)
s singlet, d doublet, t triplet, q quartet, m multiplet
and absorption corrections controlled using CrysAlisPro
[35] with data collected at 100(2) K. Data were reduced,
and multi-scan absorption corrections were applied using
CrysAlisPro [35]. The structures were solved by direct
methods with SHELXS-97 [36] and refined using full-ma-
trix least-squares procedures using SHELXL-2014/7 [37]
and TITAN2000 [38]. All non-hydrogen atoms were refined
anisotropically, and all hydrogen atoms bound to carbon
were placed in the calculated positions, and their thermal
parameters were refined isotropically with Ueq = 1.2–1.5
Ueq(C). The N–H hydrogen atoms were located in differ-
ence Fourier maps, and their coordinates were refined with
Ueq = 1.2 Ueq(N). Atoms of the C3 methylene group in 4
were disordered over two positions. Their occupancies
were refined to sum to unity, and this refinement converged
with an occupancy ratio 0.51(2):0.49(2). Data for 4 were
not of the highest quality with the final R1 [ 8%. How-
ever, these data were the best that could be obtained from
several data sets that were collected on different crystals
and the quality of the data is suitably reflected in the
residuals quoted. All molecular plots and packing diagrams
were drawn using Mercury [39]. Additional metrical data
were calculated using PLATON [40], and tabular material
was produced using WINGX [41].
Molecular docking studies
Molecular docking experiments were conducted using
AutoDock 4.2 docking software together with AutoDock
Tools (ADT) [42]. The ligand structures for docking
studies were prepared with MGLTool 1.5.4, and the native
structure of human BChE (Pdb: 1P0I) was recovered from
the Protein Data Bank. As required for the Lamarckian
Genetic Algorithm docking compilation, all water mole-
cules were removed from the native structure of human
BchE, hydrogen atoms were added, and Gasteiger charges
were calculated. The grid box along the x-, y- and z-axes
˚
was set to 54, 54 and 54 A. During the docking process, the
whole active site of human BChE was encompassed by
setting the coordinates x, y, z for the center of grid box to
˚
137.994, 123.01, 39.019 A, respectively. The AutoDocking
parameters used were those from the genetic algorithm
(GA) population = 150, maximum number of energy
evaluations = 250,000 and a GA crossover mode of two
123

New Schiff bases derived from benzyl carbazate with alkyl and heteroaryl ketones
Table 3 13C NMR spectral data/ppm for DMSO-d6 solutions of the compounds (1-9)
Compound
CH2/CH3
OCH2
65.57
Phenyl ring
Pyridine ring
–
C=N
C=O
1
17.20 (C3 & C30)
127.76–128.20 (C6–C10)
136.51 (C5)
152.16
154.08
2
13.71 (C5), 13.88 (C50)
18.39 (C4), 19.48 (C40)
30.44 (C3 & C30)
13.04 (C4)
65.54
127.74–128.29 (C8–C12)
136.85 (C7)
–
154.09
157.30
3
4
5
65.60
65.59
65.51
127.93–128.37 (C8–C12)
136.73 (C7)
–
–
–
153.72
153.93
154.30
156.28
163.60
157.74
33.11 (C3), 33.25 (C5)
24.33 (C4), 24.46 (C5)
28.06 (C3), 32.75 (C6)
25.55 (C5)
127.91–128.35 (C9–C13)
136.78 (C8)
127.89–128.65 (C10–C14)
136.84 (C9)
26.80 (C4), 26.83 (C6)
34.83 (C3 & C7)
27.09 (C5 & C6)
29.69 (C4), 29.78 (C7)
30.17 (C3 & C8)
12.06 (C70)
6
7
65.58
66.12
127.91–128.36 (C11–C15)
136.78 (C10)
–
154.06
153.90
160.01
155.17
128.04–128.42 (C11–C15)
136.52 (C10)
119.96 (C3)
123.69 (C5)
136.46 (C4)
148.45 (C6)
149.78 (C2)
8
9
13.75 (C70)
13.29 (C70)
66.07
66.19
128.26–128.42 (C11–C15)
136.56 (C10)
123.32 (C5)
149.60
149.87
154.04
153.93
128.02 (C3)
133.81 (C4)
147.22 (C2 & C6)
120.18 (C3 & C5)
136.46 (C4)
128.06–128.43 (C11–C15)
145.20 (C10)
146.73 (C2 & C6)
points. For each docking simulation, 100 different con-
formers were generated. The docked conformations were
visualized with the PyMoL (http://www.pymol.org) soft-
ware package, and the conformation with the lowest
binding free energy was used for further analysis.
recrystallization of the product using methanol as solvent.
Attempts to prepare the corresponding Schiff bases using
alkyl ketones, such as ethylmethyl, diethyl, methylpropyl
ketone, and benzyl carbazate were unsuccessful. The
results of chemical analyses of the products are given in
Table 1, and the analytical data agree well with the theo-
retical values within the limit of experimental error and
confirmed the general formula bc-x (x = ketone) proposed
for the new ligands. All of these ligands are stable in air at
room temperature, highly soluble in methanol, ethanol and
dimethylsulfoxide and insoluble in water.
Results and discussion
Preparations
The Schiff bases were prepared by the direct condensation
of benzyl carbazate with the ketones in methanol/metha-
nol-H2O in an appropriate molar proportion. X-ray quality
crystals of 4 and 9 were obtained upon slow evaporation of
the reaction mixture at room temperature. The remaining
compounds were obtained as polycrystalline solids.
Recrystallization of these solids in different solvent media
failed to produce suitable single crystals with the exception
of 8, for which crystals were grown by the repeated
Spectroscopic studies
Infrared spectra
Infrared spectroscopy is an invaluable tool for the identi-
fication of the products obtained by the condensation of
ketones with benzyl carbazate, and the spectra of Schiff
bases 2 and 7 are given in Fig. 1 as representative
123

P. Nithya et al.
(a)
CH CH CH
3
2
2
HN N C
CH CH CH
3
O
2
2
O
16 15 14 13 12 11 10
9
8
7
6
5
4
3
2
1
0
–1 –2
ppm
(b)
CH
3
O
N NH
N
O CH C H
6 5
2
16 15 14 13 12 11 10
9
8
7
6
5
4
3
2
1
0
–1 –2
ppm
Fig. 2 1H NMR spectra of compound 2 (a) and 7 (b)
123

New Schiff bases derived from benzyl carbazate with alkyl and heteroaryl ketones
Table 4 Crystal data and structure refinement parameters for ligands 4, 8 and 9
4
8
9
Empirical formula
Formula weight
Temperature/K
C13H12N2O2
228.25
C15H15N3O2
269.30
C15H15N3O2
269.30
100 (2)
1.54184
Triclinic
P-1
100 (2)
100 (2)
1.54184
Triclinic
P-1
˚
Wave length/A
1.54184
Monoclinic
P21/c
Crystal system
Space group
Unit cell dimensions
˚
a/A
5.2004 (7)
9.9009 (14)
12.4729 (13)
106.219 (11)
96.392 (11)
95.060 (12)
608.01 (14)
2
12.5058 (4)
8.2255 (2)
14.3043 (4)
90
7.8139 (4)
8.2623 (3)
10.9583 (5)
90.198 (3)
110.624 (4)
96.007 (4)
657.88 (5)
2
˚
b/A
˚
c/A
a/°
b/°
c/°
114.516 (4)
90
3
˚
Volume/A
1338.78 (8)
4
Z
Density (diffrn.)/Mg mm-3
Absorption coefficient/mm-1
F (000)
1.247
1.336
1.359
0.701
0.743
0.756
240
568
284
Crystal size/mm3
Reflection collected
Independent reflection/Rint
Completeness to two theta/°
Absorption correction
Data/restraints/parameters
Goodness of fit on F2
R1
0.31 9 0.24 9 0.10
8511
0.46 9 0.31 9 0.09
10,869
0.27 9 0.22 9 0.06
12,374
2503/0.0405
67.684
2768/0.0210
67.684
2626/0.0201
67.684
Multi-scan
2503/0/167
1.066
Multi-scan
2768/0/185
1.059
Multi-scan
2626/0/185
1.043
0.0829
0.0478
0.0441
wR2
0.2296
0.1411
0.1148
-3
˚
Largest diff. peak and hole/eA
0.454 and -0.419
0.337 and -0.263
0.290 and -0.334
formation of Schiff bases. The very strong peaks seen
around 1745–1695 cm-1 are attributed to the carbonyl
stretching frequency of the amide [19–22]. The N–N
stretching frequency of the hydrazinic moiety is observed
around 1050 cm-1. The peaks that appear in the range of
1577–1531 cm-1 are due to stretching of the azomethine
groups confirming Schiff base formation [13].
˚
Table 5 Selected bond lengths/A and angles/° for 4
N1–C2
1.283 (4)
1.381 (3)
1.358 (3)
1.226 (3)
1.332 (3)
1.460 (3)
115.6 (2)
119.5 (2)
124.3 (2)
121.7 (2)
114.0 (2)
114.75 (19)
N1–N2
N2–C1
C1–O1
C1–O2
O2–C7
C2–N1–N2
C1–N2–N1
O1–C1–O2
O1–C1–N2
O2–C1–N2
C1–O2–C7
NMR spectra
1H and 13C NMR spectral data for 1–9 and their interpre-
1
tations are shown in Tables 2 and 3. Representative H
spectra for 2 and 7 are shown in Fig. 2. These are entirely
consistent with the proposed molecular structures.
Single-crystal X-ray diffraction studies
examples. The IR spectra of the Schiff bases showed strong
bands around 3200 cm-1 which are attributed to the N–H
stretching of carbazate group [20] revealing that the ter-
minal nitrogen of the amine group is involved in the
Among the Schiff bases prepared, compounds 4, 8 and 9
were obtained as single crystals suitable for X-ray
123

P. Nithya et al.
diffraction studies. As expected, the condensed products
have a monomeric structure. The crystal data including
experimental details are presented in Table 4 with selected
bond lengths and angles for 4 in Table 5 and those for 8
and 9 in Table 6. Hydrogen bonds for 4, 8 and 9 are
detailed in Table 7. All bond distances, angles and torsion
angles are given in Tables S1 for 4, S2 for 8 and S3 for 9.
The molecular structure of 4
Compound 4, benzyl 2-cyclopentylidenehydrazinecarboxy-
late, crystallizes in the triclinic system of space group P-1
with Z = 2 and one molecule in the asymmetric unit. The
crystal structure reveals that the Schiff base crystallizes in
the amide tautomeric form with the H-atom on N2 (Fig. 3).
In the structure, atom C3 of the cyclopentyl ring was disor-
dered over two positions with a 0.51(2):0.49(2) occupancy
ratio. This disorder was also taken into account in assigning
the H atoms on the adjacent C4 carbon atom. In the molecular
structure of 4, the central C7O2C1(O1)N2N1 segment of the
˚
Table 6 Selected bond lengths/A and angles/° for 8 and 9
8
9
C7–N2
1.2897 (16)
1.5013 (17)
1.3714 (14)
1.3590 (17)
1.2088 (17)
1.3572 (16)
1.4463 (16)
116.11 (11)
125.53 (11)
118.35 (11)
116.69 (10)
118.59 (11)
125.08 (12)
127.66 (13)
107.26 (11)
116.43 (11)
1.2893 (18)
1.5027 (19)
1.3686 (16)
1.3598 (18)
1.2204 (17)
1.3397 (17)
1.4630 (16)
114.39 (12)
126.24 (13)
119.35 (12)
118.29 (12)
120.39 (11)
124.51 (12)
122.03 (13)
113.45 (12)
115.44 (11)
C7–C71
N2–N3
N3–C8
C8–O8
C8–O9
˚
molecule is reasonably planar (rms deviation 0.0486 A) and
O9–C9
subtends an angle of 74.06(9)° to the plane of the adjacent
phenyl ring. The cyclopentyl ring adopts an envelope con-
formation with atom C2 at the flap.
N2–C7–C5(4)
N2–C7–C71
C5–C7–C71
C7–N2–N3
C8–N3–N2
O8–C8–O9
O8–C8–N3
O9–C8–N3
C8–O9–C9
Structural description of 8 and 9
The molecular structures of the (E)-benzyl 2-(1-(pyridine-
3-yl) ethylidene)hydrazinecarboxylate (8) and (E)-benzyl
2-(1-(pyridin-4-yl) ethylidene)hydrazinecarboxylate (9)
with atom numbering schemes are shown in Fig. 4a, b and
are sufficiently similar to be discussed together. As was
Table 7 Hydrogen bonds for 4, 8 and 9
D–H…A
\(DHA)/o
˚
d(D–H)/A
˚
d(H–A)/A
˚
d(D–H…A)/A
Compound 4
N(2)–H(2N)…O(1)4i
C(6)–H(6A)…O(1)4i
C(7)–H(7B)…N(1)4ii
C(7)–H(7B)…O(2)4ii
Compound 8
0.92 (3)
0.99
1.96 (3)
2.65
2.875 (3)
3.202 (3)
3.563 (3)
3.458 (3)
172 (3)
116
0.99
2.68
149
0.99
2.81
123
N(3)–H(3 N)…N(1)8i
C(71)–H(71C)…N(1)8i
C(2)–H(2)…O(8)8ii
C(3)–H(3)…Cg(2)8iii
Compound 9
0.871 (18)
0.98
2.045 (19)
2.58
2.9094 (16)
3.1933 (18)
3.5594 (17)
3.4704 (17)
171.1 (16)
121
0.95
2.66
159
0.95
2.55
164
N(3)–H(3 N)…O(8)9i
C(71)–H(71A)…O(8)9i
C(2)–H(2)…N(1)9ii
C(12)–H(12)…N(1)9iii
C(71)–H(71A)…Cg(1)9iv
C(9)–H(9A)…Cg(2)9v
0.885
0.98
2.014
2.33
2.8895 (16)
3.2958 (18)
3.518
169.8 (17)
170
0.950
0.980
0.980
0.99
2.636
2.326
2.738
2.80
154.57
169.89
135.57
126
3.296
3.505
3.4758 (16)
Symmetry operations: 4i = -x ? 1, -y, -z ? 2; 4ii = -x ? 1, -y ? 1, -z ? 2; 8i = x, -y ? 3/2, z - 1/2; 8ii = -x ? 1, y ? 1/2, -z ? 3/
2; 8iii = -x ? 1, -y ? 2, -z ? 1; 9i = -x, -y, -z ? 1; 9ii = -x - 1, -y ? 2, -z ? 1; 9iii = x ? 1, y - 1, z; 9iv = -x - 1, -y ? 1,
-z ? 2; 9v = -x ? 1, -y, -z ? 2. Cg1 and Cg2 are the centroids of the N1C2…C5 and C10…C15 rings, respectively
123

New Schiff bases derived from benzyl carbazate with alkyl and heteroaryl ketones
Fig. 3 Molecular structure of
compound 4 with ellipsoids
drawn at the 50% probability
C3A
level. For clarity, only the major
C4
disorder component of the
disordered C3 methylene group
is shown
C13
C2
N1
C7
O2
C5
C12
C11
C8
C6
N2
C1
C9
O1
C10
Fig. 4 a Molecular structure of
compound 8 with ellipsoids
drawn at the 50% probability
level. b The molecular structure
of compound 9 with ellipsoids
drawn at the 50% probability
level
(a)
C71
C11
C12
C13
O9
C4
C9
C10
N3
C7
C8
C5
C6
C3
N2
C15
C14
O8
C2
N1
C71
(b)
C3
O8
C7
C4
C5
N3
C8
C2
N1
N2
C11
O9
C9
C12
C6
C10
C15
C13
C14
found with 4, the central C9O9C8(O8)N3N2 segments of
both molecules 8 and 9 are reasonably planar with rms
˚
deviations of 0.0873 for 8 and 0.0162 A for 9. The planes
the benzyl substituents are almost orthogonal to the central
planes subtending angles of 78.77(3) for 8 and 72.91(4) for
9. Both molecules adopt E configurations with respect to
the C7=N2 double bonds, but the N2 and O8 atoms are cis
in the solid state for 8 and trans for 9. As with 4, both
of the two pyridine rings subtend angles of only 0.052(7)°
and 4.64(6)°, respectively. In contrast, the phenyl rings of
123

P. Nithya et al.
Table 8 Thermal data of Schiff bases 1–9 in air
Compound
DTA peak temp./°C
Thermogravimetry
Decomposition
phenomena/possible
intermediates
Temp. range/°C
Mass loss/%
Obsd.
Calcd.
1
2
3
4
5
6
7
8
9
85 (?)
205 (?)
245 (-)
385 (-)
90 (?)
–
–
–
Melting
120–260
78.00
79.13
Formation of CH3–CH=NH
260–500
–
100.00
–
100.00
–
Complete decomposition
Melting
220 (?)
245 (-)
380 (-)
80 (?)
130–300
84.00
83.59
Formation of CH3–CH=NH
300–520
–
100.00
–
100.00
–
Complete decomposition
Melting
190 (?)
215 (-)
530 (-)
95 (?)
125–320
80.00
80.28
Formation of CH3–CH=NH
320–600
–
100.00
–
100.00
–
Complete decomposition
Melting
220 (?)
245 (-)
510 (-)
100 (?)
215 (?)
230 (-)
510 (-)
130 (?)
220 (?)
245 (-)
480 (-)
120 (?)
240 (?)
275 (-)
515 (-)
130 (?)
205 (?)
240 (-)
565 (-)
150 (?)
195 (?)
230 (-)
520 (-)
150–360
82.00
81.47
Formation of CH3–CH=NH
360–580
–
100.00
–
100.00
–
Complete decomposition
Melting
135–295
84.00
82.52
Formation of CH3–CH=NH
295–650
–
100.00
–
100.00
–
Complete decomposition
Melting
150–295
84.00
83.46
Formation of CH3–CH=NH
295–530
–
100.00
–
100.00
–
Complete decomposition
Melting
160–370
85.50
84.01
Formation of CH3–CH=NH
370–650
–
100.00
–
100.00
–
Complete decomposition
Melting
160–390
84.00
84.01
Formation of CH3–CH=NH
420–650
–
100.00
–
100.00
–
Complete decomposition
Melting
170–350
84.00
84.01
Formation of CH3–CH=NH
350–620
100.00
100.00
Complete decomposition
? Endothermic, - exothermic
Crystal packing for 4
molecules adopt the amide tautomer in the solid state with
H atoms on N3. Bond distances (Table 7) show C7=N3 and
C8=O8 to be double bonds in each case, but the other
distances in these parts of the molecules suggest a con-
siderable degree of delocalisation in both instances which
presumably also contributes to the planarity of these
sections.
In the crystal structure of 4, atom O1 acts as a bifurcated
acceptor forming N2–H2N…O1 hydrogen bonds flanked
by C6-H6A…O1 contacts forming inversion dimers and
generating R22(8) and R12(7) ring motifs, respectively [43]
(Table 8). These dimers are linked by inversion-related C7-
123

New Schiff bases derived from benzyl carbazate with alkyl and heteroaryl ketones
Fig. 5 a Zigzag chains of
compound 4 propagated along
(a)
c. In these subsequent packing
diagrams, hydrogen bonds are
drawn as dashed lines. b Overall
packing for 4 viewed along a
a
O
b
H7B
N2
H2N
C6
O1
C7
N1
H6A
C
(b)
b
a
O
C
H7B…N1 hydrogen bonds that generate R22(12) rings
forming zigzag chains of molecules along the b axis
direction (Fig. 5a). Very weak C7-H7B…O2 contacts stack
these independent chains along a (Fig. 5b), resulting in a
three-dimensional network structure.
4.0 A identified as the maximum centroid-to-centroid dis-
tance that constitutes a p…p stacking interaction of rea-
sonable magnitude [44, 45]. These contacts form chains of
molecules along the ac diagonal (Fig. 6c). This plethora of
intermolecular contacts combines to generate an extensive
three-dimensional network of molecules stacked along the
b axis direction (Fig. 6d).
˚
Crystal packing for 8
In the crystal structure of 8, atom N1 acts as a bifurcated
acceptor forming N3-H3N…N1 and weaker C71-
H71C…N1 hydrogen bonds (Table 7) that generate R12(7)
ring motifs and link the molecules in a head-to-head fashion
into chains along the c axis direction (Fig. 6a). Additional
C2–H2…O8 hydrogen bonds stack the molecules head-to-
head along c (Fig. 6b). Compound 8 also forms C3–H3…p
contacts (Table 7) and offset p…p stacking interactions both
of which involve the C10…C15 phenyl ring of the benzyl
substituent. In the p…p contacts, the centroid-to-centroid
Crystal packing for 9
The propensity for the formation of inversion dimers
observed in the crystal structure of 4 returns in abundance
in the packing of 9. Classical N3–H3N…O8 hydrogen
bonds flanked by weaker C71–H71A…O8 contacts form
inversion dimers and generate R22(8) and R21(7) rings. These
dimers are linked, again with inversion dimer formation,
through pairs of C2-H2…N1 hydrogen bonds with R22(6)
ring motifs to form chains of molecules approximately
parallel to (320) (Fig. 7a). Parallel chains are linked by
˚
distance, Cg2…Cg2, is 3.7898(9) A, well below the value of
123

P. Nithya et al.
(c)
(a)
a
b
O
C
N3
H3N
N1
H71C
C3
H3
C71
C
O
Cg2
Cg2
b
a
(d)
(b)
a
a
O8
H2
C2
b
C
O
b
C
O
Fig. 6 a Chains of molecules of 8 along b. b Stacks of molecules of 8
along b. c C–H…p and p…p contacts in the crystal structure of 8.
Intermolecular C–H…p and p…p contacts are shown as green dotted
lines. d Overall packing for 8 with representative C–H…p and p…p
interactions shown as green dotted lines. (Color figure online)
C71–H71B…N2 inversion dimers forming R22(8) rings to
generate parallel layers (Fig. 7b). The extensive set of
intermolecular contacts in the packing of 9 is completed by
two sets of C–H…p interactions, C71–H71C…Cg1 and
C9–H9A…Cg2 (Table 7), both of which are again inver-
sion related and form chains of molecules along the ac
diagonal (Fig. 7c). Ultimately, these contacts combine to
form an extensive three-dimensional network with mole-
cules stacked along the b axis direction (Fig. 7d).
experiments. The thermogravimetric results are in good
agreement with the DTA data. Simultaneous TG–DTA tra-
ces for 2, 4, 6 and 8 are shown in Fig. 8, as representative
examples and the remaining curves are available in the
electronic supplementary information (Fig. S1).
The thermal decomposition pattern of 1 and 2 are almost
identical, showing two stage mass losses in accordance with
the DTA results. These compounds exhibit an endotherm at
85 °C (1) and 90 °C (2), respectively, due to melting. In the
first step, the melts undergo endo- followed by exothermic
decomposition probably producing ethanimine, CH3–
CH=NH as an intermediate, and the observed mass loss
corresponds to the formation of ethanimine at around
245 °C. Finally, this intermediate decomposes exothermi-
cally to give gaseous products at approximately 500 °C.
The Schiff bases (3–6) derived from benzyl carbazate
and cyclic ketones also show two steps of decomposition in
the TG experiments, again in accordance with the DTA
measurements, showing melting between 80 and 130 °C.
Next, the melts undergo endothermic followed by
Thermal behavior
Thermal decomposition of Schiff bases 1–9 in air
In order to investigate the thermal properties of the Schiff
bases, simultaneous TG–DTA measurements were taken
from room temperature to 800 °C for all samples. The
thermal decomposition behavior for 1–9 is detailed in
Table 8. The decomposition intermediates and the final
products are those that fit the observed mass losses in the TG
123

New Schiff bases derived from benzyl carbazate with alkyl and heteroaryl ketones
(a)
(c)
c
C9
b
H9A
a
O8
O
H71A
N1
Cg2
C71
H2
H3N
N3
C2
C71
Cg1
H71C
O
b
c
a
(b)
(d)
C71
H71B
N2
Fig. 7 a Inversion dimers formed by molecules of 9. b Parallel layers
of molecules of 9. c Chains of molecules of 9 formed by inversion-
related C–H…p contacts. d Overall packing for 9 viewed along b with
representative C–H…p interactions shown as green dotted lines.
(Color figure online)
exothermic decomposition in the DTA, between 190 and
245 °C with a mass loss of 80–84%. This again corre-
sponds to the formation of ethanimine which subsequently
decomposes to gaseous products, exothermically in the
range 350–600 °C, as observed in compounds 1 and 2.
Similarly, the isomeric acetylpyridine Schiff bases (7–9)
also exhibit clear melting behavior at 120, 130 and 150 °C,
and 9) show closely similar thermal decomposition
behavior to that of the 2-acetylpyridine analogue.
The thermal decomposition behavior of the entire range
of Schiff bases (1–9) is reasonably similar with only slight
variations in the temperature ranges in the TG experiments.
In order to confirm the proposed intermediate in the
decomposition of Schiff bases (1–9), as a representative
example, compound 4 was heated up to 250 °C at a con-
trolled heating rate (5 °C min-1) in a furnace. The resulting
intermediate material was then removed after cooling, and
its IR spectrum recorded. The spectrum of the intermediate
(Fig. 9) displayed a characteristic band in the region of
3420 cm-1 corresponding to the N–H stretching mode. A
moderate peak around 2925 cm-1 is attributed to the C-H
stretching vibration. Strong characteristic absorption bands
respectively. Upon melting, compound
7 undergoes
endothermic (240 °C) followed by exothermic decompo-
sition (275 °C) again forming the CH3–CH=NH interme-
diate. This decomposition is supported by the mass loss in
the TG experiment (obsd 85.50%; calcd 84.01%). The final
step is the decomposition of this intermediate to give
gaseous products at 515 °C, in the DTA, as in the other
cases. The isomeric 3- and 4-acetylpyridine Schiff bases (8
123

P. Nithya et al.
100.2
80
0.6572
100.1
0.5838
2
4
–5
–5
80
60
40
20
–10
–15
–10
–15
60
40
20
–20
–25
–20
–25
–30
–30
–4.015
–32.27
805.7
–3.799
–31.77
31.05 100
200
300
400
500
600
700
29.47 100
200
300
400
500
600
700
805.3
Temperature/°C
Temperature/°C
100.2
80
0.4771
100.04
80
0.885
6
8
–5
–5
–10
–15
–20
–25
60
60
40
–10
–15
–20
40
20
20
–30
–31.68
804.8
–2.305
–4.999
–25.39
805.2
33 100
200
300
400
500
600
700
26.71 100
200
300
400
500
600
700
Temperature/°C
Temperature/°C
Fig. 8 Simultaneous TG–DTA curves for compounds 2, 4, 6 and 8 in air
seen around 1634 and 1383 cm-1 are assigned to the C=N
stretching and CH3 bending vibrations, respectively, thus
confirming the formation of the proposed ethanimine
intermediate.
100
95
90
Thermal decomposition of Schiff bases 1–9
under a nitrogen atmosphere
85
80
75
In order to compare the simultaneous TG–DTA behavior
of the Schiff bases 1–9 under different conditions, the
experiments have also been performed under a nitrogen
atmosphere over the temperature range 30–800 °C at a
heating rate of 10 °C min-1. The thermoanalytical results
are summarized in Table 9, and the simultaneous TG–
DTA curves for the Schiff bases 2, 4, 6 and 8 are
70
4000 3500 3000 2500 2000 1500 1000 500
Wavenumber/cm–1
Fig. 9 FT-IR spectrum of ethanimine intermediate
123

New Schiff bases derived from benzyl carbazate with alkyl and heteroaryl ketones
Table 9 Thermal data of Schiff bases 1-9 under a nitrogen atmosphere
Compound
DTA peak temp./°C
Thermogravimetry
Decomposition phenomena
Temp. range/°C
Mass loss/%
Obsd.
Calcd.
1
2
3
4
5
6
75 (?)
230 (?)
270 (-)
85 (?)
–
–
–
Melting
115–360
100.00
100.00
Complete decomposition
–
–
–
Melting
220 (?)
280 (-)
95 (?)
135–360
100.00
100.00
Complete decomposition
–
–
–
–
Melting
215 (?)
250 (-)
85 (?)
150–450
97.00
Carbon residue
–
–
–
–
Melting
230 (?)
260 (-)
100 (?)
215 (?)
260 (-)
135 (?)
230 (?)
250 (-)
290 (-)
115 (?)
245 (?)
280 (-)
130 (?)
215 (?)
245 (-)
150 (?)
220 (?)
245 (-)
150–485
91.00
Carbon residue
–
–
–
Melting
130–415
100.00
100.00
Complete decomposition
–
–
–
Melting
150–325
100.00
100.00
Complete decomposition
7
8
9
–
–
–
–
Melting
165–500
90.00
Carbon residue
–
–
–
–
Melting
160–535
90.00
Carbon residue
–
–
–
Melting
180–450
100.00
100.00
Complete decomposition
? Endothermic, - exothermic
illustrated in Fig. 10 as representative examples, and the
remaining curves are available in the electronic supple-
mentary information (Fig. S2), including the simultane-
ous TG-DTG curves for the compounds (1–9) in Fig. S3.
Here also, all of the compounds show clear melting as
sharp endotherms, in the DTA, between 75 and 150 °C.
The melts then undergo endo- and exothermic decom-
positions in the range 215–245 and 245–290 °C,
respectively, as was also found in experiments in air to
give gaseous products. A close examination of the TG
results shows a single decomposition step unlike two
steps observed in air but again resulting in gaseous
products. In the TG, compounds 1, 2, 5, 6 and 9 exhibit
100% mass loss, whereas compounds 3, 4, 7 and 8 show
only 90% and above with carbon as the final residue.
This kind of incomplete combustion has been observed
previously [5, 10] in the case of carbon-rich aromatic
compounds, and it was found that this is most likely to
occur under inert (nitrogen) atmosphere conditions.
123

P. Nithya et al.
20
100
80
60
40
20
0
2
10
4
100
80
60
40
20
0
10
0
0
–10
–20
–30
–40
–10
–20
–30
–40
100
200
300 400 500
Temperature/°C
600
700 800
100 200
300 400 500
Temperature/°C
600
700 800
20
6
100
8
10
100
80
10
80
60
40
0
0
–10
–20
–30
–40
60
40
–10
–20
–30
–40
20
0
20
0
100 200
300 400
500
600 700 800
100 200
300 400 500
Temperature/°C
600
700 800
Temperature/°C
Fig. 10 Simultaneous TG–DTA curves for compounds 2, 4, 6 and 8 under a nitrogen atmosphere
Docking study
compounds occurs through nucleophilic attack at the
active site of serine on the phosphorus atom. The active
sites of serine residues for both AChE and BChE are
located at the bottom of a deep gorge [48, 49]. BChE has
broader substrate specificity and interacts with a wider
range of inhibitors compared to AChE. Consequently,
Neurodegenerative diseases involving impairment of
cognitive functions, such as dementia of the Alzheimer’s
type, are characterized by damage neurons of the basal
forebrain, with reduced cortical and hippocampal levels
of acetylcholine (ACh) [46]. Acetylcholinesterase
(AChE) and butyrylcholinesterase (BChE) are serine
hydrolases that contribute to the degradation of the
neurotransmitter ACh. Also the cholinergic system is
important in the regulation of memory and learning
processes in the central nerve system [47]. The inhibition
of both AChE and BChE by organophosphorous
BChE is designated as
a
possible stoichiometric
bioscavenger in organophosphorus nerve agent poisoning
[50]. Thus, the discovery of selective BChE inhibitors
may be of considerable interest both to elucidate the
physiological role of this enzyme and to afford novel
therapeutics for various diseases. Numerous compounds
including
carbamates
(e.g.,
neostigmine
and
123

New Schiff bases derived from benzyl carbazate with alkyl and heteroaryl ketones
Fig. 11 a Docked conformations of human BChE with compound 2.
b Binding modes of compound 2, magenta dotted lines indicate
hydrogen bond (for interpretation of the references to color in this
Fig. 12 a Docked conformations of human BChE with compound 4.
figure legend, the reader is referred to the Web version of this article).
(Color figure online)
b Binding modes of compound 4, red dotted lines indicate hydrogen
bond (for interpretation of the references to color in this figure legend,
the reader is referred to the Web version of this article). (Color
figure online)
physostigmine etc.), organophosphates, coumarin and
cinnamide derivatives are known to be inhibitors of
cholinesterases [51]. Recently, the binding of hydrazine
derivatives such as aminoguanidine salts and guanyl
hydrazones to human BChE has been reported [52, 53].
In the present study, we attempt to examine the inhibi-
tory potential of benzyl carbazate-based Schiff bases and
also to clarify the nature of their interaction with BChE,
using compounds 2, 4 and 9 as representative examples.
These were docked into the active site of BChE utilizing
the AutoDock program. Out of 25 different conformers
found during the docking process, the lowest binding
energy conformer was chosen and used for further analysis.
The best ranked conformers with the lowest free energy for
compounds 2, 4 and 9 are shown in Figs. 11–13. The
docking results of human BChE with these benzyl car-
bazate Schiff bases thus afford convincing evidence of the
likely binding location for these bases on human BChE. A
feature of these results for all three compounds is the
observation of hydrogen bonds between the bases and
BChE. Analyses of docking results revealed that compound
2 forms four hydrogen bonds with His438, Ser198, Gly117
˚
and Gly116 with bond lengths of 1.9, 2.0, 2.1 and 1.9 A
and the binding energy was found to be -24.52 kJ mol-1
as shown in Fig. 11. The docked conformations of com-
pound 4 and 9 with human BChE are depicted in Figs. 12
and 13. As shown in Figs. 12 and 13, compounds 4 and 9
form five hydrogen bonds with His438, Ser198, Ala199,
Gly116 and Gly117 with bond lengths of 2.0, 1.8, 2.2, 1.7
˚
˚
and 2.2 A, 2.0, 2.1, 2.5, 1.9 and 2.1 A for 4 and 9,
respectively. The corresponding binding energies are
-23.77 kJ mol-1 for 4 and -20.63 kJ mol-1 for 9. It is
important to note from the docking results that a common
feature is that both of the oxygen atoms of benzyl carbazate
in compounds 2, 4 and 9 interact with the active site, viz.,
the acyl pocket of BChE. Therefore, the results of
123

P. Nithya et al.
reveal that compound 2 forms four hydrogen bonds with
His438, Ser198, Gly117 and Gly116, while compounds 4
and 9 form five hydrogen bonds with His438, Ser198,
Ala199, Gly117 and Gly116, respectively. The lowest
binding energies are found to be -24.52, -23.77 and
-20.63 kJ mol-1 for 2, 4 and 9, respectively. The synthesis
of metal complexes using these Schiff bases and also the use
of related methyl and ethyl carbazate analogues as ligands is
in progress and will be reported in due course.
Acknowledgements P. Nithya acknowledges University Grant
Commission (UGC-SAP), New Delhi, for the award of BSR—Senior
Research Fellowship. We thank the University of Otago for the
purchase of the diffractometer, and the Chemistry Department,
University of Otago, for the support of the work of JS. Our sincere
thanks go to the SIF, VIT University, Vellore, for providing access to
their NMR spectral facilities. COE-AMGT, Amrita Vishwa Vidya-
peetham University, Coimbatore, is gratefully acknowledged for
permitting us to record the TG–DTA under a nitrogen atmosphere.
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