Spectral characterization and crystal structure of tetrahydropyran-4-one thiosemicarbazones

Article abstract of DOI:10.1016/j.molstruc.2010.11.072

(E)-1-(Tetrahydro-3-methyl-2,6-diphenylpyran-4-ylidene) thiosemicarbazide (3) and (E)-1-(2,6-bis(4-chlorophenyl)-tetrahydro-3,5-dimethylpyran-4-ylidene) thiosemicarbazide (4) were obtained and characterized by FT-IR, ¹H NMR, ¹³C NMR,

Full text of DOI:10.1016/j.molstruc.2010.11.072

Journal of Molecular Structure 989 (2011) 1–9
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Spectral characterization and crystal structure of tetrahydropyran-4-one
thiosemicarbazones
S. Umamatheswari a,b, J. Jaya Pratha a, S. Kabilan a,
⇑
a Department of Chemistry, Annamalai University, Annamalainagar 608 002, India
b Department of Pharmacology, PSG College of Pharmacy, Coimbatore 641 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
(E)-1-(Tetrahydro-3-methyl-2,6-diphenylpyran-4-ylidene) thiosemicarbazide (3) and (E)-1-(2,6-bis(4-
chlorophenyl)-tetrahydro-3,5-dimethylpyran-4-ylidene) thiosemicarbazide (4) were obtained and char-
acterized by FT-IR, 1H NMR, 13C NMR, NOESY spectroscopy and X-ray single-crystal diffraction analysis.
Molecular orbital calculations have been carried out for 3 and 4 by using an ab initio method (HF) and
also density functional method (B3LYP) at 6-31G basis set. Compound 4 crystallizes in the monoclinic
system, space group P21/c, with a = 11.9645(3) Å, b = 20.0690(6) Å, c = 8.7441(2) Å, b = 105.5220(10)°,
V = 2023.02(9) Å3, and Z = 4. Compounds 3 and 4 exist in chair conformation with equatorial orientation
of all the substituents at pyran ring except the methyl group at C-5 of compound 4 which is oriented at
axial disposition to stabilise the chair conformation and the configuration about the C@N double bond is
syn to C-5 carbon (E-form).
Received 21 September 2010
Received in revised form 27 November 2010
Accepted 29 November 2010
Available online 4 December 2010
Keywords:
Tetrahydropyran
Thiosemicarbazone
Conformation
Crystal structure
Density functional theory
HF
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
2. Experimental
Thiosemicarbazide H2NANHAC(@S)ANH2 is a promising unit to
synthesize new polyfunctional organic compounds, named as
thiosemicarbazone, that are used as a precursor to produce new
transition metal complexes with a wide range of application in
recent years [1]. They have been evaluated over the last 50 years
as antiviral, antibacterial, and anticancer therapeutics, and their
biological activities are a function of parent aldehyde or ketone
moiety [2–7]. Thiosemicarbazone is an important group of multid-
entate ligands and usually coordinates with the metal through the
imine nitrogen and sulfur atom [8–15].
Heterocyclic compounds carrying pyran skeleton are attractive
targets of organic synthesis owing to their presence in numerous
naturally occurring carbohydrates and synthetic compounds with
interesting biological and pharmacological properties [16–19].
In view of these findings and in a further stage of our work on
the synthesis of heterocycles [20–24], here we have report the
spectral characterization and crystal structure of thiosemicarba-
zone compounds derived from tetrahydro-3-methyl-2,6-diph-
TLC was carried out to monitor the course of the reaction and
purity of the product. 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 NMR spectra were recorded at 400 MHz on
BRUKER AMX 400 MHz spectrophotometer using CDCl3 as solvent
and TMS as internal standard. 13C NMR spectra were recorded at
100.6 MHz on BRUKER AMX 400 MHz spectrometer in CDCl3 and
the NOESY correlation spectra were recorded on BRUKER DRX
500 MHz NMR spectrometer using standard parameters. 0.05 M
solutions of the sample prepared in CDCl3 were used for recording
2D NMR spectra. The Electron Spray High Resolution Mass Spec-
trum was recorded on QTof-Mico YA 263 instrument and microa-
nalyses were performed on Heraeus Carlo Erba 1108 CHN analyzer.
2.1. X-ray data collection, structure solution and refinement
enylpyran-4-one
and
2,6-bis(4-chlorophenyl)-tetrahydro-3,
Single crystals suitable for diffraction were obtained by the slow
evaporation of a solution of the compound in ethanol. The colour-
less crystal of the compound having appropriate dimensions of
0.30 ꢀ 0.20 ꢀ 0.16 mm was mounted on a glass fiber with epoxy
cement for the X-ray crystallographic study. Table 1 lists the
selected crystal data and data collection parameters of the
compound collected at 293 K. Bruker axs kappa apex2 CCD
5-dimethylpyran-4-one (Scheme 1). The synthesized compounds
3 and 4 were characterized by ES-HRMS, FT-IR and 1H NMR,
13C NMR, NOESY spectroscopy and X-ray diffraction techniques.
⇑
Corresponding author. Tel.: +91 9944930543.
E-mail address: skabilan08@gmail.com (S. Kabilan).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.11.072

2
S. Umamatheswari et al. / Journal of Molecular Structure 989 (2011) 1–9
O
O
+
CH3
CH3
KOH / EtOH-H2O
O
O
O
15 day stirring
1
H
H
MeOH / H+
reflux, 3h
H2NNHCSNH2
H
N
S
H
N
H
N
CH3
O
3
O
O
CH3
H3C
H3C
CH3
KOH / EtOH-H2O
O
O
+
O
2
2 h stirring
H
H
Cl
Cl
Cl
Cl
MeOH / H+
reflux, 74h
H2NNHCSNH2
H
N
S
H
N
H
N
H3C
CH3
O
4
Cl
Cl
Scheme 1. Schematic diagram showing the synthesis of 2,6-diaryltetrahydropyran-4-one thiosemicarbazones 3 and 4.
diffractometer equipped with graphite monochromated Mo K
a
basis set was employed. Several useful concepts derived from
DFT have been applied to the study of the chemical reactivity
of the more stable forms of isomeric thiosemicarbazone. The
parameters have been obtained from calculations made in the
context of the Hartree–Fock and nonlocal (B3LYP) density func-
tional approximations. The results indicate that B3LYP with the
6-31G basis set is a useful method [27–30]. All HF and DFT
calculations were performed using the Gaussian 98 R-A.9 package
[31].
(k = 0.71073 Å) radiation was used for the measurement of data.
The collected data were reduced using the SAINT program and
structural refinement was carried out by Full-matrix least-squares
on F2 (SHELXL-97) [25]. Molecular graphics employed include
ORTEP and PLATON [26]. Data center allocated the deposition
number CCDC 699754.
2.2. Theoretical methods
Molecular parameters (bond distances, torsion and bond an-
gles, and the theoretically structures) of the compound 3 and 4
have been computed in an ab initio comparative study involving
HF and density functional theory (DFT) calculations. The 6-31G
2.3. Synthesis of compound 3
As per literature [32] 2,6-diaryltetrahydropyran-4-ones 1 and 2
were prepared by the condensation of appropriate ketones

S. Umamatheswari et al. / Journal of Molecular Structure 989 (2011) 1–9
3
Table 1
Crystal data of compound 4.
3.2. NMR spectral and conformational studies of compounds 3 and 4
The structure of compounds 3 and 4 is established using 1H
NMR spectral data. The proton chemical shift assignment has been
made based on characteristic signal positions of functional groups,
spin multiplicity, and comparison with those of parent ketones.
Even though four and eight enantiomeric pairs of diastereomers
were expected for the thiosemicarbazones of compounds 3 and 4
(since the heterocyclic rings of compounds 3 and 4 have three
and four stereogenic centers), only a single set of 1H NMR signals
for the compounds 3 and 4 were observed. These observations im-
ply that an enantiomeric pair of the possible diastereomers of the
thiosemicarbazones was formed exclusively in each case. Aromatic
proton peaks of the phenyl rings of the compounds 3 and 4 ap-
peared in the region of 7.32–7.40 ppm as multiplets. Two broad
signals resonate at 8.76/8.93 ppm with one proton integral, and
6.29/6.41 ppm with two proton integrals which are due to NH
and NH2 protons of thiosemicarbazone moiety of compounds 3
and 4 respectively.
In the proton NMR spectrum of compound 3, there are two pro-
ton signals in the deshielded region appearing as a double doublet
at 4.62 ppm with coupling constant value 11.45/2.26 Hz and dou-
blet at 4.26 ppm with coupling constant value 10.08 Hz with one
proton integral each which are due to two protons of C-5 and
one proton of C-3 respectively. Hence, the signals at 4.26 and
4.62 ppm are assigned for benzylic protons H-2a and H-6a, respec-
tively. A signal resonates at 2.67 ppm, as the sextet proton is due to
the proton on methyl bearing C-3 carbon (H-3a).
Moreover, there are two double doublets one at 3.02 ppm with
coupling constant values 14.39 Hz (J25a;5e)/2.26 Hz (J36a;5e) and the
other at 2.35 ppm with coupling constant values 14.22 Hz (J25a;5e)/
11.66 Hz (J36a;5a). The large vicinal and germinal coupling constant
value reveals that the double doublet at 2.35 ppm is due to the res-
onance of axial proton at C-5 (H-5a). The remaining proton signal
at 3.02 ppm is unambiguously assigned for H-5e which is further
confirmed from the NOESY correlation (the axial protons show
NOE correlation with ortho protons to phenyl ipso carbons present
at C-2 and C-6 whereas the equatorial protons does not show such
a correlation [33]) spectral data of compound 3 (Fig. 1). NOESY
spectrum of compound 3 is shown in Fig. 2.
Empirical formula
C20H21Cl2N3OS
Formula weight
Temperature
Wavelength
Crystal system, space group
Unit cell dimensions
422.36
293(2) K
0.71073 Å
Monoclinic, P21/c
a = 11.9645(3) Å,
a
= 90°
b = 20.0690(6) Å, b = 105.5220(10)°
c = 8.7441(2) Å,
2023.02(9) A3
4, 1.387 Mg/m3
0.439 mmꢁ1
880
c = 90°
Volume
Z, Calculated density
Absorption coefficient
F(0 0 0)
Crystal size
Theta range for data collection
Limiting indices
Reflections collected/unique
Completeness to theta = 25.00
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
0.30 ꢀ 0.20 ꢀ 0.16 mm
1.77–31.33°
ꢁ17 6 h 6 16, ꢁ29 6 k 6 29, ꢁ12 6 l 6 12
28,280/6618 [R(int) = 0.0254]
99.9%
Semi-empirical from equivalents
0.9330 and 0.8795
Full-matrix least-squares on F2
6618/0/274
1.031
R1 = 0.0445, wR2 = 0.1149
R1 = 0.0735, wR2 = 0.1406
0.477 and ꢁ0.280 e Aꢁ3
Largest diff. peak and hole
(2-pentanone for 1 and 3-pentanone for 2) and benzaldehydes
(benzaldehyde for 1 p-chlorobenzaldehyde for 2) in 1:2 ratio in
the presence of potassium hydroxide in water–ethanol medium.
To the boiling solution of 3-methyl-2,6-diphenyl-tetrahydropy-
ran-4-one 1 (0.01 mol) in methanol (45 ml) and a few drops of
concentrated hydrochloric acid, the methanolic solution of thio-
semicarbazide (0.01 mol) was added drop wise by stirring. The
reaction was refluxed for 3 h on a water bath. After cooling, the so-
lid product was filtered and recrystallized from methanol to get the
thiosemicarbazone 3. Yield: 90%, m.p. 110–112° C, ES-HRMS (m/
z) = 340.0281 (M + H)+.
2.4. Synthesis of compound 4
The coupling constant values and position of the chemical shifts
were used to predict the conformation of the compound. The
observations of large vicinal coupling constant values between
To the boiling solution of 3,5-dimethyl-2,6-bis(p-chlorophenyl)-
tetrahydropyran-4-one 2 (0.01 mol) in methanol (45 ml) and a few
drops of concentrated hydrochloric acid, the methanolic solution of
thiosemicarbazide (0.01 mol) was added drop wise by stirring. The
reaction was refluxed for 50 h on a water bath. After cooling,
the solid product was filtered to get the thiosemicarbazone 4.
The crude product was purified by column chromatography using
neutral alumina as adsorbent and chloroform eluent. Yield: 80%,
m.p. 212–214° C, ES-HRMS (m/z) = 423.3702 (M + H)+.
H
6.29
H
N
8.76
H
S
H
7.30-7.42
N
4.46
H
3. Results and discussion
4.26
H
3.02
H
N
6
3.1. IR spectral studies
4
5
1
CH3
IR spectral data confirms the presence of characteristic groups
present in the compound. In the IR spectrum of 3 and 4, the
disappearance of strong absorption band in the region of
1702–1710 cmꢁ1 which are characteristic stretching frequency of
carbonyl group of 2,6-diarylpyran-4ones (1 and 2) and the appear-
ance absorption bands at around 3426–3140 cmꢁ1 which are due
to NAH stretching frequency confirms that the formation of 2,6-
diarylpyran-4ones thiosemicarbazones 2 and 4. Aromatic CAH
O
2
2.35
3
H
2.67
H
H
7.30-7.42
stretching bands occur in the region 3042–2628 cmꢁ1
.
Fig. 1. NOESY correlations of compound 3.

4
S. Umamatheswari et al. / Journal of Molecular Structure 989 (2011) 1–9
Fig. 2. NOESY spectrum of compound 3.
Table 2
10.08 (J32a;3a) and 11.45 Hz (J53a;5a) and of small value of the vicinal
coupling constant of 2.26 Hz (J36a;5e) for the protons of C-6 and C-
2 of compound 3 indicate that the six-member heterocyclic ring
of compound 3 adopts normal chair conformation with equatorial
orientation of phenyl groups at C-2 and C-6, and equatorial orien-
tation of methyl group at C-3. Furthermore, equatorial disposition
of phenyl groups at C-2 and C-6 makes the chair conformation
more rigid thereby preventing interconversion from one chair into
another (Since the axial–axial vicinal coupling constant of proton
of C-2 is around 1.5 Hz less than that of the axial–axial vicinal cou-
pling constant of proton of C-6, the difference in coupling constant
cannot be due to an electronegativity effect of methyl group since
the electronegativity of the methyl group is only slightly different
from that of hydrogen). The probable reason is that the heterocy-
clic ring may be flattened or distorted about the C2AC3 bond to de-
crease gauche interaction between the equatorial phenyl group
and the equatorial methyl group at C-2 and C-3, respectively.
Due to the formation of double bond imino group at C-4 carbon,
two geometrical isomers are possible (E and Z form), but the
position of chemical shift value of the H-5e proton is about
0.3 ppm deshielded than the parent ketone (see Table 2) which
indicates that the NANHACSANH2 bond is syn to C-5 which is also
confirmed from the observed NOESY correlation between NH
proton signal at 8.76 ppm and H-5e proton signal at 3.02 ppm
(Fig. 2). The deshielding is due to the non-bonding interaction
between H-5e proton and NAH proton of thiosemicarbazones
moiety as shown in Fig. 3. Hence the conformation of 3-methyl-
2,6-diphenyltetrahydropyran-4-one thiosemicarbazone 3 exists in
chair conformation with equatorial orientation of phenyl groups
at C-2, C-6, methyl group at C-3 carbon and NANHACSANH2 bond
syn to C-5 carbon (E-form) as shown in Fig. 3.
Proton chemical shift values of compounds 3 and 4 along with parent ketones 1 and 2
[d (ppm)].
Compound
H-2a
H-3a
H-5a
H-5e
H-6a
3-CH3/C2H5
5-CH3
3
4
1
2
4.26
4.75
4.33
4.29
2.67
2.76
2.60–2.82
2.80 2.80
2.35
–
3.01
3.10
4.62
4.21
4.81
4.29
0.93
0.97
0.86
0.86
–
0.91
–
–
0.86
H
H
N
H
S
N
N
H
δ+
H
H
6
δ-
R1
4
5
1
CH3
O
2
3
R
H
R1
Compound
R
H
R1
H
3
4
CH3 Cl
In proton NMR spectrum of compound 4 (methyl substitution at
C-3 and C-5 carbon), there are two doublets observed at 4.75 ppm
Fig. 3. Configuration of NANHꢂ ꢂ ꢂ bond syn to carbon 5.

S. Umamatheswari et al. / Journal of Molecular Structure 989 (2011) 1–9
5
(H-6) and 4.20 ppm (H-2) confirms that compound 4 exists in chair
conformation with equatorial orientation of aryl groups at C-2
and C-6 which is also substantiated from their observed coupling
constant values. Moreover the NOE between H-5 proton and
NAH proton of thiosemicarbazones moiety reveals that the
NANHACSANH2 moiety is syn to C-5 carbon (E-form). NOESY spec-
trum of compound 4 is depicted in Fig. 5.
H
6.41
H
N
8.93
H
7.09-7.41
S
H
N
4.75
Another interesting point to be noted is, the methyl at C-5
adopts axial orientation in order to avoid the 1,3 spatial interac-
tion between the methyl and NANHACSANH2 and to retain the
chair conformation. The equatorial orientation of the H-5e proton
is substantiated by its vicinal coupling constant (J36a;5e = 2.4 Hz).
The axial orientation of H-3a was confirmed by the diaxial cou-
pling constant value (J32a;3a = 10.6 Hz). These observations suggest
that the six-member heterocyclic ring for compound 4 may take
a chair conformation with equatorial orientation of both the phe-
nyl groups (C-2 and C-6), methyl group at C-3 in equatorial and a
methyl group at C-5 in axial. Hence, the six-member heterocyclic
ring in 3,5-dimethyl-2,6-diaryltetrahydropyran-4-one thiosemi-
carbazone 4 adopts a chair conformation with the orientation of
NANHACSANH2 moiety syn to the C-5 carbon (Fig. 5). The proton
NMR spectral data of the compounds 3 and 4 along with their
parent ketones 1 and 2 are given in Table 2.
H
4.20
H
3.11
H
N
6
Cl
4
5
1
CH3
O
2
3
CH3
H
2.76
H
7.09-7.41
Cl
Fig. 4. NOESY correlations of compound 4.
with vicinal coupling constant value of 2.5 Hz and 4.20 ppm with
vicinal coupling constant value of 10.4 Hz for one proton integral
each. Of the two signals, the deshielded one at 4.75 ppm is due
to the resonance of H-6 benzylic proton and the signal at
4.20 ppm is due to the resonance of H-2 benzylic proton. In the
NOESY correlation spectra, the H-2 proton signal shows strong cor-
relation with sextet at 3.11 ppm which is unambiguously assigned
for H-3 proton and the sextet at 2.76 ppm shows correlation with
H-6 which is due to the presence of H-5 proton (Fig. 4). Of the four
proton signals in the aliphatic region, 4.75, 4.20 and 3.11 ppm have
NOESY correlation with ortho aryl protons which reveal that these
signals are due to the axial protons at C-5, C-2 and C-3, respec-
tively. Moreover the observed strong NOE between 4.75 ppm
The chemical shifts of 13C NMR of the thiosemicarbazones 3–4
and the differences between those of thiosemicarbazones and the
corresponding ketones are listed in Tables 3 and 4, respectively.
13C NMR spectra of compounds 3 and 4 are used as examples to
discuss the conformations of the thiosemicarbazones. Aromatic
carbons of compounds 3 and 4 are distinguished from other car-
bons by their characteristic absorption in the region of 125.87–
128.86 ppm. Ipso carbons of phenyl group at C-2 and C-6 carbons,
and benzyl group resonate between 136.84 and 140.68 ppm. The
carbon of thiocarbonyl groups of compounds 3 and 4 absorb
at 179.70 and 180.07 ppm respectively. The carbons of C@N group
of compounds 3 and 4 absorb downfield at 153.55 and 157.03 ppm
Fig. 5. NOESY spectrum of compound 4.

6
S. Umamatheswari et al. / Journal of Molecular Structure 989 (2011) 1–9
Table 3
13C NMR Chemical shift values of compounds 3 and 4 along with parent ketones 1 and 2 [d (ppm)].
Compound
C-2
C-3
C-4
C-5
C-6
C@S
Alkyl and ipso carbons
3
4
1
2
86.81
86.20
85.97
85.64
44.76
40.32
51.65
51.73
153.55
157.03
207.09
208.13
35.69
35.96
50.16
51.73
78.47
79.27
79.39
85.64
179.70
180.07
–
–
11.44 (3-CH3); 140.68 (C-60), 139.98 (C-20)
11.14 (3-CH3); 11.24 (5-CH3) 138.54 (C-20); 136.84 (C-60)
9.48 (3-CH3); 138.54 (C-20); 136.84 (C-60)
9.69 (3,5-CH3); 140.64 (C-20); 139.54 (C-20)
Table 4
13C NMR chemical shift difference between pyran-4-one (1 and 2) and corresponding thiosemicarbazones (3 and 4) (dpyranone–dthiosemicarbazone) [
D
d (ppm)].
Compound
C-2
C-3
6.89
11.41
C-4 (C@N)
C-5
C-6
ACH3 at C-3
ACH3 at C-5
3
4
ꢁ0.84
ꢁ0.56
53.54
51.10
14.47
15.77
0.92
6.37
ꢁ1.96
ꢁ1.45
–
ꢁ1.55
Negative sign denotes deshielding.
respectively, due to electronegativity of nitrogen and anisotropic
effect. Of the heterocyclic ring carbons for compound 3 with
methyl group at C-3, the peaks of C-2 and C-6 carbons are observed
in the downfield region compared to C-3 and C-5 carbons. It is
known that the presence of a methyl group at an equatorial posi-
tion on the six-member ring makes the nearby carbon shift down-
ward appreciably due to the b-effect of the methyl group [33].
Thus, the peak appearing in the downfield of the two signals
(86.81 ppm) is for C-2 carbon and the upfield one (78.47 ppm)
for C-6 carbon. Of the remaining two upfield signals (44.76 and
35.69 ppm) for the ring carbons compared to those of C-2 and C-
6 carbons, the one at 35.69 ppm is for C-5 carbon and the other
one is for C-3 carbon.
A similar trend is observed for the six-member heterocyclic ring
of compound 4. However, the difference in the magnitude of
shielding and deshielding effects is noted for compounds 3 and
4. The chemical shifts of heterocyclic ring carbons of compounds
3 and 4 are shielded compared to their values of the parent ketones
(1 and 2) except C-2 carbon. It is known that a decrease in the elec-
tronegativity of a group on a six-membered heterocyclic ring
the electronegativity of nitrogen of the C@NANHCSNH2 moiety
must be less than that of oxygen of the C@O group, shielding of
the a-carbons (C-3 and C-5) is thus in accordance with the electro-
negativity effect. Of the two b-carbons (C-2 and C-6), the syn car-
bon (C-6) to the NANH bond of the thiosemicarbazone moiety is
shielded unlike the other (C-2). A comparison between the absorp-
tion of C-3 and C-5 carbons of the thiosemicarbazones (compounds
3 and 4) and their corresponding ketones (1 and 2) shows that the
shielding effect for C-5 carbon, which is syn to the NANH bond is
higher than that of the anti carbon (C-3) due to the induced polar-
ity of the equatorial bond of C-5 carbon by the electronegativity of
thiosemicarbazone moiety. The electronegativity effect of the thio-
semicarbazone moiety on the C-5 carbon is transmitted to a small
extent to the C-6 carbon and the shielding thus outweighs the
deshielding produced by the electronegativity effect. The absorp-
tion of equatorial methyl carbon of compound 3 is downward
about 1.96 ppm compared to its corresponding ketone 1. This
may probably be due to the less polar effect of the C@N in thiosem-
icarbazone than that of C@O moiety. The two methyl carbons at
C-3 and C-5 of compound 4 resonate at 11.14 and 11.24 ppm and
the difference between the absorption of two methyl groups of
shields the a-carbon and deshields the b- and c-carbons [34]. Since
Fig. 6. ORTEP diagram of the compound 4.

S. Umamatheswari et al. / Journal of Molecular Structure 989 (2011) 1–9
7
compound 4 is small (0.10 ppm). This also supports the normal
chair conformation of compound 4 which is further confirmed
from its single crystal XRD studies.
3.3. Crystal structure
Compound 4 crystallizes into a monoclinic lattice with P21/c.
Crystal data and structure refinement of compound 4 is shown in
Table 1. The ORTEP diagram (Fig. 6) of compound 4 and displace-
ment ellipsoids are drawn at 50% probability level. The saturated
pyran ring adopts a distorted chair conformation, as shown by
the torsion angles around the bonds involving the ring atoms.
These torsion angles deviate from the ideal value of 56° reported
for the chair conformation of cyclohexane [35]. The CAC bond
lengths of the aryl rings are in the range 1.365(4)–1.390(4) Å, while
the bond angles are in the range 118.3(3)–121.4(4)°. The equatorial
dispositions of the 4-chlorophenyl groups are revealed by the
torsion angles involving the exo atom and the other three ring
atoms. These vary from 178.0 to 174.78, as observed in a pentasub-
stituted cyclohexan-1-one derivative [36] also. Torsion angle of
60.95° and ꢁ171.44° perceived by H(4)AC(4)AC(5)AH(5) and
H(1)AC(1)AC(2)A(H2) respectively, confirms that the methyl
group present at C-5 is in axial and the methyl group at C-3 is in
equatorial orientation. Similarly, the configuration along the
C(3)AN(1) bond is cis, as agreed by the C(2)AC(3)AN(1)AN(2) tor-
sion angle value of 3°. The bond angle of C(3)AN(1)AN(2)
119.23(13)° reveals that the thiosemicarbazone moiety
(NANHACSANH2) is in planar with E configuration along the
N(1)AN(2) bond. The selected bond lengths and bond angles are
depicted in Table 5. The geometrical details of hydrogen bonds in
compound 4 are summarized in Table 6. In the crystal structure
of compound 4, the molecules are connected by NAHꢂ ꢂ ꢂS hydrogen
bonds (N(2)AH(2)ꢂ ꢂ ꢂS) and N(3)AH(3A)ꢂ ꢂ ꢂS(1) but no significant
interaction is observed.
Fig. 7. The B3LYP/6-31G optimized structure for E-form of compound
(63.059 kcal/mol).
3
3.4. Theoretical studies
Since the restricted rotation about C@N bond of compounds 3
and 4, formation of either geometrical E (Figs. 7 and 9) or Z (Figs.
Table 5
Crystal data of compound 4.
Fig. 8. The B3LYP/6-31G optimized structure for Z-form of compound
3
Geometric parameters
XRD
HF/6-31G
B3LYP/6-31G
(77.381 kcal/mol).
C(3)AN(1)
N(1)AN(2)
C(18)AN(2)
C(18)AN(3)
C(18)AS(1)
C(6)AC(7)
C(6)AC(11)
C(2)AC(3)AC(4)
N(3)AC(18)AN(2)
N(3)AC(18)AS(1)
N(2)AC(18)AS(1)
C(3)AN(1)AN(2)
C(18)AN(2)AN(1)
H(4)AC(4)AC(5)AH5)
H(1)AC(1)AC(2)AH2)
1.2764(19) Å
1.379(2) Å
1.3507(19) Å
1.325(2) Å
1.6725(18) Å
1.376(2) Å
1.390(2) Å
114.99(12)°
116.22(16)°
122.83(13)°
120.95(12)°
119.23(13)°
118.15(13)°
61.05°
1.362 Å
1.383 Å
1.428 Å
1.401 Å
1.746 Å
1.472 Å
1.416 Å
115.43°
116.96°
123.01°
120.02°
121.11°
119.92°
62.23°
1.242 Å
1.366 Å
1.321 Å
1.311 Å
1.653 Å
1.389 Å
1.401 Å
115.43°
115.48°
124.43°
122.08°
120.01°
119.01°
61.89°
ꢁ171.44°
ꢁ173.32°
ꢁ172.118°
Table 6
Selected bond length, angles and torsion angles of compound 4.
DAHꢂ ꢂ ꢂA
d(DAH)
d(Hꢂ ꢂ ꢂA)
2.88(2)
2.60(3)
d(Dꢂ ꢂ ꢂA)
3.7427(15)
3.4524(16)
(DHꢂ ꢂ ꢂA)
173.8(19)
169(2)
N(2)AH(2)ꢂ ꢂ ꢂS(1)i
0.87(2)
0.86(2)
N(3)AH(3A)ꢂ ꢂ ꢂS(1)ii
Fig. 9. The B3LYP/6-31G optimized structure for E-form of compound
(53.673 kcal/mol).
4
Symmetry codes: (i) x, ꢁy + 1/2, z + 1/2 (ii) x, ꢁy + 1/2, z ꢁ 1/2.

8
S. Umamatheswari et al. / Journal of Molecular Structure 989 (2011) 1–9
state. A comparison between the theoretical and the experimental
values of 4 shows that there is quite resemblance in the structural
parameters (such as bond distances, and bond angles) of the title
compounds obtained theoretically and experimentally obtained
by X-ray crystallography. Moreover, the DFT calculation gives bet-
ter agreement with XRD data of compound 4 which may be due to
the much larger size of the molecule having four stereogenic center
[29].
In view of the extensive
p delocalization over the thiosemicar-
bazone backbone, the single point DFT calculation on the opti-
mized structures was done and the natures of the frontier
orbitals are shown in Figs. 11 and 12. The HOMO orbital (at the
B3LYP/6-31G) in compounds 3 and 4 is mainly localized on the
pC@S double bond orbital (Figs. 11a and 12a).
4. Conclusion
Fig. 10. The B3LYP/6-31G optimized structure for Z-form of compound
4
(64.573 kcal/mol).
Conformation of compounds 3 and 4 were carried out using
NOESY correlation spectral data. The stereo chemistry of 4 was
confirmed by X-ray diffraction. Molecular orbital calculations have
been carried out for 3 and 4 by using an ab initio method (HF) and
also density functional method (B3LYP) at 6-31G basis set. The re-
sults show that the compound 3 exist in chair conformation with
equatorial orientations of all the substituents at pyran ring and
the configuration about the C@N double bond is syn to C-5 carbon
(E-form). In the case of compound 4 the six-membered hetero cyc-
lic ring exist in chair conformation with equatorial orientation of
all the substituents except methyl group at C-5 which is oriented
at axial disposition in order to stabilise the chair conformation
and the configuration about the C@N double bond is syn to C-5
carbon (E-form). The results obtained from NMR spectra are in
8 and 10) is expected. Hence the B3LYP/6-31G optimization were
done for both the possible conformers. The optimization energy re-
veals that the C@NAN bond syn configuration to C-5 carbon is ther-
modynamically stable form. In other words, an enantiomeric pair
of the diastereomers with
(Fig. 7) and 4 (Fig. 9) is more stable than Z configuration.
Furthermore, the B3LYP/6-31G optimized structure of com-
pound 4 discussed during the computational investigations is pre-
sented in Fig. 9. Some optimized geometric parameters are also
listed in Table 5. However, the theoretical calculations are per-
formed in gaseous phase and the experimental results are in a solid
E configuration of compounds 3
Fig. 11. Frontier orbitals in compound 3, from DFT calculations: (a) HOMO and (b) LUMO.
Fig. 12. Frontier orbitals in compound 4, from DFT calculations: (a) HOMO and (b) LUMO.

S. Umamatheswari et al. / Journal of Molecular Structure 989 (2011) 1–9
9
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Acknowledgements
The authors are thankful to the Council of Scientific and Indus-
trial Research, New Delhi, India for financial support. The authors
would like to acknowledge NMR research center, IISc-Bangalore
and SAIF, IIT-Madras, respectively for recording NMR and single
crystal XRD.
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