A joint theoretical and experimental structural study of two novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives

Article abstract of DOI:10.1007/s11224-010-9613-y

In this study, two novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives, 3-[2-(4-methoxyphenyl)ethyl]-6-phenyl-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine (compound 1) and 3-[2-(3,4,5-trimethoxyphenyl)ethyl]-6-phenyl-7H-1,2,4-triazolo[3,4-b]-1,3,4-thi

Full text of DOI:10.1007/s11224-010-9613-y

Struct Chem (2010) 21:795–802
DOI 10.1007/s11224-010-9613-y
ORIGINAL RESEARCH
A joint theoretical and experimental structural study of two novel
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives
•
•
Filiz Betu¨l Kaynak Sevim Peri Aytac¸
Birsen Tozkoparan
Received: 19 February 2010 / Accepted: 12 April 2010 / Published online: 23 April 2010
Ó Springer Science+Business Media, LLC 2010
Abstract In this study, two novel 1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazine derivatives, 3-[2-(4-methoxyphenyl)ethyl]
-6-phenyl-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine (com-
pound 1) and 3-[2-(3,4,5-trimethoxyphenyl)ethyl]-6-phe-
nyl-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine (compound
2), having analgesic–anti-inflammatory activity were syn-
thesized and characterized by IR, 1H-NMR, and mass
spectroscopic techniques besides elementary analysis.
Additionally, the structures and molecular packings of the
mentioned compounds have been investigated by X-ray
single crystal diffraction. The six-membered thiadiazine ring
adopts the screw boat conformation in both the compounds.
In the crystal packings of the compounds 1 and 2, C–HꢀꢀꢀN
and C–HꢀꢀꢀO interactions link the molecules into a two-
dimensional network and generate infinite chains. Further-
more, C–Hꢀꢀꢀp intermolecular interactions provide further
stability to the molecular packing in both the molecules. The
conformers have been predicted by the potential energy
surface scan employing the AM1 method. Geometry opti-
mizations and electrostatic properties have been obtained
using AM1 and ab initio quantum methods.
Introduction
Development of new analgesic/anti-inflammatory com-
pounds with safer and as effective as opioids for the treat-
ment of pain and inflammation has been in interest of us for
many years. In earlier studies, we have synthesized many
substances derived from 1,2,4-triazole-5-thiones and tested
their analgesic/anti-inflammatory activity. A considerable
number of the prepared compounds have been found to
have analgesic/anti-inflammatory activity comparable to or
higher than the reference compounds besides lower ulcero-
genic risks in the stomach [1–7]. Finally, we have synthesized
a series of 4-amino-3-substituted-1,2,4-triazole-5-thiones and
their corresponding condensed derivatives, 3,6-disubstituted
7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines, with possible
anti-inflammatory–analgesic properties [8, 9]. The concerned
compounds, 3-[2-(4-methoxyphenyl)ethyl]-6-phenyl-7H-1,2,
4-triazolo[3,4-b]-1,3,4-thiadiazine (compound 1) and 3-[2-
(3,4,5-trimethoxyphenyl)ethyl]-6-phenyl-7H-1,2,4-triazolo
[3,4-b]-1,3,4-thiadiazine (compound 2), are two members of
this series having analgesic/anti-inflammatory activity [9].
To the best of our knowledge, neither spectral data nor
X-ray crystallographic analysis and theoretical calculations
on these two compounds have been available till now. Here,
we present synthesis and characterizations of the compounds
1 and 2 as well as X-ray crystallographic analysis and some
theoretical calculations. In order to gain further information
on the conformational features of the given compounds, a
potential energy scan was performed by using the semi-
empirical AM1 method. For the most stable conformations
ab initio geometry optimization at restricted Hartree-Fock
level using the 6-31G basis set was performed. The geo-
metrical features predicted by AM1 and RHF/6-31G calcu-
lations and those determined by X-ray crystallographic
analysis are compared and some other comparisons are also
Keywords X-ray analysis ꢀ Triazolo[3,4-b]-1,3,
4-thiadiazine ꢀ Theoretical calculations ꢀ Structural study
F. B. Kaynak (&)
Department of Physics Engineering, Faculty of Engineering,
Hacettepe University, Beytepe, 06800 Ankara, Turkey
e-mail: gulsen@hacettepe.edu.tr
S. P. Aytac¸ ꢀ B. Tozkoparan
Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Hacettepe University, Sihhiye, 06100 Ankara, Turkey
123

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Struct Chem (2010) 21:795–802
3-[2-(3,4,5-Trimethoxyphenyl)ethyl]-6-phenyl-7H-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazine (compound 2)
made between several properties (dipole moments, frontier
orbitals).
Yield 34%; mp 158–159 °C (ethanol); IR (KBr): 1587
(C=N), 1305 (C–N), 1234 (C–O) cm-1. 1H-NMR d (ppm):
2.96 (2H, t, CH2CH2), 3.17 (2H, t, CH2CH2), 3.49 (3H, s,
OCH3), 3.68 (6H, s, OCH3), 4.29 (2H, s, SCH2), 6.47 (2H,
s, arom. H-2, H-6), 7.51–7.59 (3H, m, arom. H-30, H-40, H-
50), 7.95 (2H, d, arom H-20, H-60). MS (70 eV, EI): m/z
(%): 412 (M?ꢀ?2, 2.86%), 410 (M?ꢀ, 37.86%), 395 (M?ꢀ
–CH3, 9.64%), 379 (M?ꢀ–OCH3, 2.86%), 292 ([M?ꢀ–(C6H5
CN?CH3)], 7.86%), 181 ((CH3O)3C6H2CH2, 100%), 77
(C6H5, 17.14%). Anal. Calcd. for C21H22N4O3S: C, 61.45;
H, 5.40; N, 13.65; S, 7.81. Found: C, 61.71; H, 5.11; N,
13.81; S, 7.98.
Experimental and computational procedures
Synthesis
Synthesis of the compounds was realized in two steps. In
the first step, aminomercaptotriazoles required as starting
material was prepared by heating 3-(4-methoxyphenyl)/
(3,4,5-trimethoxyphenyl)propionic acids with thiocarbo-
hydrazide at the melting temperature (160–170 °C) [8, 9].
Aminomercaptotriazoles were converted into 6-phenyl-7H-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines in one step by
reacting them with phenacyl bromide in anhydrous ethanol
under reflux [9–11] (Scheme 1). The structures of the
compounds are characterized by elementary analysis, IR,
1H-NMR, and mass spectra. The spectral data are in good
agreement with the proposed structures.
Structure determination
Light yellow prismatic single crystals suitable for X-ray
diffraction were chosen for the structure determination for
compounds 1 and 2. X-ray intensity data were collected at
room temperature on an Enraf-Nonius CAD4 diffractometer
[12] using graphite monochromated MoKa radiation
3-[2-(4-Methoxyphenyl)ethyl]-6-phenyl-7H-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazine (compound 1)
˚
(k = 0.71073 A). w/2h scan mode was applied for data
collections. The cell parameters were refined from accu-
rately determined 25 reflections in the range of 9.50 B
h B 18.21° for compound 1 and 10.03 B h B 20.14° for
compound 2. Extinction correction was applied for com-
pound 1.
Yield 64%; mp 142–143 °C (ethanol); IR (KBr): 1610
(C=N), 1300 (C–N), 1244 (C–O) cm-1. 1H-NMR d (ppm):
3.11 (2H, t, CH2CH2), 3.28 (2H, t, CH2CH2), 3.70 (3H, s,
OCH3), 3.90 (2H, s, SCH2), 6.75 (2H, d, arom. H-3, H-5),
7.11 (2H, d, arom. H-2, H-6), 7.52–7.59 (3H, m, arom.
H-30, H-40, H-50), 7.84 (2H, d, arom. H-20, H-60). MS
(70 eV, EI): m/z (%): 352 (M?ꢀ?2, 5.26%), 350 (M?ꢀ,
66.67%), 335 (M?ꢀ–CH3, 6.14%), 317 (M?ꢀ–SH, 1.75%),
247 (M?ꢀ–C6H5CN, 3.51%), 232 ([M?ꢀ–(C6H5CN?CH3)],
48.25%), 134 (CH3OC6H4CHCH2, 16.23%), 121 (CH3OC6
H4CH2, 100%), 77 (C6H5, 39.91%). Anal. Calcd for
C19H18N4OS: C, 65.12; H, 5.18; N, 15.99; S, 9.15. Found:
C, 65.10; H, 4.93; N, 15.90; S, 9.38.
The structures were solved by direct methods using the
SIR92 [13] for compound 1 and SHELXS-97 [14] for
compound 2. The positional parameters of non-H atoms
were refined by a full-matrix least squares method with
anisotropic thermal parameters using the program SHEL-
XL-97 [15]. All hydrogen atoms were calculated on the
basis of their stereochemical requirement at distances 0.93,
˚
0.96, and 0.97 A for aromatic, methylene, and methyl H
atoms, respectively, and refined riding on their parent
Scheme 1 Synthesis of 3,6-
disubstituted-7H-triazolo
[3,4-b]-1,3,4-thiadiazines
R
R
N
N
H
R
S
+
CH3O
CH3O
CH2CH2COOH
H2NNH-C-NHNH2
CH3O
CH2CH2
S
N
NH2
R
N
N
R
O
N
N
H
R
EtOH
+
CH3O
CH2CH2
C
CH2-X
S
N
N
CH2CH2
S
N
R
NH2
R
R: -H, compound 1
R: -OCH3, compound 2
123

Struct Chem (2010) 21:795–802
797
atoms (for compounds 1 and 2). Crystal data, a summary of
intensity data collection and structure refinement, are given
in Table 1. The dihedral angles were calculated using the
PARST program [16], and the value of the dihedral angles
for the planes (1, 2, 3) are given in Table 2. Ortep-3 [17]
drawings with atom numbering are shown in Figs. 1 and 2
for compound 1 and 2, respectively.
Table 2 Dihedral angles (°) for compounds 1 and 2
Plane
Compound 1
Compound 2
1
2
1
2
C1–C2–C3–C4–C5–C6
N1–N2–C9–N3–C10
56.46(7)
62.87(7)
12.52(7)
37.64(8)
C13–C14–C15–C16–
C17–C18
6.49(6)
33.74(8)
The additional material available from the Cambridge
Crystallographic Data Centre (CCDC No. 699818 &
699819) comprises the final atomic coordinates for all
atoms, thermal parameters and a complete listing of bond
distances and angles (excluding structure factors). Copies
of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1 EZ, UK [Fax:
?44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
Table 1 Crystal data and details of the structure determination of the
title compounds
Compound 1
Compound 2
Formula
C19H18N4OS
350.43
C21H22N4O3S
410.49
Formula weight
Crystal system
Space group
Cell constants
Monoclinic
P21/c
Monoclinic
P21/c
Fig. 1 ORTEP-3 view of the compound 1, showing the atom-
numbering scheme. Displacement ellipsoids are drawn at the 50%
probability level
˚
a (A)
13.238(3)
13.827(5)
9.889(4)
70.93(3)
4; 1.361
0.204
11.7272(12)
7.6172(12)
23.0201(19)
94.735(8)
2; 1.330
˚
b (A)
˚
c (A)
b (°)
Z; Dcalc (g cm-3
l (MoKa) (mm-1
)
)
0.188
Crystal size (mm)
Radiation
0.30 9 0.36 9 0.60 0.18 9 0.30 9 0.60
MoKa MoKa
(k = 0.71073 A) (k = 0.71073 A)
293(2) 293(2)
˚
˚
Temp. (K)
h limits (°)
Index ranges
2.63–26.32
2.38–26.29
-14 B h B 14
0 B k B 9
-28 B l B 28
8311
-16 B h B 15
-17 B k B 17
-12 B l B 0
Reflections collected 7189
Reflections observed 2584 [I [ 2r(I)]
2566 [I [ 2r(I)]
4169
Reflns. used in
refinement
3475
Fig. 2 ORTEP-3 view of the compound 2, showing the atom-
numbering scheme. Displacement ellipsoids are drawn at the 50%
probability level
No. of refined
parameters
227
261
Extinction coefficient 0.045(4)
–
Rint
0.0344
0.0589
Computational procedures
R/Rw values
GOF
0.0559/0.1384
1.104
0.0406/0.1239
1.052
All calculations were carried out using Gaussian03W
program [18]. For modeling, the initial guess of the mol-
ecules was obtained from the X-ray coordinates and
transformed into the Gaussian Z-matrix format with Babel
Final shift
0.000
0.000
(Dq)min, (Dq)max
-0.548, 0.558
-0.302, 0.267
-3
˚
(e A
)
123

798
Struct Chem (2010) 21:795–802
˚
program [19]. In order to explore the whole energy sur-
faces, conformational energies were calculated as a one-
dimensional scan with rotation from -180° to ?180° for
u1(N2–C9–C8–C7), u2(C9–C8–C7–C1), u3(C8–C7–C1–
C2), and u4(C11–C12–C13–C14) [u4(C11–C12–C13–
C18) for compound 2] torsion angles in 10° steps at the
AM1 level. The minima obtained by the scan for the title
compounds were optimized by AM1 method and at the
ab initio restricted Hartree-Fock level of theory with
the 6-31G basis set.
Table 3 Hydrogen bonding geometry (A, °) for compounds 1 and 2
D–HꢀꢀꢀA
D–H
HꢀꢀꢀA
DꢀꢀꢀA
D–HꢀꢀꢀA
Compound 1
C11–H11BꢀꢀꢀN2i
C20–H20CꢀꢀꢀCg(3)ii
Compound 2
0.97
0.96
2.610
2.665
3.318(3)
3.605(3)
130
122
C19–H19ꢀꢀꢀO1iii
C21–H21CꢀꢀꢀN2iv
C21–H21BꢀꢀꢀCg(3)v
0.96
0.96
0.96
2.350
2.580
2.840
3.190(3)
3.413(3)
3.687(2)
146
146
148
Cg(3): C1–C2–C3–C4–C5–C6
Symmetry code: (i) -x, 1/2 ? y, 1/2 - z, (ii) x, -1/2 - y, 1/2 ? z,
(iii) x, 1 ? y, z, (iv) 2 - x, -1/2 ? y, 1/2 - z, (v) 2 - x, 1 - y, -z
Result and discussions
Crystallography
˚
mean distance 1.770(2) A] and C–N [with a mean distance
˚
1.327(2) A] bond lengths are comparable to those in related
The structures predicted from spectral analysis are con-
firmed by X-ray analysis of the single crystal. The X-ray
structure analysis indicates that compound 1 consists of
one methoxyphenyl ring, one phenyl ring, and a thiadiazine
ring bearing the triazole ring. In compound 2, there is tri-
methoxyphenyl ring instead of methoxyphenyl ring. The
four rings do not share a common plane. The dihedral
angles between the two phenyl rings are 62.87(7)° and
37.64(8)° for compounds 1 and 2, respectively. The dihe-
dral angle between the triazole ring and the benzene ring
bearing the methoxy substituent is 6.49(6)° for compound 1
[33.74(8)° for compound 2] (Table 2). In compound 1, C1,
C7, C8, C9 atoms are nearly linear and the related torsion
angle is 173.4(2)°.
compounds [23, 24].
In the crystal structures, weak C–HꢀꢀꢀN and C–HꢀꢀꢀO
intermolecular hydrogen-bonding interactions link the
molecules into a two-dimensional network and generate
infinite chains (Table 3; Figs. 3, 4). Furthermore, C–Hꢀꢀꢀp
intermolecular interactions lend further stability to the
molecular packing in both molecules.
Theoretical computations
In order to find all the conformers of 1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazine derivatives, AM1 method has been used
for the potential energy surface scan. The potential energy
surface maps are shown in Figs. 5 and 6.
The triazole and phenyl rings are planar. The bond
lengths and angles of the triazole ring are in good agree-
ment with literature values [20, 21]. The O2 atom is located
over the best plane of C1–C6 phenyl ring, while the C7
Compound 1
The rotations around N2–C9–C8–C7 (u1), C9–C8–C7–C1
(u2), and C8–C7–C1–C2 (u3) show several conformations.
The X-ray structure shows the u1, u2, and u3 torsion
˚
atom is oriented -0.114(2) A below that ring for com-
pound 1. The orientation of the methoxy groups in com-
pound 2 shows difference. While O1 and O2 atoms are
above the best plane of the C1–C6 phenyl group, O3 atom
is oriented to the downward. The C7 atom is almost in the
˚
best plane of the phenyl ring with -0.026(2) A.
The six-membered thiadiazine ring, N3/N4/C12/C11/S1/
C10, is distorted from planarity, with maximum r.m.s.
˚
deviation of -0.555(2) and -0.635(2) A for compounds 1
and 2, respectively. Structural results show that thiadiazine
ring adopts the screw boat conformation in both compounds
˚
having spherical polar set values [22] Q = 0.5533(17) A,
h = 66.76(18)° and u = 326.1(2)° for compound 1 and
˚
Q = 0.6027(18) A, h = 115.13(18)° and u = 148.3(2)° for
compound 2. Atoms C11 and C12 are displaced from the S1/
˚
C10/N3/N4 mean plane by -0.946(2) and -0.378(2) A,
respectively, for compound 1. In compound 2, C11 and C12
atoms are located above the best plane of S1/C10/N3/N4 by
˚
1.024(2) and 0.424(2) A, respectively. Both S–C [with a
Fig. 3 Crystal packing of the compound 1 projected onto bc plane.
The dashed lines indicate the intermolecular hydrogen bonds
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Struct Chem (2010) 21:795–802
799
could not predict the minimum energy structure. However,
AM1 method has predicted the most stable conformation.
Compound 2
In compound 2, similar torsion angles are effective in the
conformation of the molecule. The rotation around C8–C9
bond shows two minima occurring at -105° and the other
at 75°. In both conformations, 1,2,4-triazolo-1,3,4-thiadi-
azine moiety is parallel to the trimethoxyphenyl ring.
However, the only difference is the trimethoxyphenyl ring
located on the mirror image side with respect to C8–C9
bond (Fig. 7). The conformational energy versus the C9–
C8–C7–C1 torsion angle diagram predicts four conformers
(Fig. 8). The most stable conformation is predicted at 175°.
Rotation around C7–C1 is obtained with plateau between
150° and 180°. The energy curve u4 shows that a minimal
energy is obtained for -170°, with a plateau between
-180° and 50° and another between 75° and 180°. The
minimum energy structure for compound 2 predicted by
AM1 and RHF/6-31G methods compare in general quite
well with the experimental data.
Fig. 4 Crystal packing of the compound 2 projected onto ac plane.
The dashed lines indicate the intermolecular hydrogen bonds
angles to be -16.9(3)°, 167.7(2)°, and -109.1(2)°; while
the theoretical calculations found for u1 to be -5.6° at
semi-empirical AM1 level and 174.4° at RHF/6-31G level.
For u2 and u3, full optimized AM1 geometry found to be
-178.7° and -107.5°, respectively. In the case of ab initio
calculations, u2 and u3 torsion angles are found as 179.1°
and 82.9°, respectively. When compared with the X-ray
results, the RHF/6-31G optimization indicates different
conformation for u1. Rotation around C12–C13 bond
shows large plateau and the barrier at -150°. This result
suggests that phenyl moiety can rotate around 1,2,4-triaz-
olo-1,3,4-thiadiazine moiety. The RHF level of theory
The geometrical features predicted by AM1 and RHF/6-
31G calculations and those determined by X-ray crystal-
lography analysis are listed in Tables 4 and 5, showing the
most relevant bond distances, valence angles, and torsion
angles of compounds 1 and 2. It has been noticed that the
level of RHF/6-31G theory estimate the bond lengths C=N
Fig. 5 AM1 calculated
1.6
1.4
1.2
1.0
0.8
0.6
1.6
(a)
(b)
conformation energies for X-ray
starting geometry of compound
1 versus the a u1(N2–C9–
C8–C7), b u2(C9–C8–C7–C1),
c u3(C8–C7–C1–C2),
1.4
1.2
1.0
0.8
0.6
d u4(C11–C12–C13–C14)
-150
-100
-50
0
50
100
150
-150
-100
-50
0
50
100
150
ϕ (N2−C9−C8−C7) (o)
ϕ (C9−C8−C7−C1) (o)
1
2
(c)
(d)10
0.644
8
0.643
0.642
0.641
0.640
0.639
6
4
2
0
-150
-100
-50
0
50
100
150
-150
-100
-50
0
50
100
150
ϕ (C8−C7−C1−C2) (o)
3
ϕ (C11−C12−C13−C14) (o)
4
123

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Struct Chem (2010) 21:795–802
Fig. 6 AM1 calculated
(a)
(b)1.8
conformation energies for X-ray
starting geometry of compound
2 versus the a u1(N2–C9–C8–
C7), b u2(C9–C8–C7–C1),
c u3(C8–C7–C1–C2),
1.4
1.6
1.4
1.2
1.0
0.8
0.6
1.2
1.0
0.8
0.6
d u4(C11–C12–C13–C14)
-150
-100
-50
0
50
100
150
-150
-100
-50
0
50
100
150
ϕ (N2−C9−C8−C7) (o)
ϕ (C9−C8−C7−C1) (o)
1
2
14
12
10
8
(d) 10
(c)
8
6
4
2
0
6
4
2
0
-150
-100
-50
0
50
100
150
-150
-100
-50
0
50
100
150
o (
o (
(
ϕ C11−C12−C13−C14) (
(
ϕ C8−C7−C1−C2) (
4
3
C9-C8-C7-C1= -30°
C9-C8-C7-C1=175°
N2-C9-C8-C7=105°
N2-C9-C8-C7=75°
Fig. 7 Two different conformations of compound 2 predicted by
AM1 theoretical calculations for the rotation about C8–C9 bond
and N–N accurately. Comparing the values of bond angles
between RHF/6-31G calculated geometry and experimental
geometry, it is observed that the bond angles in 1,2,4-tri-
azole ring are predicted by 0.2° on the average for com-
pound 1 (0.5° for compound 2) at the RHF/6-31G level.
For the 1,3,4-thiadiazine ring, the bond angles are predicted
on the average 1.0° for compound 1 (1.1° for compound 2)
at the RHF/6-31G level. Comparisons of experimental
bond lengths with the calculated values show that for RHF/
C9-C8-C7-C1=0°
C9-C8-C7-C1=25°
Fig. 8 Four different conformations of compound 2 predicted by
AM1 theoretical calculations for the rotation about C8–C7 bond
˚
6-31G method, the biggest bond difference is 0.075 A for
˚
C11–S1 bond for compound 1 (0.072 A for C11–S1 bond
and angles better than AM1 method. In spite of the dif-
ferences, both methods give satisfactory calculational
precision, which shows that the optimized geometries
calculated by AM1 and RHF/6-31G methods can well
reproduce the crystal structure of the title compounds.
Inspection of Fig. 9 reveals the similarity between the
X-ray and RHF/6-31G geometries that were obtained by
using the overlay procedure in HyperChem [25] with
for compound 2). In view of the bond angles difference
between the experimental and calculated values, the big-
gest bond angle difference is 3.0° for C12–N4–N3 bond
angle for compound 1 (3.4° for C12–N4–N3 bond angle for
compound 2). In both the cases, AM1 method gives biggest
difference, and RHF/6-31G method predicts bond lengths
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Struct Chem (2010) 21:795–802
801
˚
˚
Table 4 Selected geometric parameters (A, °) for compound 1
Table 5 Selected geometric parameters (A, °) for compound 2
Compound 1
Compound 2
X-ray
1.506(3)
AM1
RHF/6-31G
X-ray
1.509(3)
AM1
RHF/6-31G
C1–C7
1.488
1.519
1.485
1.359
1.432
1.36
1.512
1.538
1.488
1.297
1.375
1.286
1.372
1.792
1.507
1.881
1.275
1.483
1.402
1.373
111.7
112.5
117.1
129.9
127.5
120.9
123
C1–C7
1.49
1.512
1.545
1.485
1.297
1.375
1.287
1.371
1.79
C7–C8
1.525(3)
1.484(3)
C7–C8
1.528(3)
1.482(3)
1.303(2)
1.371(2)
1.303(2)
1.372(2)
1.730(2)
1.509(3)
1.809(2)
1.286(2)
1.478(3)
1.410(2)
1.385(2)
112.52(17)
112.31(17)
116.67(19)
129.93(16)
127.54(17)
120.3(2)
122.17(18)
-170.6(2)
173.4(2)
-83.0(3)
-105.3(2)
-87.6(2)
-179.3(2)
4.1(3)
1.52
C8–C9
C8–C9
1.485
1.36
C9–N2
1.303(2)
C9–N2
C9–N3
1.373(2)
C9–N3
1.43
C10–N1
1.301(3)
C10–N1
1.361
1.433
1.679
1.498
1.772
1.317
1.475
1.321
1.333
110.8
110.9
118.8
129.8
128.4
119.9
126
C10–N3
1.369(2)
1.433
1.679
1.496
1.773
1.316
1.476
1.322
1.333
110.8
112
C10–N3
C10–S1
1.733(2)
C10–S1
C11–C12
1.507(3)
C11–C12
1.509
1.881
1.275
1.482
1.402
1.371
111.8
112.5
117
C11–S1
1.806(2)
C11–S1
C12–N4
1.283(2)
C12–N4
C12–C13
1.479(3)
C12–C13
N1–N2
1.405(2)
N1–N2
N3–N4
1.385(2)
N3–N4
C1–C7–C8
C9–C8–C7
N4–C12–C13
N1–C10–S1
N2–C9–C8
C6–C1–C7
N4–C12–C11
C14–C13–C12–C11
C9–C8–C7–C1
C8–C7–C1–C2
N2–C9–C8–C7
C20–O2–C4–C5
110.91(16)
113.84(16)
115.89(16)
129.41(15)
128.51(18)
120.96(19)
123.59(17)
32.4(3)
C1–C7–C8
C9–C8–C7
N4–C12–C13
N1–C10–S1
N2–C9–C8
C6–C1–C7
N4–C12–C11
C18–C13–C12–C11
C9–C8–C7–C1
C8–C7–C1–C2
N2–C9–C8–C7
C20–O2–C4–C5
C19–O1–C5–C4
C21–O3–C3–C2
118.5
129.7
129.7
120.1
126.4
57.2
129.9
126.9
120.2
123.5
-138.4
-179.5
-87.7
-102
-93.2
-171.7
-7.4
28.7
-155.6
175.6
-76.4
-100.2
-76.1
-171.5
-8.6
-167.7(2)
-109.1(2)
-16.9(3)
-164.3(2)
-178.7
-107.5
-5.6
178.5
179.1
82.9
174.4
178.4
default parameters. Agreement between the calculated
structures and the experimentally determined X-ray crystal
structures were excellent (RMS values 5.5910-3 A for
˚
compound 1 and 5.7910-3 A for compound 2).
˚
No experimental dipole moments have been reported for
the compounds covered by this article. Using the ab initio
calculations, the electric dipole moments were obtained
from both Mulliken and molecular electrostatic potential
charges for both the compounds. The theoretical calcula-
tions indicate similar values for both the compounds
(l = 6.11 D for compound 1 and l = 5.85 D for com-
pound 2).
Fig. 9 An overlay of the X-ray (yellow) and RHF/6-31G optimized
geometries of compound 1 (a) and 2 (b)
optimized geometry indicate that the frontier molecular
orbitals are mainly composed of s orbitals. As seen from
Figs. 10 and 11, in the HOMO, electrons are mainly
delocalized on the methoxyphenyl-ethyl group in com-
pound 1 and trimethoxyphenyl-ethyl group in compound 2.
However, when electron transitions take place, some
electrons will enter into the LUMO, then, in the LUMO,
the electrons will mainly be delocalized on triazole ring,
thiadiazine ring, and phenyl rings as well as the O atoms.
The energies of the wave functions associated with the
frontier (and those close in energy) molecular orbitals were
calculated at the RHF/6-31G level and are given in
Table 6. The respective energies associated with the fron-
tier orbitals (HOMO and LUMO) for both compounds at
the optimized structures are similar. Figures 10 and 11
show the wave function associated with the HOMO and
LUMO. The population analyses based on the RHF/6-31G
123

802
Struct Chem (2010) 21:795–802
Acknowledgment The authors would like to acknowledge the
support of Hacettepe University Research Fund (project no: 030260
2001 and 0701301001).
Table 6 Energy (eV) of the wave function associated with the frontier
(and those close in energy) molecular orbitals for the optimized
compounds 1 and 2 molecules
Compound 1
E(eV)
Compound 2
MO
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?6.77
?4.86
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Conclusions
Two novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine deriva-
tives, 3-[2-(4-methoxyphenyl)ethyl]-6-phenyl-7H-1,2,4-triazolo
[3,4-b]-1,3,4-thiadiazine (compound 1) and 3-[2-(3,4,5-trime-
thoxyphenyl)ethyl]-6-phenyl-7H-1,2,4-triazolo[3,4-b]-1,3,4-thi-
adiazine (compound 2), having analgesic–anti-inflammatory
1
activity were synthesized and characterized by IR, H-NMR,
mass spectroscopic techniques, and X-ray single crystal dif-
fraction. Potential energy surface scans were drawn. AM1 and
RHF/6-31G calculations for the title compounds show that the
optimized geometries resemble the crystal structure. RHF/6-31G
level of theory has predicted geometrical features better than
AM1.
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123