Synthesis and dynamic stereochemistry of 4-aryl-thiomorpholine-3,5-dione derivatives

Article abstract of DOI:10.1016/j.molstruc.2014.08.046

A series of new N-aryl-substituted thiomorpholine-3,5-diones were synthesized. Crystal structures of seven compounds were established on the basis of X-ray crystallography. Stable at room temperature diastereomers were detected for (2-phenyl)-substituted derivatives using ¹H NMR. The dynamic stereochemistry of compound 36 was studied with variable-temperature ¹H NMR and the mechanism of diastereomers interconversion was proposed on the basis of quantum chemical calculations.

Full text of DOI:10.1016/j.molstruc.2014.08.046

Journal of Molecular Structure 1079 (2015) 383–390
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis and dynamic stereochemistry of 4-aryl-thiomorpholine-3,5-
dione derivatives
b
a,
Joanna Szawkało a, Jan K. Maurin b,c, Franciszek Plucinski , Zbigniew Czarnocki
⇑
´
a Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
b National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland
c
´
National Centre for Nuclear Research, 05-400 Otwock-Swierk, Poland
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
Seven new N-aryl-substituted thiomorpholine-3,5-diones have been characterized by X-ray diffraction method.
Five orto-substituted N-aryl thiomorpholine-3,5-diones exhibited restricted rotations around N-aryl bond.
Temperature-depended NMR and quantum chemical calculations were applied for the estimation of the energy barriers.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2014
Received in revised form 25 August 2014
Accepted 26 August 2014
Available online 3 September 2014
A series of new N-aryl-substituted thiomorpholine-3,5-diones were synthesized. Crystal structures of
seven compounds were established on the basis of X-ray crystallography. Stable at room temperature
diastereomers were detected for (2-phenyl)-substituted derivatives using 1H NMR. The dynamic stereo-
chemistry of compound 36 was studied with variable-temperature 1H NMR and the mechanism of dia-
stereomers interconversion was proposed on the basis of quantum chemical calculations.
Ó 2014 Elsevier B.V. All rights reserved.
Keywords:
Imides
Atropisomerism
Heterocyclic compounds
Dynamic stereochemistry
Introduction
undergo interesting intramolecular amidoalkylations giving effi-
cient access to novel heterocyclic systems [9].
The thiomorpholine-3,5-dione (3-thiaglutaric acid imide) struc-
tural motif is present in many pharmacologically active com-
pounds. The synthesis of these derivatives was undertaken for
evaluation as potentially useful hypnotics, sedatives and anticon-
vulsants [1–3]. Alkyl-substituted thiomorpholine-3,5-diones were
found to have marked anticonvulsant activity against metrazol
shock [2] and were considered as hypotensive agents [4]. More
recently, these imides proved to be important pharmacophores in
derivatives having antipsychotic [5], antimicrobial and antitumor
activity [6]. From a chemical point of view, N-thiodiglicolyl deriv-
atives of pharmacologically important glucosamine were found
useful as glycosyl donors [7]. Relatively simple deprotonation of
the methylene group in thiomorpholine-3,5-dione allows it subse-
quent alkylation giving rise to a variety of substituted structures
[8]. The hydroxy or ethoxy lactams derived from thiazinediones
Despite its interesting and useful reactivity, the thiomorpho-
line-3,5-dione system has not yet been structurally evaluated
and the Cambridge Crystallographic Database does not provide
examples of compounds bearing this structural motif.
During our recent studies on potential antimicrobial agents, we
turned our attention to selected thio- and thia-imides of dicarbox-
ylic acids. Therefore in this work the synthesis as well as structural
and spectroscopic studies of several new N-aryl-thiomorpholine-
3,5-diones are presented.
Results and discussion
Synthesis of imides
The most straightforward and conventional method for prepa-
ration of cyclic imides is based on direct pyrolysis of the monoa-
mide derived from a reaction of the corresponding anhydride and
amine [10]. Acetic anhydride may also be used as dehydrating
agent [11].
⇑
Corresponding author. Tel.: +48 22 822 02 11; fax: +48 22 822 59 96.
E-mail address: czarnoz@chem.uw.edu.pl (Z. Czarnocki).
http://dx.doi.org/10.1016/j.molstruc.2014.08.046
0022-2860/Ó 2014 Elsevier B.V. All rights reserved.

384
J. Szawkało et al. / Journal of Molecular Structure 1079 (2015) 383–390
Table 1
We have already found that BOP reagent [(benzotriazol-1-yloxy)
Physical data and CCDC deposit numbers for imides 26–37.
tris(dimethyl-amino)phosphonium hexafluorophosphate, Castro
reagent] may effectively be used at this step [12] and we applied
this procedure to the synthesis of all described imides. Thus, the
reaction of 1 with the corresponding aniline gave the mono-amide
in quantitative yield which was then cyclized under mild condi-
tions (BOP, THF, r.t.) to produce the desired imides in good yield
(Scheme 1). The results are summarized in Table 1.
Imide
R
Mp (°C)
Yield (%)a
CCDCc Deposit no.
26
27
28
29
30
31
32
33
34
35
36
37
-H
-4-CH3
211.5–213.0b
205.5–207.0
137.0–138.0
193.5–195.5
196.0–197.0
151.5–153.0
94.5–95.5
217.0–218.0
141.5–142.5
144.0–146.0
160.0–161.0
172.5–174.0
66
88
59
72
77
78
77
72
80
90
97
78
-2,5-diCH3
-4-NO2
-4-OCH3
-2-OCH3
-2,5-diOEt
-3,4-O2CH2
-4-Cl
-2,4-diCl
-2,4-diF
-2-tBu
963,333
963,336
963,337
963,338
963,335
963,334
963,339
Crystallographic characterization of imides
In the case of compounds 29, 30 and 33–37 we were able to
obtain monocrystals suitable for X-ray experiments. Although mol-
ecules of all compounds were similar and contained the thioimide
moiety linked through its nitrogen atom with a substituted phenyl
ring, the crystal symmetry and crystal packing were different. The
crystal and experimental parameters for all studied structures are
compiled in Table 2. Structures can be divided at least into three
different groups. The first one consists of structures of compounds
30, 33 and 34. The second one is formed by compounds 29 and 36
whereas the last one consists of structures of 35 and 37. The first
group formed by three monoclinic structures belonging to the
P21/c space group has a common feature which is a pair of centro-
symmetric C(5)AH(5A)ꢁ ꢁ ꢁO(2) hydrogen bonds between thioimide
CH2 fragments and respective carbonyl oxygen atoms.
a
b
c
Based on compound 1.
Lit. [10] mp 214.5–215.5 °C.
Cambridge Crystallographic Data Centre.
Different packing pattern was observed in the structure of 34.
Here also the hydrogen-bonded dimers are formed but they are
linked via series of C(10)AH(10)ꢁ ꢁ ꢁO(2) and C(7)AH(7)ꢁ ꢁ ꢁO(2)
intermolecular hydrogen bonds producing (1 0 0) double layers
of molecules – highlighted in the center of the drawing in Fig. 3.
Structures of 29 and 36
In the second structural group, thioimide hydrogen atoms and
carbonyl oxygens are also involved in CAHꢁ ꢁ ꢁO intermolecular
hydrogen bonds but rather than forming centrosymmetric dim-
mers, they form infinite catemeric chains. In Fig. 4 the crystal pack-
ing of 29 molecules is shown along the c-axis.
The aforementioned catemeric chain is shown in Fig. 5. The
molecules are related with twofold screw-axis symmetry in the
0 1 0 direction with the C(5)AH(52)ꢁ ꢁ ꢁO(2) intermolecular hydro-
gen bonds. Additionally, translation-related molecules in the
b-direction are linked with the C(12)AH(12)ꢁ ꢁ ꢁO(1) bonds.
Apart from the above interactions, there are other weaker
hydrogen bonds in the structure (not shown in the drawing) and
involving other H-atoms and e.g. nitro group oxygens.
Structures of 30, 33 and 34
In Fig. 1 the crystal packing of 30 along the b-axis is shown.
The aforementioned dimers are additionally linked by series of
weaker hydrogen bonds between phenyl ring H(11) hydrogen
atoms and methoxy O(3) oxygens forming infinite dimeric zig-
zag chains of molecules approximately in the 1 0 0 direction. Such
chain is shown in Fig. 2.
The dimeric chains are additionally linked by CAHꢁ ꢁ ꢁO hydro-
gen bonds between H(9) phenyl hydrogen atoms and O(1) carbonyl
oxygen atoms of the adjacent molecules.
Similar situation can be observed in the crystal structure of 33.
Although both unit cell parameters and the space group symmetry
are very similar in these structures, the crystals are not isostructur-
al. As before, molecules of 33 form infinite dimeric zig-zag chains
but now, differently than in structure of 30, the chains pass
approximately in the 1 0 1 direction.
In the crystal structure of 36, the thioimide methylene hydrogens
and carbonyl oxygen atoms of the molecules are related by both n-
and a-glide plane symmetry and are involved in a series of
C(6)AH(6A)ꢁ ꢁ ꢁO(1) and C(2)AH(2B)ꢁ ꢁ ꢁO(2) hydrogen bonds forma-
tions. Additionally, molecules related by the twofold screw axes
symmetry are hydrogen-bonded with the series of C(9)AH(9)ꢁ ꢁ ꢁO(2)
Scheme 1. Synthesis of 3-thiaglutaric acid imides.

J. Szawkało et al. / Journal of Molecular Structure 1079 (2015) 383–390
385
Table 2
Crystal data and structure refinement.
Identification code
29
30
34
Empirical formula
Crystal system
Space group
C
10H8N2O4S
C11H11NO3S
Monoclinic
P21/c
C10H8ClNO2S
Monoclinic
P21/c
Monoclinic
C2/c
Unit cell dimensions
a = 20.6161(3) Å
b = 5.33630(10) Å, b = 116.267(2)°
c = 21.4366(3) Å
2114.80(6) Å3
a = 16.1404(2) Å,
b = 5.13560(10) Å, b = 101.3510(10)°
c = 13.6780(2) Å,
1111.60(3) Å3
a = 16.1139(8) Å
b = 5.1000(3) Å, b = 106.538(4)°
c = 13.6329(5) Å
1074.02(9) Å3
Volume
Z
8
4
4
Goodness-of-fit on F2
1.092
1.052
0.832
Final R indices [I > 2
R indices (all data)
r(I)]
R1 = 0.0347, wR2 = 0.1064
R1 = 0.0386, wR2 = 0.1087
R1 = 0.0360, wR2 = 0.1096
R1 = 0.0380, wR2 = 0.1114
R1 = 0.0380, wR2 = 0.0889
R1 = 0.0639, wR2 = 0.0961
Identification code
33
36
35
37
Empirical formula
Crystal system
Space group
C
11H9NO4S
C10H7F2NO2S
Orthorhombic
Pna21
C10 H7Cl2NO2S
Orthorhombic
Pbca
C14H17NO2S
Monoclinic
P21/c
Monoclinic
P21/c
Unit cell dimensions
a = 16.4661(7) Å
b = 5.1098(2) Å, b = 108.471(4)°
c = 13.5614(6) Å
1082.25(8) Å3
4
a = 13.70550(10) Å
b = 5.49340(10) Å
c = 13.53920(10) Å
1019.36(2) Å3
a = 13.20240(10) Å
b = 12.3947(2) Å
c = 14.43880(10) Å
2362.76(5) Å3
a = 14.06660(10) Å
b = 13.88180(10) Å, b = 98.8120(10)°
c = 14.05910(10) Å
2712.91(3) Å3
Volume
Z
4
8
8
Data/restraints/parameters
2014/0/154
1.052
1919/1/156
1.075
2254/0/145
1.074
5174/1/325
1.058
Goodness-of-fit on F2
Final R indices [I > 2
R indices (all data)
r(I)]
R1 = 0.0455, wR2 = 0.1382
R1 = 0.0576, wR2 = 0.1459
R1 = 0.0292, wR2 = 0.0846
R1 = 0.0297, wR2 = 0.0850
R1 = 0.0429, wR2 = 0.1232
R1 = 0.0490, wR2 = 0.1270
R1 = 0.0473, wR2 = 0.1457
R1 = 0.0501, wR2 = 0.1489
Fig. 1. The crystal packing of 30 shown along the b-axis. The CAHꢁ ꢁ ꢁO hydrogen bonds are shown as the dashed lines.
Fig. 2. The dimeric chain of molecules of 30. The non-H atoms are shown as 30% probability ellipsoids.

386
J. Szawkało et al. / Journal of Molecular Structure 1079 (2015) 383–390
Fig. 3. The crystal packing of 34 shown in the b-direction.
Fig. 4. Crystal packing in the structure of 29. The CAHꢁ ꢁ ꢁO hydrogen bonds are shown as the dashed lines.
bonds. The three-dimensional hydrogen bonds system is completed
with C(11)AH11ꢁ ꢁ ꢁO(2) bonds.
mation between molecules related by the glide planes symmetry
(Fig. 6).
In this crystal structure series of C(9)AH(9)ꢁ ꢁ ꢁO(1) and
C(11)AH(11)ꢁ ꢁ ꢁO(1) hydrogen bonds could be seen. One can
notice chain structures involving e.g. molecules related by
the a-glide plane symmetry. Such chain is shown below in
Fig. 7.
Structures of 35 and 37
In the last group no relatively strong H-bonds involving thioi-
mide CH2 hydrogen atoms are observed. Instead, hydrogen atoms
of the activated phenyl rings are involved in hydrogen bonds for-

J. Szawkało et al. / Journal of Molecular Structure 1079 (2015) 383–390
387
Hydrogen bonds geometry
In Table 3 the geometry of potential CAHꢁ ꢁ ꢁO interactions
observed in the crystal structures of imides are summarized. The
idea of weak hydrogen bonds, where a carbon atom acts as a donor,
are generally accepted by crystallographic community starting
from the important work of Taylor and Kennard (1982) [13], in
which, basing on the neutron diffraction data the directionality
of the CAHꢁ ꢁ ꢁO interaction was detected and revealed that some
Hꢁ ꢁ ꢁO distances were significantly shorter than the sum of the
van der Waals distances (2.4 Å). These two features make the
CAHꢁ ꢁ ꢁO interactions similar to that of OAHꢁ ꢁ ꢁO hydrogen bonds.
The hydrogen bonds investigated by Taylor and Kennard were
strong CAHꢁ ꢁ ꢁO bonds with the most frequently observed bond
angles of 150–160° [14]. The interactions observed in reported
here structures might be considered as weak or medium-strong
CAHꢁ ꢁ ꢁO hydrogen bonds, although the bond length criterion of
the bond strength is often misleading [14,15]. In some cases other
factors e.g. steric repulsion operate, as in the case of compound 37
where they prevent the formation of CAHꢁ ꢁ ꢁO bonds between
thioimide CAH and carbonyl oxygens from the neighboring
molecules.
NMR spectroscopy (in solution) and computational analysis
The 1H NMR spectra of compounds 29, 33 and 34 have relatively
simple structure due to the symmetry of molecules. In all cases sig-
nals corresponding to methylene protons in the heterocyclic part
of the molecule appear as singlets at approx 3.70 ppm. Only in
the case of compound 29, this signal is shifted to 3.73 ppm reflect-
ing the electron-withdrawing effect of the nitro group. The reso-
nance of the aromatic protons appears as group of multiplets at
6.50–7.50 ppm. The 13C NMR spectra were also simplified due to
the symmetry of molecules and the signal corresponding to C-3
carbon atom is located at approx. 32 ppm whereas the C@O group
resonance is observed at approx. 168 ppm.
Fig. 5. The catemeric chain of molecules in the structure of 29. The non-hydrogen
atoms are shown as 30% probability ellipsoids. Hydrogen bonds are shown as the
dashed lines.
Independent part of the unit cell of 37 is composed of two,
slightly differing in geometry, molecules. Molecule B is partly dis-
ordered in its t-butyl substituent (Fig. 8).
The 1H NMR spectra of compounds 28, 31, 32, 35–37 showed
more interesting features. The presence of ortho-substituent at
the phenyl ring apparently caused a restricted rotation around
the CAN bond resulting in diastereotopicity (at least at the NMR
time scale) of the methylene protons at C-3. As a consequence,
the signal at approximately 3.60 ppm splits into two doublets of
ca. Jgem = 17 Hz. The effect of hindered rotation and non-planar
Molecules are linked together in chains by weak CAHꢁ ꢁ ꢁO
hydrogen bonds (Fig. 9).
The neighboring chains are additionally linked with pairs of
intermolecular centrosymmetric dimeric C16AAH16Aꢁ ꢁ ꢁS1A
bonds.
Fig. 6. Crystal packing in 35 shown along b-direction. The CAHꢁ ꢁ ꢁO hydrogen bonds are shown as dashed lines.

388
J. Szawkało et al. / Journal of Molecular Structure 1079 (2015) 383–390
Fig. 7. Hydrogen-bonded chain of molecules formed by series of C(9)AH(9)ꢁ ꢁ ꢁO(1) hydrogen bonds. The non-hydrogen atoms are shown as 30% probability ellipsoids.
Fig. 8. Independent part of the unit cell of the structure of 37. The non-H atoms are shown as the 30% probability ellipsoids. Atom C(15) from the molecule B is partly
disordered.
conformations about the CAN bond in aryl-imides has already
been documented by several authors [16,11]. The dynamic 1H
NMR study of rotational energy barrier provided valuable informa-
tion concerning conformer interconversion [17]. In the case of
compounds 28, 31, 32, and 35–37, possible isomerization of diaste-
reomers might be caused by two distinct mechanisms. According
to the first one, the diastereomers may interconvert due to a con-
formational change taking place in the heterocyclic part of the
molecule as shown in Fig. 10 for compound 37.
Alternatively, the same result might be obtained via the rotation
around N-aryl bond. In order to estimate the energy requirements
for both processes, we initially calculated the activation energy for
the conformational change involving the heterocyclic part of the
molecule. This calculation was done only for 36 since the thioimide
ring is the part of all studied compounds and due to that its inver-
sion energy is expected to be similar. The obtained value of energy
of the thioimide ring inversion was 6.0 kcal/mol. This energy value
suggests rather unrestricted conformational changes in the hetero-
cyclic part.
In order to estimate the energy requirements for the alternative
mechanism involving the NACaryl bond rotation, we performed a
set of additional calculations. The results are given in Table 4.
As shown in Table 4, the rotation around the NACaryl bond is a
medium-energy process except for compound 37, in which the
rotation is stopped. The calculations were done by ab initio DFT
method with the implemented B3LYP electron density functional
and 6-31G⁄ function basis [18]. After geometry optimization of
the initial structures, their rotation energy profiles were deter-
mined as the result of rotation of the aryl substituent around
Fig. 9. The H-bonded chain of molecules passing along the c-direction. The
consecutive A and B molecules in the chain are related by a c-glide plane symmetry.

J. Szawkało et al. / Journal of Molecular Structure 1079 (2015) 383–390
389
Table 3
CAHꢁ ꢁ ꢁO hydrogen bonds geometry (Å and °).
Compound
DAHꢁ ꢁ ꢁA
Distances
<(DHA)
Symmetry operations generating equivalentsa
DAH
Hꢁ ꢁ ꢁA
Dꢁ ꢁ ꢁA
1)
2)
3)
4)
1)
2)
3)
1)
2)
3)
1)
2)
3)
4)
5)
1)
2)
3)
4)
1)
2)
1)
2)
29
C(12)AH(12)ꢁ ꢁ ꢁO(1)1)
C(5)AH(52)ꢁ ꢁ ꢁO(2)2)
C(9)AH(9)ꢁ ꢁ ꢁO(4)3)
0.93(2)
0.93(2)
0.91(2)
0.93(2)
0.97(3)
0.91(2)
0.96(2)
0.94(3)
0.94(3)
0.89(3)
0.88(4)
0.87(3)
1.08(4)
1.20(4)
1.20(4)
0.82(4)
1.05(3)
0.92(3)
0.95(3)
0.89(3)
0.91(3)
0.89(3)
0.93
2.49(2)
2.56(2)
2.62(2)
2.65(2)
2.33(3)
2.57(2)
2.52(2)
2.41(3)
2.47(3)
2.58(3)
2.44(4)
2.63(3)
2.49(4)
2.69(4)
2.69(4)
2.62(4)
2.43(3)
2.61(3)
2.54(3)
2.52(3)
2.40(3)
2.59(3)
2.68
3.381(2)
3.268(2)
3.331(3)
3.304(2)
3.293(2)
3.452(2)
3.430(2)
3.308(4)
3.393(4)
3.432(4)
3.302(4)
3.446(3)
3.250(4)
3.178(5)
3.674(4)
3.259(3)
3.472(3)
3.178(2)
3.374(2)
3.383(3)
3.309(3)
3.201(3)
3.348(3)
159.5(17)
x, y + 1, z
133.2(17)
135.8(17)
128.4(17)
171(2)
162.2(17)
158.3(18)
ꢃx + 1/2, y ꢃ 1/2, ꢃz + 1/2
ꢃx, ꢃy ꢃ 1, ꢃz
C(5)AH(52)ꢁ ꢁ ꢁO(4)4)
C(5)AH(5A)ꢁ ꢁ ꢁO(2)1)
C(9)AH(9)ꢁ ꢁ ꢁO(1)2)
x + 1/2, ꢃy ꢃ 1/2, z + 1/2
ꢃx + 2, ꢃy, ꢃz + 1
x, ꢃy + 11/2, z + 1/2
ꢃx + 1, ꢃy, ꢃz + 1
ꢃx + 1, ꢃy + 1, ꢃz + 1
x, ꢃy + 21/2, z ꢃ 1/2
x, y ꢃ 1, z
30
34
33
C(11)AH(11)ꢁ ꢁ ꢁO(3)3)
C(3)AH(31)ꢁ ꢁ ꢁO(1)1)
C(10)AH(10)ꢁ ꢁ ꢁO(2)2)
C(7)AH(7)ꢁ ꢁ ꢁO(2)3)
158(3)
166(3)
160(3)
167(3)
156(2)
126(3)
103(2)
138(2)
136(3)
172(2)
121(2)
146(2)
165(3)
178(3)
126(2)
C(6)AH(6B)ꢁ ꢁ ꢁO(2)1)
C(8)AH(8)ꢁ ꢁ ꢁO(1)2)
ꢃx + 1, ꢃy + 1, ꢃz
x, y ꢃ 1, z
C(13)AH(13A)ꢁ ꢁ ꢁO(4)3)
C(13)AH(13B)ꢁ ꢁ ꢁO(3)4)
C(13)AH(13B)ꢁ ꢁ ꢁO(1)5)
C(6)AH(6A)ꢁ ꢁ ꢁO(1)1)
C(11)AH(11)ꢁ ꢁ ꢁO(1)2)
C(2)AH(2B)ꢁ ꢁ ꢁO(2)3)
C(9)AH(9)ꢁ ꢁ ꢁO(2)4)
ꢃx, ꢃy + 1, ꢃz ꢃ 1
ꢃx, y + 1/2, ꢃz ꢃ 1/2
ꢃx, y ꢃ 1/2, ꢃz ꢃ 1/2
ꢃx + 1/2, y + 1/2, z ꢃ 1/2
x ꢃ 1/2, ꢃy + 1/2, z
x + 1/2, ꢃy + 11/2, z
ꢃx, ꢃy + 2, z + 1/2
x ꢃ 1/2, y, ꢃz + 1/2
ꢃx, y + 1/2, ꢃz + 1/2
ꢃx + 1, y ꢃ 1/2, ꢃz ꢃ 1/2
ꢃx + 1, ꢃy + 2, ꢃz ꢃ 1
36
35
37
C(9)AH(9)ꢁ ꢁ ꢁO(1)1)
C(11)AH(11)ꢁ ꢁ ꢁO(1)2)
C(2B)AH(2B1)ꢁ ꢁ ꢁO(1A)1)
C(11A)AH(11A)ꢁ ꢁ ꢁO(1B)2)
129.5
a
The numbers correspond to the respective structures.
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
p
ð
m
ꢃ
mBÞ2þ6J2
2
A pffiffi
AB. Parameters mA
, mB and JAB stand for: chemical shift
Table 4
k ¼
The energy of rotational barrier of imides 28, 31, 32, 35–37.
of proton A, chemical shift of proton B and coupling constant
between proton A and B in AB spin system, respectively. The calcu-
Imide
Substituents
Energy of rotational barrier (kcal/mol)
lated values are: mA
ꢃ
mB = 12.8 Hz and JAB = 16.0 Hz. For simplifica-
28
31
32
35
36
37
-2,5-diCH3
-2-OCH3
-2,5-diOEt
-2,4-diCl
-2,4-diF
50.2
8.1
12.4
17.1
13.6
100.9
tion, the AB spin system was assumed in the calculation. This
form of the Eyring’s equation was chosen assuming that the popu-
lations of both isomers are the same and the observed protons in
the NMR spectrum being in structurally equivalent positions form
an AB spin system. In the case of compound 36 it refers to equato-
rial and axial protons in 2 and 6 positions in the thioimide ring.
-2-tBu
Fig. 10. Diastereomers of 37 resulting from conformational change of
3,5-thiomorpholine-3.5-dione ring.
NAC bond by 180°. This rotation range was divided into ten even
angular steps and on each of them the energy of the molecule
was calculated after its prior geometry optimization.
We also performed variable temperature 1H NMR experiments
on compound 36 observing changes in signals corresponding to
protons at C-2 and C-6 positions of the heterocycle. The results
seen in Fig. 11 indicate the temperature dependence of the signals.
The signals observed at 25 °C were found to become closer as
the temperature was raised, and coalesced at 120 °C. These NMR
spectra may be considered as AB spin system only slightly per-
turbed toward AA0BB0 one. The activation energy of 19.7 kcal/mol
has been then calculated for the conformational interconversion
of atropisomers with the help of Eyring’s equation.
ꢂ
ꢀ
ꢁꢃ
Tc
k
D
G ¼ aTc 10:319 þ log
where a = 4.575 ꢂ 10ꢃ3 for units of kcal/mol, Tc and k denote coales-
cence temperature and the rate constant of isomerisation
Fig. 11. Dynamic 1H NMR experiment on compound 36.

390
J. Szawkało et al. / Journal of Molecular Structure 1079 (2015) 383–390
These both types of protons form an AB spin system slightly devi-
ated toward AA0BB0 which degenerates into A2 one at the coales-
cence temperature. The difference in the experimental (19.7 kcal/
mol) and theoretical (13.6 kcal/mol) value of the rotation barrier
for compound 36 may be attributed to the solvent (DMSO) effect
that is difficult to incorporate in the calculations. Nevertheless,
the energy calculation seems to be a useful tool for a preliminary
estimation of the dynamic stereochemistry of conformationally
mobile molecules.
Similar experiment of temperature-dependent NMR was per-
formed for compound 37, for which quantum chemical calcula-
tions predicted blocking the rotation of the phenyl ring. As
expected, the coalescence of the signals of protons at the positions
2 and 6 in the thioimide ring (AB spin system) was not observed up
to 185 °C illustrating the existence of an intrinsic anisochrony of
the system [19].
General method for synthesis of imides 26–37
Anhydride 1 (100 mg, 0.757 mmol) was dissolved in a minimal
amount of dry CH2Cl2 and corresponding aniline 2–13 (1 eq) was
added in dry CH2Cl2. The solution was stirred for 24 h at room tem-
perature. The solvent was evaporated and the monoamides 14–25
were air-dried, and used without further purification.
Appropriate monoamide (14–25) (0.5 mmole) was dissolved in
dry, freshly distilled THF (10 ml) at room temperature under argon.
BOP (1.05 eq) was added to the mixture followed by the solution of
triethylamine (TEA) (0.5 ml) in THF (1 ml). The reaction mixture
was then stirred at room temperature for 20 min and another por-
tion of BOP (0.5 eq) was added. After 40 min the solvent was evap-
orated. The residue was dissolved in CHCl3 and washed with 10%
citric acid solution, sat. Na2CO3 solution, water and brine. Com-
bined organic layers were dried over MgSO4, filtered and evapo-
rated to dryness. Imides 26–37 were purified by column
chromatography on silica gel using mixture hexan/EtOAc (0–15%
v/v) as eluent. Yields are listed in Table 1.
Conclusions
In a search for novel antibacterial compounds possessing sulfur
heterocyclic motif, we prepared a series of new N-aryl-substituted
thiomorpholine-3,5-diones. The structures of seven compounds
were established on the basis of X-ray crystallography. In the case
of (2-phenyl)-substituted derivatives, diastereomers stable at
room temperature were detected in 1H NMR. The dynamic stereo-
chemistry of compound 36 was subjected to a more detailed study
with variable-temperature 1H NMR observing changes in signals
corresponding to protons at C-2 and C-6 positions of the heterocy-
cle. On the basis of detected coalescence temperature, the energy
barrier to rotation was calculated and this value was compared
with the calculated one. The mechanism of diastereomers inter-
conversion was proposed on the basis of quantum chemical
calculations.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2014.
08.046.
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Experimental
The NMR spectra were recorded on a Varian Unity Plus spec-
trometer operating at 200 MHz or at 500 MHz for 1H NMR and at
50 MHz or at 125 MHz for 13C NMR. The spectra were measured
in CDCl3 or DMSO-d6 and are given as d values (in ppm) relative
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a
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consecutively refine structures using SHELXS97 and SHELXL97
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