Axial chirality of N,N'-disubstituted 3,4-ethylenedioxythiophene-2,5- dicarboxamides

Article abstract of DOI:10.1007/s11224-011-9885-x

A series of N,N'-disubstituted 3,4-ethylenedioxythiophene- 2,5-dicarboxamides was synthesised by amide bond formation between 3,4-ethylenedioxythiophene- 2,5-dicarbonyl chloride and corresponding primary amines, where the size and the nature of the substi

Full text of DOI:10.1007/s11224-011-9885-x

Struct Chem (2012) 23:425–432
DOI 10.1007/s11224-011-9885-x
ORIGINAL RESEARCH
Axial chirality of N,N0-disubstituted 3,4-ethylenedioxythiophene-
2,5-dicarboxamides
•
Ivana Stolic Kresimir Molcanov Goran Kovacevic
•
•
´
ˇ
ˇ
Biserka Kojic-Prodic Miroslav Bajic
ˇ
´
•
´
´
´
Received: 11 April 2011 / Accepted: 17 September 2011 / Published online: 5 October 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of N,N’-disubstituted 3,4-ethylene-
dioxythiophene-2,5-dicarboxamides was synthesised by
amide bond formation between 3,4-ethylenedioxy-
thiophene-2,5-dicarbonyl chloride and corresponding pri-
mary amines, where the size and the nature of the sub-
stituent were varied. The crystal structures of prepared
compounds were determined by X-ray structure analysis.
Mechanism and reaction rates of interconversion between
conformational isomers were obtained by DFT calcula-
tions. All studied compounds reveal axial chirality with
molecular symmetry C2. Amide bond isomerisation and
twisting of the dioxane ring in studied compounds results
in the formation of series of conformers of which the s-
trans/s-trans conformer is energetically most favourable.
Introduction
3,4-Ethylenedioxythiophene (EDOT) is a very well-docu-
mented building block used in design and synthesis of
various classes of polymers [1–4], and potential biologi-
cally active molecules [5, 6]. In recent years syntheses,
motivated by the properties and utility of EDOT, have been
focused on development of new organic molecules with
EDOT moiety as key structural element [7–12].
In our previous papers [5, 6], we have described the
effect of 3,4-ethylenedioxy-extension of thiophene core on
the DNA/RNA binding properties and antitumour activity
of compounds with different diarylamidines linked by
EDOT ring. It was found that DNA/RNA affinity and
biological activity of studied compounds depends on the
structure of functional groups bonded to EDOT but also on
structure of terminal, alkyl substituted or cyclic amidine
moieties. Physicochemical properties of these functional
groups affect the DNA binding interactions through
stacking with the minor groove, hydrogen bonding, and
polyelectrolyte interactions [13, 14]. To test flexibility and
structural characteristics of these linkers, we prepared
compounds with N-alkyl and N-phenyl derivatives of 3,4-
diethylendioxythiophene-2,5-dicarboxamide.
Keywords 3,4-Ethylenedioxythiophene ꢀ Crystal
structure ꢀ Axial chirality ꢀ DFT
Until now, only a few crystal structures containing a
EDOT ring system were reported [15–20]. They reveal a
non-planar C2-symmetric EDOT moiety. Such a structural
feature pointed out to flexibility of these linkers that might
lead to axial chirality, which is an ubiquitous phenomenon.
The majority of organic molecules reveal no symmetry
elements in their molecular structures in the solid state (the
Cambridge Crystallographic Database). Therefore, the
axial chirality has no limitations to occur. However,
the existing literature has not offered any systematics on
axial chirality [21, 22].
Electronic supplementary material The online version of this
article (doi:10.1007/s11224-011-9885-x) contains supplementary
material, which is available to authorized users.
´
´
I. Stolic ꢀ M. Bajic (&)
Department of Chemistry and Biochemistry, Faculty of
Veterinary Medicine, University of Zagreb, Heinzelova 55,
10000 Zagreb, Croatia
e-mail: mbajic@vef.hr
ˇ
ˇ
´
´
´
K. Molcanov ꢀ G. Kovacevic ꢀ B. Kojic-Prodic
ˇ ´ ˇ
Rudjer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
123

426
Struct Chem (2012) 23:425–432
3,4-Ethylenedioxythiophene-2,5-di(N-
isobutylcarboxamide) (4)
Experimental
Synthesis
A mixture of 3,4-ethylenedioxythiophene-2,5-dicarbonyl
chloride (2) (1.88 g, 7.0 mmol) and isobutylamine (1.47 g,
20.1 mmol) in 60 mL of dry CHCl3 was stirred for 3 days
at room temperature. The solvent was removed under
reduced pressure, and the residue was suspended in the
water. The crude product was filtered off and washed with
10% HCl, 10% NaHCO3 and water. The product was
recrystallised from CHCl3–diethyl-ether to yield 0.98 g
(41.2%) of white solid, mp 127–128 °C; e (292 nm) =
The synthesis and physical properties of the compound 6
has been described previously [6]. Solvents were dried over
CaCl2. TLC was carried out on DC-plastikfolien Kieselgel
60 F254, Merck. Melting points were determined on a
Bu¨chi 519 melting point apparatus and were uncorrected.
IR spectra (mmax./cm-1) were obtained on a Bruker Vertex
70 spectrophotometer. The 1H- and 13C-NMR spectra were
recorded in CDCl3 at 25 °C on a Bruker Avance 300 MHz
spectrometer. Chemical shifts (d/ppm) are referred to TMS.
Elemental analyses were performed by Microanalytical
26.18 9 103/dm3 mol-1 cm-1
;
IR (mmax/cm-1): 3298,
1
2943, 1633, 1521, 1292, 1155, 1089, 906, 659, 624; H-
NMR (d/ppm): 6.81 (s, 2H, NH), 4.46 (s, 4H, OCH2CH2O),
3.27 (t, 4H, J = 6.41 Hz, CH2), 1.89 (m, 2H, J = 6.72 Hz,
CH), 0.98 (d, 12H, J = 6.69 Hz, CH3); 13C-NMR (d/ppm):
159, 140, 115, 65, 46, 28, 19; MS (m/z): 341,2 (M?H)?.
Anal. calcd. for C16H24N2O4S (Mr = 340.44): C, 56.45, H,
7.11, N, 8.23. Found: C, 56.29, H, 6.91, N, 8.36.
ˇ ´
laboratory at the Rudjer Boskovic Institute.
Single crystals for diffraction experiments were pre-
pared by slow evaporation from chloroform solutions.
3,4-Ethylenedioxythiophene-2,5-dicarbonyl chloride
(2)
3,4-Ethylenedioxythiophene-2,5-di(N-
cyclopentylcarboxamide) (5)
A solution of 3,4-ethylenedioxythiophene-2,5-dicarboxylic
acid (3.03 g, 13.1 mmol), thionyl chloride (10 mL,
136.4 mmol) and dry DMF (10 mL) in dry benzene
(130 mL) was refluxed for 2.5 h. The solvent was removed
under reduced pressure to give a yellow solid, which was
co-evaporated with dry benzene. The obtained 3,4-ethyle-
nedioxythiophene-2,5-dicarbonyl chloride (3.13 g, 89.1%)
was used directly in the next step without purification.
A mixture of 3,4-ethylenedioxythiophene-2,5-dicarbonyl
chloride (2) (2.06 g, 7.75 mmol) and cyclopentylamine
(1.32 g, 15.5 mmol) in 50 mL of dry CHCl3 was stirred for
24 h at room temperature, and then was heated at 50 °C for
7 h. The solvent was removed under reduced pressure, and
the residue was suspended in the water. The crude product
was filtered off and washed with 10% HCl, 10% NaHCO3
and water. The product was recrystallised from CHCl3–
diethyl-ether to yield 1.46 g (72%) of white solid, mp
3,4-Ethylenedioxythiophene-2,5-di(N-
isopropylcarboxamide) (3)
193–194 °C; e (294 nm) = 22.95 9 103/dm3 mol-1 cm-1
;
IR (mmax./cm-1): 3329, 2951, 1627, 1491, 1450, 1367, 1303,
A mixture of 3,4-ethylenedioxythiophene-2,5-dicarbonyl
chloride (2) (0.37 g, 1.4 mmol) and isopropylamine
(0.69 g, 11.7 mmol) in 30 mL of dry CHCl3 was stirred for
24 h at room temperature. The solvent was removed under
reduced pressure, and the residue was suspended in the
water. The crude product was filtered off and washed with
10% HCl, 10% NaHCO3 and water. The product was re-
crystallised from CHCl3–diethyl-ether to yield 0.43 g
1
1086, 977, 860, 741, 668; H-NMR (d/ppm): 6.69 (d, 2H,
J = 7.14 Hz, NH), 4.43 (s, 4H, OCH2CH2O), 4.38 (m, 2H,
J = 6.96 Hz, CH), 2.08 (m, 4H, J = 6.31 Hz, CH2), 1.70
(m, 8H, J = 6.53 Hz, CH2), 1.49 (m, 4H, J = 6.17 Hz,
CH2); 13C-NMR (d/ppm): 160, 138, 118, 65, 51, 33, 23; MS
(m/z): 365,2 (M?H)?. Anal. calcd. for C18H24N2O4S 9
0.5H2O (Mr = 373.47): C, 57.89, H, 6.75, N, 7.50. Found: C,
57.98, H, 6.67, N, 7.73.
(43.6%) of white solid, mp 164–165 °C;
e
/
(292 nm) = 23.41 9 103/dm3 mol-1 cm-1
;
IR (mmax
cm-1): 3384, 2969, 1627, 1516, 1484, 1458, 1484, 1284,
1079, 863, 551; 1H-NMR (d/ppm): 6.55 (d, 2H,
J = 7.34 Hz, NH), 4.44 (s, 4H, OCH2CH2O), 4.24 (m, 2H,
J = 6.91 Hz, CH), 1.24 (d, 12H, J = 6.55 Hz, CH3); 13C-
NMR (d/ppm): 159, 138, 118, 65, 41, 22; MS (m/z): 313.1
(M?H)?. Anal. calcd. for C14H20N2O4S 9 H2O
(Mr = 330.41): C, 50.89, H, 6.71, N, 8.48. Found: C,
50.98, H, 6.71, N, 8.76.
X-ray structure determination
Single crystals suitable for diffraction experiments were
prepared by slow evaporation method from chloroform or
methanol solution. Compound 4 crystallises from chloro-
form solution as a chloroform solvate (4ꢀCHCl3) and the
crystals are rather unstable. Even data measured at 100 K
were of poor quality due to the crystal instability. Stable
123

Struct Chem (2012) 23:425–432
427
solvent-free crystals of 4 were grown from ethanol
solution.
benzene [29]. Diamide derivatives 3–6 were prepared by
amide bond formation between dichloride 2 and corre-
sponding primary amines. The structure of novel diamide
Single crystals were measured on an Oxford Xcalibur
Nova R diffractometer (microfocus Cu tube, CCD detector)
equipped with an Oxford Instruments CryoJet liquid
nitrogen cooling device. CrysAlis PRO [23] program
package was used for data reduction and multi-scan
absorption correction. The structures were solved using
SHELXS-97 [24] and refined by the full-matrix least-
squares method implemented in SHELXL-97 [24]. All
non-hydrogen atoms were refined anisotropically; hydro-
gen atoms were located from difference Fourier maps and
refined as constrained entities. Molecular geometries were
calculated using PLATON98 [25], and figures were drawn
using the programs ORTEP-3 [26] and CCDC-Mercury
[27].
1
derivatives has been confirmed by H- and 13C-NMR, IR,
UV, MS and elemental analysis.
The prepared molecules are good starting materials in
other syntheses; they are inexpensive and stable; the
reactions are fast and proceed at easily controlled condi-
tions, with good yields.
X-ray structure analysis
Single-crystal structures were determined for compounds 4
and 6 and a chloroform solvate 4ꢀCHCl3. The amide 3
crystallises as a monohydrate and its molecular structure
has been reported previously [20]. Amide 5 crystallised as
a hexahydrate, but losses quickly water exposed to air and
reliable intensity data could not be obtained.
Crystallographic data, data collection and refinement
details are listed in Table 1.
Skeletons of molecules 3 [20] and 4ꢀCHCl3 are of
approximate C2 symmetry, however, the overall molecular
symmetries are C1 due to different orientations of isopropyl
[20] and isobutyl groups (Fig. 1). The asymmetric unit of
4ꢀCHCl3 comprises two molecules (a and b) that are related
by pseudo-inversion symmetry implying conformational
enantiomeric relationship (Fig. 1). Both rings adopt a half-
chair conformation with an approximate C2 symmetry
Theoretical methods
All minima and transition states were located by geometry
optimisation on M06-2X/6-31?G(d,p) level of theory [28].
Frequencies were calculated on each optimised geometry
in order to characterise the nature of each stationary point:
minima by absence of imaginary frequencies and transition
states by single imaginary frequency. Normal mode that
corresponds to the imaginary frequency was visually
inspected in order to confirm that the optimised transition
state connects two enantiomeric conformers. The MP2/6-
311?(2d,2p) single point calculations were done at the
M06-2X/6-31?G(d,p) optimised geometries in order to
calculate energy barriers for conversion between two
enantiomeric conformers. In addition to calculation of
reaction barriers for conversion between two enantiomeric
conformers, reaction barrier for isomerisation about the
amide bonds is calculated. Reaction rates were calculated
within the transition state theory. The single point MP2/6-
311?(2d,2p)//M06-2X/6-31?G(d,p) energies and the
thermodynamical parameters, obtained from geometries
and frequencies at the M06-2X/6-31?G(d,p) level were
used in the reaction rate calculations.
˚
[Cremer–Pople parameters [30] Q = 0.472(8) A, H =
˚
130.4(10)°, U = 86(1)°; Q = 0.491(8) A, H = 48.6(9)°,
U = 266(1)°, respectively]. An isobutyl group of the
b molecule is disordered, with two positions of a methyl
group (occupancies are 60 and 40%, respectively) (Fig. 1b).
The asymmetric units of solvent free 4 and 6 comprise a
half of a molecule; the molecule is located on the crys-
tallographic twofold rotation axis and therefore has C2
symmetry (Figs. 2, 3). Dioxane rings have a C2-symmetric
half-chair conformation with Cremer–Pople parameters for
˚
4 and 6 [30] Q = 0.317(3) A, H = 50.8(4)° and U =
˚
270(4)°; Q = 0.46(1) A, H = 132(1)° and U = 90(1)°,
respectively].
The compounds presented in this study possess a C2-
molecular symmetry (either crystallographic or local)
imposed by non-planarity of dioxane rings leading to their
axial chirality (Fig. 4). The crystals are racemic since their
space groups are centrosymmetric (see ‘‘Experimental’’
section). EDOT rings of two symmetry-independent mol-
ecules in 4ꢀCHCl3 are also in an approximate enantiomeric
relation; the entire molecules are not enantiomeric due to
different orientations of isobutyl groups (Fig. 1).
Results and discussion
Chemistry
The synthesis of diamide derivatives 3–6 is outlined in
Scheme 1. The 3,4-ethylenedioxythiophene-2,5-dicarbonyl
chloride (2), a key precursor for substituted amides was
prepared from 3,4-ethylenedioxythiophene-2,5-dicarbox-
ylic acid (1) reacting with thionyl chloride and DMF in dry
The axial chirality is energetically preferred by the
minimum energy conformation of the dioxene ring being
C2-symmetric half-chair. Our in-depth study of conforma-
tions and dioxane ring (enantiomeric) disorder in 3 [20]
showed that conversion of the enantiomers is possible at
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Struct Chem (2012) 23:425–432
Table 1 Crystallographic data collection and refinement details
Compound
4
4ꢀCHCl3
6
Empirical formula
Molar mass (g mol-1
Crystal size (mm)
Crystal system
C16H24N2O4S
340.43
C17H29Cl3N2O4S
463.83
C20H16N2O4S
380.41
)
0.41 9 0.17 9 0.06
Orthorhombic
P b c n
0.40 9 0.20 9 0.06
Monoclinic
P 21/c
0.35 9 0.10 9 0.07
Monoclinic
C 2/c
Space group
˚
a (A)
10.4952(3)
8.8019(2)
19.1875(5)
90
9.3854(3)
16.2906(5)
28.7646(8)
90
17.3365(8)
11.9844(3)
9.4553(3)
90
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
Z
90
95.826(3)
90
115.067(5)
90
90
4
8
4
3
V (A )
qcalc (g cm-3
l (mm-1
˚
1772.50(8)
1.276
4375.2(2)
1.408
1779.5(1)
1.420
)
)
1.802
4.900
1.875
H range (°)
T (K)
4.61–76.25
293(2)
3.12–62.33
100(2)
5.63–76.22
293(2)
Range of h, k, l
-13 \ h \ 13
-10 \ k \ 7
-24 \ l \ 23
8,691
-10 \ h \ 8
-18 \ k \ 18
-25 \ l \ 32
13,473
-21 \ h \ 20
-14 \ k \ 13
-11 \ l \ 9
4,524
No. of reflections
Independent reflections
Observed reflections (I C 2r)
Absorption correction
1,844
6,758
1,809
1,525
5,278
1,584
Multi-scan
1.000; 0.4378
0.0437
Multi-scan
1.000; 0.5579
0.0426
Multi-scan
0.877; 0.404
0.0172
Tmin, Tmax
Rint
R (F2)
0.0454
0.1125
0.0441
Rw (F2)
0.1382
0.3293
0.1338
S (goodness-of-fit)
No. of parameters
No. of restraints
1.081
1.069
0.907
145
498
127
0
6
0
-3
)
˚
Dqmax, Dqmin (e A
0.445; -0.406
1.551; -0.874
0.216; -0.161
O
O
Intramolecular hydrogen bonds N–HꢀꢀꢀO between sec-
ondary amino group and dioxane oxygen atom are present
in all compounds (Figs. 1, 2, 3, Table 2), however, inter-
molecular hydrogen bonding is present only in 4 (Fig. 5,
Table 2). In the structures 4ꢀCHCl3 and 6, only weak C–
HꢀꢀꢀO, C–HꢀꢀꢀS and C–HꢀꢀꢀCl hydrogen bonds occurred
(Table 2).
O
O
O
O
i
ii
H
N
H
N
Cl
Cl
HOOC
COOH
S
R
R
S
S
O
O
1
O
O
;
2
3-6
;
;
5 R =
4 R =
6 R =
3 R =
Scheme 1 Reagents (i) SOCl2, DMF, benzene, (ii) R–NH2, CHCl3
Conversion of conformers
room temperature. While variable temperature X-ray dif-
fraction indicates that the disorder is static (i.e. there is no
conversion at room temperature), DFT calculation revealed
that the energy barrier is 8.0 kcal mol-1, which is sub-
stantially higher than kT at 293 K [20] but not high enough
to prevent conversion in solution.
The quantum-chemical calculations determined the mech-
anism as well as the energy barrier (Scheme 2) for inter-
conversion of the enantiomers. For the chiral confomers,
transitional states are achiral, having a Cs symmetry (di-
oxene ring is in a boat-conformation).
123

Struct Chem (2012) 23:425–432
429
Fig. 1 The molecular structure
of the two symmetry-
independent amide molecules of
4ꢀCHCl3. Displacement
ellipsoids are drawn at the
probability of 50%, and
hydrogen atoms are depicted as
spheres of arbitrary radii.
Molecules a and b of the
asymmetric unit are
approximate conformational
enantiomers. A methyl group of
an isobutyl moiety (bound to
N2b) is disordered over two
positions (C16b and C17b).
Intramolecular hydrogen bonds
are shown by dashed lines
Fig. 2 The molecular structure of the solvent-free amide 4. Dis-
placement ellipsoids are drawn at the probability of 50%, and
hydrogen atoms are depicted as spheres of arbitrary radii. The
molecule reveals the crystallographic C2 symmetry. Intramolecular
hydrogen bonds are shown by dashed lines
Fig. 4 Two symmetry-dependent (related by a glide plane) mole-
cules of 4 showing an enantiomeric relationship. A crystallographic
twofold rotation axis passes through a midpoint of an EDOT ring,
perpendicular to the plane of the drawing
The conformers and transition states obtained by the
DFT calculations are in agreement with the conformations
of the six-membered ring involving the double bond [31–
34]. The compounds 3–6 lack an explicit double bond,
however, the conjugation between the double bonds in the
Fig. 3 The molecular structure of the amide 6. Displacement
ellipsoids are drawn at the probability of 50%, and hydrogen atoms
are depicted as spheres of arbitrary radii. The molecule reveals the
crystallographic C2 symmetry. Intramolecular hydrogen bonds are
shown as dashed lines
123

430
Struct Chem (2012) 23:425–432
Table 2 Geometric parameters of the hydrogen bonds
˚
d(D-H) (A)
˚
˚
d(HꢀꢀꢀA) (A)
d(DꢀꢀꢀA) (A)
(D-HꢀꢀꢀA) (°)
Symm. op. on A
4ꢀCHCl3
N1A–H1AꢀꢀꢀO3A
N1B–H1BꢀꢀꢀO3B
N2A–H2AꢀꢀꢀO4A
N2B–H2BꢀꢀꢀO4B
C7A–H7AꢀꢀꢀO2B
C7A–H7BꢀꢀꢀS1A
C7A–H7BꢀꢀꢀO2A
C7B–H7Cꢀꢀꢀ2A
C7B–H7DꢀꢀꢀS1B
C7B–H7DꢀꢀꢀO1B
C8A–H8BꢀꢀꢀO1B
4
0.86
0.86
0.86
0.86
0.97
0.97
0.97
0.97
0.97
0.97
0.97
2.13
2.13
2.22
2.22
2.51
2.81
2.51
2.51
2.80
2.58
2.59
2.826(8)
2.822(8)
2.887(8)
2.893(8)
3.31(1)
3.543(8)
3.44(1)
3.31(1)
3.55(7)
3.503(9)
3.43(1)
138
137
135
135
139
133
160
140
134
159
144
x, y, z
x, y, z
x, y, z
x, y, z
x, y, z
-1 - x, -1/2 ? y, ‘ - z
-1 - x, -1/2 ? y, ‘ - z
1 ? x, y, z
-x, ‘ ? y, ‘ - z
-x, ‘ ? y, ‘ - z
-1 ? x, y, z
N1–H1ꢀꢀꢀO2
N1–H1ꢀꢀꢀO1
0.90(3)
0.90(3)
2.35(2)
2.06(2)
2.970(2)
2.813(2)
126(2)
140(2)
x, y, z
3/2 - x, -1/2 ? y, z
6
N1–H1ꢀꢀꢀO2
C7–H7ꢀꢀꢀO1
0.80(9)
0.93
2.1(1)
2.53
2.92(1)
3.46(2)
150(10)
175
x, y, z
‘ - x, ‘ - y, 1 - z
Scheme 2 Mechanism for conversion between the enantiomeric
forms of the EDOT
Table 3 Energy barriers (DE) and rate constants (k) at room tem-
perature (298 K) for interconversion between two enantiomeric
conformers for the series of compounds 3–6
Fig. 5 Crystal packing of 4. The molecules form hydrogen bonded
layers parallel to (001). Symmetry operator: (i) 3/2 - x, -1/2 ? y, z
Compd.
3
4
5
6
thiophene ring contributes to a partial double bond char-
acter of the ring junction C–C bond of the dioxane ring.
The extended conjugation affects the flexibility of dioxane
ring as already observed in the example of 1,4-dioxene and
1,4-benzodioxene [33]. This reduced flexibility of dioxane
DE (kcal mol-1
)
7.96
7.78
8.07
7.92
k (s-1
)
1.4 9 107 5.5 9 107 6.6 9 106 2.1 9 107
Energies are calculated at MP2/6-311?(2d,2p)//M06-2X/6-
31?G(d,p) level of theory and corrected for zero-point energies,
calculated at M06-2X/6-31?G(d,p)
123

Struct Chem (2012) 23:425–432
431
Scheme 3 Conformations of
the compounds 3–6 that are
result of the amide bond
isomerisation
Table 4 Energy barriers (kcal mol-1) for amide bond isomerisation
Compound
Reaction barriers (DE, kcal mol-1
)
a ? c
c ? a
c ? e
e ? c
c ? d
d ? c
e ? d
d ? e
3
4
5
6
19.97
21.9
14.57
17.09
14.07
15.03
20.45
19.19
19.88
17.07
14.49
14.41
15.12
15.01
20.4
13.98
13.88
13.8
3.92
6.37
4.66
6.41
3.45
5.77
3.3
19.26
19.91
11.64
19.66
16.63
10.01
6.85
Energies are calculated at MP2/6-311?(2d,2p)//M06-2X/6-31?G(d,p) level of theory and corrected for zero-point energies, calculated at M06-
2X/6-31?G(d,p)
ring together with the eclipsed-hydrogen atoms of the CH2
groups contribute to the occurrence of barrier between the
two twisted structures (energy minima) [32]. The calcu-
lated reaction rates, for the interconversion of the con-
formers indicate that the reactions are very fast at room
temperature. The chiral sample would be effectively race-
mised in less than a microsecond (Table 3).
The chirality of the dioxane ring makes these two (c, c0)
conformations inequivalent. The rotation of second amide
bond makes four s-cis/s-cis conformers; two with C2 sym-
metry (e) and two with C1 symmetry (d). The energy barriers
(Table 4) for the amide bond isomerisation are significantly
higher that the barriers for dioxane ring twisting. Therefore,
at room temperature the isomerisations around amide bonds
are orders of magnitude slower than the isomerisation of
dioxane ring.
The amide bond isomerisation leads to the several new
conformers (Scheme 3). The experimentally observed
conformers (a) are energetically favourable s-trans/s-trans.
The large steric repulsions prevent the amide bond in the s-
cis conformation to become planar.
Conclusions
The studied compounds reveal axial chirality. They crys-
tallise in centrosymmetric space groups where axially
Therefore, two s-cis/s-trans conformations (c) can be
accomplished by the rotation around the single amide bond.
123

432
Struct Chem (2012) 23:425–432
´
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6. Stolic I, Miskovic K, Piantanida I, Baus-Loncar M, Glavas-
´
chiral enatiomers are related by symmetry operations that
allow enantiomeric relationship. The conversion between
the chiral enantiomers occurs across the two achiral tran-
sition states. The interconversion of axial enantiomers is
hindered in crystals, whereas very fast exchanges are
possible in a solution at room temperature. Data obtained
from DFT calculations reveal that in the case of each
studied compound, isomerisation of amide bond and
twisting of dioxane ring results in the formation of series of
conformers of which the s-trans/s-trans is energetically
most favourable.
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Supplementary crystallographic data for this article can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: ?44-1223-336033; or deposit@ccdc.cam.ac.uk).
CCDC 804828–804830 contain the supplementary crys-
tallographic data for this article.
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