Structure, thermal and spectral study of 16α,17-epoxypregn-4-ene-3, 11,20-trione monohydate

Article abstract of DOI:10.1016/j.molstruc.2005.06.013

16α,17-epoxypregn-4-ene-3,11,20-trione is an important steroid intermediate in synthesis of many hormone pharmaceuticals, such as cortisone acetate and betamethason. It does not dissolve in water, but the single crystals grown from acetone with some water shows evident hydration behavior. The thermal analyses by DSC and TG-DTA and the IR spectra characterization of the anhydrous and hydrous crystals were performed and compared. The hydrate was also proved by IR spectral and thermal analyses. Single crystal structure of the hydrate indicates one water molecule per host molecule is included into the host lattice. The incorporation of water molecules does not change the crystal cell dimensions significantly, except for some increment of the cell along the axis b. In the crystal cell, two steroid molecules are linked through the water molecules as a bridge by forming two different hydrogen bonds. The incorporation of one water molecule makes some conformation changes of the molecules in the crystal unit cell.

Full text of DOI:10.1016/j.molstruc.2005.06.013

Journal of Molecular Structure 752 (2005) 186–191
www.elsevier.com/locate/molstruc
Structure, thermal and spectral study of 16a,17-epoxypregn-4-ene-3,11,
0-trione monohydate
2
Qiang Nie, JingKang Wang
*
School of Chemical Engineering and Technology, Tianjin University, 92 Weijin Road, Tianjin, People’s Republic of China
Received 20 May 2005; revised 3 June 2005; accepted 3 June 2005
Available online 20 July 2005
Abstract
6a,17-epoxypregn-4-ene-3,11,20-trione is an important steroid intermediate in synthesis of many hormone pharmaceuticals, such as
1
cortisone acetate and betamethason. It does not dissolve in water, but the single crystals grown from acetone with some water shows evident
hydration behavior. The thermal analyses by DSC and TG-DTA and the IR spectra characterization of the anhydrous and hydrous crystals
were performed and compared. The hydrate was also proved by IR spectral and thermal analyses. Single crystal structure of the hydrate
indicates one water molecule per host molecule is included into the host lattice. The incorporation of water molecules does not change the
crystal cell dimensions significantly, except for some increment of the cell along the axis b. In the crystal cell, two steroid molecules are
linked through the water molecules as a bridge by forming two different hydrogen bonds. The incorporation of one water molecule makes
some conformation changes of the molecules in the crystal unit cell.
q 2005 Elsevier B.V. All rights reserved.
Keywords: Crystal structure; 16a,17-epoxypregn-4-ene-3,11,20-trione; X-ray diffraction; FTIR spectra; Thermal analysis
1
. Introduction
6a,17-epoxypregn-4-ene-3,11,20-trione (in this paper,
peak before melting. At the first, the polymophic trans-
formation was considered, as the solvate between the
acetone and title compound was unreasonable due to the
lack of the hydrogen-bond donor in both two molecules.
This inspires our interest to further investigation.
1
it is titled as compound (1), see Fig. 1) is an important
steroid intermediate in synthesis of many hormone
pharmaceuticals, such as cortisone acetate and betametha-
son [1]. It was first prepared from 11a-hydroxy-16a,17-
epoxyprogesterone by oxidation with chromium trioxide by
Peterson et al. [2]. The anhydrous single crystal structure of
the title compound has been reported in our previous work
In this paper, the single crystal of the hydrate of
compound (1) was grown and characterized using single
crystal X-ray diffraction, Fourier Transform Infrared
Spectroscopy (FTIR) and thermal analysis technology
(DSC and TG-DTA). The comparison between the hydrous
and anhydrous crystals of compound (1) was also
performed. The experimental results make certain that one
water molecule per host molecule is incorporated into the
unit cell. The cell dimension change slightly when the water
molecule is incorporated, with some increment along crystal
axis b. Along the b direction, the molecules of the host
molecules are linked by the water molecule through two
different hydrogen bonds, forming the hydrogen-bond
bridge. This leads to different crystal packing modes and
to different hydrogen bonding schemes. The water
molecules distributes between the crossed layers and not
easy to escape from the lattice. So the hydrate of the
compound (1) is stable at ambient conditions, and DSC
[
3]. The anhydrous single crystal was grown from chloro-
form–methanol mixture. The crystal structure shows the
compound (1) crystallizes in orthorhombic P2 2 2 space
1
1 1
group. No evident hydrogen bond was observed due to the
lack of the hydrogen-bond donor (HBD) in the molecule of
the compound (1). But when the crystals are grown from its
acetone solution with some water, the single crystals show
some solvation behavior. This behavior was first observed
when the DSC thermogram shows an evident endothermal
*
Corresponding author. Tel.: C86 22 27405754; fax: C86 22 27374971.
E-mail address: srcict_tju@yahoo.com.cn (J.K. Wang).
0022-2860/$ - see front matter q 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2005.06.013

Q. Nie, J.K. Wang / Journal of Molecular Structure 752 (2005) 186–191
187
maps and refined isotropically. All other hydrogen atoms
were located in geometric positions and included with a
riding model. Atomic scattering factors were taken from the
International tables for Crystallography [6]. Bruker SHELXTL
was used to prepare molecular graphics.
2.3. Differential scanning calorimetry (DSC)
and TG-DTA thermal analysis
DSC curves of the samples (4 mg) were recorded by a
thermal analysis system (NETZSCH DSC 204, Germany).
Following calibration with indium and lead as standards,
about 5 mg samples were heated at 10 K/min in aluminum
pans under a nitrogen atmosphere.
Fig. 1. The chemical structure of 16a,17-epoxypregn-4-ene-3,11,20-trione,
compound (1).
A Rigaku thermal gravimetric analyzer (TG-DTA) was
used to calculate percentage weight changes. About 4.8 mg
of the sample was weighted into a platinum pan and heated
from 300 to 800 K at a rate of 10 K/min, under a static
nitrogen atmosphere.
thermal analysis indicates the hydrate decomposes at
about 420 K.
2
. Experimental
2.4. Infrared spectral analysis
2
.1. Materials and preparation of single crystal
Fourier transform infrared (FTIR) spectra were recorded
K1
1
6a,17-epoxypregn-4-ene-3,11,20-trione, C H 0 ,
26 4
in the range 400–4000 cm
K1
using a Nicolet 560 IR
spectrophotometer (4 cm resolution) with reference to a
potassium bromide pellet.
2
1
was prepared in our laboratory by oxidation 11a-
hydroxy-16a,17-epoxyprogesterone (provided by Tianjin
Tianyao Pharmaceutical Co. Ltd, China). The latter
samples was dissolved in pyridine and treated with
chromium trioxide at room temperature overnight. The
product was chromatographed on silica gel and recrys-
tallized from acetone–hexane three times. The melting
point determined by Differential Scanning Calorimeter
3. Characterization
3.1. Single crystal structure analysis
(
determined by HPLC.
DSC) is 465.5 K, its purity is better than 99.0%,
The structure of the anhydrous crystals of the compound
(1) has been reported in our previous study [3]. The
compound has a typical steroid conformation with three
six-membered rings and one five-membered ring denoted A,
B, C and D, respectively. Ring A has a 1a-sofa
conformation, and rings B and C are in nearly perfect
chair conformations. The presence of the three-membered
ring constrains the five-membered D ring to have a 14a-
envelope conformation as described by Goubitz et al. [7].
The carbonyl group on C20 nearly eclipses the C13–C17
bond. The C13–C17–C20–O4 torsion angle is 7.4(4)8.
The overall conformation is similar to the parent molecule
11a-hydroxy-16a,17-epoxyprogesterone [8]. The title com-
pound crystallizes in the orthorhombic space group P2 2 2 ,
Colorless rhombic plate single crystals suitable for
X-ray diffraction were obtained by slow natural evapor-
ation of solution in acetone (with some water) at room
temperature. The acetone was purchased from Tianjin
Chemical Reagent Co., China, analytical grade, without
any treatment.
2
.2. Crystal structure determination and refinement
A suitable colorless crystal of compound (1) monohydrate
was mounted on a glass fiber. All measurements were made
on a Rigaku R-axis RAPID IP Area Detector diffractometer
with graphite monochromated Mo Ka radiation. The data
were collected at a temperature of 293(2) K to a maximum 2q
value of 54.968. 18,441 reflections were collected with the
index ranges K9!h!9, K12!k!12, K31!k!32. An
empirical absorption correction was applied.
1
1 1
similar to 11a-hydroxy-16a,17-epoxyprogesterone.
A summary of crystallographic data, experimental details
and refinement results for the hydrate of compound (1) are
given in Table 1. And the fractional atomic coordinates and
equivalent isotropic displacement coefficients are listed in
Table 2. The molecular structure of 16a,17-epoxypregn-4-
ene-3,11,20-trione as observed in the crystal structure of its
hydrate, is shown in Fig. 2. The molecular structure of the
hydrous crystal of compound (1) is similar with its
anhydrous crystal. But the incorporation of water modified
The structure was solved by direct-methods using
SHELXS-97 [4] and anisotropic displacement parameters
were applied to non-hydrogen atoms in a full-matrix least-
2
squares refinement based on F using SHELXL-97 [5].
Hydrogen atoms of water were obtained from different

188
Q. Nie, J.K. Wang / Journal of Molecular Structure 752 (2005) 186–191
Table 1
Basic crystallographic data, data collection and refinement parameters
Table 2
Atomic coordinates and equivalent isotropic displacement coefficients Ueq
Ã
Ã
for compound (1) Ueq Zð1=3Þ S i S jU a a a a
ij
i
j
i
j
Empirical formula
C
21
H
26O4 H
˚
2
O
x
y
z
U
eq
a
7.530(1) A
˚
9.853(2) A
b
C1
0.0182(2) K0.0440(2) K0.09705(7) 0.0438(3)
˚
25.276(5) A
˚
1875.4(7) A
c
C2
K0.0042(2) K0.0494(2) K0.15692(7) 0.0499(4)
K0.1665(3) K0.1248(2) K0.17230(7) 0.0552(4)
K0.3159(2) K0.1181(2) K0.13611(7) 0.0526(4)
K0.3127(2) K0.0536(2) K0.08987(6) 0.0418(3)
K0.4797(2) K0.0377(2) K0.05840(7) 0.0528(4)
K0.4552(2) K0.0785(2) K0.00065(7) 0.0499(4)
3
V
C3
Z
4
C4
K3
D (calc)
1.277 Mg m
C5
Crystal system
Space group
Orthorhombic
P212121
C6
C7
Formula Weight
m(Mo Ka)
F(000)
360.43
C8
K0.3016(2) K0.0033(2)
K0.1311(2) K0.0283(1) K0.00802(6) 0.0358(3)
0.02518(6) 0.0393(3)
K1
0.090 mm
C9
776
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
O1
K0.1450(2)
0.0349(2)
0.0118(1) K0.06754(6) 0.0374(3)
Crystal dimensions
Diffractometer and radiation
used
0.65!0.4!0.35 mm
Rigaku R-axis Rapid diffractometer
0.0246(2)
0.02035(7) 0.0429(3)
0.07701(7) 0.0481(4)
0.10853(6) 0.0430(3)
0.08078(6) 0.0400(3)
0.12278(7) 0.0489(4)
0.17283(7) 0.0524(4)
0.16422(7) 0.0478(4)
0.20740(8) 0.0643(5)
0.25764(9) 0.0782(7)
0.0582(2) K0.0204(2)
K0.1100(2) 0.0121(2)
˚
Mo Ka radiation, lZ0.71073 A
Scan technique
Range of h, k and l
Total number of reflections
measured
Oscillation scans
K9/9, K12/12, K31/32
18441
K0.2682(2) K0.0553(2)
K0.4155(2) K0.0526(2)
K0.3128(3) K0.0810(2)
K0.1233(2) K0.0467(2)
0.0047(3) K0.0131(2)
K0.0044(4) K0.0913(3)
q range
3.15–27.488
4288(0.0290)
No. of independent reflections
(Rint)
K0.1604(3)
K0.1340(3)
0.1667(2) K0.07546(8) 0.0530(4)
0.1675(2) 0.11294(8) 0.0565(4)
No. of observed reflections
Criterion for observed reflec-
tions
3729
IO2s(I)
K0.1807(3) K0.1837(2) K0.21459(7) 0.0980(7)
0.1436(2) 0.0964(1) K0.00074(5) 0.0597(4)
K0.1831(2) K0.1868(1)
0.1170(3) 0.0718(2)
O2
Absorption correction
Refinement method
Function minimized
Empirical
O3
0.16604(5) 0.0536(3)
0.19900(8) 0.1019(7)
2
Full-matrix least-squares on F
2
O4
2
o
2
uZ1½s ðF ÞCð0:0819PÞ C0:1533Pꢀ
O1W
0.0640(4) K0.2293(3) K0.29449(9) 0.0884(9)
2
o
2
c
Where PZðF C2F Þ=3
Parameters refined
Value of R
244
0.0411
0.11945
0.991
the compound (1), respectively. The hydrogen bonding
information in the crystal packing is given in Table 4.
The two hydrogen bonding are not in same strength, as is
presented in Table 4, for O1W–H2W/O1 hydrogen
bond, the D–H distance is 0.85(4) and H/A distance
Value of wR
2
Goodness-of-fit on F
3
˚
0.158, K0.211 A
Max. and min. heights in final
Dr map
Source of atomic scattering
factors
International tables for crystallography
(Vol. C)
˚
Programs used
SHELXS-97, SHELXL-97, Bruker SHELXTL
is 1.92(4) A, while in the hydrogen bonding of
O1W–H1W/O4, the D–H distance is 0.68(4) and
˚
H/A distance is 2.23(4) A. The total hydrogen bond
˚
length of O1W–H2W/O1 (2.771(3) A) is shorter than
the packing of the molecules. So this paper is focus on the
change of the arrangement and packing of the steroid
molecules in the unit cell when the water molecule
incorporates into the unit cell. The comparison of basic
crystal structure data of hydrous and anhydrous crystal of
compound (1) are listed in Table 3.
˚
that of the O1W–H1W/O4 (2.865(3) A). The angle of
O1W–H2W/O1 is 175(3)8, which is more closed to
808 compares with that of O1W–H1W/O4 (155(4)8).
1
This indicates the hydrogen bonding of O1W–H2W/O1
has more strength. This may be explained by discussing
the electronegativity of the hydrogen bond acceptors.
There is a double bond –C]C– at the adjacent position
of the carbonyl –C(4)]O(1), owing to the p-electron
conjugation effect, the oxygen atom O1 has more
electronegativity, so the interaction between O1 and
H2w is more strong and more stable.
The crystal packing of compound (1) is shown in Fig. 3
in a projection along the orthorhombic axis y. The steroid
molecules are oriented roughly parallel to the ac plane, thus
forming a layer-type packing. This is also can be seen from
Fig. 4. The water molecules are incorporated in such a way
that they form hydrogen bond bridges between pairs of
steroid molecules. There are no direct contacts between
these steroid molecules, so the contact between the adjacent
steroids molecules along c direction is entirely due to
solvent-mediated hydrogen bonds.
The water molecules are trapped in interstitial voids,
and are not free to leave. So the hydrate is stable at
room temperature. Except the hydrogen bonding along
the z direction, the main interaction between the steroid
molecules are Van de walls forces. Along the x direction,
the steroid molecules, as well as the water molecules,
forms a zigzag chain in the crystal, as is shown in Fig. 5.
The two hydrogen atoms of the water can form two
different hydrogen bonds with the O1 of one steroid
molecule and O4 of another steroid molecule of

Q. Nie, J.K. Wang / Journal of Molecular Structure 752 (2005) 186–191
189
Fig. 2. Molecular structure of compound (1) as observed in the crystal structure. Displacement ellipsoids are drawn at 30% probability level.
Table 3
Comparison of basic crystal structure data of hydrous and anhydrous crystal of compound (1)
Hydrous crystal of compound (1)
Anhydrous crystal of compound (1)
orthorhombic
˚
7.536(1) A
Crystal system
Orthorhombic
˚
7.530(1) A
a
˚
9.853(2) A
˚
9.900(2) A
b
˚
˚
c
25.276(5) A
23.288(4) A
3
˚
3
˚
V
1875.4(7) A
1737.6(5) A
Z
4
4
K3
K3
Crystal density
1.277 mg m
1.309 mg m
Fig. 3. The molecular packing of the hydrate of the compound (1), view along a axis. The dash line indicates the hydrogen bond.
3
.2. Spectral characteristics
The resulting spectrum is shown in Fig. 6. From the two IR
spectra, it can be seen that the spectra of the anhydrous and
the hydrous crystal of compound (1) are quite similar
The FTIR spectral analyses of compound (1) and its
K1
K1
hydrate were carried out between 4000 and 400 cm
.
below the wavelength at 3400 cm . The strong absorption
Fig. 4. The molecular packing of the hydrate of compound (1), along the b axis.

190
Q. Nie, J.K. Wang / Journal of Molecular Structure 752 (2005) 186–191
Table 4
Hydrogen bonding geometry for 16a,17-epoxypregn-4-ene-3,11,20-trione
˚
monohydrate (A, 8)
anhydrous
crystal
D–H/A
D–H
H/A
D/A
D–H/A
O1W–
0.85(4)
1.92(4)
2.771(3)
175(3)
hydrous
crystals
H2W/O1
O1W–
0.68(4)
2.23(4)
2.865(3)
155(4)
i
H1W/O4
Symmetry codes: (i) 1/2Kx, Ky, zK1/2
K1
at the 1670 and 1704 cm , indicates the existence of the
carbonyl group. There are three carbonyl functions in
the steroid molecules, but only two different absorption
peaks are observed. The 11-C]O and 20-C]O may
4000
3500
3000
2500
2000
1500
1000
500
Wavenumbers
Fig. 6. The FTIR spectra of the anhydrous and hydrous crystals of
compound (1).
be overlapped and represent only one absorption at
1
K1
704 cm , while the absorption of 3-C]O occurs at
K1
670 cm , due to the effect the adjacent C]C double
1
bond. And the middle strong absorption at 1613 cm
3
.3. Thermal analysis
K1
is
due to this double –C]C– at 4 position of the steroid
The DSC curves of both the anhydrous and hydrous
skeleton. A series of sharp absorption bands at 2948, 2916,
K1
crystals of the compound (1) are shown in Fig. 7. The DSC
curves of anhydrous crystals shows only one endothermal
peak in the temperature range 458–468 K, indicating a
melting behavior. The DSC curve of the hydrate crystals
shows two endothermal peaks, the first is in the temperature
range of 425–435 K and the second in the range of
2
methyl and methylene.
974, 2889 cm
characterize the –C–H vibration of
The biggest difference between the anhydrous and
hydrous crystals lies in the absorption between 3600 and
K1
3
hydrous crystals show a split and middle strong absorption
200 cm
of the wave number. The IR spectrum of the
4
58–468 K, which indicate the dehydration and melting,
K1
bands between 3200 and 3600 cm , i.e. at 3581, 3452 and
respectively. As the temperature of dehydration is some
high to 433 K, both two forms are stable in the air at room
temperature and begin to melt when the temperature up to
about 460 K.
K1
400 cm , which are the characteristic absorption of
3
n(OH) vibrations originating from the lattice water in the
crystal of the compound (1) [9]. We also found an
K1
absorption at 3400 cm in the spectrum of the anhydrous
Further study for the hydrate of compound (1) was
performed by using TG-DTA from a temperature of 300 K
up to 780 K. The TG-DTA curves are presented in Fig. 8,
two endothermal peaks are observed in the DTA curve of
the hydrate crystals in the range of 420–435 and 458–468 K,
respectively, which in accord with the results of the DSC
determination. The TG curve (the upper curve in the Fig. 8)
has a sharp decrease at the temperature of about 423 K,
indicating a weight loss. The experimental mass loss value
of 5.6% is in agreement with the calculated value 5.0% base
crystal, this may be owing to the minor water was captured
into the anhydrous crystals of the compound.
5
4
3
hydrous crystals
2
anhydrous crystals
1
0
360
380
400
420
440
460
480
500
520
Temperature/K
Fig. 5. The molecular packing of the hydrate of compound (1), along the c
axis.
Fig. 7. DSC curves of the anhydrous and hydrous compound (1).

Q. Nie, J.K. Wang / Journal of Molecular Structure 752 (2005) 186–191
191
2
0
2
4
6
2
agreement with the calculated value 5.0% weight loss based
on the dehydration of one water molecule.
The incorporation of water molecules does not change
the crystal cell dimensions significantly, only results in
some increment of the cell dimension along the axis b. In the
crystal cell, two steroids molecules are linked through the
water molecules by forming two different hydrogen-bonds.
The role which the water molecule plays is just as a ‘bridge’.
TG
422K-448K −0.27mg(−5.6%)
0
−
−
−
−2
−2.35mg(−48.9%)
DTA
−4
−6
Acknowledgements
300
400
500
600
700
800
Temperature/K
One of the authors (Q. Nie) acknowledges the supports
from The State Research Center of Industrialization for
Crystallization Technology (SRCICT) of Tianjin University
and partial materials afforded by Tianjin Tianyao Pharma-
ceutical Co. Ltd. And special thanks to Dr Ma, Institute of
Chemistry Chinese Academy of Science for his help and
some valuable discussion.
Fig. 8. TG-DTA curves of the hydrous compound (1).
on the hypothesis of dehydration of one water molecule.
The DTA curve and the TG curve together proved the
dehydration behavior at about 423 K. The DTA determi-
nation also shows the compound (1) began to decompose
when the temperature over 470 K.
References
4
. Conclusion
[
[
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determination indicates that one water molecule per host
molecule is incorporated into the host lattice. The IR
spectral of the hydrate represents evident absorption in
[
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loss in the temperature range 420–450 K, which is in
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[
[
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