Crystal structures of 3β,19-dihydroxyandrost-5-en-17-one, 5, and its monohydrate, [(5).H2O]: A survey of the structures of related di- and tri-substituted hydroxy derivatives and their solvated compounds

Article abstract of DOI:10.1016/j.steroids.2020.108624

The crystal structures of 3β,19-dihydroxyandrost-5-en-17-one, 5, and its monohydrate, [((5).H₂O]], are reported. The monohydrate, isolated from a solution of 5 in 50% aqueous methanol, recrystallizes in the orthorhombic space group, P2₁2₁2₁, while that of the anhydrous compound, isolated from solutions of THF, Me₂CO, EtOAc or dry MeOH, recrystallizes in the monoclinic space group, P2₁. Apart from the different orientation of the 3-HO group, the conformations of the steroid molecules in 5 and [(5).H₂O]: are similar. The two-dimensional structure of 5 consists of sheets of molecules formed from strong classical O3—H3?O19_(OH) and O19—H19···O3_(OH), augmented by weaker C—H?O hydrogen bonds. Noticeably the presence of the C19 hydroxyl group results in the replacement of the O3—H3?O17_(one) hydrogen bonds as the strongest intermolecular interaction found in the stable polymorphs of the mono-hydroxylated compound, 3β-hydroxyandrost-5-en-17-one (dehydroepiandrosterone). An additional structural difference between 3β-hydroxyandrost-5-en-17-one and 3β,19-dihydroxyandrost-5-en-17-one is that the steroid molecules are most strongly linked head-to-tail in the former but head-to-middle fashion in the latter. In the three dimensional structure of [((5).H₂O]], each steroid molecule is directly connected to another by a O19—H19?O3_(OH) hydrogen bond and indirectly to two others via the water molecule. Each water molecule forms three hydrogen bonds, namely O3—H3?Ow, Ow—Hw1?O17 and Ow—Hw2?O19. As found for most hydrated steroids, the hydrate molecules have strong influences on the structure. In addition to the reporting of the crystal structures of 5 and [(5).H₂O], we report on a survey of the crystal structures of related di- and tri- hydroxy-17-one derivatives as well as solvated compounds.

Full text of DOI:10.1016/j.steroids.2020.108624

Steroids159(2020)108624
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Crystal structures of 3β,19-dihydroxyandrost-5-en-17-one, 5, and its
monohydrate, [(5).H2O]: A survey of the structures of related di- and tri-
substituted hydroxy derivatives and their solvated compounds
Solange M.S.V. Wardella, James L. Wardellb,⁎
a CHEMSOL, 1 Harcourt Road, Aberdeen AB15 5NY, United Kingdom
b Department of Chemistry, University of Aberdeen, Old Aberdeen, AB 24 3UE, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Keywords:
The crystal structures of 3β,19-dihydroxyandrost-5-en-17-one, 5, and its monohydrate, [((5).H2O]], are re-
ported. The monohydrate, isolated from a solution of 5 in 50% aqueous methanol, recrystallizes in the orthor-
hombic space group, P212121, while that of the anhydrous compound, isolated from solutions of THF, Me2CO,
EtOAc or dry MeOH, recrystallizes in the monoclinic space group, P21. Apart from the different orientation of the
3-HO group, the conformations of the steroid molecules in 5 and [(5).H2O]: are similar. The two-dimensional
3-hydroxyandrostan-17-one derivatives
Crystal structures
Solvates
structure of
5 consists of sheets of molecules formed from strong classical O3—H3⋯O19(OH) and
O19—H19···O3(OH), augmented by weaker C—H⋯O hydrogen bonds. Noticeably the presence of the C19 hy-
droxyl group results in the replacement of the O3—H3⋯O17(one) hydrogen bonds as the strongest intermolecular
interaction found in the stable polymorphs of the mono-hydroxylated compound, 3β-hydroxyandrost-5-en-17-
one (dehydroepiandrosterone). An additional structural difference between 3β-hydroxyandrost-5-en-17-one and
3β,19-dihydroxyandrost-5-en-17-one is that the steroid molecules are most strongly linked head-to-tail in the
former but head-to-middle fashion in the latter. In the three dimensional structure of [((5).H2O]], each steroid
molecule is directly connected to another by a O19—H19⋯O3(OH) hydrogen bond and indirectly to two others
via the water molecule. Each water molecule forms three hydrogen bonds, namely O3—H3⋯Ow,
Ow—Hw1⋯O17 and Ow—Hw2⋯O19. As found for most hydrated steroids, the hydrate molecules have strong
influences on the structure.
In addition to the reporting of the crystal structures of 5 and [(5).H2O], we report on a survey of the crystal
structures of related di- and tri- hydroxy-17-one derivatives as well as solvated compounds.
1. Introduction
examples being 3α-hydroxy-5α-androstan-17-one (androsterone), 1,
[3–5], 3β-hydroxy-5α-androstan-17-one (epiandrosterone), 2, [6,7],
Four-ringed steroid molecules, such as androstane and its deriva-
tives, with distinct head and tail portions can take part in packing in the
solid state with head-to-tail, head-to-head or tail to tail arrangements.
The formation of such arrangements depend greatly on the substituents
and their position in the steroid [1,2]. Hydroxy and ketonic substituents
are found in many steroids and have very important influences on
structures, as well as properties. The crystal structures of many steroid
molecules, including those with 5α- and 5β- androstanyl and similar
cores having a hydroxyl group on C3 (the head) and a carbonyl group
on C17 (the tail) have been reported. For such steroidal molecules
3β-hydroxy-androst-5-en-17-one
(dehydroepiandrosterone,
pras-
terone), 3 [8–14] and 3-hydroxyestra-1,3,5(10)-trien-17-one (estrone),
4, [15–18], see Table 1. A list of other such ‘’parent’’ compounds is
provided in Table 1 [19–23]. Considering the different molecular con-
formations of the compounds in Table 1, it is not surprising that the
chains formed by the O3—H3⋯O17 classical hydrogen bonds can differ
in regards to orientations of adjacent molecules within the head-to-tail
linked chains, e.g., see Fig. 1, as well as in the different links between
the O3—H3⋯O17 hydrogen bonded chains, for example by weaker
intermolecular interactions, such as C—H⋯O interactions. Even for the
same compound, such differences can arise and result in polymorphic
forms, as shown by compounds, 1, 3 and 4, see Table 1. While all
polymorphs of compounds 1 and 4 exhibit these O3—H3⋯O17(one)
having
just
3-hydroxy
and
17-one
substituents,
strong
O3—H3⋯O17(one) classical hydrogen bonding arrangements and con-
sequently head-to-tail packing of molecules in chains, are the norm,
⁎ Corresponding author.
E-mail address: j.wardell@abdn.ac.uk (J.L. Wardell).
https://doi.org/10.1016/j.steroids.2020.108624
Received 30 October 2019; Received in revised form 1 March 2020; Accepted 2 March 2020
Availableonline07March2020
0039-128X/©2020ElsevierInc.Allrightsreserved.

S.M.S.V. Wardell and J.L. Wardell
Steroids159(2020)108624
Table 1
Complete structural reports of steroids with just 3-HO and 17-one substituents listed in the CCDC data base.
COMPOUND
NAME
MAJOR INTERACTION
O3—H3⋯O17
CCDC CODES AND [REFERENCE]
ANDOON04: 261,296 [3]
ANDOON06: 293,345 [4], see also
ANDOON: 1,102,938 [5]
O
3α-hydroxy-5α-androstan-17-one
(Androsterone), 1
O
H
3β-Hydroxy-5α-androstan-17-one
(Epiandrosterone), 2
O3—H3⋯O17
ANDRON10: 1,102,946 [6]; ANDRON11: 185,105 [7] {the same
structure)
O
O
H
H
3β-Hydroxy-5-androsten-17-one,
(Dehydroepiandrosterone) 3
O3—H3⋯O17
O3—H3⋯O17/ O3—H3⋯O3
O3—H3···O3
ZOYMOP:1315759 [8]; ZOYMOP03:1019367 [9]
ZOYMOP01:1315760 [10]; ZOYMOP08:1019368 [11]
ZOYMOP02:608307 [12]; ZOYMOP04:1019369 [13]];
ZOYMOP07:1437561 [14] ZOYMOP06:1437560; [14]
O
O
O
3-Hydroxyestra-1,3,5(10)-trien-17-
one (Estron) 4
O3—H3⋯O17
ESTRON10: 1150270 [15]
ESTRON11:1150271 [15]
O
ESTRON12:1150272 [15]
ESTRON14:618076 [16]:ESTRON13: 228076 [17]
ESTRON03:11150267 [18]
H
3-Hydroxy-9β-estra-1,3,5(10)-trien-
O3—H3⋯O17
O3—H3⋯O17
JILVOP: 1186531 [19]
GODTIC: 131056 [20]
17-one
3-Hydroxyestra-1,3,5(10),7 -tetraen-
17-one
O
O
H
3-Hydroxyestra-1,3,5,7,9-penta-17-
one (Equilenin)
O3—H3⋯O17
QQQAMM01: 1560649 [21]
O
O
O
H
3β-Hydroxy-14β- androsta-5,15-dien-
O3—H3⋯O17
O3—H3⋯O17
CICVAM: 647682 [22]
FAWHIX: 1477148 [23]
O
17-one
H
3α-Hydroxy-androsta-8(14),15-dien-
17-one
O
O
O
H
H
3β-Hydroxy-3β-Hydroxyandrost-14-
ene-17-one
3 molecules in asymmetric unit:
mix of O3O3—H3⋯O17 and
O3—H3⋯O3
FAWGIW: 1449075 [23]
O
hydrogen bonded chains, two exceptions are known for 3β-hydro-
xyandrost-5-en-17-one (dehydroepiandrosterone), 3: both monoclinic
P21 phases and both generated using a cryomodification technique
of this contains three independent molecules in the asymmetric unit
linked by O3—H3⋯O3(OH) and O3—H3⋯O17(one) strong hydrogen
bonds. Unfortunately details of its formation are unavailable, however
the presence of three independent molecules suggests that the most
stable arrangement had not been reached at the onset of crystallization.
We are interested in what effects additional substituents may have
on this fundamental O3—H3⋯O17(one) hydrogen bond and on the
packing of 3-HO-17-one substituted compounds, in particular whether
the additional substituents can result in replacement or supplementa-
tion of the O3—H3⋯O17(one) hydrogen bonds. Two factors could in-
fluence matters, one is the acceptor/donating ability of the additional
substituent, and the other is its steric effect. For the former, one po-
tentially influential substituent is the hydroxyl group. A general interest
[14]:
one
[CCDC
codes:ZOYMOP-06:
1437560]
exhibits
O3—H3⋯O3(OH) hydrogen bonds, which leads to each molecule being
linked in two others in a head-to-head fashion [14], and the other,
[CCDC codes: ZOYMOP-07: 1437561] exhibits both O3—H3⋯O3(OH)
and O3—H3⋯O17(one) hydrogen bonds and provides a more complex
packing arrangement. These phases, formed abruptly, are unstable in
contrast to the other phases formed in a more controlled manner such
as by recrystallization from solvents. A further exception exhibited by a
‘’parent’’ compound, having just 3-HO and 17-one substituents, is 3-
hydroxyandrost-14-ene-17-one [FAWGIW: 1449075 [23]. The structure
2

S.M.S.V. Wardell and J.L. Wardell
Steroids159(2020)108624
(a) Compound 2: [6]
(b) 3-Hydroxy-9ȕ-estra-1,3,5(10)-trien-17-one [19]
Fig. 1. Different orientations of adjacent molecules in the O3—H3⋯O17 hydrogen bonded chains and links between these chains in (a) compound 2 [CCDC codes:
ANDRON10: 1102946] [6], (b) 3-Hydroxy-9β-estra-1,3,5(10)-trien-17-one [CCDC codes: JILVOP: 1186531]
is the effect of solvates and co-crystals on crystal structures, as shown in
our earlier articles [24,25].
and rotary evaporated. The oily residue was crystallized from dry me-
thanol to give 5 (1.5 g), m.p., 209–211 °C, lit. [26] m.p. 214–220 °C
(recrystallized from EtOAc); lit.[27] 207–210 °C (recrystallized from
benzene).
Calcd. C19H28O3: C, 74.97; H, 9.26; Found: C, 74.92; H, 9.15%.
IR: (λ, cm−1) 3370(OH), 3131(OH), 1731 (C]O), 1055, 1027,
1005, 965.
The influence of additional substituents and solvates on the solid-
state arrangement of the very important 3β-hydroxyandrost-5-en-17-
one group of compounds is of particular interest. As a consequence of
these interests, we have studied the crystal structures of 3β,19-dihy-
droxy-androst-5-en-17-one, 5, and its monohydrate, [(5).H2O]. The
additional hydroxyl group on carbon C19, an unusual position, provides
further possibilities for different packing arrangements of 3β-hydro-
xyandrost-5-en-17-one compounds.
We now wish to report our findings on the crystal structures of
3β,19-dihydroxy-androst-5-en-17-one, 5, and its monohydrate,
[(5).H2O], and in addition we report on a survey of the structures of
related di- and tri-substituted hydroxyl derivatives as well as solvated
polyhydroxylated compounds.
1H NMR (400 MHz,DMSO‑d6) õ: 0.77–0.90(m, 5H),1.05–1.19(m,
2H), 1.21–1.34(br,d,q, 1H), 1.40–1.75(m, 6H) 1.77–1.87(m, 1H),
1.92–2.09(m, 4H), 2.09–2.15(m, 1H), 2.15–2.23(brd.d, 1H),
2.31–2.43(d,d J = 8, 18 Hz,1H), 3.26–3.40(m, 2H), 3.40(d, J = 12 Hz,
1H),3.67(d, J = 12 Hz,1H),4.35(br.s,1H), 5.49, br.s, 1H).
13C NMR (100 MHz, DMSO‑d6): õ: 13.47 [C-18], 20.60[C-11],
21.44[C-15], 30.01 [C-12], 31.58 [2], 31.71[C-7], 32.05 [C-8], 33.06
[C-1], 35.32 [C-16], 41.00[C-10], 42.54 [C-4], 47.10 [C-13], 50.28[C-
9], 51.56 [C-14], 61.70[C-19], 69.99 [C-3], 122.94 [C-6], 138.12 [C-5],
221.35 [C-17].
2. Experimental
13C NMR spectral has been reported in CDCl3 solution [28].
2.1. General
2.3. Experimental crystallography
Melting points were determined on a Griffin melting point appa-
ratus and are uncorrected. Infrared spectra of samples, as neat powders,
were recorded using a Perkin Elmer UART two, with ATR Diamond Cell,
instrument. NMR spectra were recorded on a BrukerAvance 400 spec-
trometer in DMSO‑d6 at room temperature. For the Differential
Scanning Calorimetry, a Mettler Toledo STARe System DSC1, cooled by
liquid nitrogen and calibrated using indium and zinc as standards, was
used with a time–temperature program of heating from 25 to 250 °C at
10 °C/min.
Data for compound 5 and [(5).H2O] were obtained with CuKa
(λ = 1.54184 Å) at 100 K by means of a XtaLAB AFC11 (RCD3):
quarter-chi single diffractometer, of the UK National Crystallography
Service, based at the University of Southampton, England. Data col-
lection, data reduction and unit cell refinement were achieved with
CrysAlisPro 1.171.38.41 [29]. Correction for absorption was achieved
using CrysAlisPro 1.171.38.41 [29]. Empirical absorption correction
were obtained using spherical harmonics, implemented in SCALE3
ABSPACK scaling algorithm. The programs ORTEP-3 for Windows [30]
and MERCURY [31] were used in the preparation of the Figures.
SHELXL97 [32] and PLATON [33] were used in the calculation of
molecular geometry. The structures were solved by direct methods
using SHELXS-97 [32] and fully refined by means of the program
SHELXL-97 [32]. Difference map peaks provided positions for hydro-
gens attached to the oxygen atom of the water molecule. The co-
ordinates, along with isotropic displacement parameters, were fully
refined. All other hydrogen atoms were placed in calculated positions.
Details of the refinement etc are listed in Table 2.
2.2. Synthesis
A solution of 3β,19-diacetoxyandrost-5-en-17-one (2.8 g), [26], in
75 mL of 5% methanolic sodium hydroxide was maintained at room
temperature for one hour and then neutralized with 5 N sulfuric acid
and filtered, see Scheme 1. The filtrate was rotary evaporated to 20 mL
and extracted into chloroform (200 mL). The extract was washed with
aqueous sodium carbonate (5%), dried over anhydrous sodium sulfate,
O
3. Results and discussion
O
HO
AcO
i
3.1. General
Compound 5 was prepared following a slight modification of a
published procedure [26], as detailed in the experimental section. 1H
and 13C NMR spectra are reported herein in DMSO‑d6 solution, while
13C NMR spectrum in CDCl3 solution has been reported [28]: other data
HO
AcO
Scheme 1. Reagents and conditions. (i) (a) 5% NaOH in MeOH; (b) 5 N H2SO4.
3

S.M.S.V. Wardell and J.L. Wardell
Steroids159(2020)108624
Table 2
Table 3
Experimental crystallographic details.
Puckering Parameters.
Identification code
5
[(5).H2O]
Five-membered ring
Compound
Empirical formula
Formula weight
Temperature, K
Wavelength, Å
Crystal system Space
group
C19H228O3
304.41
100(2)
1.54184
Monoclinic, P21
C19H30O4
322.43
100(2)
1.54184
Parameters
Q(2) (Å).
Phi(2) (°)
5
0.438(2)
0.4421(16)
207.0(3)
201.9(2)
Orthorhombic, P212121
[(5).H2O]
Unit cell dimensions
a, Å
6.39800(6)
7.74600(6)
100.3110(9)°.
16.40030(14)
799.655(12)
2
7.24450(7)
12.04980(10)
90
19.73980(16)
1723.18(3)
4
Six membered rings
b, Å
β,o
Compound
Ring
Parameters
Q(2) (Å).
c, Å
Volume, Å3
Z
Thetao
Phio
Density (calc.) Mg/m3
Absorption coefft mm-
1
1.264
0.660
1.243
0.683
5
5
5
A
B
C
A
B
C
0.5355(19)
0.4566(19)
0.576(2)
7.8(2)
50.3(3)
2.5(2)
97.4(15)
213.2(3)
267(4)
F(0 0 0)
332
704
[5).H2O]
[(5).H2O]
[(5).H2O]
0.5513(15)
0.4680(15)
0.5702(15)
10.67(16)
50.72(18)
3.73(15)
114.2(9)
207.6(2)
233(2)
Crystal size mm
Theta range for data
collection
0.121 × 0.090 × 0.040
2.739 to 68.240°.
0.475 × 0.252 × 0.140
4.30 to 68.15
Index ranges
−7 ≤ h ≤ 7,
−9 ≤ k ≤ 9,
−19 ≤ l ≤ 19
16,369
−8 ≤ h ≤ 8,
−14 ≤ k ≤ 14,
−23 ≤ l ≤ 23
18,422
loss indicated that about half the water had been retained and that an
anhydrous product had not been formed.
Reflections collected
Independent
2900 [R(int) = 0.0307]
3140 [R(int) = 0.0207]
reflections
3.2. Crystallography
Completeness to theta
Absorption correction
Max. and min.
99.7%
Gaussian
1.000 and 0.875
99.8
Gaussian
1.000 and 0.492
Compound 5 crystallizes in the monoclinic space group, P21, with
Z = 2, with one steroid molecule in the asymmetric unit. Compound
[(5).H2O] crystallizes in the orthorhombic space group, P212121, with
Z = 4 with one steroid and one water molecule in the asymmetric unit.
transmission
Refinement method
Full-matrix least-squares
on F2
2900/1/202
Full-matrix least-squares
on F2
3140/0/218
Data/restraints/
parameters
Goodness-of-fit on F2
Final R indices
[I > 2sigma(I)]
All data
0.742
0.028, 0.078
0.832
R1 = 0.023; wR2 = 0.063
3.3. Molecular conformations of the steroid 5 in the unsolvated and hydrate
forms
0.0281, wR2 = 0.0778
0.01(6)
R1 = 0.023; wR2 = 0.063
−0.01(4)
Absolute structure
factor
The atom arrangements and number schemes of 5 and its mono-
hydrate are shown in Fig. 2. One significant difference between the
conformations of the molecules of 5 in the two structures is the or-
ientation of the hydroxy group on C-19: in 5 it is orientated towards the
C-1 carbon and forms a C—-H1A⋯O19 intramolecular hydrogen bond,
while in the hydrate it is directed away from O3 and forms a
C8—H8⋯O19 intramolecular hydrogen bond. Confirmation of the dif-
ferent orientations of the 19-OH group is provided by the O19—HI1A
and C19—C8 distances of 2.51 and 4.00 Å in 5, compared to 3.91 and
2.44 Å in the hydrate. This change in orientation allows the different
intermolecular interactions exhibited by 5 and its hydrate, discussed
below. Apart from the positioning of the 3-HO group, the conformations
of the molecules of 5 are similar, e.g., as indicated by the puckering
parameters [34], in Table 3. The bond lengths and angles, in both 5 and
[(5).H2O], are in the expected regions and are not furthered discussed.
Largest diff. peak and
0.273 and −0.137
0.194 and −0.114
hole e.Å−3
CCDC no
1962235
1962237
are as previously reported. For this study, compound 5 was re-
crystallized from different media, by allowing slow evaporations of
dilute solutions at room temperature. Using THF, Me2CO, EtOAc or dry
MeOH as the solvent, only the un-solvated form, 5, was obtained. In
contrast, recrystallization from 50% aqueous methanol produced the
monohydrate, [(5).H2O].
Compound [(5).H2O] was shown by TGA to lose water, 3.1% by
weight, on heating between 25 and 200 °C at a heating rate of 10 °C per
minute. Complete water weight loss from the hydrate would amount to
a loss of 5.9%. The majority of the loss of water occurred between 80
and 110 °C, with a very small loss occurring after 110 °C. The weight
5
[(5).H2O]
Fig. 2. Atom arrangements and numbering schemes.
4

S.M.S.V. Wardell and J.L. Wardell
Steroids159(2020)108624
Table 4
Details of the hydrogen bonds (Å,o) in 5 and [(5).H2O].
(a)Intramolecular hydrogen bonds
Compound
D—H⋯A
D—H
H⋯A
D⋯A
D—H⋯A
5
C1—H1A⋯O19
C8—H8⋯O19
0.99
1.00
2.51
2.44
2.881(2)
3.1003(17)
102
123
[(5).H2O]
(b). Intermolecular hydrogen bonds
D—H⋯A
D—H
H⋯A
D⋯A
D—H⋯A
Symmetry code
5
5
5
5
O3—H3⋯O19
O19—H19⋯O3
C2—H2A⋯O3
C15—H15A⋯O17
Ow—Hw1⋯O17
Ow—Hw2⋯O19
O3—H3⋯Ow
0.84
0.84
0.99
0.99
0.84(2)
0.86(3)
0.84
2.00
2.01
2.48
2.54
2.10(3)
1.97(3)
1.92
2.8282(19)
2.8205(18)
3.460(2)
169
162
172
153
162(2)
175(2)
158
x,1+y,z
1 − x, − 1/2+y,-z
1 − x,−1/2+y,−z
−x,1/2 + y,1 − z
3/2 − x,−y,−1/2+z
x,y,z
3.448(3)
[(5).H2O]
[(5).H2O]
[(5).H2O]
[(5).H2O]
2.9076(16)
2.8260(16)
2.7194(16)
2.7330(14)
2 − x,1/2 + y,3/2 − z
1 − x,−1/2+y,3/2 − z
O19—H19⋯O3
0.84
1.90
174
(a)
(b)
Fig.3. Compound 5. (a)
A
part of the sheet of molecules generated from the four O3—H3⋯O19(OH), O19—H19···O3(OH)
,
C2—H2A⋯O3(OH) and
C15—H15A⋯O17(one) hydrogen bonds, looking down the a axis, (b) another view of the sheet, edge-on, illustrating the width of the sheet.
3.4. Crystal structure of the anhydrous form, 5 molecules in a head-to-middle fashion, while the C15—H15A⋯O 17
The intermolecular interactions in
hydrogen bonds link the molecules in a tail-to-middle manner. Features
of the arrangement in the sheet include (i) molecules in each row
possess the same orientation, and (ii) the alternating linking of rows by
strong and much weaker hydrogen bonding arrangements. Within each
sheet, combinations of O19—H19⋯O 3 and O3—H3⋯O19 hydrogen
bonds create R33(12) rings [35], while combinations of C15—H15A⋯O
17 and O3—H3⋯O19 hydrogen bonds form R33(12) rings. The
O3—H3⋯O19 and O19—H19⋯O3 hydrogen bonds on their own form
C(8) chains [35]. The sheet is relatively thin, as shown in Fig. 3b The
closest contacts between similar sheets involves H7B···H16Ai and
C12···H19B contacts at 2.36 and 2.87 Å, just within the contact radii
sum of 2.40 and 2.90 Å, respectively [symmetry operations:
i = 1 − x,1/2 + y,1 − z: ii = −1 + x,y,x]. Such separations indicate
the structure of 5 is essentially two-dimensional with only weak H···H
and C···H close contacts between the sheets.
5
are O3—H3⋯O19(OH),
O19—H19⋯O3(OH), C2—H2A···O3(OH) and C15—H15A⋯O17(one) hy-
drogen bonds, details of which are listed in Table 4. These four hy-
drogen bonds combine to generate sheet of molecules, a view of part of
one is shown in Fig. 3a, looking down the a axis: for reasons of clarity
the C2—H2A⋯O3(OH) hydrogen bonds are not drawn. The absence of a
O3—H3⋯O17 hydrogen bond as the major intermolecular interaction
in the dihydroxy compound, 5, contrasts with the majority finding for
the 3-HO-17-one steroids, listed in Table 1, in particular with the
polymorphs of the parent compound, 3β-hydroxy-5-androsten-17-one,
3.
The sheet shown in Fig. 3a can be considered as composed of col-
umns, two molecules wide, linked by the strong classical
O3—H3⋯O19(OH), O19—H19⋯O3(OH) hydrogen bonds. These columns
are propagated in the direction of the b axis, and are further linked by
C15—H15A⋯O17(one) hydrogen bonds to provide the sheets. The
O3—H3⋯O19(OH) and O19—H19⋯O3(OH) hydrogen bonds link the
5

S.M.S.V. Wardell and J.L. Wardell
Steroids159(2020)108624
(a)
(b)
(c )
(d)
Fig.4. Aspects of the crystal structure of [(5).H2O]. (a) The hydrogen bond connections to the reference steroid molecule (in element colours) and to the water
molecule, (b) two distinct ring formations found throughout the crystal structure, (c) a view of the packing of the steroid molecules, in green, and the water molecules
in blue, (d) another view of the packing in [(5).H2O].
3.5. The mono hydrate, [(5).H2O]
3.6. Effect of additional hydroxyl groups on the packing of 3-HO-17-one
steroids in the crystal
Details of the intermolecular classical hydrogen bonds in [(5).H2O]
are listed in Table 4. All are classical O—H⋯O hydrogen bonds, which
combine to generate a three dimension array. Each steroid molecule is
directly connected to another steroid molecule by a O19—H19⋯O3
hydrogen bond and indirectly to two others via Ow—Hw2⋯O19 and
Ow—Hw1⋯O17(one) hydrogen bonds, see Fig. 4a. Each hydrate mole-
A CCDC search carried out in May 2019 indicated about 60 struc-
tures of four-ringed steroids having at least 3-HO and 17-one sub-
stituents, with full details of hydroxyl and solvate hydrogen atoms. Of
these 12 had additional hydroxyl groups
In Table 5 are listed the major intermolecular interactions of un-
solvated 3-HO-17-one substituted steroids having additional hydroxyl
groups [19,36–43]. As shown in Table 5, the additional hydroxyl
groups take part in classical intermolecular O—H⋯O hydrogen
bonding, with only two exceptions, namely 3β,5β-dihydroxy-15β,16β-
methylene-5β-androst-6-en-17-one (HIRROQ: 672935) [41, in which
the O5-H5 group is involved in an intramolecular O5—H5⋯O3 hy-
drogen bond, and 16α-hydroxyestrone (HXESTR: 1178924) [42], in
which the 16-HO group appears to form a O16—H16⋯π(ethylene) in-
teraction involving the C3-C4 atoms of the aromatic ring. As well as the
strong hydrogen bonds involving the additional hydroxyl group(s), the
O3—H3⋯O17 classical intermolecular hydrogen bonds are still present
in seven of the ten solvate-free compounds, namely 3α,4β-dihydroxy-
5α-androstan-17-one (NAQWAD; 129769) [39], 3β,4α-dihydroxy-5β-
androstan-17-one (TELXOX: 128117) [36], 3β, 5α,6β-trihydroxy an-
drostan-17-one (URAJON01: 1897586) [39], 3β,14β-dihydroxy-an-
drost-15-en-17-one (FAWGUI: 1507591) [40], 3β,5β-dihydroxy-
cule forms three hydrogen bonds, namely
O
3—H3⋯Ow,
Ow—Hw1⋯O17 and Ow—Hw2⋯O19, as also shown in Fig. 4a. The
O19—H19⋯O3 hydrogen bonds generate a C8 chain in the direction of
the b axis. Spiral chains of molecules result from combinations of the
other hydrogen bonds. Within the network of hydrogen bonds two
largish rings of molecules are apparent, R55(30) and R77(42), see Fig. 4b.
Two views of the packing array are shown in Fig. 4c and d. In Fig. 4c,
the emphasis is on the placement of the hydrate molecules between the
steroids, while in Fig. 4d, the emphasis is on the two large rings, de-
tailed in Fig. 4b. Short H⋯H contacts include H1B⋯H12Biii and
H16B⋯H2Biii at 2.36 and 2.26 Å, respectively, within the contact radii
sum of 2.40 Å: [symmetry code: iii = ½ + x, ½ − y, 2 − z].
As found for most hydrated steroids, the water molecules have very
strong influences on the structure and results in very large changes from
the structure of the anhydrous compound.
6

S.M.S.V. Wardell and J.L. Wardell
Steroids159(2020)108624
Table 5
Major intermolecular interaction in 3-HO-17-one steroids having additional hydroxyl groups.
Structure
Name: CCDC codes
3α,4β-dihydroxy-5α-androstan-17-one
NAQWAD
Major hydrogen bonds and detailsa
O3—H3⋯O17 linked molecules: further linked by O4—H4⋯O3 hydrogen bonds into
sheets, which are further linked by C—H⋯O hydrogen bonds to provide a 3d
arrangement. The O4—H4⋯O3 hydrogen bonds generate C(5) chains
[Ref]
[36]
O
129769
O
H
OH
3β,4α-dihydroxy-5β-androstan-17-one
TELXOX
128117
O3—H3⋯O17 hydrogen bonds link molecules: further linked by O4—H4⋯O3 hydrogen
bonds: further links by C—H⋯O hydrogen bonds provide a 3d arrangement. The
O4—H4⋯O3 hydrogen bonds generate C(5) chains
[37]
O
O
H
OH
3,5,6-trihydroxyandrostan-17-one
URAJON-01
O3—H3⋯O17 hydrogen bonds link molecules: further links involve O5-H5-O3 spiral
C(7) chains and O6-H6—O5 spiral C(5) chains.
[38], see
also [39]
1897586:
3β,19-dihydroxyandrost-5-en-17-one [5]
O3—H3⋯O19 and O19—H19⋯O3 hydrogen bonds link the molecules in a head-to-
middle fashion. C—H—O hydrogen bonds link the molecules into a 3D array. The
O3—H3⋯O19 interactions generate C(8) chains.
This study
[40]
3β,14β-dihydroxy-androst-15-en-17-one
FAWGUI
1507591
Complex: three molecules, A,B and C, in the asymmetric unit; individual classical
hydrogen bonds are O3A—H3A—O17B; O3B—H3B⋯O17C; O3C—H3C⋯O3B; O14A—-
H14A⋯O3C; O14B—H14B⋯O3; O14C—H14C⋯O17A. Chains of molecules are
generated from combinations of the different hydrogen bonds listed above.
O
OH
O
H
O
3β,5β-dihydroxy-15β,16β-methylene-5β-
androst-6-en-17-one
HIRROQ
O3—H3⋯O17 hydrogen bonds link molecules in a head-to-tail manner, while the 5-HO
group forms intramolecular O5—H5⋯O3 hydrogen bonds. Involvement of C—H⋯O
hydrogen bonds results in a 3-D array.
[41]
672935
O
H
O
H
O
16α-hydroxyestrone
HXESTR
1178924
O3—H3⋯O17 hydrogen bonds link molecules: the 16-HO group forms no classical
O—H⋯O interactions, but probably forms a O16—H16⋯π(ethylene) interaction, with
C3-C4. In addition there are various C—H⋯O hydrogen bonds, whose involvement
results in a 3-D array.
[42]
[19]
OH
O
H
11β-hydroxy-9β-estrone
JAMNIU
1182477
There are no O3—H3⋯O17 hydrogen bonds, instead O3—H3⋯O11 and
O11—H11⋯O17 hydrogen bonds are present: O3—H3⋯O11 generate C(9) chains and
O11—H11⋯O17 form C(7) spiral chains. The involvement of various C—H—O
hydrogen bonds generate a 3-D array.
O
O
H
O
H
O
3,8α-dihydroxyestra-1,3,5(10),6-tetraen-
There are no O3—H3⋯O17 hydrogen bonds, instead O3—H3⋯O8 and O8—H8⋯O17
hydrogen bonds are present: O3—H3⋯O8 form C(9) chains and O8—H8—O17 form
spiral C(7) chains. The involvement of various C—H⋯O hydrogen bonds generate a 3-D
array.
[43]
17-one
LEKNIY
1205183
OH
O
H
a
The number scheme used for the compounds in this Table follow the scheme used for compound 5.
15β,16β-methylene-5βandrost-6-en-17-one (HIRROQ: 672935) [41],
16α-hydroxyestrone (HXESTR: 1178924) [42], but not in the other
three compounds, 3β,19-dihydroxy-androst-5-en-17-on [this study] and
two estrone derivatives 11β-hydroxy-9β-estrone (JAMNIU: 182477)
[19] and 3,8α-dihydroxyestra-1,3,5(10),6-tetraen-17-one (LEKNIY:
205183) [42], see Table 5. Where the O3—H3⋯O17 classical inter-
molecular hydrogen bonds are retained, with the formation of C(12)
chains, the additional hydroxyl group is involved in forming shorter
chains, C(6) or less. Where the O3—H3⋯O17 classical intermolecular
hydrogen bonds are lost, the additional hydroxyl group(s) generate
chains larger than C(7).
groups and the17-one substituent [4,14,44–49]. As is apparent in
Table 6, the solvate molecules are strongly involved in the inter-
molecular interactions. Among the compounds listed in Table 6 are
solvates and hydrates of some of the unsolvated compounds listed in
Tables 1 and 5.
There are two solvates of androsterone, namely
a hydrate,
[(1).H2O] (CCDC codes: ANDOON05: 293344) [4] and a 2-naphtholate,
[(1).naphtholate] (CCDC codes: CUTBID: 753866) [44]. As mentioned
in the Introduction, the major intermolecular interactions in all known
polymorphs of unsolvated 1 are O3—H3⋯O17 hydrogen bonds, which
directly link molecules into chains, and which are further linked by
weaker C—H⋯O hydrogen bonds into a 3-dimensional array. In
[(1).H2O] each steroid molecule is directly bonded to one other via a
strong O3—H3⋯O17 hydrogen bond and to others via other O—H⋯O
hydrogen bonds involving the water molecule. Further links with
3.7. Solvated hydroxy-17-one substituted steroids
Table 6 lists solvated compounds which solely contain hydroxyl
7

S.M.S.V. Wardell and J.L. Wardell
Steroids159(2020)108624
Table 6
Major interactions in solvated 3-HO-17-one steroids having additional hydroxyl groups.
Structure
Name: CCDC codes
Major hydrogen bonds and details
Reference
O
O
O
3α-Hydroxy-5α-androstan-17-one
[1.(H2O)]
ANDOON05
There is a direct steroid-steroid link via O3-H3—O17 hydrogen bond:
water is linked to different steroids via Ow-Hw1—O17, Ow-
Hw2—O3 and O3-H3-Ow
[4]
293344
O
H
monohydrate
3α-Hydroxy-5α-androstan-17-one
[1.(naphthol)]
CUTBID
A chain of O3-H3—O17 linked molecules, with each steroid also
forming a O3-H3—O(naphthol) hydrogen bond.
[44]
[14]
753866
O
H
.2.naphthol
3α-Hydroxy-5α-androsten-17-one [(3).H2O]
[S5]
VEFPUR01
1437562
No O3-H3—O17 hydrogen bonds. Asymmetric unit contains one
steroid and one water molecule: major hydrogen bonds are O3-
H3—Ow and Ow-Hw—O3 indirectly link steroid molecules.
One steriod and one water molecules in asymmetric unit
O
H
monohydrate
O
O
3α-Hydroxy-5α-androsten-17-one [(3).H2O]
Two steriod and two water molecules in asymmetric unit
[45]
[8]
[S1]
VEFPUR
1281337
monohydrate
O
H
3β-Hydroxy-5α-androsten-17-one [(3)4·H2O]
ZOYMUR:
1315761
Two independent molecules and two distinct bilayer domains. In
domain 1: Mol A and water lead to direct had-to-tail steroid links as
well as indirect O3A-H3A-Ow and Ow-H3B-O3B links.. In the B
domain, there are only steroids directly linked bya O3-H3-O17
hydrogen bonds. Crystal packing in the methanol half-solvate
O
H
0.25 hydrate
O
3β-Hydroxy-5α-androsten-17-one [(3)2.MeOH]
ZOYNAC01 216629
[S4]
No O3—H3⋯O17 hydrogen bonds. Steroids are directly linked head
to head via O3—H3⋯O3 hydrogen bonds and indirectly via 3-HO-
methanol-3-HO hydrogen bonds.
[8] see also
[46]
O
H
hemi.methanolate
O
3-Hydroxyestra-1,3,5(10)-trien-17-one
[(Estron).perfluoronaphthalene ]
cocrystal
RUGYEZ
1036412
O3—H3⋯O17 linked layers, which are further linked by C—H⋯F
and π···π interactions between the steroid and co-crystal.
[47]
O
H
Estrone perfluoronaphthalene
O
H
3β,19-Dihydroxy-androst-5-en-17-one.
monohydrate,
[(5).H2O]
Each steroid molecule is directly connected to another steroid
molecule by O19—H19⋯O3 hydrogen bond and indirectly to two
others via Ow—Hw2⋯O19 and Ow—Hw1⋯O17(one) hydrogen
bonds. The hydrate molecule forms three hydrogen bonds, namely
O3—H3⋯Ow, Ow—Hw1⋯O17 and Ow—Hw2⋯O19The
O19—H19⋯O3 hydrogen bonds generate C(8) chains
This study
O
O
H
monohydrate
3,7α-Dihydroxyestra-1,3,5(10)-trien-17-one
Classical O7—H7⋯O3 hydrogen bonds link the steroids directly in
forming C(8) chains. There are indirect steroid links via water,
including O3—H3⋯Ow/Ow—Hw⋯O17 and O17⋯Hw-Ow/
Ow—Hw⋯O7.
[48]
O
monohydrate
[(6).H2O]
XEXVAA
1832911
O
H
OH
monohydrate
3β,7α,15α-trihydroxy-5-androsten-17-one
No direct steroid-steroid link:
[49]
O
dehydrate
[(7).H2O].
WINLIP
hydrate molecule 1: forms four connections: Ow1—Hw⋯O3;
Ow1—Hw⋯O3, Ow1⋯H—O7, Ow2—Hw⋯Ow1
hydrate molecule 2: three connections: Ow2—Hw⋯O17,
O3—H3⋯Ow2, Ow—Hw⋯O15.
OH
667449
O
H
OH
dihydrate
weaker C—H⋯O hydrogen bonds generate a 3-dimensional array for
[(1).H2O] However, chains of molecules linked by O3—H3⋯O17 hy-
drogen bonds persist in [(1).naphtholate], with each steroid also
strongly hydrogen bonded to the 2-naphthol solvate via O—H(naph⋯O3
hydrogen bonds. The 2-naphthol solvate is also involved in two weak
C—H⋯O hydrogen bonds, which help to generate a two-dimensional
array for in [(1).naphtholate]. The closest contacts between the two
dimensional layers in [(1).naphtholate] are H⋯H at ca 2.64 Å.
8

S.M.S.V. Wardell and J.L. Wardell
Steroids159(2020)108624
Several hydrates of 3β-ol-androst-5-en-17-one, 3, have been re-
ported [8,14,45,50], these include two [(3)·H2O] polymorphs, S5
(CCDC codes: VERPUR01:1437562) [Chernyshev et. al., [14] and S2
(CCDC: VEFPUR: 1281337) [45], and [(3)4·H2O], S1 (CCDC codes:
(CCDC codes: ZOYMUV: 1315761] [8,50]: N.B. polymorphs and hy-
drates of 3β-ol-androst-5-en-17-one, 3, are also denoted and dis-
tinguished by symbols: S(number), e.g., number = 1. The most- re-
cently reported monohydrate polymorph, S5, VERPUR01 [14], was
identified from multiphase XRPD data in the cryomodification studies
[14]: this has one molecule each of water and steroid in the asymmetric
unit. The strong O3—H3⋯O17 hydrogen bonds in the stable anhydrous
forms have been replaced in the hydrate by water/3-hydroxy group
interactions, and consequently no direct steroid-steroid links remain.
The water molecule is involved in three classical O—H⋯O hydrogen
bonds to three different steroid units, [via Ow—Hw⋯O3, O3—H3⋯Ow
and Ow—Hw2⋯O17]. The other monohydrated polymorph of 3, S2,
VEFPUR: 1281337) [45], has two molecules each of water and the
steroid in the asymmetric unit. Of interest while the a and c axes of
VEFPUR and VEFPUR01are almost the same, the b axis in VEFPUR is
twice the length of that in VEFPUR01. Chernyshev et al. [14], while
reporting that the reported structure of S2 was correct, had also in-
dicated that DFT calculations had shown that dynamic disorder was a
feature, particularly for one of the water molecules, in S2. In the ori-
ginal report, Cox et al [45] had reported that extensive hydrogen
bonding was present, but fine details of the structure were obscured due
to difficulty in locating water H atoms accurately. No further comments
on the structure will be reported here. The crystal structure of S1,
[(3)4·H2O] [8], is also complex, with two independent steroid mole-
cules in the asymmetric unit with each steroid molecule having distinct
sets of intermolecular interactions, and with two distinct bilayer do-
mains. In domain 1, there are direct head-to-tail Mol A steroids steroid
links as well as indirect O3A—H3A⋯Ow and Ow—H3B⋯O3B links. In
the B domain, there are only Mol B steroids, directly linked by
O3—H3⋯O17 hydrogen bonds. Clearly there is insufficient water to
avoid completely steroid - steroid direct contacts.
O3—H3⋯O17 hydrogen bonds, which generate head-to-tail C(12)
molecular chains. This strong hydrogen bond in not present in com-
pound 5, being replaced by hydrogen bonds involving the 3 and 19
hydroxyl groups, with consequent changes in the packing of the steroid
molecules. Twelve 3-hydroxy-17-one steroids having additional hy-
droxyl groups and in ten the addition hydroxy groups take part in
classical intermolecular O—H⋯O hydrogen bonding. Two exceptions
have unique situations: in 3β,5β-dihydroxy-15β,16β-methylene-5β-an-
drost-6-en-17-one [41], the O5-H5 group is involved in forming in-
tramolecular O5—H5⋯O3 hydrogen bond while in 16α-hydro-
xyestrone [42], the 16-HO group form
a O16—H16⋯π(ethylene)
interaction. As well as the O—H⋯O hydrogen bonds involving the
addition hydroxyl groups, O3—H3⋯O17 hydrogen bonds are retained
in seven of the ten solvate-free compounds. Where the O3—H3⋯O17
classical intermolecular hydrogen bonds are retained, the additional
hydroxyl group is involved in forming shorter chains, C(6) or less.
Where the O3—H3⋯O17 classical intermolecular hydrogen bonds are
lost, the additional hydroxyl group(s) generate chains larger than C(7).
The solvate molecules, such as water and alcohols in solvated 3-
hydroxy-17-one steroids strongly effect the packing in crystal structures
in all cases. Weaker donating solvates such as 2-naphthol [44] and
especially perfluoronaphthalene [47] have reduced effects. The pro-
portions of the solvate to steroid in the solvated structures has a clear
importance on the relative ratios of directly linked to indirectly linked
steroid-steroid connections, e.g., compare the structures of the hydrates
of compound 3.
Acknowledgements
The authors thank the National Crystallographic Service, University
of Southampton for the data collection, and for their help and advice.
Appendix A. Supplementary data
Supplementary data to this article can be found online at xxxx and
have also been deposited with the Cambridge Crystallographic Data
Centre with deposition number CCDC 1962235 and 1962237 for 5 and
[(5).H2O], respectively. Copies of these can be obtained free of charge
on written application to CCDC, 12 Union Road, Cambridge, CB2 1EZ,
UK (fax:+44 1223 336033); on request by e-mail to deposit@
ccdc.cam.ac.uk or by access to http://www.ccdc.cam.ac.uk.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.steroids.2020.108624.
Two methanolates have been reported - a hemi-solvate, S4 (CCDC
codes: ZOYNAC. 1315762) [8] and a mono-solvate (CCDC codes:
ZOYNAC01. 216629) [46]. Surprisingly both have with very similar cell
dimensions. The hemi-methanolate has been the better characterized
from IR, DSC and TGA data. However, even in the case of the mono-
methanolate, the hydroxyl H atoms of both the steroid and methanol
are disordered, giving rise to an unusual linearly-propagating ‘flip-flop’
hydrogen bonding scheme. Cif-checks for both data sets raise A alerts.
Molecules are directly linked in
a head – to- tail fashion by
O3—H3⋯O3 hydrogen bonds and indirectly via the methanol mole-
cules.
References
Two hydrates of di-and trihydroxy compounds, namely 3,7α -di-
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