Ice-like encapsulated water by two cholic acid moieties

Article abstract of DOI:10.1016/j.steroids.2012.07.003

Starting from the structure of ice (in which each water molecule is surrounded by other four water molecules forming a tetrahedron with a value of 4.51 A for the edge O-O distance), and the knowledge that this value also corresponds to the O7-O12 distance of the skeleton of cholic acid, it is hypothesized that two steroid cholic acid moieties, with an appropriate steroid-steroid distance and a belly-to-belly orientation, could encapsulate a single water molecule between them. To check this hypothesis two succinyl derivatives of cholic acid (a monomer and the related head-head dimer in which the succinyl group is the linking bridge) were designed. The expected "ice-like" structure is found in the crystal of the dimer. There is a hydrogen bond synergy between those participating in the "ice-like" structure, and those in which the bridge is involved with the O7-H hydroxy group and the side chain of the steroid.

Full text of DOI:10.1016/j.steroids.2012.07.003

Steroids 77 (2012) 1228–1232
Contents lists available at SciVerse ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Ice-like encapsulated water by two cholic acid moieties
b
a
a
a
a
a
Victor H. Soto , Mercedes Alvarez , Francisco Meijide , Juan V. Trillo , Alvaro Antelo , Aida Jover ,
c
a,
⇑
L. Galantini , José Vázquez Tato
a
Departament of Physical Chemistry, Facultad de Ciencias, Universidad de Santiago de Compostela, Avda. Alfonso X El Sabio s/n, 27002 Lugo, Spain
Department of Chemistry, University of Costa Rica, San José, Costa Rica
Department of Chemistry, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from the structure of ice (in which each water molecule is surrounded by other four water mol-
ecules forming a tetrahedron with a value of 4.51 Å for the edge O–O distance), and the knowledge that
this value also corresponds to the O7–O12 distance of the skeleton of cholic acid, it is hypothesized that
two steroid cholic acid moieties, with an appropriate steroid–steroid distance and a belly-to-belly orien-
tation, could encapsulate a single water molecule between them. To check this hypothesis two succinyl
derivatives of cholic acid (a monomer and the related head–head dimer in which the succinyl group is the
linking bridge) were designed. The expected ‘‘ice-like’’ structure is found in the crystal of the dimer. There
is a hydrogen bond synergy between those participating in the ‘‘ice-like’’ structure, and those in which
the bridge is involved with the O7–H hydroxy group and the side chain of the steroid.
Received 12 March 2012
Received in revised form 24 May 2012
Accepted 3 July 2012
Available online 21 July 2012
Keywords:
Cholic acid
Bile acids
Ice-like structure
Encapsulated water
Ó 2012 Elsevier Inc. All rights reserved.
1
. Introduction
After the discovery of crown ethers by Pedersen [1], several at-
extremity. They adopt helically folded conformations in solution
and in the solid state, the diameter of the helix being larger in
the center than at each extremity forming a closed shell that
may act as a capsule. Depending on the number of pyridine rings,
one or two water molecules are bound within the capsules.
Here we will adopt a different strategy for encapsulating a sin-
gle water molecule and for designing such a device, we will refer to
the structure of ice as a starting model. In ice the intermolecular
tempts have been made for encapsulating water inside a host. For
instance, Newkome et al. [2] reported the first successful attempt
of bound water in the center of an uncharged host molecule by
hydrogen bonding. Nowadays this is a well-known phenomenon,
but usually the inclusion involves water clusters rather that indi-
vidual water molecules [3–6]. Encapsulated water polymers have
been obtained in rigid metal complexes based on mono-N-substit-
2
bonding consists primarily of hydrogen bonds and each H O is sur-
rounded by other four water molecules forming a tetrahedron with
values of 2.76 and 4.51 Å for the nearest-neighbor O–O and the
edge O–O average distances, respectively [14,15]. It may be
hypothesized that any other tetrahedral structure with four oxy-
gen atoms and the indicated O–O edge distance can possibly bound
a single water molecule inside it.
This distance condition is fulfilled by the two O7-H and O12-H
hydroxy groups of cholic acid (Fig. 1, top left) and derivatives since
the indicated value has been obtained in several crystal structures.
Thus, a priori two cholic acid skeletons, with an appropriate ste-
roid–steroid distance and a belly-to-belly orientation (see below),
could encapsulate a single water molecule between them. In a
crystal, this would require the formation of alternating hydro-
philic/hydrophobic layers, which is not an uncommon fact in crys-
tals of cholic acid and derivatives [16–26]. However although
several cholic acid crystals including water alone or as a second
guest have been obtained [21–29], none of them shows the desired
structure indicated in Fig. 1 (top right). This is also the case of
cholic acid derivatives with an extended hydrophobic region
0
ued carboxylate 4,4 -bipyridine [7] and entrapped water wires
have been prepared in peptide nanotubes [8]. They are also known
in aquaporins which are the predominant water channel in mem-
branes [9,10]. In general, as Braun et al. [11] have pointed out, the
inclusion of water molecules affects many solid state properties,
determining chemical processing.
However, the encapsulation of single water molecules is much
less common. For instance, Morris et al. [12] have found that the
cage inside potassium aryloxide aggregates contains a single
encapsulated water molecule, giving the molecular formula
t
[
(2- BuC
6 4
H OK)
6
ꢀ (H
2
1
O)ꢁ(diox)4] , and observed that encapsula-
tion by the hexameric prism does not significantly perturb the
structure of the water molecule. Garric et al. [13] have prepared
aromatic oligoamides that have alternating 1,6-diaminopyridine
and 1,6-pyridinedicarboxylic acid units at the center of the se-
quence and two 8-amino-2-quinolinecarboxylic acid units at each
⇑
Corresponding author. Tel.: +34 982824082.
E-mail address: jose.vazquez@usc.es (J.V. Tato).
[
30–32].
0
039-128X/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2012.07.003

V.H. Soto et al. / Steroids 77 (2012) 1228–1232
1229
Fig. 1. Top left: Structure and atom label of cholic acid. The number of each oxygen atom is the same of the carbon atom to which is attached. Top right: Schematic belly-to-
belly orientation of two cholic residues for encapsulating a H O molecule. Bottom: Structure of the monomer (suc-C) and the dimer (C-suc-C) derivatives of cholic acid.
2
The structure of cholic nucleus is well established and with the
restriction of the tetrahedral structure, we can infer which relative
orientation must the two steroid nuclei have in order to obtain the
ideal tetrahedron. For instance, if the angle formed by a virtual line
linking the two O7 and O12 hydroxy groups with the vertical plane
but now the water is forming a third hydrogen bond with the
O24a-H of the carboxylic group of another steroid molecule. In a
cholaphane crystal [39] five water molecules are included, two of
them forming hydrogen bonds with the O7-H and O12-H hydroxy
groups (belonging to the same steroid nucleus) and mutually
interacting.
[
33] of the steroid was 90°, the formation of the ideal tetrahedron
would require that the vertical planes of the two steroid nuclei
were also perpendicular to each other. If this angle was 45°, then
the two steroid nuclei should be parallel to each other and because
In this paper, we have explored another option based on the
linking of a hydrophilic and flexible residue at C3. For this purpose,
two succinyl derivatives of cholic acid were obtained and recrystal-
lized. The first one (suc-C), a monomer, was previously studied be-
cause of its biological properties [40,41] and the second one is the
related head–head dimer in which the succinyl group is the linking
bridge. Since it was not possible to obtain good crystals for the di-
mer in its acid form, we tested its methyl ester derivative (C-suc-C,
Fig. 1).
of the concave surface of the a-side, the two heads would probably
be in opposite directions. Since the actual angle is around 66°, an
intermediate orientation of the steroid nuclei can be expected.
Similar arguments may be use for predicting the distance between
the two complexing steroid nuclei (see below).
It is a very well-known fact that hydrogen bonds determine in
great extension the final crystal structure of bile acids [33,34]. So
the reason why the crystals of cholic acid and its derivatives (see
above) do not show the ‘‘ice-like’’ structure is probably due to
other hydrogen bonds in which the carboxylate group (tail) and
the O3-H hydroxy group (head) are involved. New derivatives with
different or additional characteristics to those of previous com-
pounds can be explored. For this purpose the O3-H hydroxy group
and the side chain at C17 (including the carboxylic group) can be
modified for finding a right derivative.
2
. Experimental
2.1. Synthesis of the 3-amide-succinyl derivative of cholic acid (suc-C)
The methyl ester of 3b-aminocholic acid is obtained from 3b-
amino-cholic acid (the synthesis of this amine derivative from
commercial cholic acid has been described elsewhere) [42,43]. Suc-
cinic anhydride (1.5 g, 15 millimol) is added to a solution of the
methyl ester derivative (6.15 g, 15 millimol) dissolved in a mixture
of THF (85 mL) and triethlamine (17 mL). The reaction was main-
tained for 4 h at room temperature. The reaction mixture was
added to 200 mL of HCl (1 M) in water and the solute extracted
with ethyl acetate. The organic phase was washed with water,
In fact some options have been explored in the literature
although the purpose of the published papers was another one.
For instance Miyata et al. [18,35] have shortened and lengthened
the C17 side chain but although water is included in those crystals
[
35], the tetrahedral structure is not present. Neither the change of
the carboxylic acid nor the O3-H hydroxy groups by amines [29],
show the desired result.
The closest results found in the literature correspond to two
hydrophobic derivatives (with the residue located at C3) [30–32,
2 4
dried (Na SO ) and evaporated under reduced pressure. The com-
pound is purified in a silica gel column using 3:2 ethyl acetate/
methanol as eluent and dried in a vacuum oven. Yield: 82%.
3
6–38] and to a cholaphane of cholic acid. One water molecule is
forming hydrogen bonds with O7-H and O12-H in a crystal of an
adamantyl derivative of cholic acid [30], but only one steroid mol-
ecule is involved and the water is forming only these two hydrogen
bonds. The ‘‘ice-like structure’’ is incomplete. A similar structure
was found for a tert-butylphenyl derivative of cholic acid [31]
2.2. Synthesis of C-suc-C
The compound is obtained by the reaction between succinic
dichloride and the methyl ester of 3b-amino-cholic acid. To syn-
thesize the succinic dichloride, succinic acid (0.24 g, 2 millimol)

1
230
V.H. Soto et al. / Steroids 77 (2012) 1228–1232
Table 1
Crystal data for the four epimers studied.
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
a (Å)
C
28
H
45NO
7
2
ꢁH O
56 90 2 11
C H N O
525.67
293 (2)
0.71069
943.28
100 (2)
0.71073
Monoclinic
P 21
10.612 (4)
22.603 (9)
10.982 (4)
90
96.966 (7)
90
Monoclínic
C
2
29.420 (5)
7.848 (5)
13.434 (5)
90.000 (5)
91.940 (5)
90.000 (5)
3100 (2)
4; 1.126
b (Å)
c (Å)
a
(°)
b (°)
(°)
c
Cell volume
Z, crystal density (g/cc)
2614.73 (18)
2; 1.198
0.082
Absorption coefficient
0.081
ꢃ1
(
mm
)
F(000)
1144
1032
3
Crystal size (mm )
Theta range for data
collection
0.41 ꢂ 0.14 ꢂ 0.09
0.68 ꢂ 0.38 ꢂ 0.19
1.39–20.81°
1.80–25.68°
Index ranges
ꢃ29 = < h = <29
ꢃ12 = < h = <12
ꢃ27 = < k = <12
0 = < l = <13
0
0
= < k = <7
= < l = <13
Data/restraints/parameters 1781/3/350
9918/27/622
0.9846 and 0.9463
Fig. 2. Molecular packing and main hydrogen bonds in the suc-C crystal.
Max. and min.
1 and 0.795537
transmission
Goodness of fit on F2
1.065
= 0.0488,
wR = 0.1361
= 0.0726,
wR = 0.1489
1.059
2
.891 Å (with O7) and 2.798 Å (with O12), and an almost perfect
Final R indices [I > 2
r
(I)]
R
1
R
1
= 0.0516,
wR = 0.1187
= 0.0726,
wR = 0.1269
2
2
tetrahedral O–O–O angle (107°) is also found. The water molecule
is forming hydrogen bonds with O7 and O12 hydroxy groups but
belonging to two different molecules. It is to say, the water mole-
cule is in a ‘‘wrong’’ place as it is not located under the steroid nu-
cleus (Fig. 2). It is forming three hydrogen bonds with three
different steroid molecules, the distances being 2.740 Å (O7, first
molecule), 2.721 Å (O12, second molecule), and 2.616 Å (O24a,
third molecule).
R indices (all data)
R
1
R
1
2
2
Largest diff. peak and hole/ 0.16 and ꢃ0.188 e Å-3 0.255 and ꢃ0.245
3
e Å
Absolute structure
parameter
4 (3)
ꢃ0.8 (9)
The C-suc-C crystal belongs to the monoclinic system, spatial
group P2 , and includes water in the structure with a 1:1 stoichi-
1
2 2
in SOCl (20 mL) is refluxed during 45 min under a CaCl trap and
concentrated under vacuum. The product is used without further
ometry. Fig. 3 shows the molecular packing along the c crystallo-
graphic axis. The packing evidences the formation of bilayers
with alternating hydrophobic–hydrophylic regions. The thickness
of the bilayer (11.302 Å) is half the value of the b crystallographic
axis. The two steroid molecules in the dimer (their geometry
parameters being almost identical but with some small differences
in lengths and angles) are disposed in an anti-parallel way (Fig. 3),
the angle between the horizontal planes [33] of the two steroid nu-
clei in the dimer being only 1.4° (i.e., they are almost parallel). Fur-
thermore, these planes are also almost parallel to the bilayer plane
since values of 4.5 or 5.5° (depending on the steroid nucleus of the
dimer) are obtained.
The most remarkable result for the purposes of this paper is that
water accommodates in the hydrophilic region of the bilayer estab-
lishing hydrogen bonds with the hydroxy groups O7 and O12 of
two steroid residues (located at opposite sides of the bilayer)
belonging to two dimers. These four oxygen atoms form a distorted
tetrahedral structure with a water molecule in its center (Fig. 4),
i.e., water is encapsulated in an ice-like structure. The main edge
length values, corresponding to distances between the hydroxy
groups of the steroids, are 4.52 ± 0.03 Å (O7–O12), 4.012 Å (O7–
O7) and 4.549 Å (O12–O12). The first one can be considered as
an imposed length as the two hydroxy groups belong to the same
steroid residue (Fig. 1, top right) but the other two distances are
the result of the formation of the ice-like encapsulated water, fix-
ing the steroid distance as well (see below). The average tetrahe-
dral angle is 110 ± 12°.
purification. The methyl ester of 3b-aminocholic acid (1.89 g,
4
.5 millimol) and dried triethylamine (0.72 mL, 4.5 millimol) were
dissolved in dried CHCl (50 mL). The mixture is cooled to 0 °C and
succinic dichloride (0.31 g, 2 mM) in CHCl (5 mL) was added drop-
wise. The reaction mixture is stirred for 12 h. The precipitated is
washed with CHCl and the solid is filtered off. The organic phase
is washed with water (2 ꢂ 20 mL) and NaOH (10%) in water
2 ꢂ 15 mL) and again with water (20 mL). The solution is dried
with MgSO and the compound is purified in a silica gel column
3
3
3
(
4
using 9:1 ethyl acetate/methanol as eluent.
Data for the colorless prismatic crystals of the two compounds
were collected on a Bruker Smart-CCD-1000. Molecular graphics
were from Mercury (http://www.ccdc.cam.ac.uk/prods/mercury).
A summary of the crystal data and experimental details are listed
in Table 1. Cif files are available as electronic supporting material.
CCDC 867498 and 867499 contain the supplementary crystallo-
graphic data for suc-C and C-suc-C crystals. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Center via www.ccdc.cam.ac.uk/data_request/cif.
3
. Results and discussion
The monomer suc-C was recrystallized from ethyl acetate/
water. The crystal belongs to the monoclinic system, spatial group
C2, and includes water in the structure with a 1:1 stoichiometry.
The packing shows a layer structure and a closer inspection reveals
that the place where, according to our expectations, the water
should be located, is occupied by the carbonyl (C = O26) of the
amide group at C3 (Fig. 2) of another steroid. The lengths of the
hydrogen bonds involving water are within standard values of
The average hydrogen bond lengths are 2.70 ± 0.06 Å and
2.94 ± 0.01 Å for O7ꢁꢁꢁH–OH (water being the donor) and H OꢁꢁꢁH–
2
O12 (water being the acceptor), respectively. All these values
favorably compare with those mentioned above for water in ice.

V.H. Soto et al. / Steroids 77 (2012) 1228–1232
1231
Fig. 3. Left: Bilayer structure in the C-suc-C crystal (view along the c crystallographic axis). Right: Detail of the dimer located in opposite sides of the bilayer with the linking
bridge crossing the hydrophilic layer.
Fig. 4. Hydrogen bonds of (i) the central water molecule with two steroid residues belonging to two dimers, (ii) bridge of a third steroid dimer [located behind the previous
two dimers] forming a clamp, and (iii) N25–HꢁꢁꢁO24b which mutually link each C24 carboxylic end of the one cholic residue with the nitrogen atom of the more distant amide
group of the bridge of the other cholic moiety. Location of the two centroids of the steroid residues participating in the formation of the ‘‘ice’’ tetrahedron.
It is interesting to notice that water being donor only towards O7
and acceptor only towards O12 guarantees the existence of only
one kind of hydrogen bond for each hydroxy group. This would
not be the case if water was simultaneously donor and acceptor to-
wards both hydroxy groups. This is a clear difference with what is
observed in the crystals of the adamantyl [30] and tert-butylphenyl
chain) length (6.117 Å) is close to the C3–N25 (succinyl bridge)
length (6.930 Å), together with the verticality of the two centroids.
The ‘‘ice-like’’ network, the clamp and the N25–HꢁꢁꢁO24b bonds
undoubtedly lead the whole structure towards the minimum free
energy. To the stabilization of the bilayers also contribute the
hydrophobic interactions between the b faces of the steroids (with
a b interdigitation of C18 and C19 methyl groups). This synergy
suggests that the whole structure will only be favored by a right
choice of the geometry of the bridge which must also carry hydro-
gen binding groups.
[
31] derivatives of cholic acid, where water is simultaneously do-
nor towards O7 and O12 and the ice-like structure is incomplete.
Another remarkable result in this structure is that each moiety
of the dimer is located in opposite sides of the bilayer with the
linking bridge crossing the hydrophilic layer (Fig. 3). The oxygen
atoms of the two amide groups of the bridge act as a clamp since
they establish hydrogen bonds with the two O7-H hydroxy groups
The suitability of the previous structure to specifically trap a
H O molecule is supported by the fact that water was not the ma-
2
jor component of the solvent [methanol/ethyl acetate] used for the
recrystallization. The major components are not included guests in
the crystal, so the minor component (water, approx. 0.3%) is in fact
extracted from the bulk solvent.
This also suggests that other packings for inclusion of specific
molecules can be designed by varying the bridge or by using other
pair of hydroxyl groups of the steroid nucleus. Since the O3–O7
and O3–O12 distances (5.0 and 5.7 Å, respectively) are larger than
(
O7-HꢁꢁꢁO26, 2.655–2.672 Å) which participate in the formation of
the tetrahedron. The bridge belongs to a third molecule. Those
hydrogen bonds together with the O7-water-O7 mentioned above
form a cycle (Fig. 4). The clamp helps in fixing the distance
between the two steroid nuclei which encapsulate the water
molecule. The two centroids of the C1/C5–C17 carbon atoms of
the steroid skeleton are on the same vertical line crossing the oxy-
gen atom of water (Fig. 4), the distance between them being
the O7–O12 used here, bile acids with those a-hydroxy groups can
6
.580 Å.
The hydrogen bond network in the crystal is completed by the
also be used for the inclusion of molecules with appropriate geom-
etries through hydrogen bonds interactions. Since bile acid crystals
are useful for the enantioresolution of different compounds (see
[32] and references therein) such an ability can advantageously
be used for developing new resolving systems. Attaching appropri-
ate groups on these sites of the steroid nucleus is an additional op-
tion already found in the literature. Resolution of enantiomers [32],
formation of N25–HꢁꢁꢁO24b hydrogen bonds (2.958–2.982 Å)
which mutually link each end of one cholic residue with the nitro-
gen atom of the more distant amide group of the bridge of the
other cholic moiety. These interactions are possible because of a
fully favorable geometry of the dimer since the C17–O24b (side

1
232
V.H. Soto et al. / Steroids 77 (2012) 1228–1232
or recognition of ions [44–48] and molecules [39,49–51] by modi-
fied bile acids are nice published examples.
[24] Dastidar P. Crystal structure of the inclusion complex of cholic acid with 4-
aminopyridine: a novel supramolecular architecture of cholic acid. Cryst Eng
Commun 2000:8.
[
25] Hishikawa Y, Watanabe R, Sada K, Miyata M. Molecular arrangements in chiral
sheets of N-alkylcholamides bilayered crystals. Chirality 1998;10:600–18.
26] Yoswathananont N, Kita H, Tohnai N, Sada K, Miyata M. A novel three-
component pseudo-polymorphism in the cholamide inclusion crystals
promoted by the combination of organic guest and water. Chem Lett
Acknowledgment
[
The authors thank the Ministerio de Ciencia y Tecnología, Spain
Projects MAT2007-61721 and MAT2010-19440] for financial sup-
port. J. V. Trillo also thanks for a scholarship. We thank Sapienza
Università di Roma [Project C26A08SZ38] for financial support.
2
002:1234–5.
[
[
27] Lessinger L, Low BW. Crystal structure and hydrogen-bonding system of cholic
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