Syntheses and crystal structures of diethylated daidzein sulfonates

Article abstract of DOI:10.3987/COM-05-10405

The water soluble derivatives of daidzein, sodium 4′,7- diethoxyisoflavone-3′-sulfonate (1), magnesium 4′,7- diethoxyisoflavone-3′-sulfonate (2) and zinc 4′,7- diethoxylisoflavone-3′-sulfonate (3) have been synthesized. 1 was characterized by ¹

Full text of DOI:10.3987/COM-05-10405

HETEROCYCLES, Vol. 65, No. 8, 2005
1947
HETEROCYCLES, Vol. 65, No. 8, 2005, pp. 1947 - 1956
Received, 23rd March, 2005, Accepted, 13th May, 2005, Published online, 17th May, 2005
SYNTHESES AND CRYSTAL STRUCTURES OF DIETHYLATED
DAIDZEIN SULFONATES
Zun-Ting Zhang a* and Qiu-Ya Wang b
aSchool of Chemistry and Materials Science, Shaanxi Normal University, Xi'an,
China, 710062, Tel.: 86-29-85303940
bDepartment of Chemistry and Chemical Engineering, WeiNan Teachers College,
WeiNan, China, 714000
(E-mail: zhangzt@snnu.edu.cn)
Abstract – The water soluble derivatives of daidzein, sodium 4',7-
diethoxyisoflavone-3'-sulfonate (1), magnesium 4',7-diethoxyisoflavone-3'-
sulfonate (2) and zinc 4',7-diethoxylisoflavone-3'-sulfonate (3) have been
1
synthesized. 1 was characterized by H NMR and IR spectra, 2 and 3 were
determined by single-crystal X-Ray diffraction analysis. The molecular structural
characteristic of 2 is similar to that of 3. Their molecular contents are
-
[Mg(H2O)]6(X)2·8H2O and [Zn(H2O)]6(X)2·8H2O (X=C19H17O4SO3 ), respectively.
Two isoflavone skeletons of them have two different conformations. Twelve H
atoms of six coordinated water molecules form hydrogen bonds with four oxygen
atoms of sulfo-groups of two isoflavone skeletons and eight oxygen atoms of
eight lattice water molecules. In addition, the π-π stacking interaction exists
between isoflavone skeletons in the crystal structure of 2 and 3, which together
with many kinds of hydrogen bonds lead to supramolecular formation with a
three-dimensional network structure.
INTRODUCTION
Flavonoids are a broad class of polyphenolic secondary metabolites abundant in vascular plants and in
various foods such as apples, soy, onions and tea. They possess a number of pharmacological properties,
including anti-oxidant, anti-cancer, anti-viral and anti-inflammatory properties.1 Daidzein, a natural soy
isoflavone, has been pharmacologically shown to be antidysrhythmic2 and antioxidant,3-4 to remove
hyperkinesias,5 to inhibit cancer cells growth,6-8 to accelerate the formation of bones cells9 and to mimic a

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HETEROCYCLES, Vol. 65, No. 8, 2005
female hormone.10 However, the pharmacological utilization rate of daidzein is low and the dose is high
for the poor solubility.11 Thus, the route to synthesize a water soluble derivative of daidzein is required in
order to study its possible biological effects. We have synthesized several derivatives of daidzein, namely
sodium 7-methoxy-4'-hydroxyisoflavone-3'-sulfonate,12 sodium 4',7-dihydroxyisoflavone-3'-sulfonate13
and sodium 5,7-dihydroxy-4',6-dimethoxyisoflavone-3'-sulfonate,14 and have studied their crystal
structures and biological activities. The results showed that they possess better biological activity than
daidzein. In this paper, three water soluble derivatives of daidzein, sodium 4',7-diethoxy-
isoflavone-3'-sulfonate(1), magnesium 4',7-diethoxyisoflavone-3'-sulfonate(2) and zinc 4',7-diethoxy-
isoflavone-3'-sulfonate(3) were synthesized. 1 was characterized by 1H NMR and IR spectra, and 2 and 3
were determined by single-crystal X-Ray diffraction analysis. In the crystal structures, the molecular
-
contents of 2 and 3 are [Mg(H2O)]6(X)2·8H2O and [Zn(H2O)]6(X)2·8H2O (X=C19H17O4SO3 ). Hydrogen
bonding and π-π stacking interaction exist in them, which together with the electrostatic interaction
assemble 2 and 3 into a three-dimensional network structure, respectively.
RESULTS AND DISCUSSION
THE SULFONATION OF 4',7-DIETHOXYLISOFLAVONE
The sulfonation reaction between 4',7-diethoxyisoflavone and the concentrated sulfuric acid has been
carried out for half an hour at the room temperature. Although there is also an ethoxy group at C-7
position, the ring A can not be sulfonated. The reason is that the proton from the concentrated H2SO4
combines with the oxygen atom of ring C to form an oxonium ion (Scheme 1). The oxonium ion with
positive charge dramatically passivates ring A, so it is hard to be sulfonated.
1
H+
O
8
C2H5O
O
2
3
C2H5O
O+
C2H5O
H+
7
A
C
6'
B
6
5'
4
1'
2'
5
O
OH
OC2H5
O
4'
OC2H5
3'
OC2H5
Scheme 1 The isomer of 4',7-diethoxyisoflavone in the concentrated H2SO4.
1H NMR, IR SPECTRA OF COMPOUND (1)
In IR spectra of 1, the characteristic absorption at 1626.3 cm-1 belongs to the –C=O vibration of the group
in the isoflavone skeleton. And two strong absorptions were increased at 1097.3 cm-1and 1033.5 cm-1
compared with IR spectra of daidzein, validating the existence of sulfo-group in 1. In the 1H NMR spectra
of 1, compared with that of daidzein, the shapes, chemical shifts and coupling constants of protons in the
benzopyranone moiety have no obvious alterations, while for ring B, one doublet was replaced by one

HETEROCYCLES, Vol. 65, No. 8, 2005
1949
singlet, and one proton resonance was decreased. From the chemical shifts and coupling constant, we can
infer that the sulfo-group was at C3' or C5' position in ring B.
THE CRYSTAL STRUCTURE OF COMPOUNDS 2 AND 3
DESCRIPTION OF THE MOLECULAR STRUCTURE
The molecular structures of 2 and 3 are illustrated in Figure 1 and Figure 2, respectively. Their contents
are [Mg(H2O)]6(X)2·8H2O and [Zn(H2O)]6(X)2·8H2O. Every one of them contain two 4',7-diethoxy-
isoflavone-3'-sulfonate anions, which can be labeled as X1(C1-C19, O1-O7, S1) and X2(C20-C38,
O8-O14, S2). Both X1 and X2 consist of a benzopyranone moiety, a phenyl moiety, two ethoxy group
and a sulfonate monoanion. Two metal cations are both coordinated by six water molecules, which form
distorted octahedral complex cations, the average bond length of Mg–O and Zn–O are 2.75 Å and 2.77 Å,
respectively. In X1and X2, the bonds lengths and angles of isoflavone skeleton are similar to those of
magnesium 7-methoxy-4'-hydroxyisoflavone-3'-sulfonate.15 The atoms of benzopyranone moiety of 2 and
3 are nearly coplanar. For 2, the dihedral angle between ring A(C4-C9) and C(C1-C4,C9,O1 ) is 2.6° in
X1; the dihedral angle between ring A(C23-C28) and C (C20-C23,C28,O8 ) is 1.0° in X2. And those of 3
are 3.1° and 1.2°, respectively. All ethoxyl groups of 2 and 3 are slightly twisted out of benzopyranone
moiety or phenyl ring with small torsion angles. However, X1 and X2 are two different conformers of the
4',7-diethoxyisoflavone-3'-sulfonate anion. The two rigid ring systems, phenyl ring and benzopyranone
moiety are rotated by an angle with respect to each other. In the structure of 2, the torsion angle
C11-C10-C2-C1 and C30-C29-C21-C22 are -26.21˚ and 33.40˚, respectively, which generate two
different notational conformations: the carbonyl group and sulfo-group are on the different sides of
isoflavone skeleton by and large in X1, while they lie on the same side basically in X2. Being similar to 2,
the isoflavone skeletons of 3 also have two comformations. In X1, the torsion angle C11-C10-C2-C1 is
-27.73˚; In X2, C30-C29-C21- C22 is 33.64.
HYDROGEN BONDS
As shown in Figure 1, twelve H atoms (H38-H50) of six coordinated water molecules, as donor, form 12
hydrogen bonds with four oxygen atoms (O6, O7, O12, O14) of sulfo-group of X1, X2 and eight oxygen
atoms (O21-O28) of eight lattice water molecules. In the molecular structure of 2, O19–H47···O7,
O20–H50···O6 are the hydrogen bonds between coordinated water molecules and X1; O16–H42···O14,
O17–H44···O12 are the hydrogen bonds between coordinated water molecules and X2. The hydrogen
bonds O15–H40···O25, O15–H39···O21, O16–H41···O28, O17–H43···O27, O18–H45···O23, O18–
H46···O26, O19–H48···O22, O20–H49···O24 exist between coordinated water molecules and eight lattice
water molecules (Details of bond lengths and angles are given in Table 1). The H···O bond distances of all

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HETEROCYCLES, Vol. 65, No. 8, 2005
the hydrogen bonds range from 1.850 Å to 2.040 Å, which indicates all of them are strong. Being similar
to 2, in the molecular structure of 3, twelve H atoms of six coordinated water molecules also form
hydrogen bonds with the oxygen atoms of sulfo-group of X1 and X2 and eight oxygen atoms of eight
lattice water molecules (Details of the hydrogen bonds in 3 are also listed in Table 1). The hydrogen
bonds not only link the isoflavone skeletons, coordinated water molecules and lattice water molecules
together, but also play very important roles in the formation, stability and crystallization of two title
compounds.
Figure 1 The molecular structure of 2 showing 30% probability displacement ellipsoids. For clarity, all H atoms have
been omitted apart from the H atoms of six coordinated water molecules. Thin dashed lines indicate the O–H···O
hydrogen bonds.
Figure 2 The molecular structure of 3 showing 30% probability displacement ellipsoids. For clarity, all H atoms have
been omitted apart from the H atoms of six coordinated water molecules. Thin dashed lines indicate the O–H···O
hydrogen bonds.

HETEROCYCLES, Vol. 65, No. 8, 2005
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Table1 Typical hydrogen bond lengths (nm × 10-1) and bond angles ( ˚ ) for 2 and 3
Bond
C–H
H···O
1.972
1.896
1.921
1.937
1.850
1.898
1.906
1.893
1.896
1.891
1.875
2.040
1.997
2.021
2.035
2.039
1.941
1.967
2.122
1.895
1.932
2.147
1.896
1.896
1.964
1.885
1.949
1.995
1.921
1.863
1.889
1.939
2.105
1.970
1.870
2.003
2.116
1.864
1.959
2.139
1.838
2.073
2.030
2.130
2.250
2.028
1.873
1.930
1.926
1.910
2.040
1.980
1.967
2.150
Distance
2.846
2.786
2.817
2.782
2.739
2.786
2.784
2.772
2.782
2.778
2.747
2.828
2.875
2.875
2.825
2.929
2.838
2.865
2.943
2.772
2.752
2.927
2.783
2.781
2.859
2.778
2.832
2.775
2.807
2.724
2.781
2.754
2.812
2.736
2.741
2.770
2.731
2.724
2.828
2.949
2.734
2.920
2.825
2.895
2.902
2.882
2.733
2.757
2.785
2.784
2.897
2.775
2.860
2.757
Angle
164.08
172.73
178.40
156.16
173.99
170.42
167.93
166.42
171.61
172.59
163.53
145.61
163.72
157.94
145.94
169.31
179.12
174.37
150.83
164.38
154.41
145.00
170.02
166.57
172.27
170.66
168.24
144.42
175.06
176.07
174.07
150.00
135.00
142.62
163.16
143.43
125.35
158.72
164.00
150.11
171.45
156.71
145.70
142.68
129.82
157.76
160.63
153.75
158.71
166.25
160.58
147.58
169.88
125.23
Symmetric code
O16–H42···O14
O17–H44···O12
O19–H47···O7
O20–H50···O6
O15–H40···O25
O15–H39···O21
O16–H41···O28
O17–H43···O27
O18–H45···O23
O18–H46···O26
O19–H48···O22
O20–H49···O24
O21–H52···O5
O22–H54···O5
O23–H55···O13
O24–H58···O14
O25–H60···O12
O26–H61···O6
O28–H65···O13
O21–H51···O22
O22–H53···O26
O23–H56···O24
O25–H59···O28
O26–H62···O25
O27–H63···O21
O28–H66···O23
O15–H39···O13
O16–H41···O6
O18–H45···O5
O19–H48···O12
O15–H40···O23
O16–H42···O24
O17–H43···O22
O17–H44···O25
O18–H46···O28
O19–H47···O27
O20–H49···O26
O20–H50···O21
O21–H51···O12
O23–H55···O14
O24–H57···O9
O24–H58···O13
O25–H60···O14
O26–H61···O7
O27–H64···O5
O28–H65···O7
O21–H52···O23
O22–H53···O28
O22–H54···O21
O23–H56···O25
O25–H59···O24
O26–H62···O28
O27–H63···O26
O28–H66···O22
0.898
0.894
0.895
0.898
0.893
0.897
0.891
0.896
0.892
0.893
0.897
0.899
0.902
0.900
0.899
0.901
0.897
0.901
0.902
0.899
0.901
0.897
0.897
0.901
0.901
0.900
0.896
0.892
0.895
0.903
0.897
0.901
0.899
0.899
0.891
0.897
0.900
0.900
0.897
0.896
0.903
0.900
0.897
0.897
0.903
0.901
0.898
0.899
0.901
0.897
0.899
0.897
0.902
0.897
I
II
-x+3, -y, -z+1
-x+2, -y, -z+1
-x+1, -y+1, -z+1
-x+2, -y+1, -z+1
x+1, y, z
x-1, y, z
-x+2, -y+1, -z+1
-x+2, -y, -z+1
2
III
IV
I
x-1, y, z
-x+2, -y+1, -z+1
II
x-1, y, z
3
-x, -y, -z+1
-x, -y, -z+1
-x, -y, -z+1
III
-x+1, -y, -z+1
-x-1, -y+1, -z+1
-x, -y+1, -z+1
-x, -y+1, -z+1
x+1, y, z
-x, -y, -z+1
IV
-x, -y+1, -z+1
I: the hydrogen bonds between the coordinated water molecules and X1, X2.
II: the hydrogen bonds between the coordinated water molecules and lattice water molecules.
III: the hydrogen bonds between lattice water molecules and X1, X2.
IV: the hydrogen bonds between lattice water molecules

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HETEROCYCLES, Vol. 65, No. 8, 2005
Figure 3 The zig-zag chain along the (1 0) direction in 2 or 3. For clarity, some H atoms have been omitted. Thin
dashed lines between X1 and X2 represent hydrogen bonds C37–H37···O2, Thin dashed lines between X1 and X1 or X2
and X2 indicate π-π stacking interactions.
AROMATIC π-π STACKING
Furthermore, two kinds of dimers exist in the structures of 2 and 3. One kind of dimer is formed via π-π
stacking interactions between X1 and X1. In two X1 molecules arranged in an antiparallel fashion, the
stacking exists between ring A, ring C of an isoflavone skeleton and ring C, ring A of another isoflavone
skeleton. In the structure of 2, their centriod-centriod distance is 3.575 Å, and the separation between two
planes is 3.341 Å. And those of 3 are 3.557 Å and 3.374 Å, respectively. The other kind of dimer is
formed via π-π stacking interactions between X2 and X2. In like manner, they are arranged in an
antiparallel fashion, and the stacking exist between ring A, ring C of an isoflavone skeleton and ring C,
ring A of another isoflavone skeleton. the centriod-centriod distance is 3.582 Å, and the separation
between two planes is 3.4063 Å in 2. And in 3, the centriod-centriod distance and the separation are 3.655
Å and 3.4342 Å, respectively. And two kinds of dimers are further linked into a zig-zag chain along the
(1 0) direction by the intermolecular hydrogen bond C37–H37···O2 (Figure 3). For the hydrogen bond
C37–H37···O2, the distances of C37···O2 and H37···O2 are 3.204 Å and 2.401 Å, the bond angle
C37–H37···O2 being 139.90º in 2, and those of 3 are 3.228 Å and 2.419 Å, 140.64º, respectively.
CONCLUSION
As is shown in Figure 4, 2 has a special packing motif. In its structure, the coordinated water molecules,
sulfo-group and carbonyl are all hydrophilic. The distance between them is short and the areas which are
surrounded by them are filled with the lattice water molecules. Therefore, there are hydrogen bond
networks in the areas. Apart from the hydrogen bonds involved in the Figure 1, the hydrogen bonds
O21–H51···O22, O22–H53···O26, O23–H56···O24, O24–H57···O23, O25–H59···O28, O26–H62···O25,
O27–H63···O21, O28–H66···O23 all exist between the lattice water molecules. And O21–H52···O5,
O22–H54···O5, O23–H55···O13, O24–H58···O14, O25–H60···O12, O26–H61···O6, O28–H65···O13 are

HETEROCYCLES, Vol. 65, No. 8, 2005
1953
all the hydrogen bonds between the oxygen atom of sulfo-group and lattice water molecules. The
hydrogen bonds linked the cations [Mg(H2O)6]2+ and sulfo-group into columns, which consist of the
hydrophilic areas of 2. On the contrary, there are not any hydrophilic groups and hydrogen bonds in the
hydrophobic areas formed by isoflavone moieties. The sulfo-group is an important bridge as a structural
link between the hydrophilic region and the hydrophobic region. 3 has the same packing manner with 2.
In 2 or 3, hydrogen bonding, π-π stacking interactions and the electrostatic interaction between the cation
-
[Mg(H2O)6]2+ or [Zn(H2O)6]2+ and the anion sulfonate C17H13O6SO3 lead to the formation of
supramolecule in three-dimensions.
Figure 4
The unit cell packing diagram of 2
EXPERIMENTAL
Syntheses of Compounds (1, 2 and 3)
Chemicals were of analytical reagent grade and used directly without further purification. The infrared
spectra were recorded as KBr pellets on a Nicolet 170SX FT-IR spectrophotometer. The 1H NMR spectra
were recorded on a Bruker-1000 CCD spectrometer with TMS as internal reference and DMSO-d6 as
solvent. The crystal structures were determined with a Bruker Smart-1000 CCD diffractometer. The
sodium 4',7-diethoxyisoflavone-3'-sulfonate was synthesized according to the following procedures
(Scheme 2).

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HETEROCYCLES, Vol. 65, No. 8, 2005
1
8
C2H5O
O
HO
O
O
C2H5O
O
2
3
(C2H5)2SO4
H2SO4
NaCl
7
A
C
6'
B
6
5'
4
1'
2'
5
O
O
OC2H5
OH
OC2H5
4'
3'
SO3Na
Scheme 2
Daidzein (4 g, 15.74 mmol) was dissolved into 5% NaOH (50 mL, 62.50 mmol). Diethyl sulfate (6 mL,
45.97 mmol) was added dropwise to the solution with vigorous stirring. The mixture was stirred at rt for 3
h and a precipitation appeared. The precipitate was filtered and washed with water until the pH of the
filtrate was 7, then recrystallized in ethanol for three times, giving 4',7-diethoxyisoflavone (2.8 g, 9.03
mmol). 4',7-Diethoxyisoflavone (2 g, 6.45 mmol) was slowly added to the concentrated sulfuric acid (8
mL), the mixture was stirred at rt for 1 h and poured into a saturated NaCl solution (60 mL) and a white
precipitate formed. This precipitate was collected by filtration and washed with saturated NaCl solution
until the pH value of the filtrate was 7. Finally, the precipitate has been recrystallized in water for three
1
times and dried in vacuo to afford sodium 4', 7-diethoxylisoflavone-3'-sulfonate (2.2 g, 82.76%). H
NMR(DMSO-d6, 300 MHz)δ: 8.34(s, 1H, 2-H), 8.05(d, 1H, J = 9 Hz, 5-H), 7.91(s, 1H, 2'-H), 7.45(d, 1H,
J = 8.4 Hz, 6'-H), 7.13(s, 1H, 8-H), 7.08 (d, 1H, J = 9 Hz, 6-H), 6.99( d, 1H, J = 8.4 Hz, 5'- H), 4.20(q,
2H, J = 6.9 Hz, 4'-OCH2-CH3), 4.10(q, 2H, J = 6.9 Hz, 7-OCH2-CH3), 1.39(t, 3H, J = 6.9 Hz,
4'-OCH2-CH3), 1.33 (t, 3H, J = 6.9 Hz, 7-OCH2-CH3). IR(KBr) ν: 3440.7, 2982.0, 2932.9, 1626.3, 1566.0,
1491.6, 1445.0, 1394.3, 1256.8, 1202.3, 1097.3, 1033.5cm-1.
1(2 g, 4.85 mmol) was dissolved in water (20 mL), then divided them into two shares and mixed with
saturated MgSO4·7H2O solution (5 mL) and saturated ZnSO4·7H2O solution, respectively. Crystals of 2
and 3 were obtained after 24 h from water in good yield. 2 was recrystallized from ethanol-water (V:V,
1:1) solution to give colorless prism crystal. Colorless and transparent thin crystals of 3 were grown by
slow evaporation from its water solution.
X-Ray Crystal Structure Analysis
In the determination of the structures of the crystals 2 and 3, X-Ray determination data were collected on
a Bruker Smart-1000 CCD diffractometer with graphite-monochromated Mo Kα radiation (λ＝0.71073
Å ) using ω-2θ scan technique. The structures were solved by direct methods and refined on F2 by full
matrix least-squares with the SHELXL-9716 program. All non-hydrogen atoms were refined
anisotropically. All hydrogen atoms were treated using a riding model. The crystals used for the
diffraction study showed no decomposition during data collection. The crystals data, experimental details,
and refinement results are summarized in Table 2.

HETEROCYCLES, Vol. 65, No. 8, 2005
1955
CCDC-261245 and 261246 contain the supplementary crystallographic data for this paper. These data can
be obtained free of charge at www.ccdc.cam.ac.uk /conts/ retrieving.html [or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax:
44(0)1223-336033; email: deposit@ ccdc .cam.ac.uk ].
Table 2 Crystal Data and Structure Refinement for 2 and 3
2
3
Empirical formula
Formula weight
Crystal size
C38H62O28MgS2
1055.31
0.32 × 0.19 × 0.11 mm
571(2) K
C38H62O28S2Zn
1096.37
0.47 × 0.23 × 0.19 mm
571(2) K
Temperature
Crystal system
Space group
Unit cell dimensions
Triclinic
P
Triclinic
P
a = 9.036(3) Å, α = 72.379(6)º
b = 16.442(6) Å, β = 87.346(6)º
c = 18.212(7) Å, γ = 82.888(6)º
2558.7(16) Å3 , 2
1.370 Mg/m3
a = 9.018(5) Å, α = 72.326(7)º
b = 16.406(9) Å, β = 87.456(8)º
c = 18.164(9) Å, γ = 82.772(8)º
2540(2) Å3 , 2
Volume, Z
Density(calculated)
1.433 Mg/m3
0.204 mm-1
2.27 to 25.03º
0.654 mm-1
Absorption coefficient
Θ range for data collection
Limiting indices
Reflections collected / unique
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2σ(I)]
R indices (all data)
2.32 to 25.03º
-10≤ h ≤ 10, -19≤ k≤ 19, -21≤ l≤ 20 -8≤ h≤ 10, -19≤ k≤ 19, -21≤ l≤ 20
13600/8934 [R int= 0.0669]
0.9779 and 0.9375
12712/8505 [R int = 0.0495]
0.8858 and 0.7485
Full-matrix least-squares on F2
8934/42/706
Full-matrix least-squares on F2
8505/44/706
0.995
1.007
R1 = 0.0721, wR2 = 0.1025
R1 = 0.2162, wR2 = 0.1366
0.590 and -0.362 e. Å-3
R1 = 0.0777, wR2 = 0.1729
R1 = 0.1605, wR2 = 0.2338
1.032 and -0.456 e. Å-3
Largest diff. peak and hole
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