Syntheses and crystal structures of two apigenin alkylation derivatives

Article abstract of DOI:10.1007/s10870-007-9271-0

Two apigenin alkylation derivatives, 4′,7-dimethoxyl-5-hydroxyflavone (I) and 4′,7-diethoxyl-5-hydroxyflavone (II), have been synthesized and their crystal structures were determined by ¹H NMR and single crystal X-ray diffraction study. (I) is triclinic, space group P-1 with a = 7.120(5) A, b = 7.297(5) A, c = 13.559(10) A, α = 89.313(12)°, β = 86.298(12)°, γ = 83.999(13)° and Z = 2. (II) is monoclinic, space group P 2₁ /c with a = 16. 309(4) A, b = 7.303(2) A, c = 15.185(4) A, α = 90.00°, β = 115.70(2)°, γ = 90.00° and Z = 4. They have the same flavone skeleton which is composed of a benzopyranone moiety and a phenyl moiety. Molecules of (I) are linked into a two-dimensional network by a combination of C-H...O hydrogen bond and π-π stacking interactions. (II) shows some discrepancies with (I) and the molecules are linked into a column by π-π stacking interaction.

Full text of DOI:10.1007/s10870-007-9271-0

J Chem Crystallogr (2008) 38:21–25
DOI 10.1007/s10870-007-9271-0
ORIGINAL PAPER
Syntheses and Crystal Structures of Two Apigenin Alkylation
Derivatives
Li-qun Kou Æ Xin-Li Cheng Æ Zun-Ting Zhang
Received: 1 December 2005 / Accepted: 9 October 2007 / Published online: 27 October 2007
ꢀ
Springer Science+Business Media, LLC 2007
0
Abstract Two apigenin alkylation derivatives, 4 ,7-di-
0
common flavonoids, is widely distributed in many fruits
and vegetables including parsley, onions, orange, tea,
chamomile, wheat sprouts and in some seasonings [1].
Apigenin has been shown to possess anti-inflammatory,
anti-carcinogenic effects for skin and free radical scav-
enging properties [2]. In some cells, apigenin has been
shown to display a variety of anti-tumor effects including
stimulation of gap junctional and intracellular communi-
cation [3], inhibition of mutagenesis [4], transformation
[5], angiogenesis [6] and tumorigenesis [7]. In this paper,
methoxyl-5-hydroxyflavone (I) and 4 ,7-diethoxyl-5-
hydroxyflavone (II), have been synthesized and their crystal
1
structures were determined by H NMR and single crystal
X-ray diffraction study. (I) is triclinic, space group P–1
˚
with a = 7.120(5) A, b = 7.297(5) A, c = 13.559(10) A,
˚
˚
a = 89.313(12)ꢁ, b = 86.298(12)ꢁ, c = 83.999(13)ꢁ and
Z = 2. (II) is monoclinic, space group P 2 /c with a = 16.
˚
1
˚
˚
3
09(4) A, b = 7.303(2) A, c = 15.185(4) A, a = 90.00ꢁ,
b = 115.70(2)ꢁ, c = 90.00ꢁ and Z = 4. They have the same
flavone skeleton which is composed of a benzopyranone
moiety and a phenyl moiety. Molecules of (I) are linked into
a two-dimensional network by a combination of C–HꢀꢀꢀO
hydrogen bond and p–p stacking interactions. (II) shows
some discrepancies with (I) and the molecules are linked
into a column by p–p stacking interaction.
0
the derivatives, 4 ,7-dimethoxyl-5-hydroxyflavone (I) and
0
4 ,7-diethoxyl-5-hydroxyflavone (II), resulting from alkyl-
0
ation of apigenin, at the 4 and 7 positions are obtained.
Both I and II are of interest due to their potential medical
applications. Here, we report the crystal structures of (I)
and (II) (Scheme 1).
Keywords Apigenin ꢀ Crystal structure ꢀ
0
4
4
,7-Dimethoxyl-5-hydroxyflavone ꢀ
Experimental
0
,7-Diethoxyl-5-hydroxyflavone ꢀ p–p Stacking
Reagent grade chemicals were used directly without further
1
purification. The H NMR spectra were recorded on a
Introduction
Bruker-1000 CCD spectrometer with TMS as internal
reference and DMSO-d as solvent. The crystal structure of
6
Flavonoids are diphenyl propanoids that occur far and wide
in plant foods and form important constituents of human
(I) was determined using Bruker Smart-1000 CCD Dif-
fractometer instrument, the crystal structure of (II) was
determined using Siemens P4 four-circle diffractometer
instrument. Melting points were obtained with an X4
melting point apparatus and uncorrected.
0
diet. Apigenin (4 ,5,7,-trihydroxyflavone), one of the most
L.-q. Kou ꢀ X.-L. Cheng ꢀ Z.-T. Zhang (&)
School of Chemistry and Materials Science, ShaanXi Normal
University, Xi’an 710062, P.R. China
Synthesis of Derivatives (I) and (II)
e-mail: zhangzt@snnu.edu.cn
For the preparation of (I), apigenin (1.0 g) was dissolved into
acetone (30 mL) and KOH (1 mL, 0.3%). Dimethyl sulfate
L.-q. Kou
Shaanxi Radio & TV University, Xi’an 710068, P.R. China
123

2
2
J Chem Crystallogr (2008) 38:21–25
Scheme 1 Routes of synthesis
I) and (II)
3'
2
'
'
1
8
(
HO
HO
O
O
H CO
8a O
3
7
2 1'
3
4'
(
CH ) SO
OH
3 2
4
B
OCH3
A
C
6
5'
6
KOH
4a
5
4
OH
OH
O
(I)
2
6
'
'
3'
1
8
O
C H O
8a O
(
C H ) SO
2
5
7
2
1'
4'
2
5 2
4
OH
B
OC H
2 5
A
C
6
3
5'
KOH
4a
5
4
OH
O
OH
O
(II)
Table 1 Crystal data and structure refinement for (I) and (II)
(
1 mL) was added dropwise to the solution with strong stir-
ring. The mixture was stirred at room temperature for 4 h and
then poured into 50 mL water, resulting in appearance of
yellow precipitation. After settlement for 2 h, the precipitate
was filtered and dissolved in 50 mL NaOH (3 mol/L). The
insoluble matter in NaOH (3 mol/L) was filtered and washed
Compound
(I)
(II)
CCDC deposit No.
Empirical formula
Formula weight
Temperature
291112
291113
C
17
14
H O
5
19 18 5
C H O
298.28
298(2) K
326.33
296(2) K
0
with water until the pH was 7, the title compound (I), 4 ,7-
˚
˚
0.71073 A
Wavelength
0.71073 A
Triclinic
P-1
dimethoxyl-5-hydroxyflavone was obtained, which was
recrystallized from benzene to give colorless needle crystal
Crystal system
Space group
Monoclinic
1
P 2 /c
after 5 days at room temperature. The yield is 80%, m.p:
1
˚
a = 7.120(5) A
˚
a = 16.309(4) A
Unit cell dimensions
4
8
46 K. H NMR (DMSO-d , ppm) d: 12.92(s, 1H, HO–C ),
6
5
˚
b = 7.297(5) A
˚
b = 7.303(2) A
.06(d, 2H, J = 8.8 Hz, H–C2
,C5
s, 1H, H–C ), 3.87(s, 3H, CH O–C ), 3.86(s, 3H, CH O–
0
,C6
0
), 7.12 (d, 2H, J = 8.8 Hz,
˚
˚
c = 15.185(4) A
0
0
), 6.94(s, 1H, H–C ), 6.79(s, 1H, H–C ), 6.38
3 8
c = 13.559(10) A
a = 89.313(12)ꢁ
b = 86.298(12)ꢁ
c = 83.999(13)ꢁ
H–C3
a = 90.00ꢁ
b = 115.70(2)ꢁ
c = 90.00ꢁ
(
6
3
7
3
C4
0
). The process of preparing (II) is similar to that of (I),
except that dimethyl sulfate is substituted by diethyl sulfate.
Crystals of (II) suitable for X-ray diffraction analysis were
obtained by slow evaporation from 95% ethanol solution after
–
3
–3
˚
˚
Volume
699.1(9) A
1629.7(7) A
Z
2
4
–
3
–3
3
days at room temperature. The yield is 60%, m.p: 452 K.
Density (calculated)
1.417 mg m
–1
Absorption coefficient 0.105 mm
1.330 mg m
–1
0.096 mm
1
H NMR (DMSO-d , ppm) d: 13.10(s, 1H, HO–C ), 8.33
6
5
(
d, 2H, J = 8.8 Hz, H–C2
H–C3 ,C5
H–C ), 4.12(m, 4H, –OCH –), 1.34(m, 6H, –OC–OCH ).
0
,C6
0
), 7.02 (d, 2H, J = 8.8 Hz,
F(000)
312
688
0
0
), 6.98(s, 1H, H–C ), 6.81(s, 1H, H–C ), 6.39(s, 1H,
h range for data
collection
2.81–25.01ꢁ
3.07–14.60ꢁ
3
8
6
2
3
Limiting indices
–8 £ h £ 8
–20 £ h £ 18
–9 £ k £ 0
0 £ l £ 18
–
8 £ k £ 6
16 £ l £ 16
–
X-ray Crystal Structure Determinations
Independent
reflections
3720/2448
[R(int) = 0.0497]
3713/3194
[R(int) = 0.0224]
The data of (I) and (II) were collected with graphite-
˚
Absorption
correction
Semi-empirical from Multi-scan
equivalents
monochromated Mo Ka radiation (k = 0.71073 A) using
x-2h scan technique. The structures were solved using
direct methods and refined by full-matrix least-squares
techniques. All non-hydrogen atoms were assigned aniso-
tropic displacement parameters in the refinement. All
hydrogen atoms were added at calculated positions and
refined using a riding model. Four C–H bond lengths for (I)
Data/restraints/
parameters
2448/4/256
3194/0/224
2
Goodness-of-fit on F
1.002
0.935
Final R indices
[
R = 0.0573,
1
R = 0.0472,
1
I [ 2sigma(I)]
R indices (all data)
wR
= 0.1893,
wR = 0.1146
2
= 0.0857
wR
= 0.1217,
wR = 0.1049
2
= 0.0924
R
1
R
1
2
2
2
were restrained. The structures were refined on F using
Extinction coefficient
0.007(3)
0.0098(7)
SHELXTL-97 [8]. The crystal used for the diffraction
study showed no decomposition during data collection.
The crystal data and refinement data are list in Table 1.
Largest diff. peak
and hole
0.338 and
–0.226 e. A
0.244 and
˚
–0.127 e. A
–
3
–3
˚
1
23

J Chem Crystallogr (2008) 38:21–25
23
˚
˚
Table 2 Selected bond lengths (A) and angles (ꢁ) for (I) and (II)
Table 3 Typical hydrogen bond lengths (A) and bond angles (ꢁ) for
(
I) and (II)
(
I)
(II)
D–H(A) HꢀꢀꢀA( A˚ ) DꢀꢀꢀA( A˚ ) D–HꢀꢀꢀA(ꢁ)
˚
D–HꢀꢀꢀA
˚
Bond lengths (A)
(
I) O3–H3OꢀꢀꢀO4
0.83(4) 1.80(4)
0.97(3) 2.60(3)
0.97(4) 2.44(4)
2.582(5) 156(4)
3.543(6) 165(3)
3.390(6) 166(3)
3.375(8) 171(4)
2.566(3) 156(3)
O1–C9
1.362(4)
1.389(4)
1.357(5)
1.440(6)
1.369(5)
1.252(5)
1.376(5)
1.381(5)
1.377(6)
1.384(6)
1.349(6)
1.415(6)
1.426(6)
1.434(5)
1.343(5)
1.465(5)
1.391(5)
1.388(5)
1.369(6)
1.374(6)
1.367(2)
a
C8–H8ꢀꢀꢀO4
O1–C1
1.379(2)
1.356(2)
1.437(3)
1.362(3)
1.264(2)
1.364(2)
1.381(3)
1.388(3)
1.397(3)
1.363(3)
1.413(3)
1.438(3)
1.422(3)
1.336(3)
1.466(3)
1.375(3)
1.391(3)
1.365(3)
1.368(3)
a
C15–H15ꢀꢀꢀO4
C16–H16AꢀꢀꢀO5 0.97(4) 2.41(4)
O2–C3
b
O2–C16
(
II) O3–H3OꢀꢀꢀO4
0.92(3) 1.70(3)
O3–C5
a
Symmetry code: (1 – x, 3 – y, –z); (x, y, 1 + z).
b
O4–C7
O5–C13
C1–C6
Selected bond lengths and bond angles are given in Table 2
for (I) and (II).
C1–C2
C3–C4
CCDC-291112 and CCDC-291113 contain the supple-
mentary crystallographic data for this paper. These data
can be obtained free of charge at http://www.ccdc.cam.
ac.uk/conts/retrieving.html [or from the Cambridge Crys-
tallographic Data Centre (CCDC), 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033; email:
deposit@ccdc.cam.ac.uk].
C4–C5
C5–C6
C6–C7
C7–C8
C8–C9
C9–C10
C10–C11
C11–C12
C12–C13
C14–C15
Bond angles (ꢁ)
C9–O1–C1
C3–O2–C16
O1–C1–C6
O1–C1–C2
C6–C1–C2
C1–C2–C3
O2–C3–C2
O2–C3–C4
C2–C3–C4
C5–C4–C3
O3–C5–C6
C4–C5–C6
C1–C6–C7
C5–C6–C7
O4–C7–C6
C8–C7–C6
C9–C8–C7
O1–C9–C10
C11–C10–C15
C15–C10–C9
C10–C11–C12
C13–C12–C11
O5–C13–C14
C12–C13–C14
C14–C15–C10
119.6(3)
117.8(4)
120.2(4)
115.0(4)
124.8(4)
116.7(5)
123.3(5)
114.7(4)
122.0(5)
118.9(5)
117.8(5)
122.8(5)
121.2(4)
124.0(5)
121.5(4)
115.2(4)
122.0(5)
127.5(4)
119.0(4)
119.8(4)
118.1(4)
122.0(4)
115.3(4)
120.3(4)
122.1(5)
119.52(17)
118.44(18)
121.1(2)
115.59(19)
123.3(2)
117.5(2)
123.8(2)
115.1(2)
121.1(2)
119.8(2)
118.6(2)
121.2(2)
119.9(2)
123.0(2)
121.1(2)
115.8(2)
122.3(2)
126.5(2)
117.2(2)
120.6(2)
122.0(2)
119.5(2)
115.3(2)
119.3(2)
121.1(2)
Fig. 1 A view of the molecules of (I) and (II), showing the atom-
labelling schemes. Displacement ellipsoids are drawn at the 30%
probability level
123

2
4
J Chem Crystallogr (2008) 38:21–25
Results and Discussion
as indicated by the torsion angles separately being C16–O2–
C3–C4 = 178.3(5)ꢁ and C17–O5–C13–C14 = 179.2(5)ꢁ. In
the crystal structure of (II), the ethoxy groups bonded to C3
and C13 are nearly coplanar with their attached rings, A
and B, as indicated by the torsion angles being C16–O2–
C3–C2 = 179.0(4)ꢁ and C18–O5–C13–C12 = 175.8(4)ꢁ,
respectively. Each of the molecule (I) and (II) has an
independent O3–H3OꢀꢀꢀO4 intramolecular hydrogen bond,
which generates a characteristic intramolecular S(6) motif.
In the crystal structure of (I), hydrogen bonding and
offset face-to-face aromatic p–p stacking interactions lead
In the crystal structures of (I) and (II) (Fig. 1), the atoms of
benzopyranone moiety containing rings A(C1–C6) and
C(O1/C1/C6–C9), display an almost coplanar configuration
with the dihedral angles being 178.6(2)ꢁ of (I) and 178.8(6)
of (II). The phenyl ring B(C10–C15) and benzopyranone
moiety are also almost coplanar with the dihedral angles
being 179.3ꢁ of (I) and 173.3ꢁ of (II), respectively. In the
crystal structure of (I), methoxyl groups bonded to C3 and
C13 are nearly coplanar with their attached rings, A and B,
Fig. 2 Part of the crystal
structure of (I), showing the
formation of bi-chains and sheet
via hydrogen bonds and p–p
stacking interactions. For
clarity, some hydrogen atoms
are omitted. Symmetry code:
*
1
(1 – x, 3 – y, –z); # (x, y,
+ z)
Fig. 3 Part of the crystal
structure of (II), showing the
formation of column by p–p
stacking interactions. For
clarity, all hydrogen atoms are
omitted
1
23

J Chem Crystallogr (2008) 38:21–25
25
to the formation of a (200) sheet (Fig. 2). The flavone
skeletons are arranged in an anti-parallel fashion; ring B
stacking interaction of (II) results in the formation of a
column along b-axis.
(
C10–C15) [symmetry code: (x, y, z)] of one molecular
stacks with ring C (O1/C1/C6–C9) [symmetry code:
x + 1, y, z)] of a neighbouring molecule with the inter-
Acknowledgment The authors thank the Science and Technology
Key Project of Education Ministry, P.R. China (No: 07138) for
financial support.
(
˚
planar distance of 3.347 A and the intercentroid of
˚ ˚
.546 A, the displacement of the two rings is 1.171 A. A
3
dimer is formed by the p–p stacking between two flavone
moieties. Paired hydrogen bonds C16–H16AꢀꢀꢀO5#
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˚
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123