Synthesis and crystal structure of heptyl 3-(3,4-dihydroxyphenyl)-2- propenoate

Article abstract of DOI:10.1007/s10870-008-9341-y

The title compound, C₁₆H₂₂O₄, synthesized by modified Knoevenagel condensation of protocatechualdehyde with monoheptyl-malonate and recrystallized from benzene, was confirmed by single-crystal X-ray diffraction (CCDC 27282

Full text of DOI:10.1007/s10870-008-9341-y

J Chem Crystallogr (2008) 38:583–586
DOI 10.1007/s10870-008-9341-y
ORIGINAL PAPER
Synthesis and Crystal Structure of Heptyl
3-(3,4-dihydroxyphenyl)-2-propenoate
Chun-nian Xia Æ Wei-xiao Hu Æ Wei Zhou Æ
Guo-hong Wang
Received: 1 April 2006 / Accepted: 27 March 2008 / Published online: 10 April 2008
Ó Springer Science+Business Media, LLC 2008
Abstract The title compound, C16H22O4, synthesized by
modified Knoevenagel condensation of protocatechualde-
hyde with monoheptyl-malonate and recrystallized from
benzene, was confirmed by single-crystal X-ray diffraction
(CCDC 272827). The compound crystallizes in triclinic space
major biologically active compounds [10]. Caffeic acid
esters have been synthesized previously by methods such
as: acid-catalyzed esterification [7a, 11]. alkylation of
caffeic acid with halohydrocarbons [2, 12], esterification
via acyl chlorides [8a, 13], coupling reaction with DCC as
coupling agent [14], transesterification [1, 15] and Wittig
reaction [7a, 11b, 16]. Comparing with the reported
methods, a more convenient synthetic route was found as
outlined in Scheme 1. The properties of caffeic acid esters
are affected by the length of ester moiety [17], so the
knowledge of the structural characteristic of these ana-
logues is of the utmost importance of the understanding of
the quantitative structure–activity relationships (QSARs)
underlying their biological activity. Encouraged by the
aforementioned information, it was considered valuable to
synthesize compound 3 characterized by X-ray studies.
˚
group P¯ı with cell parameters a = 5.296(3) A, b = 10.711
˚
˚
(13) A, c = 13.870(4) A, a = 98.84(7)°, b = 90.97(4)°,
c = 96.77(7)° and Z = 2. The structure is the E isomer and its
packing is stabilized by intermolecular O–HÁÁÁO and C–HÁÁÁO
hydrogen bonds.
Keywords Caffeic acid ester Á Synthesis Á
Crystal structure Á Knoevenagel condensation Á
X-ray diffraction
Introduction
Some naturally occurring caffeic acid esters are widely
distributed in plant kingdom [1, 2]. Most of them have
bioactivities such as antibacterial [3], antiviral [4], anti-
inflammatory [5], antiatherosclerotic [6], anti-HIV [4, 7],
antitumor [8] and so on. Epidemiological studies indicate
that a rich diet in fruits and vegetables reduces cancer risk
in humans, suggesting that certain dietary constituents may
be effective in preventing cancer [9]. Especially, caffeic
acid phenethyl ester (CAPE) have been identified as the
Experimental
Diheptyl-malonate (1)
Malonic acid (10.4 g, 0.1 mol), heptyl alcohol (23.2 g,
0.2 mol) and DPAT (Diphenyammonium triflate) [18]
(0.64 g, 0.002 mol) were heated to 80 °C in toluene
monitoring by TLC (about 6 h). After evaporation of tol-
uene in vacuum, the crude material was washed with
diluted HCl solution, saturated NaHCO3 solution and water
respectively to afford diheptyl-malonate 29.5 g (98.3%).
C. Xia Á W. Hu (&) Á W. Zhou
College of Pharmaceutical Science, Zhejiang University of
Technology, Hangzhou 310032, People’s Republic of China
e-mail: huyang@mail.hz.zj.cn
Monoheptyl-malonate (2)
KOH (5.6 g, 0.1 mol) in ethanol (64 mL) was added into a
solution of diheptyl-malonate (0.1 mol) and absolute eth-
anol (64 mL) at the temperature below 0 °C in 0.5 h, and
G. Wang
Zhejiang Shou & Fu Chemical Ltd., Dongdu Qiaotou, Jinyun,
Zhejiang 321400, People’s Republic of China
123

584
J Chem Crystallogr (2008) 38:583–586
HO
HO
HO
HO
COOH
COOR
COOR
COOH
COOR
Scheme 1 The synthesis route
of caffeic acid heptyl ester
+/H2O
<°
CHO
NH
H
KOH/EtOH
<0°
Toluene
2ROH
DPAT/80°
+
N
O
COOH
R
O
1
2
3
N
-O2
+
H
O
F
DPAT:
S
R=
O
F
F
stirred an additional 0.5 h. The white precipitate of mono-
potassium malonate was collected by suction filtration. The
potassium salt was dissolved in 20 mL water cooled to
0 °C, concentrated HCl was added till pH to 2 then was
extracted by diethyl ether. After removal of the ether, the
monoheptyl-malonate (15.6 g, 77.2%) was obtained.
standard reflections were monitored at intervals of 60 min.
The ranges of h, k, l are -6 B h B 6, -1B k B 12,
-16 B l B 16. The intensities were corrected for Lorentz
and polarization effects but not for absorption correction.
The details of crystal data and refinement are given in
Table 1.
Heptyl 3-(3,4-dihydroxyphenyl)-2-propenoate (3)
3,4-Dihydroxybenzaldehyde (1.4 g, 10 mmol) and mono-
heptyl malonate (5.1 g, 25 mmol) were dissolved in a
mixture of pyridine (5 mL) and piperidine (0.2 mL). The
solution was stirred at room temperature for 16.5 h and
concentrated in vacuo to give a dark-brown mixture. The
mixture was dissolved in diethyl ether (30 mL), washed
with saturated NaHCO3 solution, diluted HCl solution and
distilled water respectively; then dried with anhydrous
MgSO4. The solution was filtered and concentrated to yield
a light yellow crystalline product (1.9 g, 68.3%). Recrys-
tallization from a mixture of benzene and diethyl ether
(1:1) gave colorless crystalline prisms (m.p. 381–382 K).
Single crystals of 3 suitable for X-ray analysis were
obtained by slow evaporation from benzene.
IR (KBr)/cm-1: 3489, 3317, 1682, 1604, 1441, 1282; 1H
NMR(DMSO-d6): d9.57(s, 1H, OH),9.11(s, 1H, OH),7.46(d,
1H, J = 15.9 Hz, a-H), 7.04 (d, 1H, J = 1.9Hz, Ph-H), 7.00
(dd, 1H, J = 1.9, 8.4 Hz, Ph-H), 6.78 (d, 1H, J = 8.1 Hz,
Ph-H), 6.25 (d, 1H, J = 15.9 Hz, b-H), 4.10 (t, 2H, CH2),
1.62 (m, 2H, CH2), 1.13 (m, 8H, 4CH2), 0.86 (t, 3H, CH3).
MS: m/z 278(M+, 67%) 180(100), 163(76), 136(38),
134(47), 89(59), 55(44), 41(59). Anal. Cal. for C16H22O4: C,
69.04; H, 7.97. Found: C, 69.43; H, 7.97%.
Table 1 Crystal data and experimental crystallographic details
Empirical formula
Formula weight
Temperature (K)
Wavelength
C16H22O4
278.34
293(2)
˚
k = 0.71073 A
Triclinic
P¯ı
Crystal system
Space group
Cell dimensions
˚
a(A)
5.296(3)
˚
b(A)
10.711(13)
˚
c(A)
13.870(4)
a(°)
b(°)
c(°)
98.84(7)
90.97(4)
96.77(7)
3
˚
Volume(A )
771.5(11)
Z
2
Density(calculated) (Mg/m3)
Absorption coefficient (mm-1
F000
1.198
)
0.085
300
Crystal size
0.40 9 0.30 9 0.20 mm
1.49 to 25.17°
-6 B h B 6
h range for data collection
Index ranges
-1 B k B 12
Crystal Structure Determination of 3
-16 B l B 16
3258/2769 [R(int) = 0.0312]
2769
Reflections collected
Independent reflections
Refinement method
A single crystal of 3 of dimensions 0.40 9 0.30 9
0.20 mm was chosen for X-ray diffraction studies. The
measurements were made on an Enraf-Nonius CAD-4
diffractometer [19] with graphite MoKa monochromated
Full-matrix least-squares on F2
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I [ 2r(I)]
R indices (all data)
2769/0/182
1.020
˚
radiation (k = 0.71073 A). Intensity data were collected
R1 = 0.0749, wR2 = 0.1937
R1 = 0.1785, wR2 = 0.2730
0.464 and -0.336
272827
up to a hmax of 25.2° by the x/2h scan. A total of 3258
reflections were collected, resulting in 2769 independent
reflections of which 1145 had I [ 2r(I) and these are
considered as observed. During data collection three
-3
)
˚
Largest diff. peak and hole (e A
CCDC deposit no.
123

J Chem Crystallogr (2008) 38:583–586
585
˚
Table 2 Bond lengths (A) and bond angles (°)
Bond length
O(1)–C(3)
1.372(4)
1.361(5)
1.202(5)
1.335(5)
1.448(5)
1.397(5)
1.400(5)
1.449(5)
1.358(5)
1.395(5)
C(4)–C(5)
1.377(6)
1.369(6)
1.326(6)
1.432(6)
1.518(5)
1.501(5)
1.523(5)
1.497(5)
1.552(6)
1.425(6)
O(2)–C(4)
C(5)–C(6)
O(3)–C(9)
C(7)–C(8)
O(4)–C(9)
C(8)–C(9)
O(4)–C(10)
C(10)–C(11)
C(11)–C(12)
C(12)–C(13)
C(13)–C(14)
C(14)–C(15)
C(15)–C(16)
Fig. 1 ORTEP of the molecule at 30% probability
C(1)–C(6)
C(1)–C(2)
all the non-hydrogen atoms were included in the full-matrix
least-squares refinement using SHELXL97 program [21].
Table 2 gives the bond distances and angles of non-hydrogen
atoms respectively. The C15–C16 bond is too short (at
C(1)–C(7)
C(2)–C(3)
C(3)–C(4)
˚
1.425 A) for a C–C single bond. Maybe it is short because of
Bond angle
too much motion at the end of the alkyl chain. Figure 1
represents the ORTEP diagram [22] of the molecule 3 with
thermalellipsoids at30% probability. H atoms were included
at calculated positions and refined using a riding model. H
atoms were given isotropic displacement parameters equal to
1.2 times (1.5 times for methyl) the equivalent isotropic
displacement parameters of their parent atoms, and C–H
C(9)–O(4)–C(10)
C(2)–C(1)–C(6)
C(1)–C(2)–O(1)
C(1)–C(2)–C(3)
O(1)–C(2)–C(3)
O(2)–C(3)–C(4)
O(2)–C(3)–C(2)
C(4)–C(3)–C(2)
C(5)–C(4)–C(3)
lC(4)–C(5)–C(6)
C(5)–C(6)–C(1)
118.5(3)
122.4(3)
124.3(3)
119.7(4)
116.0(3)
119.0(3)
122.1(4)
119.0(3)
121.2(4)
120.8(4)
116.9(3)
C(5)–C(6)–C(7)
C(1)–C(6)–C(7)
C(8)–C(7)–C(6)
C(7)–C(8)–C(9)
O(3)–C(9)–O(4)
O(3)–C(9)–C(8)
O(4)–C(9)–C(8)
O(4)–C(10)–C(11)
C(14)–C(13)–C(12)
C(13)–C(14)–C(15)
C(16)–C(15)–C(14)
123.5(4)
119.6(3)
128.2(4)
122.8(4)
121.6(4)
126.6(4)
111.8(3)
105.7(3)
115.3(4)
112.3(5)
116.4(6)
˚
distances were set to 0.97 A for the methylene H atoms,
˚
0.96 A for the methyl H atoms and 0.93 A for the remainder.
˚
˚
O–H banded to the benzene distances were fixed at 0.83 A.
After refinement, the hydrogen atoms were placed at
chemically acceptable positions.
Benzene ring is planar within experimental observation
and it makes an angle of 0.6(8)° to the linker (C7–C8–C9–
O3). In the case of caffeic esters, the presence of an eth-
ylenic spacer allows the formation of a conjugated system,
strongly stabilized through p-electron delocalization. The
Results and Discussion
The structure was solved by direct methods procedures as
implemented in SHELXS97 program [20]. The positions of
Fig. 2 Packing of the
molecules down a axis. Dashed
lines represent the hydrogen
bonds
123

586
J Chem Crystallogr (2008) 38:583–586
˚
4. Fesen MR, Kohn KW, Leteurtre F, Pommier Y (1993) Proceed-
ings of the National Academy of Sciences of the United States of
America. 90(6):2399
5. Orban Z, Mitsiades N, Burke TR Jr, Tsokos M, Chrousos GP
(2000) Neuroimmunomodulation 7(2):99
6. Natarajan K, Singh S, Burke TR Jr, Grunberger D, Aggarwal BB
(1996) Proceedings of the National Academy of Sciences of the
United States of America. 93(17):9090
Table 3 Hydrogen-bonding geometry (A, °)
˚
˚
˚
D–HÁÁÁA
D–H (A) HÁÁÁA (A) DÁÁÁA (A) D–HÁÁÁA (°)
O1–H1ÁÁÁO3ii
0.83
1.97
2.53
2.52
2.790(4)
2.862(5)
3.227(5)
169.4
105.2
133.5
O2–H2ÁÁÁO1i
0.83
C2–H2AÁÁÁO3ii 0.93
Symmetry codes: (i) 1 - x; -1 - y; 1 - z; (ii) -x, -y, 1 - z
7. (a) Burke TR Jr, Fesen MR, Mazumde A (1995) J Med Chem
38:4171; (b) Fesen MR, Pommier Y, Leteurtre F, Hirogushi S,
Yung J, Kohn K (1994) Biochem Pharmcol 48:595
8. (a) Huang MT, Ma W, Yen P, Xie JG, Han J, Frenkel K, Grun-
berger D, Conney AH (1996) Carcinogenesis 17(4):761; (b) Li
SC, Li H, Zhang F, Li ZJ, Cui JR (2003) J Chin Pharm Sci
12(4):184
9. Mahmoud NN, Carothers AM, Grunberger D, Bilinshi RT,
Churchill MR, Martucci C, Newmark HL, Bertagnolli MM
(2000) Carcinogenesis 21:921
bond C7=C8 is a trans-double bond (E form) which seem
to be essential for the cytotoxic activity [12, 23]. The
crystal packing (Fig. 2) is stabilized by intermolecular
O–HÁÁÁO and C–HÁÁÁO hydrogen bonds (Table 3). The
molecules of the caffeic acid ester form stacks along the
a axis in a head-to head manner to form dimeric struc-
ture [24] One dimmer interacts another dimmer with
C2–H2AÁÁÁO3 and O1–H1ÁÁÁO3 hydrogen bonds to form
network. The electrostatic factors, molecular hydrogen
bonds, E conformation, dimeric structure and ester groups
in the structure are important determinants for some potent
biological activities which are worth to research further.
10. Grunberger D, Banerjee R, Eisinger K, Oltz EM, Efros L,
Caldwell M, Estevez V, Nakanishi
44(3):230
K (1998) Experientia
11. (a) Nakanishi K, Oltz EM, Grunberger D (1989) WO Patent
8,900,851, 9 Feb 1989; (b) Etzenhouser B, Hansch C, Kapur S,
Selassie CD (2001) Bioorg Med Chem 9(1):199
12. Son S, Lobkowsky EB, Lewis BA (2001) Chem Pharm Bull
49(2):236
13. (a) Nigel EB, Peter SJC (1997) US Patent 6,066,311, 14 Mar
1997; (b) Lee YJ, Liao PH, Chen WK, Yang CC (2000) Cancer
Lett 153:51
Supplementary Material
14. Jiang HC, Ho CT (1997) J Agric Food Chem 45:2374
15. Eisinger M, Marko O, Shun-Ichiro O (1985) Science 229:984
16. (a) Bankova VS (1990) J Nat Prod 53(4):821; (b) Piechucki C
(1976) Synthesis 3:187; (c) Kazumasa Y, Chikara F, Masanori S,
Youichiro N, Tadakazu S (1998) US Patent 4,733,002, 22 March
1998
17. Fiuza SM, Gomes C, Teixeira LJ, Girao da Cruz MT, Cordeiro
MNDS, Milhazes N, Borgesa F, Marques MPM (2004) Bioorg
Med Chem 12:3581
CCDC-272827 contains the supplementary crystallo-
graphic 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; e-mail: deposit@ccdc.cam.ac.uk.
18. Wakasugi K, Misaki T, Yamada K, Tanabe Y (2002) Tetrahedron
Lett 41:5249
19. Frenz BA (1989) Enraf-Nonius CAD-4 software. Delft University
Press, The Netherlands
20. Sheldrick GM (1997) SHELXS-97, program for solution of
crystal structures. University of Gottingen, Germany
21. Sheldrick GM (1997) SHELXS-97, program for crystal structure
refinement. University of Gottingen, Germany
22. Johnson CK, Burnett MN (2000) Ortep-3 for windows. Report
ORNL-6895. OakRidge National Laboratory, Oak Ridge, Ten-
nessee, USA
Acknowledgments We are very grateful to the National Natural
and Scientific Foundation (grant No. 20272053). We also acknowl-
edge the financial support by the Science and Technology Department
of Zhejiang Province (grant No.2005C23022).
References
1. (a) Greenaway W, Whatley FR (1991) J Chromato 54:3113; (b)
Banskota AH, Tezuka Y, Kadota S (2001) Phytother Res
15(7):561; (c) Sahinler N, Kaftanoglu O (2005) Nat Prod Res
19(2):183
2. Son S, Lewis BA (2002) J Agric Food Chem 50:486
3. Kujumgiev A, Bankova V, Ignatova A, Popov S (1993) Phar-
mazie 48(10):785
23. Nam N, You Y, Kim Y, Hong D, Kim H, Ahn BZ (2001) Bioorg
Med Chem Lett 11:1173
24. Fiuza SM, Van Besien E, Milhazes N, Borges F, Marques MPM
(2004) J Mol Struct 693(1–3):103
123