Caffeic acid phenethyl ester (CAPE): Synthesis and X-ray crystallographic analysis

Article abstract of DOI:10.1248/cpb.49.236

The structure of caffeic acid phenethyl ester [2-propenoic acid, 3-(3,4-dihydroxyphenyl)-, 2-phenethyl ester] (1), C₁₇H₁₆O₄·1/2C₆H ₆, synthesized by base-catalyzed alkylation of caffeic acid salt with

Full text of DOI:10.1248/cpb.49.236

236
Notes
Chem. Pharm. Bull. 49(2) 236—238 (2001)
Vol. 49, No. 2
Caffeic Acid Phenethyl Ester (CAPE): Synthesis and X-Ray
Crystallographic Analysis
a
b
,c
*
Sopheak SON, Emil B. LOBKOWSKY, and Betty A. LEWIS
Department of Food Science,a Department of Chemistry and Chemical Biology,b and Division of Nutritional Sciences,c
Cornell University, Ithaca, NY 14853, U.S.A. Received July 3, 2000; accepted November 10, 2000
The structure of caffeic acid phenethyl ester [2-propenoic acid, 3-(3,4-dihydroxyphenyl)-, 2-phenethyl ester]
(I), C17H16O4·1/2C6H6, synthesized by base-catalyzed alkylation of caffeic acid salt with b-bromoethylbenzene in
HMPA (hexamethylphosphoramide) and recrystallized from benzene, was confirmed by single crystal X-ray dif-
¯
fraction. The crystals are triclinic, space group P1, Z؍2, unit cell dimension a؍5.8129 (9) Å, b؍11.122 (2) Å, c؍
13. 226 (2) Å, a؍97.080 (3)°, b؍101.467 (3)°, g؍95.405 (3)°, V؍825.4 (2) Å3, Dcalc؍1.301 g/cm3, F(000)؍342. The
packing of the molecule is stabilized by intermolecular O1H···O4 (2.69 Å) and O1···HO2 (2.82 Å) hydrogen
bonds.
Key words caffeic acid phenethyl ester; alkylation reaction; X-ray diffraction; hydroxycinnamic acid derivative; phenolic com-
pound
acetate were from Aldrich.
Caffeic acid phenethyl ester (CAPE), a plant-derived phe-
Synthesis CAPE was synthesized according to Hashimoto et al.21) To a
nolic compound and an active component of propolis from
solution of caffeic acid (1.98 g) in 25 ml of HMPA, 2.28 ml of 25% NaOH
honeybee hives, is known to have antiviral,1) antibacterial,2)
was added. After stirring for 1 h, a solution of b-bromoethylbenzene (5.7 ml)
anti-inflammatory,3,4) antiatherosclerotic,5) antioxidative,6,7)
in 10 ml HMPA was added dropwise with a separatory funnel and the solu-
immunostimulatory8) and tumor growth inhibition activ- tion was stirred for 52 h at room temperature. The reaction mixture was
ity.9,10) This compound has also been shown to be a potential
poured into ice water (50 ml), and the product was extracted with diethyl
ether (2ϫ50 ml). The ether extract was washed successively with 1 N HCl
(20 ml) and water (20 ml), dried over MgSO4 (10—15 g), and evaporated
under vacuum. The product dissolved in ether was chromatographed on a
silica gel column (150 g), eluted with CHCl3 and then with increasing pro-
portions of ethyl acetate. The fraction eluted with 30% ethyl acetate con-
tained the desired product. Recrystallization from ether/n-hexane gave com-
inhibitor of some enzymes such as ornithine carboxylase,11)
5-a reductase,12) protease,13) lipoxygenase,14,15) cyclooxyge-
nase,15,16) and human immunodeficiency virus (HIV)-1 inte-
grase.17,18)
CAPE has been chemically synthesized from caffeic acid
pound (I) (CAPE) as a pale-yellow powder; mp 124.5—126 °C; yield ca.
and phenethyl alcohol via acid-catalyzed esterification using
p-toluenesulfonic acid as a catalyst,6,14,17,19) and via the cou-
pling reaction with dicyclohexylcarbodiimide (DCC) as a
coupling agent.6,20) It can also be prepared by base-catalyzed
alkylation of caffeic acid with b-bromoethylbenzene in dipo-
lar aprotic solvents such as hexamethylphosphoramide
(HMPA).21) The latter reaction has been reported to give a
high yield (ca. 70%) of product compared to the first two re-
actions which give only 40% yield.
70%. IR (neat) cmϪ1: 3490, 3100, 1685, 1640—1610, 1100.
Single-Crystal X-Ray Analysis of CAPE Single crystals of I suitable
for X-ray analysis were obtained by slow evaporation from benzene. Data
were collected from a colorless thin plate crystal of dimensions 0.20ϫ0.10ϫ
0.02 mm on a Bruker SMART with 1K CCD detector with MoKa radiation
(lϭ0.71073 Å; graphite monochromated) employing 0.3°w scanning tech-
nique. The final refinement of the structure was achieved by the full-matrix
least-squares method with anisotropic displacement parameters for all non-
hydrogen atoms and fixed isotropic displacement parameters for all hydro-
gen atoms. Crystallographic data are listed in Table 1.
To confirm the structure of CAPE, which we synthesized
by alkylation of caffeic acid salt with b-bromoethylbenzene
using HMPA as solvent, we subjected the product of the re-
action to single crystal X-ray crystallography. The X-ray dif-
fraction data showed that the ester structure (I) is the reaction
product and not the ethers (II, III) (Chart 1).
Results and Discussion
The IR spectrum showed a peak for phenolic OH (br,
3490 cmϪ1), a peak for C–H stretch (m, 3100 cmϪ1), a peak
Experimental
Thin-layer chromatography (TLC) was performed on precoated Silica gel
F254 plates (Merck) and on microscope slides (2.5ϫ7.5 cm) coated with sil-
ica gel G containing fluorescent indicator (Fluorescent Brightener 80). De-
tection was by iodine vapor and by UV light (UV lamp, model UVG-54).
Column chromatography was performed on Silica gel H (32—63 mesh)
from Selecto Scientific. MgSO4 was used as the drying agent for organic ex-
tracts. Solvents were evaporated under vacuum. Melting points were deter-
mined on a Fisher–Johns melting point apparatus and are uncorrected. IR
spectra were recorded on a Perkin-Elmer 683 IR spectrophotometer. Single
crystal X-ray analysis was performed using a Bruker SMART with 1K CCD
detector. Data were collected using SMART Software. Cell refinement and
data reduction were performed using the SAINT program. SHELXS8622) was
used to solve the structure and SHELXL9323) to refine the structure.
SHELXTL was used to display molecular graphics and to prepare publica-
tion material.
Materials Caffeic acid (3,4-dihydroxycinnamic acid, 98%); b-bro-
moethylbenzene (phenethylbromide); HMPA (99%); diethyl ether; and ethyl Chart 1. Possible Products of the Alkylation of Caffeic Acid
To whom correspondence should be addressed. e-mail: bal4@cornell.edu
© 2001 Pharmaceutical Society of Japan

February 2001
237
Table 2. Atomic Coordinates [ϫ104] and Equivalent Isotropic Displace-
ment Parameters [Å2ϫ103]
Atom
x
y
z
U (eq)
O (1)
O (2)
O (3)
O (4)
C (1)
C (2)
C (3)
C (4)
C (5)
C (6)
C (7)
C (8)
C (9)
C (10)
C (11)
C (12)
C (13)
C (14)
C (15)
C (16)
C (17)
C (1S)
C (2S)
C (3S)
6080 (8)
1499 (7)
6427 (6)
10237 (7)
5646 (9)
4777 (9)
2417 (9)
946 (9)
1849 (9)
4228 (9)
5088 (9)
7358 (9)
8155 (11)
7119 (11)
5459 (11)
5998 (10)
4692 (9)
5157 (10)
7015 (10)
8375 (9)
7877 (10)
608 (12)
1398 (4)
585 (3)
5115 (4)
4318 (3)
2952 (3)
3567 (3)
4342 (3)
4540 (4)
4137 (4)
3546 (4)
3350 (4)
3743 (3)
3494 (3)
3665 (3)
3403 (4)
2712 (5)
1840 (4)
1545 (4)
1742 (4)
1470 (4)
997 (4)
46 (1)
47 (1)
54 (1)
48 (1)
30 (1)
30 (1)
30 (1)
32 (1)
30 (1)
25 (1)
31 (1)
32 (1)
35 (1)
76 (2)
61 (2)
35 (1)
40 (1)
42 (2)
40 (2)
43 (2)
44 (2)
42 (2)
48 (2)
47 (2)
7362 (3)
7210 (3)
3249 (4)
2142 (4)
1690 (4)
2362 (4)
3490 (4)
3955 (4)
5121 (4)
5604 (4)
6788 (4)
8568 (5)
8819 (4)
10064 (4)
10986 (5)
12127 (5)
12374 (5)
11462 (5)
10320 (5)
5784 (5)
4999 (6)
4218 (5)
Fig. 1. A Perspective View of (I) Showing the Atom Numbering Scheme
Displacement ellipsoids are drawn at the 50% probability level; H atoms are shown
as spheres of arbitrary radii.
Table 1. X-Ray Crystallographic Data of CAPE
Molecular formula
Formula weight
Crystal size (mm3)
Crystal system
Space group
a (Å)
C17H16O4·1/2C6H6
323.35
0.20ϫ0.10ϫ0.02, colorless plates
Triclinic
¯
P1
795 (4)
1064 (4)
939 (5)
659 (5)
Ϫ282 (6)
5.8129 (9)
b (Å)
11.122 (2)
c (Å)
13.226 (2)
2144 (11)
1522 (12)
a (°)
97.080 (3)
101.467 (3)
95.405 (3)
825.4
1.301
2
b (°)
g (°)
U (eq) is defined as one-third of the trace of the orthogonalized Uij tensor. Carbons
C (1S), C (2S), and C (3S) derived from one-half molecule of solvent benzene in the
crystal unit cell.
V (Å3)
Dcalc (g·cmϪ3
Z
)
F(000)
Diffractomer
342
Table 3. Selected Geometric Parameters (Å, °)
Bruker SMART with 1K CCD
detector
MoKa, lϭ0.71073 Å;
graphite monochromated
173
0.090
0.3°w
0.566—1.0
O(1)–C(2)
O(2)–C(3)
O(3)–C(9)
O(4)–C(9)
O(3)–C(10)
C(4)–C(5)
C(9)–O(3)–C(10)
C(1)–C(2)–O(1)
O(1)–C(2)–C(3)
O(2)–C(3)–C(4)
C(3)–C(4)–C(5)
C(1)–C(6)–C(5)
C(5)–C(6)–C(7)
C(7)–C(8)–C(9)
O(4)–C(9)–O(3)
1.372 (6)
1.361 (5)
1.322 (6)
1.223 (6)
1.455 (5)
1.388 (6)
116.3 (4)
124.7 (5)
115.4 (4)
118.5 (5)
119.4 (5)
117.6 (4)
118.8 (5)
124.6 (5)
122.6 (5)
C(1)–C(6)
C(2)–C(3)
C(12)–C(17)
C(16)–C(15)
C(13)–C(14)
1.393 (6)
1.390 (6)
1.393 (6)
1.375 (6)
1.378 (6)
Radiation
Temperature (K)
m (mmϪ1
)
Scan mode
Transmission coefficients
Reflections collected
Independent reflections
O(4)–C(9)–O(3)
122.6 (5)
109.7 (5)
113.6 (5)
122.3 (5)
121.0 (5)
118.8 (5)
121.7 (5)
117.3 (5)
121.0 (5)
4064
2761 (Rintϭ0.0492)
26.22
C(11)–C(10)–O(3)
C(10)–C(11)–C(12)
C(12)–C(13)–C(14)
C(16)–C(17)–C(12)
C(16)–C(15)–C(14)
C(13)–C(12)–C(11)
C(13)–C(12)–C(17)
C(17)–C(12)–C(11)
q
max (°)
Limiting indices
Ϫ6ՅhՅ5, Ϫ12ՅkՅ13,
Ϫ16ՅlՅ15
Refined method
Full-matrix least-squares on F2
1681/0/238
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [IϾ2s(I)]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole
1.047
R1ϭ0.0599, wR2ϭ0.1197
R1ϭ0.1931, wR2ϭ0.1917
0.02335
0.216 and Ϫ0.248 eÅϪ3
Table 4. Hydrogen-Bonding Geometry (Å, °)
D–H···A D–H H···A
D···A
D–H···A
O1–H1a···O4i 0.66 (0.05) 2.03 (0.05) 2.69 (0.01) 171.66 (6.37)
O2–H2a···O1ii 0.80 (0.05) 2.07 (0.05) 2.82 (0.01) 155.97 (5.64)
for carbonyl group (s, 1685 cmϪ1), peaks for CϭC stretch
(m, 1610—1640 cmϪ1) and a peak for C–O stretch
(1100 cmϪ1) consistent with structure I. However, the one di-
mensional 1H-NMR spectrum was not of sufficient quality to
Symmetry codes: (i) 2Ϫx, 1Ϫy, 1Ϫz; (ii) 1Ϫx, Ϫy, 1Ϫz.
allow reliable assignment of proton signals to distinguish be- O3–C10). The linker makes an angle of 10.75 (0.21)° to ring
tween structures I, II, and III. X-ray analysis showed that the A. This ring makes an angle of 52.96 (0.13)° with the best
reaction product had structure I corresponding to CAPE.
plane through B. The bond C7–C8 is a trans-double bond.
A perspective view of compound (I) with atomic number- The molecules are linked in unit cell by two types of inter-
ing is shown in Fig. 1. The X-ray crystallographic data and molecular hydrogen bonds O1H···O4 (2.69 Å) and O1···HO2
the selected geometric patterns are shown in Tables 1—4. (2.82 Å) (Fig. 2, Table 3). X-ray data has also shown that the
The structure of compound (I) has two rings, A and B. Both crystal of I (recrystallized from benzene) contains one-half
rings are planar within experimental observations. Ring B molecule of solvent benzene for each molecule of CAPE giv-
makes an angle of 42.21 (0.15)° to the linker (C7–C8–C9– ing a molecular formula of C17H16O4·1/2C6H6.

238
Vol. 49, No. 2
Fig. 2. A View of the Molecular Packing and H-Bonding Interactions of I
Symmetry codes are given in Table 4. For clarity the molecule of solvent benzene per two molecules of CAPE in the crystal structure has been omitted from the Figure.
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with b-bromoethylbenzene in HMPA solvent is CAPE and
not the two ethers II and III.
Acknowledgements The authors would like to thank Dr. Barry K. Car-
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