Oxidative dimers produced from protocatechuic and gallic esters in the DPPH radical scavenging reaction

Article abstract of DOI:10.1021/jf020347g

DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging reactions of protocatechuic and gallic acids, and their methyl esters, have been investigated by NMR. In acetone, methyl protocatechuate was gradually converted to a Diels-Alder adduct of two molecul

Full text of DOI:10.1021/jf020347g

5468 J. Agric. Food Chem. 2002, 50, 5468−5471
Oxidative Dimers Produced from Protocatechuic and Gallic
Esters in the DPPH Radical Scavenging Reaction
JUN KAWABATA,* YASUKO OKAMOTO, ASUKA KODAMA,
TERUMASA MAKIMOTO, AND TAKANORI KASAI
Laboratory of Food Biochemistry, Division of Applied Bioscience, Graduate School of Agriculture,
Hokkaido University, Sapporo 060-8589, Japan
DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging reactions of protocatechuic and gallic acids,
and their methyl esters, have been investigated by NMR. In acetone, methyl protocatechuate was
gradually converted to a Diels-Alder adduct of two molecules of the intermediate quinone in the
reaction with DPPH radical, whereas methyl gallate rapidly gave a symmetrical dimer via a putative
quinone precursor. Both dimers are rather unstable and their structures have been deduced by in
situ NMR measurements of the reaction mixtures. Gallic acid also gave a corresponding symmetrical
dimer in the same reaction as methyl gallate, although protocatechuquinone produced from
protocatechuic acid did not yield a Diels-Alder adduct, unlike its methyl ester. Interestingly, these
dimer formations were not observed in methanol solution.
KEYWORDS: Protocatechuic acid; gallic acid; DPPH radical; antiradical activity; ortho-quinone; dimer-
ization
INTRODUCTION
Phenolic acids and their esters are common plant constituents
that are known for their antioxidant activities (1-10). The
radical scavenging abilities of these acids depend greatly on
the number and arrangement of phenolic hydroxyl groups. Thus,
gallic acid (3,4,5-trihydroxybenzoic acid) possesses a higher
antiradical activity than protocatechuic acid (3,4-dihydroxyben-
zoic acid), whereas 4-hydroxybenzoic acid shows little radical
scavenging activity (1, 2, 5, 6, 8). Hence, pyrogallol-type
triphenols carrying three adjacent hydroxyl groups on a benzene
ring effectively scavenge more radicals than catechol-type
o-diphenols. Although gallic and protocatechuic acids show
notable radical scavenging activities, the reaction mechanism
and difference in antiradical reactivities between these pyro-
gallol- and catechol-type phenolic acids are still unclear. In the
course of our research on the radical scavenging mechanism of
pyrogallol and catechol type polyphenols, we have found by in
situ NMR measurements (11, 12) that protocatechuic and gallic
esters (Figure 1) gave oxidative dimers with different connec-
tivities in the reaction with 2,2-diphenyl-1-picrylhydrazyl
Figure 1. Structures of phenolic acids and methyl esters.
protocatechuic acid by heating it with methanol containing 10%
hydrogen chloride. All solvents used were of technical grade. Deuterated
solvents used in NMR were obtained from Aldrich Chemical Co.
Colorimetric Radical Scavenging Tests. To a solution of DPPH
radical (500 µM, 1 mL) was added a phenol solution (12.5 µM, 4 mL)
in a test tube. Final molar ratio of the radical and phenols was 10:1.
The solution was immediately mixed vigorously for 10 s by a Vortex
mixer and transferred to a cuvette. After the solution in the cuvette sat
3
0 min at room temperature, the absorbance at 517 nm was measured
by a Hitachi U-3210 instrument. Acetone and ethanol were chosen as
aprotic and protic solvents, respectively. An ethanol solution of
R-tocopherol in the same concentration was measured as a positive
control. A reduction of the absorbance, 0.228, by the positive control
was regarded as corresponding to the consumption of two molecules
of DPPH radical (13, 15).
(DPPH) radical (13, 14) in an aprotic solvent.
NMR Measurements. NMR spectra were determined with a Bruker
1
13
MATERIALS AND METHODS
AMX500 instrument ( H, 500 MHz; C, 125 MHz). Acetone-d
6
and
methanol-d were used as aprotic and protic solvents, respectively, while
4
Reagents. Protocatechuic acid (1) (Sigma Chemical Co.), gallic acid
no significant difference in the spectral patterns was observed in
methanol and ethanol. For the purpose of identification of the reaction
products, chemical shifts were calculated from the residual solvent
(3) and methyl gallate (4) (Tokyo Kasei Kogyo Co., Ltd.), and DPPH
radical (Wako Pure Chemical Industries, Ltd.) were purchased from
the indicated supplier. Methyl protocatechuate (2) was prepared from
signals of δ
H
C 6
2.04 and δ 29.8 ppm in acetone-d . 2D COSY, HMQC,
and HMBC spectra were obtained using Bruker programs. All assign-
ments of signals, including those buried under strong peaks of 2,2-
diphenyl-1-picrylhydrazine produced by the reduction of DPPH radical,
*
To whom correspondence should be addressed. Telephone: +81-11-
7
06-4140. Fax: +81-11-706-2496. E-mail: junk@chem.agr.hokudai.ac.jp.
1
0.1021/jf020347g CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/09/2002

Oxidative Dimers from Protocatechuic and Gallic Esters
J. Agric. Food Chem., Vol. 50, No. 19, 2002 5469
Figure 2. Oxidation of methyl protocatechuate (2) and protocatechuic acid (1) with DPPH radical.
were done by the 2D spectral data. Peak areas were standardized against
DPPH radical consumption when changing the solvent from
aprotic acetone to protic ethanol, whereas 1 as well as 3 and 4
showed little change in their antiradical activity in either solvent.
6
that of the residual peak of acetone-d for determining the conversion
rate.
Reaction of Methyl Protocatechuate (2) and DPPH Radical. To
DPPH radical (14.5 mg, 37 µmol, 2.8 equiv) was added a solution of
The NMR measurements of the reaction mixture of 2 and
DPPH radical in acetone showed that 2 was rapidly converted
to protocatechuquinone methyl ester (5) (16). The oxidation to
5 was complete in a few minutes, as the signals from the starting
2 completely disappeared within 10 min. And then, dimerization
of the resultant 5 gradually occurred in the reaction mixture to
give the dimer (6) (Figure 2). The yield of 6 was 4% in 15
min based on 2 and reached 50% in 6 h. After 12 h, the quinone
peaks almost disappeared, whereas the peaks due to 6 still
remained. The amount of 6 then decreased during prolonged
standing, changing to a complex mixture indicated by the
methyl protocatechuate (2, 2.1 mg, 13 µmol) in acetone-d
6
(0.4 mL).
The mixture was immediately transferred to a NMR tube and mixed
1
13
vigorously. H NMR spectra were recorded periodically. C NMR,
COSY, HMQC, and HMBC spectra were consecutively measured from
3
h after mixing.
Protocatechuquinone methyl ester (5). H NMR δ (acetone-d
3H, s, H-8), 6.47 (1H, d, J ) 10.3 Hz, H-5), 6.89 (1H, d, J ) 2.0 Hz,
1
6
): 3.91
(
1
3
H-2), 7.54 (1H, dd, J ) 10.3, 2.0 Hz, H-6). C NMR δ (acetone-d
3.6 (C-8), 131.2 (C-5), 132.7 (C-2), 137.6 (C-6), 139.7 (C-1), 165.3
C-7), 179.8 (C-4), 181.4 (C-3).; HMBC correlation peaks: H-8/C-7,
H-5/C-1, 3, H-2/C-4, 6, 7, H-6/C-2, 4.
6
):
5
(
1
1
complicated methoxyl proton signals in the H NMR spectrum.
Protocatechuquinone methyl ester dimer (6). H NMR δ (acetone-
): 3.72 (3H, s, H-8′), 3.76 (3H, s, H-8), 4.32 (1H, d, J ) 2.4 Hz,
d
6
The structural determination of 6 was done by in situ NMR
measurements of the reaction mixture, as attempted isolation
of 6 from the reaction mixture failed because of its instability.
In the reaction mixture, a characteristic doublet at δH 6.47 for
H-5 of 5 diminished, and a new doublet at δH 6.58 appeared
instead. In addition, three proton signals at δH 4.32, 4.34, and
H-2), 4.34 (1H, d, J ) 6.9 Hz, H-5′), 4.50 (1H, dd, J ) 2.4, 2.1 Hz,
H-2′), 6.58 (1H, d, J ) 10.7 Hz, H-5), 7.37 (1H, d, J ) 10.7 Hz, H-6),
3
7
.42 (1H, dd, J ) 6.9, 2.1 Hz, H-6′). 1 C NMR δ (acetone-d
6
): 51.9
(C-2′), 53.0 (C-8′), 53.1 (C-2), 54.4 (C-8), 55.5 (C-1), 58.5 (C-5′), 132.0
C-5), 135.8 (C-1′), 139.3 (C-6′), 149.7 (C-6), 163.0 (C-7′), 172.3 (C-
(
7
), 178.9 (C-4), 185.8 (C-3′), 186.0 (C-4′), 190.1 (C-3). HMBC
correlation peaks: H-8′/C-7′, H-8/C-7, H-2/C-2′, 1′, 7, 3, H-5′/C-2, 1,
′, 6′, 6, 3′ and/or 4′, H-2′/C-1, 1′, 6′, 3′ and/or 4′, H-5/C-1, 3, H-6/
4
.50, each 1 H, also appeared. The methoxyl proton region
contained two singlets of nearly similar height at δH 3.72 and
.76, together with a methoxyl signal of 5 at δH 3.91. The 2D
1
3
C-2, 5′, 4, H-6′/C-2′, 5′, 7′, 3′ and/or 4′.
COSY, HMQC, and HMBC spectra of the reaction mixture
unambiguously indicated 6 to be a Diels-Alder adduct of two
molecules of 5 (Figure 2). This type of dimerization products
of o-benzoquinone derivatives has been previously reported
Reaction of Methyl Gallate (4) and DPPH Radical. To DPPH
radical (14.7 mg, 37 µmol, 2.6 equiv) was added a solution of methyl
gallate (4, 2.5 mg, 14 µmol) in acetone-d
6
(0.4 mL). The mixture was
1
immediately transferred to a NMR tube and mixed vigorously. H NMR
1
3
spectra were recorded periodically. C NMR, HMQC, and HMBC
spectra were consecutively measured from 20 min after mixing. No
signals from galloquinone methyl ester were observed during the
(17-21). Among them, a dimer 8 (21) produced from 5-meth-
oxyprotocatechuquinone methyl ester by treatment with cupric
acetate hydrate corresponds to a dimethoxyl derivative of 6.
The NMR data of 6 are consistent with those of the hydrate
form of 8. The relative stereochemistry of the Diels-Alder
addition in 6 is presumed to be exo as shown because the
corresponding dimethoxyl derivative 8 easily underwent an
intramolecular hemiacetalization between carbonyls of C-3 and
C-3′ (21).
reaction.
1
Oxidative methyl gallate dimer (7). H NMR δ (acetone-d
6
): 3.86
(
4
6H, s, H-8, 8′), 4.21 (2H, d, J ) 0.5 Hz, H-2, 2′), 6.17 (2H, s, OH-4,
′), 6.98 (2H, d, J ) 0.5 Hz, H-6, 6′). 1 C NMR δ (acetone-d
3
6
): 53.8
(
1
C-8, 8′), 59.3 (C-2, 2′), 91.1 (C-4, 4′), 132.6 (C-6, 6′), 146.5 (C-1,
′), 164.8 (C-7, 7′), 194.2 (C-5, 5′), 196.9 (C-3, 3′). HMBC correlation
peaks: H-8/C-7, H-2/C-4 and/or 4′, 6, 1, 7, 5′, 3 and/or 3′, OH-4/C-2′,
, 5, 3, H-6/C-2, 4, 7.
4
In contrast, in a protic solvent such as methanol, the intensity
of the signals of 5 generated in the reaction with DPPH radical
was even smaller than those in aprotic acetone, and many other
small signals were simultaneously observed, which suggests that
a complex reaction proceeded compared to that of the acetone
solution. The signals of 6, however, were not observed in
methanol. Hence 5, once generated in the methanol solution,
would react quickly to give further oxidation products by excess
DPPH radical in the protic solvent (7). On the contrary, in
acetone, the lifetime of 5 was longer compared to that in the
methanol solution and thus dimerization could gradually occur.
RESULTS AND DISCUSSION
The DPPH radical scavenging abilities of protocatechuic acid
(
1), methyl protocatechuate (2), gallic acid (3), and methyl
gallate (4) were determined by the colorimetric method. After
0 min, the relative radical scavenging equivalence of each
3
compound, when that of R-tocopherol in ethanol as standard
was designated as 2, was as follows: 1, 2.1; 2, 2.0; 3, 4.7; 4,
4
.0 in acetone; and 1, 2.3; 2, 4.7, 3, 4.6; 4, 4.5 in ethanol,
respectively. Interestingly, 2 showed a dramatic increase of

5470 J. Agric. Food Chem., Vol. 50, No. 19, 2002
Kawabata et al.
Figure 3. Oxidation of methyl gallate (4) and gallic acid (3) with DPPH
radical.
In the protic solvent, the presence of solvent molecules might
directly accelerate a further oxidation reaction probably due to
a high reactivity of 5 against the nucleophilic attack with the
alcohol molecule, resulting in a regenaration of the catechol
structure, which accounts for the higher DPPH radical scaveng-
ing ability in ethanol than that in acetone as found in the
colorimetric measurements.
In the case of the acid 1, the reaction course was significantly
different from that of 2. In acetone, 1 was quickly oxidized to
the quinone 9 by DPPH radical. After that, however, the signals
of protocatechuquinone remained unchanged in the NMR
spectrum, and no dimerization product was detected at all in
several hours. This resistance to dimerization by 9 seems to
arise from the difference in electronic properties of the quinones
Figure 4. Formation and relative stereochemistry of galloquinone methyl
ester dimer (7).
10 (Figure 4) in the acetone solution of an oxidation product
prepared from 4 with o-chloranil in ether at -40 °C. Interest-
ingly, the NMR data of both dimers, 7 and 10, are very similar
except those of C-2 (δH 4.21/δC 59.3 for 7 and δH 4.36/δC 53.2
for 10) and C-4 (δC 91.1 for 7 and δC 96.0 for 10), which
suggests that the coupling manners of 7 and 10 are different.
The dimer 10 is proposed to be a head-to-head coupling (2-2′
and 4-4′) product, whereas 7 should be derived through head-
to-tail coupling (2-4′ and 4-2′), which was confirmed by the
inter-residual HMBC correlations of H-2/C-5′ and OH-4/C-2′.
This type of symmetrical dimers has been reported as an
oxidation product of pyrogallol derivatives, and both head-to-
head and head-to-tail structures are present (19, 20, 23, 24).
Hence, the formation of 7 and its regioselectivity might depend
on the difference in structures and reaction conditions such as
temperature. Although the relative stereochemistry of those
symmetrical dimers has not yet been proposed in the literature,
7 is tentatively assigned as an anti-isomer because steric
repulsion must arise in the syn-addition when the second C-C
coupling occurs via a hypothetical quinone precursor (Figure
4). Furthermore, the interresidue intense HMBC cross-peak of
three-bond H-2/C-3′ also supports their antiperiplanar arrange-
ment adopted in the anti-isomer (7) in contrast to the dihedral
angle of approximately 120° in the syn-isomer (7′), while a
contribution of an intraresidue two-bond H-2/C-3 correlation
should be weak. Sawai and Moon (12) reported the reaction of
ethyl gallate with DPPH radical in acetone. However, signals
from the corresponding dimer were not detected on their
spectrum. In contrast, ethyl gallate was also converted to its
symmetrical dimer through the reaction with DPPH radical in
our experiment (data not shown). The apparent difference might
5
and 9. The strong electron-withdrawing nature of the quinone
carbonyls in 9 might enhance the acidity of the carboxyl group
conjugated to the parent quinone skeleton compared to that of
1. As a result, the number of deprotonated molecules increases
in 9. The electronic nature of carboxylic and ester groups, and
its dissociated carboxylate form is clearly different, as is
reflected in substituent effects in the aromatic electrophilic
substitution reaction (22). Deprotonation of the carboxyl group
reduces its electron-withdrawing nature and hence might
decrease the reactivity of 9 as a dienophile. In protic methanol,
the intensity of the signals from 9 that appeared soon after
mixing was larger than that of 5 from 2. Also, the peak patterns
within the reaction mixture of 1 with DPPH radical in methanol
were relatively simple compared to those in 2. Hence, further
reaction with DPPH radical after conversion to 9 was consider-
ably slower compared to the rapid and complex reaction that
proceeded with 5. This low reactivity of 9 accounts well for
the difference in the relative radical scavenging equivalence of
1
and 2 after 30 min reaction in ethanol.
Methyl gallate (4) also gave a dimerization product 7, when
reacted with DPPH radical in acetone (Figure 3). Production
of 7 was rapid compared to that of 6, and the yield reached
6
2% in 10 min based on 4. This dimer was relatively stable in
the NMR tube and survived even after a few days, although its
separation from the reaction mixture also resulted in its
decomposition as with 6. Thus, the structure of 7 was determined
by direct measurements of a series of 2D NMR spectra in the
reaction mixture. The NMR signal pattern of 7 was simple,
consisting of three singlets at δH 4.21, 6.17, and 6.98, as well
as that of a methoxyl at δH 3.86, and its symmetric structure
was deduced mainly by HMBC data. Quideau and Feldman (23)
reported the formation of a similar unstable symmetric dimer
1
3
arise from the C measurement conditions.
In contrast to the fact that protocatechuic acid (1) gave no
signals of the Diels-Alder dimer from the intermediate quinone
in the NMR spectrum, unlike its ester 2, gallic acid (3) yielded
the corresponding dimer (11) although its conversion rate was
lower than that from 4. The oxidative coupling reaction of 4

Oxidative Dimers from Protocatechuic and Gallic Esters
J. Agric. Food Chem., Vol. 50, No. 19, 2002 5471
might start from an intermediate o-quinone 12 as proposed
previously (21). In protic methanol, no dimerization product
was detected from both 3 and 4 as has been seen in 1 and 2.
Protic solvents would enhance a radical scavenging reaction via
the highly reactive hydroxyquinone intermediates (12 and 13).
In conclusion, both methyl protocatechuate and gallate gave
their quinone dimers with different coupling selectivities when
reacting with DPPH radical in aprotic acetone. However,
protocatechuquinone was the only product from protocatechuic
acid and no such dimer was produced under the same reaction
condition, whereas gallic acid was converted to a dimer similar
to that observed with its methyl ester. In contrast, dimer
formation from both esters was not found in protic methanol.
The difference in radical scavenging ability of protocatechuic
acid and its methyl ester in alcoholic solvents might be partly
accounted for by the reactivity of the resulting quinone toward
an attack of the solvent molecule, although the direct evidence
must be disclosed by further experiments. It is also unclear what
causes the marked difference in radical scavenging abilities
between catechol-type protocatechuate and pyrogallol-type
gallate. Further efforts to identify the reaction course of these
phenolic acids and esters are now in progress.
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Received for review March 20, 2002. Revised manuscript received June
2
7, 2002. Accepted June 28, 2002.
JF020347G