Extraordinary radical scavengers: 4-mercaptostilbenes

Article abstract of DOI:10.1002/chem.201103897

In the past decade, there was a great deal of interest and excitement in developing more active antioxidants and cancer chemoprevention agents than resveratrol, a naturally occurring stilbene. In this work, eight resveratrol-directed 4-mercaptostilbenes were constructed based on the inspiration that thiophenol should be a stronger radical scavenger than phenol, and their reaction rates with galvinoxyl (GO^.) and 2,2-diphenyl-1-picrylhydrazyl (DPPH^.) radicals in methanol and ethyl acetate were measured by using stopped-flow UV/Vis spectroscopy at 25 °C. Kinetic analysis demonstrates that 4-mercaptostilbenes are extraordinary radical scavengers, and the substitution of the 4-SH group for the 4-OH group in the stilbene scaffold is an important strategy to improve the radical-scavenging activity of resveratrol. Surprisingly, in methanol, some of the 4-mercaptostilbenes are 10⁴-times more active than resveratrol, dozens of times to hundreds of times more effective than known antioxidants (α-tocopherol, ascorbic acid, quercetin, and trolox). The detailed radical-scavenging mechanisms were discussed based on acidified-kinetic analysis. Addition of acetic acid remarkably reduced the GO^. and DPPH^. radical-scavenging rates of the 4-mercaptostilbenes in methanol, a solvent that supports ionization, suggesting that the reactions proceed mainly through a sequential proton loss electron transfer mechanism. In contrast, an interesting acid-promoted kinetics was observed for the reactions of the 4-mercaptostilbenes with DPPH^. in ethyl acetate, a solvent that weakly supports ionization. The increased ratio in rates is closely correlated with the electron-rich environment in the molecules, suggesting that the acceleration could benefit from the contribution of the electron transfer from the 4-mercaptostilbenes and DPPH^.. However, the addition of acetic acid had no influence on the GO^.-scavenging rates of the 4-mercaptostilbenes in ethyl acetate, due to the occurrence of the direct hydrogen atom transfer. Our results show that the radical-scavenging activity and mechanisms of 4-mercaptostilbenes depends significantly on the molecular structure and acidity, the nature of the attacking radical, and the ionizing capacity of the solvent. Copyright

Full text of DOI:10.1002/chem.201103897

DOI: 10.1002/chem.201103897
Extraordinary Radical Scavengers: 4-Mercaptostilbenes
Xiao-Yan Cao, Jie Yang, Fang Dai, De-Jun Ding, Yan-Fei Kang, Fu Wang,
Xiu-Zhuang Li, Guo-Yun Liu, Sha-Sha Yu, Xiao-Ling Jin, and Bo Zhou*[a]
Abstract: In the past decade, there was
a great deal of interest and excitement
in developing more active antioxidants
and cancer chemoprevention agents
than resveratrol, a naturally occurring
stilbene. In this work, eight resveratrol-
directed 4-mercaptostilbenes were con-
structed based on the inspiration that
thiophenol should be a stronger radical
scavenger than phenol, and their reac-
methanol, some of the 4-mercaptostil-
benes are 104-times more active than
resveratrol, dozens of times to hun-
dreds of times more effective than
known antioxidants (a-tocopherol, as-
corbic acid, quercetin, and trolox). The
detailed radical-scavenging mecha-
nisms were discussed based on acidi-
fied-kinetic analysis. Addition of acetic
an interesting acid-promoted kinetics
was observed for the reactions of the 4-
C
mercaptostilbenes with DPPH in ethyl
acetate, a solvent that weakly supports
ionization. The increased ratio in rates
is closely correlated with the electron-
rich environment in the molecules, sug-
gesting that the acceleration could ben-
efit from the contribution of the elec-
tron transfer from the 4-mercaptostil-
C
acid remarkably reduced the GO and
C
C
C
tion rates with galvinoxyl (GO ) and
DPPH radical-scavenging rates of the
benes and DPPH . However, the addi-
C
2,2-diphenyl-1-picrylhydrazyl (DPPH )
4-mercaptostilbenes in methanol, a sol-
vent that supports ionization, suggest-
ing that the reactions proceed mainly
through a sequential proton loss elec-
tron transfer mechanism. In contrast,
tion of acetic acid had no influence on
C
radicals in methanol and ethyl acetate
were measured by using stopped-flow
UV/Vis spectroscopy at 258C. Kinetic
analysis demonstrates that 4-mercap-
tostilbenes are extraordinary radical
scavengers, and the substitution of the
4-SH group for the 4-OH group in the
stilbene scaffold is an important strat-
egy to improve the radical-scavenging
activity of resveratrol. Surprisingly, in
the GO -scavenging rates of the 4-mer-
captostilbenes in ethyl acetate, due to
the occurrence of the direct hydrogen
atom transfer. Our results show that
the radical-scavenging activity and
mechanisms of 4-mercaptostilbenes de-
pends significantly on the molecular
structure and acidity, the nature of the
attacking radical, and the ionizing ca-
pacity of the solvent.
Keywords: antioxidants · mercap-
tostilbenes · radical reactions · reac-
tion mechanisms
scavengers
· resveratrol ·
Introduction
cancer, cardiovascular disease, and aging.[2] The truly unique
biochemical profile of resveratrol has been attributed to its
intrinsic antioxidant ability, because free radical-mediated
oxidative damage to biomolecules (e.g., DNA, proteins, and
lipids) has been suggested to be a major factor in the devel-
opment of cancer, atherosclerosis, and aging.[3] Therefore, in
the past decade, considerable effort has been devoted to the
development of free radical scavengers (antioxidants) that
are more effective than resveratrol, and the mechanistic
studies on the related free radical-scavenging reactions.[4] In
this context, we have also found that structural modifica-
tions in the stilbene scaffold of resveratrol including the in-
troduction of electron-donating groups at the positions
ortho and para to the 4-OH or 4’-OH group,[5] construction
of the hybrid molecules by incorporating a chroman moiety
of vitamin E,[6] and elongation of the conjugated double
bond links,[7] are the important strategies to improve the
radical-scavenging activity of this parent molecule.
Stilbenes are a small family of plant secondary metabolites
derived from the phenylpropanoid pathway with numerous
implications in plant disease resistance and human health.[1]
One of the most extensively studied stilbenes is resveratrol
(3,5,4’-trihydroxy-trans-stilbene), a phytoalexin in grapes
and other food products, endowed with a surprising array of
biological activities against various disease states including
[a] X.-Y. Cao, J. Yang, Dr. F. Dai, D.-J. Ding, Y.-F. Kang, F. Wang,
X.-Z. Li, G.-Y. Liu, S.-S. Yu, Dr. X.-L. Jin, Prof. Dr. B. Zhou
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
222 Tianshui Street S., Lanzhou 730000 (P. R. China)
Fax : (+86)931-8915557
E-mail: bozhou@lzu.edu.cn
1
Supporting information (including the synthetic procedures, H and
13C NMR, HRMS (ESI), EI-MS spectra, and HPLC analysis
(Table S1) of the 4-mercaptostilbenes; stability of the 4-mercaptostil-
benes (Figure S1); spectral and kinetic measurements (Figure S2 and
Tables S2 and S3), and measurements for the pKa values of the 4-mer-
captostilbenes and the 4-hydroxystilbenes (Figure S3)) for this article
is available on the WWW under http://dx.doi.org/10.1002/
chem.201103897.
Depending on the nature of the attacking radical, the sol-
vent used, and the molecular structure, the formal abstrac-
tion of an hydrogen atom from an antioxidant (AH) by
C
a free radical (X ) can occur by at least four different chemi-
cal pathways: direct (single-step) hydrogen atom transfer
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Chem. Eur. J. 2012, 18, 5898 – 5905

FULL PAPER
[HAT, Eq. (1)], proton-coupled electron transfer [PCET
Eq. (2)], sequential proton loss electron transfer [SPLET,
Eq. (3)], and electron transfer then proton transfer [ETPT,
Eq. (4)].[8] Generally speaking, for a given radical and sol-
vent, the rate of HAT (including PCET) is strictly controlled
tivity of resveratrol. In view of the fact that the 4’-OH
group in the stilbene scaffold of resveratrol is more active
than the 3- and 5-OH groups for radical-scavenging reac-
tion,[4g,h,j,l,m,5] we report herein the synthesis of eight 4-mer-
captostilbenes (Scheme 1) with the introduction of electron-
ꢀ
by the bond dissociation enthalpy (BDE) of the A H bond.
ꢀ
The weaker the strength of the A H bond, the faster is the
HAT process. SPLET is essentially differentiated from HAT
by the fact that it occurs when AH first loses a proton to
form the corresponding anion (Aꢀ) followed by rapid elec-
tron transfer to an electron-deficient radical in an ionizing
solvents. This makes the amount (the acid dissociation con-
stant, pKa, of AH) and oxidation (ionization) potential of
this anion (Aꢀ) the key parameters in SPLET. ETPT also
consists of a stepwise process involving first electron transfer
from AH to an electrophilic radical and then proton transfer
from the radical cation (AH +) to the radical anion (Xꢀ).
C
Obviously, the oxidation (ionization) potential of AH plays
a pivotal role in ETPT. All of the four different mechanisms
C
eventually lead to the same net result (A and XH); thus,
free radical-scavenging activity of an antioxidant is governed
C
by the resonance stabilization of the resulting radical (A ).
C
C
AHþX ! A þXH
ð1Þ
ð2Þ
ð3Þ
ð4Þ
ꢀ
C
C
Cþ
C
AHþX ! ½AH ꢁ ꢁ ꢁ X ꢂ ! ½AH ꢁ ꢁ ꢁ X ꢂ ! A þXH
þ
þX
þHþ
AH ꢀH Aꢀ
A þX
A þXH
C
ꢀ
C
C
ƒƒ! ƒƒ!
ƒƒ!
ꢀ
C
Cþ
C
AHþX ! AH þX ! A þXH
Understanding the above mechanisms is of great impor-
tance for designing a well free radical scavenger. The signifi-
ꢀ
cant difference of the BDE between O H (369.4–
378.2 kJmolꢀ1)[9] and S H (331.0–349.4 kJmolꢀ1)[10] for
ꢀ
phenol (ArOH; Ar=aryl) and thiophenol (ArSH) makes
the latter more susceptible to a HAT reaction than the
former. The pKa values of ArOH and ArSH have been re-
ported to be 10.0 and 6.6,[11] respectively; Additionally, the
Scheme 1. Molecular structures of resveratrol, 4-mercaptostilbenes, and
4-hydroxystilbenes
(MS=mercaptostilbene,
HS=hydroxystilbene,
DMS=dimercaptostilbene, DHS=dihydroxystilbene, DMeO=dime-
thoxy, TMeO=trimethoxy).
o
ꢀ
o
ꢀ
C
C
reduction potentials (E (ArO /ArO ) and E (ArS /ArS ))
relative to the normal hydrogen electrode (NHE) for phe-
[12]
C
C
noxyl (ArO ) and phenylthiyl (ArS ) radicals are 0.79 and
0.69 V,[13] respectively. This indicates clearly that there is
a high amount of ArSꢀ in ionizing solvents and that it is
a stronger electron donor than ArOꢀ. Consequently, in com-
parison with ArOH, ArSH should exhibit increased reactivi-
ty towards electrophilic radicals by SPLET mechanism in
ionizing solvents. Furthermore, a comparison of the reduc-
donating (ED) and electron-withdrawing (EW) groups, and
the quantitative kinetic and mechanistic study of the scav-
C
enging reaction of them against galvinoxyl (GO ) and 2,2-di-
C
phenyl-1-picrylhydrazyl (DPPH ) radicals in ethyl acetate
and methanol. To our knowledge, there is no reported quan-
titative determination of the radical-scavenging activity of
mercaptostilbenes, and we indeed found that all of these 4-
mercaptostilbenes exhibit much more effective radical-scav-
enging activity than the corresponding 4-hydroxystilbenes,
and surprisingly, some of them show about 104-fold in-
creased radical-scavenging activity in methanol relative to
naturally-occurring resveratrol (see below).
o
+
o
+
C
C
tion potentials (E (ArO ,H /ArOH) and E (ArS ,H /ArSH)
being 1.38 and 1.08 V versus NHE, respectively)[13] for ArO
C
C
and ArS , suggests that ArSH is more active than ArOH in
ETPT reactions. Taken together, these data support the
notion that no matter what kind of mechanism is employed,
ArSH should be a more effective radical scavenger than
ArOH.
Inspired by the above data, we believe that direct attach-
ment of the mercapto group to the aromatic ring of stilbene
is an effective strategy to improve the radical-scavenging ac-
Chem. Eur. J. 2012, 18, 5898 – 5905
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B. Zhou et al.
Results and Discussion
their typical UV absorbance. The 4-mercaptostilbenes
showed no signs of decomposition over a 10 h period (see
Figure S1 in the Supporting Information), and they were
also stable in either solid or solution form under air during
the following experiments.
Synthesis of the 4-mercaptostilbenes: Construction of 4-mer-
captostilbenes was accomplished by the conversion of
phenol to thiophenol with reference to a previously reported
procedure with some modifications[14] (Scheme 2). The con-
Radical-scavenging activity of
C
the 4-mercaptostilbenes: GO
C
and DPPH are relatively stable
oxygen and nitrogen radicals, as
the prototypic models for per-
oxyl radicals, respectively, and
have been widely used to
screen the relative radical-scav-
enging ability.[8l,16] We next
tested the radical-scavenging
property of the 4-mercaptostil-
benes in ethyl acetate and
methanol by using the two
kinds of radicals. The selection
for two types of solvents is
based on their significantly dif-
ferent ionizing ability, as ethyl
acetate has a much lower die-
lectric constant (e=6.02)[17]
than methanol (e=32.63)[17]
and hence, has a lower ability
to support ionization of the
substrate. The second-order
C
rate constants (k) of GO and
Scheme 2. Synthesis of 4-mercaptostilbenes (Ac=acyl, DABCO=1,4-diazobicycloACTHNUGTRNEUNG[2.2.2]octane).
C
DPPH -scavenging reactions of
4-mercaptostilbenes at 258C
were measured by monitoring
version involved a three-step procedure of thiocarbamoyla-
tion and Newan–Kwart-rearrangement, followed by cleav-
age under hydrolytic conditions. These compounds investi-
gated were trans-4-mercaptostilbene (4-MS), trans-4’,4-di-
mercaptostilbene (4’,4-DMS), trans-4’-methoxy-4-mercaptos-
the decrease in absorbance at l=428 and 517 nm, respec-
tively, by using the stopped-flow technique (see Figure S2 in
the Supporting Information). The rate constants obtained
are listed in Table 1 together with the values for known anti-
oxidants (a-tocopherol, ascorbic acid, quercetin, and trolox)
and our previous data for 4-hydroxystilbenes (Scheme 1),[5]
which are given for comparison. As can be seen from the k
tilbene
(4’-MeO-4-MS),
trans-3’,4’-dimethoxy-4-
mercaptostilbene (3’,4’-DMeO-4-MS), trans-3’,5’-dimethoxy-
4-mercaptostilbene (3’,5’-DMeO-4-MS), trans-3’,4’,5’-trime-
thoxy-4-mercaptostilbene (3’,4’,5’-TMeO-4-MS), trans-4’-tri-
fluoromethyl-4-mercaptostilbene (4’-CF3-4-MS), and trans-
4’-nitro-4-mercaptostilbene (4’-NO2-4-MS), among which 4’-
MeO-4-MS, 3’,4’-DMeO-4-MS, 3’,4’,5’-TMeO-4-MS, and 4’-
CF3-4-MS are the new compounds (Scheme 1), and only the
3’,5’-DMeO-4-MS was previously used in the studies of algi-
cidal activity[14c] and inhibitory activity against colon cancer
cell.[15]
C
C
values in Table 1 the GO - and DPPH -scavenging activity of
the 4-mercaptostilbenes in ethyl acetate follows the sequen-
ces
3’,4’,5’-TMeO-4-MSꢃ3’,5’-DMeO-4-MS>4-MS>4’-CF3-4-
MS and 3’,4’-DMeO-4-MS>3’,4’,5’-TMeO-4-MS>4’,4-
of
4’,4-DMS>3’,4’-DMeO-4-MS>4’-MeO-4-MS>
DMS>3’,5’-DMeO-4-MSꢃ4’-MeO-4-MS>4-MS> 4’-NO2-
4-MS>4’-CF3-4-MS, respectively, whereas the order in
methanol is 3’,4’-DMeO-4-MS>4’,4-DMS>4’-MeO-4-MS>
3’,4’,5’-TMeO-4-MS>4-MS>3’,5’-DMeO-4-MS>4’-CF3-4-
MS and 3’,4’-DMeO-4-MS>4’,4-DMS>4’-MeO-4-MS>
3’,5’-DMeO-4-MSꢃ3’,4’,5’-TMeO-4-MS>4’-NO2-4-MS>4-
MS>4’-CF3-4-MS, respectively. Although these activity se-
quences are not completely consistent, the k values increase
generally with the introduction of ED groups (methoxy and
mercapto) at the position para to the 4-SH and decrease
with the introduction of EW groups (nitro and trifluoro-
methyl) with the exception of 4’-NO2-4-MS in the case of
Stability of the 4-mercaptostilbenes: Generally, the mole-
cules with lower ionization potential are endowed with
higher electron transfer ability, but very low ionization po-
tentials also lead to their air instability due to the direct re-
action with oxygen, thereby limiting their radical-scavenging
efficacy. Thus, we first examined the stability of the 4-mer-
captostilbenes towards air in DMSO at 308C by monitoring
5900
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Extraordinary Radical Scavengers
FULL PAPER
Table 1. Rate constants for radical-scavenging reaction of 4-mercaptostilbenes at 258C.[a]
than that in ethyl acetate (see
Table 1). This remarkable kinet-
ic difference between methanol
and ethyl acetate should arise
from the different mechanisms.
Litwinienko and Ingold have
observed previously an abnor-
mal increase of the rate con-
k [Lmolꢀ1 sꢀ1] (GO )
k [Lmolꢀ1 sꢀ1] (DPPH )
C
C
ethyl acetate[b]
methanol[c]
ethyl acetate[b]
methanol[c]
resveratrol
4-MS
4,4’-DMS
4’-MeO-4-MS
3’,4’-DMeO-4-MS
3’,5’-DMeO-4-MS
3’,4’,5’-TMeO-4-MS
4’-CF3-4-MS
4’-NO2-4-MS
trolox
(15.6ꢄ0.2)
(50.3ꢄ0.9)
(1.05ꢄ0.01)ꢁ102
(86.0ꢄ0.9)
(94.7ꢄ5.1)
(61.8ꢄ5.4)
(62.7ꢄ2.8)
(46.9ꢄ1.5)
(1.03ꢄ0.02)
(18.0ꢄ0.1)
(24.6ꢄ1.6)
(19.2ꢄ0.3)
(28.7ꢄ0.1)
(21.1ꢄ0.6)
(27.6ꢄ0.2)
(9.95ꢄ0.49)
(16.7ꢄ0.8)
(2.09ꢄ0.01)ꢁ102
(8.81ꢄ0.08)ꢁ105
(1.90ꢄ0.01)ꢁ106
(1.40ꢄ0.02)ꢁ106
(2.08ꢄ0.03)ꢁ106
(1.06ꢄ0.03)ꢁ106
(1.02ꢄ0.02)ꢁ106
(6.87ꢄ0.08)ꢁ105
(9.48ꢄ0.21)ꢁ105
(9.99ꢄ0.01)ꢁ102
(1.32ꢄ0.02)ꢁ104
(3.22ꢄ0.01)ꢁ104
(1.71ꢄ0.02)ꢁ103
(2.93ꢄ0.02)ꢁ102[b]
(1.48ꢄ0.14)ꢁ104[b]
(2.04ꢄ0.15)ꢁ103[b]
(94.1ꢄ5.4)[b]
(8.89ꢄ0.02)ꢁ105
(1.50ꢄ0.01)ꢁ106
(1.07ꢄ0.01)ꢁ106
(1.70ꢄ0.01)ꢁ106
(8.54ꢄ0.03)ꢁ105
(9.69ꢄ0.02)ꢁ105
C
stants for the DPPH -scaveng-
(27.6ꢄ0.7)
(3.20ꢄ0.01)ꢁ105
ing reaction of phenols in alco-
holic media, and clearly demon-
strated by comparing the kinet-
ic differences between acidified
alcoholic and nonalcoholic sol-
vents that this is attributed to
partial ionization of phenols
and a very fast electron transfer
from the phenolate anion to
[d]
[d]
(7.65ꢄ0.01)ꢁ104
(1.36ꢄ0.01)ꢁ104
(4.33ꢄ0.02)ꢁ104
(2.51ꢄ0.01)ꢁ103
(88.7ꢄ1.7)[b]
quercetin
ascorbic acid
a-tocopherol
4-HS
9.7[e]
108.6[e]
33.0[e]
3.2[e]
0.6[e]
6.4[e]
1.9[e]
0.7[e]
0.3[e]
4,4’-DHS
(1.22ꢄ0.01)ꢁ103[b]
(3.88ꢄ0.01)ꢁ102[b]
(10.9ꢄ0.5)[b]
4’-MeO-4-HS
4’-CF3-4-HS
4’-NO2-4-HS
(21.1ꢄ1.2)[b]
DPPH (SPLET).[8a] These ex-
C
[a] All of the rate constants were detected by the stopped-flow technique and data are expressed as the mean
ꢄSD for three determinations. [b] Detected by following the pseudo-first-order decay of radical. [c] Detected
using second-order kinetics with the concentration ratio of compound and radical being 1:1. [d] Reaction rate
could not be measured for spectral overlapping. [e] Cited from reference [5].
cellent studies[8a] together with
our recent results for hydroxys-
tilbenes[5] indicate that in meth-
anol, a solvent which supports
C
ionization, the GO - and
C
C
DPPH /methanol. A comparison of the k values of the 4-
DPPH -scavenging reaction of the 4-mercaptostilbenes may
occur primarily by the SPLET mechanism. To further eluci-
date this point, we examined the effect of added acetic acid
mercaptostilbenes and their corresponding 4-hydroxystil-
benes in ethyl acetate and methanol clearly indicates that
C
C
C
C
the GO - and DPPH -scavenging activity of the former is
much more active than the latter, highlighting the impor-
tance of the substitution of the 4-SH group for the 4-OH
group in the stilbene scaffold. A striking feature of our data
on the GO - and DPPH -scavenging reaction of the 4-mer-
captostilbenes in methanol (Figure 1). As shown in Figure 1,
all of the rate constants for 4’-MeO-4-MS, 4-MS, and 4’-CF3-
4-MS including resveratrol in methanol decreased remarka-
bly, with an increasing acetic acid concentration, to reach
the different limiting values (see also Tables S2A and B in
the Supporting Information). This outcome strongly suggests
that in nonacidified methanol, the observed kinetic data of
the 4-mercaptostilbenes are a cooperation result of SPLET
and HAT reactions, and the kinetics is mostly governed by
the former (the actual electron donor is the thiolate anion),
whereas the addition of acetic acid remarkably reduces the
rate by eliminating the SPLET mechanism to only leave the
HAT mechanism due to the suppression of ionization for
the acid compounds (Scheme 3).
C
is that in methanol, the acceleration of the GO - and
DPPH -scavenging reaction for some of the 4-mercaptostil-
C
benes, such as 3’,4’-DMeO-4-MS, 4’,4-DMS, and 4’-MeO-4-
MS, in comparison to resveratrol reaches about four orders
of magnitude. Additionally, the radical-scavenging activity
of 4’,4-DMS, 3’,4’-DMeO-4-MS, and 4’-MeO-4-MS in metha-
nol also increases dozens of times to hundreds of times over
that of the known antioxidants (a-tocopherol, ascorbic acid,
quercetin, and trolox). For example, the k value of 3’,4’-
DMeO-4-MS (1.70ꢁ106 mꢀ1 s ) for the GO -scavenging reac-
ꢀ1
C
tion in methanol is approximately 3.6ꢁ104, 677, 39, 125, and
22 times larger than that of resveratrol (46.9mꢀ1 sꢀ1), a-toco-
pherol (2.51ꢁ103 mꢀ1 sꢀ1), ascor-
bic acid (4.33ꢁ104 mꢀ1 sꢀ1), quer-
cetin (1.36ꢁ104 mꢀ1 sꢀ1), and
trolox (7.65ꢁ104 mꢀ1 sꢀ1), re-
spectively.
Effect of added acetic acid on
the radical-scavenging reactions
of the 4-mercaptostilbenes in
methanol: The k values for the
C
C
GO - and DPPH -scavenging re-
actions of the 4-mercaptostil-
benes in methanol are roughly
Scheme 3. Radical-scavenging mechanisms of 4-mercaptostilbene in methanol: HAT mechanism (dot line) and
four orders of magnitude larger SPLET mechanism (solid line).
Chem. Eur. J. 2012, 18, 5898 – 5905
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5901

B. Zhou et al.
Acidity constants of the 4-mercaptostilbenes: Recently, Lit-
winienko and co-workers have determined the pKa values
C
and DPPH -scavenging rate of multi-hydroxyl flavonoids
and demonstrated clearly that the kinetics and reaction sites
in alcoholic media are noticeably affected by the acidity of
the hydroxyl groups.[8c] Consequently, the acidity of the HS
group in the 4-mercaptostilbenes is of great importance for
C
C
the kinetics of their SPLET reactions with GO and DPPH
in methanol that support ionization. We also determined the
pKa values of the 4-mercaptostilbenes and their correspond-
ing 4-hydroxystilbenes in methanol/phosphate-buffered
saline (PBS; pH 7.4) (v/v=2:1) by monitoring their UV/Vis
absorption changes with different pH values (Figures 2 and
Figure 2. Top: Absorption spectra of 4’-CF3-4-MS in methanol/PBS (v/v,
2:1) as a function of the pH. Curves 1–17 correspond to pH 2.2, 3.2, 4.5,
4.9, 5.4, 6.0, 6.5, 6.8, 7.1, 7.5, 7.9, 8.2, 8.6, 8.9, 9.3, 9.7, and 10.1, respective-
ly. Bottom: Titration curves at l=325 (dot line) and 366 nm (solid line).
S3 in the Supporting Information). As exemplified in
Figure 2, upon increase of the pH from 2.2 to 10.1 the ab-
sorption band of 4’-CF3-4-MS at l=325 nm gradually de-
creased along with the appearance of a new absorption
band at l=366 nm. The isosbestic point at l=344 nm sug-
gests a ground state acid–base equilibrium involving the
neutral (l=325 nm) and anionic (l=366 nm) forms of 4’-
CF3-4-MS. From the inflection point of the spectrophoto-
metric titration curves (Figure 2, bottom), its pKa value of
7.14 was obtained. The pKa values of other compounds are
presented in Table 2. As can be seen from Table 2, all 4-mer-
C
C
Figure 1. Effect of added acetic acid on the GO - (A) and DPPH -scav-
!
*
*
enging (B) rate of 4-mercaptostilbenes ( =4-MS, =4’-MeO-4-MS,
=
&
4’-CF3-4-MS) or resveratrol ( ) in methanol.
5902
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5898 – 5905

Extraordinary Radical Scavengers
FULL PAPER
Table 2. The pKa values of 4-mercaptostilbenes and 4-hydroxystilbenes
in methanol/phosphate-buffered saline (v/v=2:1).[a]
4-Mercaptostilbene
pKa
4-Hydroxystilbene
pKa
(10.9ꢄ0.1)
(10.8ꢄ0.1)
(10.5ꢄ0.1)
(10.3ꢄ0.1)
4-MS
(7.32ꢄ0.02)
(7.43ꢄ0.03)
(7.14ꢄ0.07)
(7.00ꢄ0.05)
4-HS
ACHTUNGTRENNUNG
4’-MeO-4-MS
4’-CF3-4-MS
4’-NO2-4-MS
4’-MeO-4-HS
4’-CF3-4-HS
4’-NO2-4-HS
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] Data are expressed as the mean ꢄSD for three determinations.
captostilbenes are three orders of magnitude more acidic
than their corresponding 4-hydroxystilbenes, which is closely
correlated with the remarkable increase of radical-scaveng-
ing rate constants in methanol for the former compared
with the latter. Moreover, the above-mentioned exception,
C
that is, the relatively high DPPH -scavenging rate constants
of 4’-NO2-4-MS (9.48ꢁ105 mꢀ1 sꢀ1) compared with 4-MS
(8.81ꢁ105 mꢀ1 sꢀ1) in methanol also confirm a crucial role of
the acidity in the SPLET reaction. However, it should be
pointed out that the introduction of EW groups (nitro and
trifluoromethyl) can augment the acidity of 4-mercaptostil-
benes, as indicated by the pKa values from Table 2, and
hence increase the concentration of thiolate anion, but this
stabilizing effect on the anion will decrease its oxidation po-
tential and electron transfer ability. This paradox effect on
the contribution of SPLET results in the experimental fact
that the most acidic compounds (4’-NO2-4-MS and 4’-CF3-4-
MS) are not the most effective radical scavengers, in con-
trast, 3’,4’-DMeO-4-MS, 4’,4-DMS, and 4’-MeO-4-MS are
the most active ones among the 4-mercaptostilbenes exam-
ined.
C
C
Figure 3. Effect of added acetic acid on the GO - (A) and DPPH -scav-
~
!
*
enging (B) rate of 4-mercaptostilbenes ( =4’-MeO-4-MS, =4-MS,
=
&
4’-CF3-4-MS) or resveratrol ( ) in ethyl acetate.
Effect of added acetic acid on the radical-scavenging reac-
tions of the 4-mercaptostilbenes in ethyl acetate: To ration-
alize the reaction mechanism of the 4-mercaptostilbenes in
a solvent that weakly supports ionization, we finally investi-
gated the effect of added acetic acid on their radical-scav-
enging rate in ethyl acetate. As expected, each of the 4-mer-
captostilbenes and resveratrol
a propensity toward the ETPT mechanism rather than the
C
HAT mechanism in the case of 4-mercaptostilbenes/DPPH
reactions in ethyl acetate (Scheme 4). In other words, the
ETPT reaction might contribute to the increased rate in the
presence of acid. Recently, unexpected acid-promoted kinet-
ics has also been found in reactions of peroxyl radicals with
C
showed a constant GO -scav-
enging rate in the presence of
acid (Figure 3A). Consequently,
only the HAT reaction takes
place under the present condi-
tion. However, in the case of
C
DPPH , an interesting acid-pro-
moted reaction kinetics was ob-
served for 4’-MeO-4-MS, 4-MS,
C
Scheme 4. Proposed mechanism for the acid-promoted reaction of 4-mercaptostilbene with DPPH in ethyl
acetate.
and 4’-CF3-4-MS. Specifically,
their reaction rate constants in-
creased somewhat by 76, 48,
phenols in acetonitrile,[8b] and reactions of DPPH with bilir-
C
and 43%, respectively, when the concentration of acetic
acid was 100 mmolLꢀ1 (Figure 3B and Table S3A in the
Supporting Information). It is also noticeable that the ratios
increase with increasing the electron-rich environment in
the molecules, that is, the electron richer the molecule, the
larger is the increased ratio of the k value, as demonstrated
by the three 4-mercaptostilbenes. This might be indicative of
ubin ester and dipyrrinone in methanol.[8f] The acid-promot-
ed kinetics can be understood because the protonation of
C
DPPH can be initiated by the addition of acid, leading to
an increase in the electrophilicity of the radical and hence,
facilitating the electron-transfer step;[8b,f] additionally, the
equilibrium toward DPPH2 can be promoted by the pres-
Chem. Eur. J. 2012, 18, 5898 – 5905
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5903

B. Zhou et al.
ence of acid,[8f] as exemplified in Scheme 4. Such a contrast
effect (constant and acceleration in the rate) of added acetic
trans-4’-Methoxy-4-mercaptostilbene (5c): Pale-yellow solid; m.p. 198–
2008C; 1H NMR (400 MHz, CDCl3): d=3.47 (s, 1H; SH), 3.83 (s, 3H;
OCH3), 6.90 (d, J=8.0 Hz, 2H; H3’, H5’), 6.91 (d, J=16.4 Hz, 1H; H8),
7.02 (d, J=16.4 Hz, 1H; H7), 7.25 (d, J=8.0 Hz, 2H; H2’, H6’), 7.36 (d,
J=8.0 Hz, 2H; H3, H5), 7.44 ppm (d, J=8.0 Hz, 2H; H2, H6); 13C NMR
(100 MHz, CDCl3): d=55.3, 114.2, 125.7, 126.9, 127.7, 128.0, 129.3, 129.7,
130.0, 135.4, 159.4 ppm.
C
acid can be attributed to the fact that in contrast to GO
(Eored vs. saturated calomel electrode (SCE)=0.05 V),[18]
o
C
DPPH has a relatively high reduction potential (Ered vs.
SCE=0.18 V),[18] is thereby prone to undergo electron-
trans-3’,4’-Dimethoxy-4-mercaptostilbene (5d): Pale-yellow solid; m.p.
129–1318C; 1H NMR (400 MHz, CDCl3): d=3.48 (s, 1H; SH), 3.90 (s,
3H; OCH3), 3.94 (s, 3H; OCH3), 6.86 (d, J=8.4 Hz, 1H; H3’), 6.90 (d,
J=16.4 Hz, 1H; H8), 6.98–7.06 (m, 3H; 3H (H2’, H6’, H7’), 7.25 (d, J=
8.4 Hz, 2H; H3, H5), 7.37 ppm (d, J=8.4 Hz, 2H; H2, H6); 13C NMR
(100 MHz, CDCl3): d=55.8, 55.9, 108.7, 111.2, 119.9, 125.9, 126.8, 128.2,
129.4, 129.7, 130.3, 135.2, 148.9, 149.1 ppm; HRMS (ESI): m/z calcd for
[M+H]+: 273.0944; found: 274.2739.
transfer reaction. Nevertheless, for resveratrol, no accelera-
C
tion was observed even in the case of DPPH (Figure 3B)
probably due to its high oxidation potential compared to the
4-mercaptostilbenes.
Conclusion
trans-3’,5’-Dimethoxy-4-mercaptostilbene (5e): Pale-yellow solid; m.p.
88–908C; 1H NMR (400 MHz, CDCl3): d=3.51 (s, 1H; SH), 3.85 (s, 6H;
OCH3), 6.42 (t, J=2.4 Hz, 1H; H4’), 6.67 (d, J=2.4 Hz, 2H; H2’, H6’),
6.99 (d, J=16.4 Hz, 1H; H8), 7.04 (d, J=16.4 Hz, 1H; H7), 7.27 (d, J=
8.0 Hz, 2H; H3, H5), 7.39 ppm (d, J=8.0 Hz, 2H; H2, H6); 13C NMR
(100 MHz, CDCl3): d=55.6, 100.2, 104.7, 127.4, 128.5, 128.6, 129.8, 130.4,
134.9, 139.4, 161.2 ppm; MS: m/z (%): 272 (100), 208 (22.08), 152 (24.27).
In conclusion, eight resveratrol-directed 4-mercaptostilbenes
were constructed based on the inspiration that ArSH should
be a stronger radical scavenger than ArOH. This work dem-
onstrates that 4-mercaptostilbenes are extraordinary radical
scavengers, and the substitution of the 4-SH group for the 4-
OH group in the stilbene scaffold is an important strategy
to improve the radical-scavenging activity of resveratrol.
Most impressively, in methanol, some of the 4-mercaptostil-
benes are 104-times more active than resveratrol, dozens of
times to hundreds of times more effective than known anti-
oxidants (a-tocopherol, ascorbic acid, quercetin, and trolox).
Their radical-scavenging activity and mechanisms are
strongly influenced by various factors including the molecu-
lar structure and acidity, the nature of the attacking radical,
and the ionizing capacity of the solvent. Additionally, all of
the synthesized 4-mercaptostilbenes have no smell, which is
entirely different from the mercaptans. Based on the above-
described results, the 4-mercaptostilbenes may be consid-
ered as a novel type of resveratrol-directed antioxidants.
trans-3’,4’,5’-Trimethoxy-4-mercaptostilbene (5 f): Pale-yellow solid; m.p.
154–1558C; 1H NMR (400 MHz, CDCl3): d=3.49 (s, 1H; SH), 3.87 (s,
3H; OCH3), 3.91 (s, 6H; OCH3), 6.72 (s, 2H; H2’, H6’), 6.93 (d, J=
16.0 Hz, 1H; H8), 6.99 (d, J=16.0 Hz, 1H; H7), 7.25 (d, J=8.0 Hz, 2H;
H3, H5), 7.37 ppm (d, J=8.0 Hz, 2H; H2, H6); 13C NMR (100 MHz,
CDCl3): d=56.1, 60.9, 103.5, 127.0, 127.3, 128.3, 129.6, 129.9, 132.9, 134.8,
137.9, 153.4 ppm; HRMS (ESI): m/z calcd for [M+H]+: 303.1049; found:
303.1043.
trans-4’-Trifluoromethyl-4-mercaptostilbene (5g): Pale-yellow solid; m.p.
179–1818C; 1H NMR (400 MHz, (CD3)2CO), d=4.42 (s, 1H; SH), 7.29
(d, J=16.4 Hz, 1H; H8), 7.34 (d, J=8.0 Hz, 2H; H3, H5), 7.37 (d, J=
16.4 Hz, 1H; H7), 7.40 (d, J=8.4 Hz, 2H; H2, H6), 7.69 (d, J=8.4 Hz,
2H; H2’, H6’), 7.79 ppm (d, J=8.4 Hz, 2H; H3’, H5’); 13C NMR
(100 MHz, (CD3)2CO): d=126.0 (q, J=270 Hz), 127.0 (q, J=4 Hz),
127.9, 128.4, 129.0, 129.9 (q, J=30 Hz), 130.4, 132.2, 133.7, 135.5,
143.0 ppm.
trans-4’-Nitro-4-mercaptostilbene (5h): Yellow solid; m.p. 184–1868C;
1H NMR (400 MHz, CDCl3): d=3.53 (s, 1H; SH), 7.08 (d, J=16.0 Hz,
1H; H8), 7.19 (d, J=16.0 Hz, 1H; H7), 7.28 (d, J=8.4 Hz, 2H; H3, H5),
7.41 (d, J=8.4 Hz, 2H; H2, H6), 7.60 (d, J=8.8 Hz, 2H; H2’, H6’),
8.20 ppm (d, J=8.8 Hz, 2H; H3’, H5’); 13C NMR (100 MHz, CDCl3): d=
124.1, 125.8, 126.7, 127.6, 129.4, 132.0, 132.4, 133.6, 143.7, 146.7 ppm; MS:
m/z (%): 257 (100), 178 (83.05), 89 (41.95)
Experimental Section
Materials: a-Tocopherol was purchased from Calbiochem. Quercetin and
Stability of the 4-mercaptostilbenes: The stability of the 4-mercaptostil-
benes (26.7 mmolLꢀ1) towards air in DMSO solution at 308C was moni-
tored at the band maximum (lACHTNUTRGNE(NUG 4-MS)=331, (4’-MeO-4-MS)=340, (3’,4’-
DMeO-4-MS)=346, (resveratrol)=327 nm) by using UV/Vis spectrosco-
py.
C
the 2,2-diphenyl-1-picrylhydrazyl (DPPH ) radical were purchased from
C
Aldrich–Sigma. The galvinoxyl (GO ) radical, trolox, and ascorbic acid
were obtained from Acros Organics. Methanol was of HPLC grade and
used directly, whereas ethyl acetate and acetic acid were of analytical
grade and purified by standard techniques.
Spectral and kinetic measurements
Synthesis of compounds: The 4-mercaptostilbenes (5) were synthesized
mainly referred to the published method[14a,b,c] and their structures and
purity were confirmed by 1H and 13C NMR spectroscopy, HRMS (ESI),
EI-MS, and HPLC (see the Supporting Information for all synthetic pro-
cedures).
Pseudo-first-order kinetics: An aliquot of a 4-mercaptostilbene at more
than 10-fold excess of the concentration of the radical, was rapidly mixed
ꢀ1
with GO (5 mmolL ) or DPPH (25 mmolLꢀ1) by using a stopped-flow
C
C
C
SFA-20 accessory. The pseudo-first-order decay of GO (428 nm) or
C
DPPH (517 nm) in ethyl acetate at 258C was monitored by using
trans-4-Mercaptostilbene (5a): Pale-yellow solid; m.p. 159–1618C;
1H NMR (400 MHz, (CD3)2CO): d=4.37 (s, 1H; SH), 7.21 (s, 2H; H7,
H8), 7.26 (t, J=7.2 Hz, 1H; H4’), 7.32 (d, J=8.4 Hz, 2H; H3, H5), 7.36
(t, J=7.2 Hz, 2H; H3’, H5’), 7.50 (d, J=7.2 Hz, 2H; H2’, H6’), 7.58 ppm
(d, J=8.4 Hz, 2H; H2, H6); 13C NMR (100 MHz, (CD3)2CO): d=127.2,
127.3, 127.5, 127.8, 128.1, 128.3, 128.6, 129.0, 131.1, 134.7, 135.9,
137.5 ppm; MS: m:z (%): 212 (100), 178 (99.27), 89 (49.5).
a Varian Cary 300 Spectrophotometer. The second-order rate constants
(k) were obtained by the plots of the pseudo-first-order constants versus
[4-mercaptostilbene]. The second-order rate constants in the presence of
acid were determined in the same manner.
Second-order kinetics: As the radical-scavenging rates of the 4-mercap-
tostilbenes in methanol are very fast, their second-order rate constants
(k) were measured by using second-order kinetics with the concentration
ratio of the compound and the radical being 1:1 and the stopped-flow
trans-4,4’-Dimercaptostilbene (5b): Brown–yellow solid; m.p. 233–2358C;
1H NMR (400 MHz, [D6]DMSO): d=5.51 (s, 2H; SH), 7.12 (s, 2H; H7,
H8), 7.28 (d, J=8.0 Hz, 4H; H3, H5); 7.45 ppm (d, J=8.0 Hz, 4H; H2,
H6); 13C NMR (100 MHz, [D6]DMSO): d=127.0, 128.6, 131.6,
133.8 ppm; MS: m/z (%): 244 (100), 178 (61.18), 165 (28.79).
C
C
technique. The concentrations of GO and DPPH in methanol were mea-
sured from their molar extinction coefficient values, e=1.153ꢁ105 (lmax
428) and 1.023ꢁ104 mꢀ1 cmꢀ1 (517 nm), respectively.
=
5904
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5898 – 5905

Extraordinary Radical Scavengers
FULL PAPER
Measurements for pKa values of the 4-mercaptostilbenes and 4-hydroxys-
tilbenes: The pKa values in methanol/PBS (v/v=2:1) were measured
using the spectrophotometric titration methods as described previously.[8c]
A precision pH meter (Mettler Toledo EL20 pH-meter) was used with
a combined pH glass electrode calibrated on primary pH standards for
the mixed solvent. Briefly, small volumes of titrant (2 mol Lꢀ1 KOH or
HCl in methanol/PBS) were used to adjust pH of the system (3 mL solu-
tion of the 40 mmol L 1 4-mercaptostilbenes or 4-hydroxystilbenes) to the
appropriate values at 258C under a nitrogen atmosphere. After each ad-
dition of titrant and when the pH value was stable, 2 mL samples of ti-
trated solution were transferred to quartz cuvettes (10 mm i.d.), and the
UV/Vis spectra in the range 200–650 nm were recorded using a Varian
Cary 300 Spectrophotometer.
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Acknowledgements
This work was supported by the National Natural Science Foundation of
China (Grant No. 20972063), the 111 Project, Program for New Century
Excellent Talents in University (NCET-06-0906) and the Fundamental
Research Funds for the Central Universities.
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Received: December 12, 2011
Published online: March 27, 2012
Chem. Eur. J. 2012, 18, 5898 – 5905
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5905