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.
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acid can be attributed to the fact that in contrast to GO
(Eored vs. saturated calomel electrode (SCE)=0.05 V),[18]
o
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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-
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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.
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the 2,2-diphenyl-1-picrylhydrazyl (DPPH ) radical were purchased from
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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
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SFA-20 accessory. The pseudo-first-order decay of GO (428 nm) or
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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).
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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
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5898 – 5905