Substituent effect on the radical scavenging activity of 6-chromanol derivatives

Article abstract of DOI:10.1039/c4ra05782a

Several 6-chromanol derivatives with various substituents (one or two amino, acetylamino, chloro or nitro substituents at the 5-, 7-, 8- or 5,7-positions on the phenyl ring of 2,2-dimethyl-6-chromanol) were synthesized, and their second order rate constan

Full text of DOI:10.1039/c4ra05782a

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Substituent effect on the radical scavenging activity
of 6-chromanol derivatives†
ab
Cite this: RSC Adv., 2014, 4, 43882
Mariko Suzuki,a Azusa Shimizu,a Miyuki Furukawa,b Mine Moritab
*
Keiko Inami,
and Masataka Mochizukiab
Several 6-chromanol derivatives with various substituents (one or two amino, acetylamino, chloro or nitro
substituents at the 5-, 7-, 8- or 5,7-positions on the phenyl ring of 2,2-dimethyl-6-chromanol) were
synthesized, and their second order rate constants (k) for
a reaction that demonstrates radical
scavenging activity (reaction with the galvinoxyl radical) were determined. Three monoacetylamino
compounds, 8-nitro compound, and 5,7-diamino, 5,7-diacetylamino, and 5,7-dinitro compounds were
newly synthesized. log k was plotted against the Hammett sigma (sm) or Taft sigma (s*) constants for the
compounds containing each of the four substituents to obtain their reaction constants (r) from the
slopes. The s plots representing radical scavenging activity showed a linear correlation with negative
r values for all compounds with substituted positions. The results indicate that the electron-donating
effect of the amino and acetylamino groups on the chroman ring enhanced radical scavenging activity,
whereas the electron-withdrawing effect of the chloro and nitro groups decreased this activity.
Furthermore, the magnitude of r for the substituted compounds increased in the following order with
respect to the substitution position: meta-substituted (ꢀ3.71 for 6a–d), ortho-monosubstituted (ꢀ0.86
for 4a–d, ꢀ0.87 for 5a–d), and ortho-disubstituted (ꢀ0.47 for 7a–d). The greater r magnitudes for the
meta-substituted compound indicated that the radical scavenging reactions were more sensitive to
inductive substituent effects than for the ortho-substituent compounds. The r values for ortho-mono-
and ortho-disubstituted compounds were smaller than that for the meta-substituted compound, despite
the fact that the k values for the ortho-substituted compounds were higher than those for the meta-
substituted compounds. Thus, electron-donating groups in ortho-substituted 6-chromanols accelerate
the reaction rate through resonance stabilization in addition to the inductive substituent effect.
Received 16th June 2014
Accepted 1st September 2014
DOI: 10.1039/c4ra05782a
www.rsc.org/advances
scavenging activity,12–14 O–H bond dissociation enthalpy
(BDE),14–17 and ionizationenthalpy.18 Despite the largenumber of
Introduction
reports focused on the effect of substituents on the relationship
betweenradical scavengingactivityand calculated BDE in simple
phenols,19–26 few reports have examined the effect of substituents
inthechromanringon radicalscavengingactivity.24–27 The aimof
this study was to understand the structure–activity relationships
of 6-chromanol derivatives in radical scavenging reactions. A
series of 6-chromanol derivatives with substituents ortho or meta
to the phenolic group was synthesized. The radical scavenging
activities of these derivatives were then investigated based on the
rate constants (k) of their reactions with the galvinoxyl radical
(Gc), and then compared with substituent sensitivity for each
positions, which obtained from the correlation of log k and
Hammett sigma (sm) or Ta sigma (s*) constants.
a-Tocopherol (1) is involved in immune function, cell signaling,
gene expression regulation, and other metabolic processes.1,2 In
addition to its physiological activities, a-tocopherol is an antioxi-
dant and protects cells from damage caused by reactive oxygen
species. Thus, a-tocopherol is thought to serve in preventing
oxidative damage, such as that in cancer and ischemia/reperfusion
tissuedamage.3,4 Theantioxidantactivitiesof1areattributedtothe
radical scavenging function of their phenolic hydroxyl groups.5–7
A
large number of tocopherol derivatives have been synthesized and
assayed for their antioxidant and physiological activities.8–11
The chemical properties of phenols have been widely studied
and correlated with antioxidant activity that has radical
aFaculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki,
Noda-shi, Chiba 278-8510, Japan. E-mail: inami@rs.noda.tus.ac.jp; Fax: +81-4-
7121-3641; Tel: +81-4-7121-3641
Experimental methods
Material and methods
bKyoritsu University of Pharmacy, Shibako-en 1-5-30, Minato-ku, Tokyo 105-8512,
Japan
2-Methyl-3-buten-2-ol was obtained from Tokyo Kasei Kogyo
Co., Ltd. (Tokyo, Japan). The galvinoxyl radical was purchased
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra05782a
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from Kanto Chemical Co., Inc. (Tokyo, Japan). Acetonitrile, d 169.8, 168.2, 152.4, 139.1, 127.3, 120.6, 120.3, 116.9, 74.2, 32.0,
which was used for spectral measurements, was obtained from 26.7, 23.3, 20.9, 19.5; IR (cmꢀ1, neat) 3266, 2932, 1766, 1660;
Dojindo Laboratories (Kumamoto, Japan). Other reagents were HRMS (FAB) 278.1394 (calcd for C15H19NO4 277.1314).
purchased from Wako Pure Chemical Industries (Osaka, Japan).
5b-OAc; white needle-like crystals (recrystallized from ether
All of the reagents and solvents used were of the best and hexane); yield 27%; mp 147.5–150.0 ꢁC; 1H NMR (400 MHz,
commercially available quality and were not further puried CDCl3) d 7.51 (s, 1H), 6.99 (br, 1H), 6.80 (s, 1H), 2.71 (t, J ¼ 6.6
unless otherwise noted.
Hz, 2H), 2.32 (s, 3H), 2.14 (s, 3H), 1.77 (t, J ¼ 6.6 Hz, 2H), 1.31
Reaction progression was monitored using thin-layer chro- (s, 6H); 13C NMR (100 MHz, CDCl3) d 169.3, 167.8, 151.9, 133.9,
matography (TLC) on silica gel 60 F254 (0.25 mm, Merck, 128.3, 121.9, 117.4, 111.7, 74.4, 32.5, 26.9, 24.5, 22.2, 21.0; IR
Darmstadt, Germany). Column chromatography was performed (cmꢀ1, neat) 3315, 2976, 1752, 1669; HRMS (FAB) 278.1392
using silica gel 60 (230–400 mesh, Merck). Melting points were (calcd for C15H19NO4 277.1314).
determined using a Yanaco micro-melting point apparatus
without correction. NMR spectra were recorded with a JEOL
JNM-LA400 spectrometer (Tokyo, Japan). Chemical shis were
expressed in terms of ppm downeld shied from TMS. High-
resolution mass spectra were collected using a JEOL JMS-
SX102A mass spectrometer. FT-IR spectra were recorded with a
Perkin Elmer Spectrum 100 (Waltham, USA). UV-Vis spectro-
Synthesis of 6-acetoxy-8-acetylaminochroman (6b-OAc)
6-Acetoxy-8-amino-2,2-dimethylchroman (39.7 mg, 0.17 mmol)
was dissolved in pyridine (0.5 mL), followed by the addition of
an excess of acetic anhydride (1 mL). The reaction mixture was
stirred at room temperature for 3 h. The reaction mixture was
then poured onto crushed ice, and the precipitate was ltered
via suction to afford the desired product.
6b-OAc; white needle-like crystals (recrystallized from
ethanol and H2O); yield 40%; mp 186.0–187.5 ꢁC; 1H NMR (400
MHz, CDCl3) d 8.00 (d, J ¼ 2.7 Hz, 1H) 7.72 (br, 1H), 6.54 (d, J ¼
2.9 Hz, 1H), 2.75 (t, J ¼ 6.8 Hz, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.81
(t, J ¼ 6.8 Hz, 2H), 1.36 (s, 6H); 13C NMR (100 MHz, CDCl3) d
170.2, 168.0, 143.0, 139.6, 127.8, 120.5, 116.2, 111.0, 75.7, 32.6,
27.0, 25.0, 22.4, 21.1; IR (cmꢀ1, neat) 3339, 1744, 1675; HRMS
(FAB) 278.1394 (calcd for C15H19NO4 277.1314).
photometry was obtained using
a Hewlett-Packard 8453
photodiode array spectrophotometer (Hanover, USA) equipped
with an Applied Photophysics RX 2000 stopped-ow device
(Leatherhead, UK).
2,2-Dimethyl-6-chromanol (3) was synthesized using the
method described by Nilsson et al. (mp: 75.3–76.0 ꢁC).28 Amino
(4a, 5a, 6a), chloro (4c, 5c, 6c, 7c), and nitro (4d, 5d) 6-chro-
manols and 6-acetoxy-2,2-dimethyl-8-nitrochroman (mp: 56.5–
57.0 ꢁC) and 6-acetoxy-8-amino-2,2-dimethylchroman (mp:
86.5–87.5 C) were synthesized as reported previously.29,30
ꢁ
Syntheses of acetylamino-6-chromanols via acetylated
Syntheses of 6-acetoxyacetylaminochromans (4b-OAc, 5b-OAc)
compound hydrolyses
4d or 5d was dissolved in methanol, followed by the addition of The puried acetylated compounds were dissolved in methanol
an excess of acetic anhydride and palladium/carbon (5%). The and treated with 1 M sodium methoxide. Aer the disappear-
reaction mixture was stirred overnight at room temperature ance of the starting material observed by TLC, the reaction
under a hydrogen atmosphere to produce the following two mixture was neutralized with 0.5 M HCl and extracted twice with
distinct spots via TLC: acetylamino (4b, 5b) and acetoxylated CH2Cl2. The combined organic layer was washed with water,
acetylamino compounds (4b-OAc, 5b-OAc). The reaction dried over anhydrous sodium sulfate and ltered. Following
mixture was ltered through celite, and the lter cake was concentration under reduced pressure, the product was puried
washed with CH2Cl2. Water was added to the ltrate, and the on a short silica gel column, even when a single compound was
organic layer was extracted twice with CH2Cl2. The combined obtained.
ꢁ
organic layer was washed with saturated NaHCO3 and water and
4b; tan yellow solid; yield 96%; mp 184.0–186.0 C (decom-
dried over anhydrous sodium sulfate, ltered, and then the position); 1H NMR (400 MHz, CDCl3) d 7.51 (s, 1H), 7.12 (br, 1H),
solvent was evaporated under reduced pressure. The crude 6.85 (d, J ¼ 9.0 Hz, 1H), 6.67 (d, J ¼ 8.8 Hz, 1H), 2.59 (t, J ¼ 6.8
product was dissolved in pyridine, followed by the addition of Hz, 2H), 2.28 (s, 3H), 1.81 (t, J ¼ 6.8 Hz, 2H), 1.30 (s, 6H); 13C
an excess of acetic anhydride. The reaction mixture was stirred NMR (100 MHz, CDCl3) d 170.3, 147.8, 143.2, 123.5, 119.1, 116.8,
at room temperature for 2 h to produce a single spot by TLC. 113.3, 73.1, 32.1, 26.4, 23.6, 19.4; IR (cmꢀ1, neat) 3267, 2974,
The reaction mixture was poured onto crushed ice and extracted 2929, 1639; HRMS (FAB) 236.1209 (calcd for C13H17NO3
twice with CH2Cl2. The combined organic layer was washed 235.1208).
ꢁ
with saturated NaHCO3, water, 1 M HCl, and water, then dried
5b; tan yellow solid; yield 97%; mp 205.0–206.5 C (decom-
1
over anhydrous sodium sulfate, ltered, and the solvent evap- position); H NMR (400 MHz, CDCl3) d 8.02 (s, 1H), 7.48 (br,
orated under reduced pressure. The crude product was puried 1H), 6.72 (s, 1H), 6.41 (s, 1H), 2.71 (t, J ¼ 6.3 Hz, 2H), 2.23 (s,
on a silica gel column to afford the single desired product.
4b-OAc; white needle-like crystals (recrystallized from ether CDCl3) d 170.3, 147.5, 141.8, 124.4, 120.2, 119.8, 110.0, 74.1,
and hexane); yield 40%; mp 121.0–123.0 ꢁC; 1H NMR (400 MHz, 32.7, 26.7, 23.7, 22.1; IR (cmꢀ1, neat) 3415, 2970, 2929, 1655,
3H), 1.76 (t, J ¼ 6.8 Hz, 2H), 1.29 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 6.85 (d, J ¼ 9.0 Hz, 1H), 6.75 (d, J ¼ 9.0 Hz, 1H), 6.66 1608; HRMS (FAB) 235.1287 (calcd for C13H17NO3 235.1208).
ꢁ
(br, 1H), 2.64 (t, J ¼ 6.8 Hz, 2H), 2.29 (s, 3H), 2.15 (s, 3H), 1.76
6b; tan yellow solid; yield 99%; mp 193.0–194.5 C (decom-
(t, J ¼ 6.8 Hz, 2H), 1.33 (s, 6H); 13C NMR (100 MHz, CDCl3) position); 1H NMR (400 MHz, CDCl3) d 8.62 (s, 1H), 8.24 (d, J ¼
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2.9 Hz, 1H), 7.87 (br, 1H), 6.37 (d, J ¼ 2.9 Hz, 1H), 2.72 (t, J ¼ 6.7 could not be obtained owing to the compound's high instability
Hz, 2H), 2.24 (s, 3H), 1.78 (t, J ¼ 6.7 Hz, 2H), 1.33 (s, 6H); 13C in air.
NMR (100 MHz, CDCl3) d 169.2, 150.0, 135.2, 126.8, 121.0, 110.1,
105.5, 74.9, 32.9, 26.8, 24.9, 22.4; IR (cmꢀ1, neat) 3560, 2978,
Synthesis of 5,7-diacetylamino-2,2-dimethyl-6-chromanol (7b)
2933, 1637; HRMS (FAB) 235.1203 (calcd for C13H17NO3
7d (55 mg, 0.21 mmol) was dissolved in methanol (10 mL),
235.1208).
followed by the addition of an excess of acetic anhydride
(4.2 mL) and 5% palladium/carbon (26 mg). The reaction
Synthesis of 2,2-dimethyl-8-nitro-6-chromanol (6d)
mixture was stirred under a hydrogen atmosphere at room
temperature for 9.5 h. The reaction mixture was ltered through
celite, and the lter cake was washed with CH2Cl2. The ltrate
was acidied to pH 3 upon 1 M HCl addition and extracted three
times with CH2Cl2. The combined organic layer was washed
with water, dried over anhydrous sodium sulfate, ltered, and
the solvent was evaporated under reduced pressure. The resi-
dues were termed 7b and acetoxylated 7b (7b-OAc). The mixture
was then dissolved in methanol (2 mL), and 0.5 M NaOMe
(0.2 mL) was added. The mixture was stirred for 10 min at room
temperature under an argon atmosphere. The mixture was
neutralized by the addition of 1 M HCl and then extracted three
times with CH2Cl2. The combined organic layer was washed
with water, dried over anhydrous sodium sulfate, ltered, and
the solvent was evaporated under reduced pressure. The crude
product was puried on a silica gel column (ethyl acetate–CHCl3
¼ 1 : 1) to afford the desired single product.
6-Acetoxy-2,2-dimethyl-8-nitrochroman (27 mg, 0.1 mmol) was
dissolved in methanol (1 mL). Sodium methoxide (0.2 mL) was
then added to the solution, and this mixture was stirred for
0.5 h at room temperature. The reaction mixture was acidied
with 1 M HCl and extracted three times with CH2Cl2. The
combined organic phase was washed with 5% NaHCO3 and
H2O, dried over Na2SO4, ltered, and evaporated to give an
orange oil. The crude product was puried using silica gel
column chromatography (silica gel 60, 4% methanol–chloro-
form) to afford a yellow solid.
6d; yellow solid; yield 101%; mp 88.0–91.0 ꢁC; 1H NMR (400
MHz, CDCl3) d 7.17 (d, J ¼ 3.2 Hz, 1H), 6.83 (d, J ¼ 3.2 Hz, 1H),
2.80 (t, J ¼ 6.8 Hz, 2H), 1.85 (t, J ¼ 6.8 Hz, 2H), 1.36 (s, 6H); 13
C
NMR (100 MHz, CDCl3) d 147.1, 142.5, 139.0, 125.5, 121.3, 110.1,
76.1, 32.0, 26.6, 22.7; IR (cmꢀ1, neat) 3539, 3413, 2975, 1524,
1358; HRMS (EI) 223.0842 (calcd for C11H13NO4 223.0845).
7b-OAc; 1H-NMR (400 MHz, CDCl3) d 6.79 (s, 1H), 2.56 (t, 2H,
J ¼ 6.1 Hz), 2.30 (s, 3H), 2.14 (s, 6H), 1.75 (t, 2H, J ¼ 6.7 Hz), 1.31
(s, 6H).
Synthesis of 2,2-dimethyl-5,7-dinitro-6-chromanol (7d)
2,2-Dimethyl-6-chromanol (592 mg, 3.33 mmol) was dissolved
in acetic acid (40 mL) and cooled to below 15 ꢁC while stirring.
Nitric acid (422 mL, 2 eq.) was then added to the solution, and
7b; white prism crystals (recrystallized from ethanol); yield
64%; mp 224.0–224.2 ꢁC; 1H NMR (400 MHz, CDCl3) d 8.20
(s, 1H), 8.03 (br, 1H), 7.48 (s, 1H), 2.55 (t, J ¼ 6.7 Hz, 2H), 2.29
(s, 3H), 2.19 (s, 3H), 1.77 (t, J ¼ 6.7 Hz, 2H), 1.27 (s, 6H); 13C
NMR (100 MHz, CDCl3) d 170.6, 168.8, 147.5, 133.2, 127.9, 123.3,
109.2, 107.9, 73.3, 32.1, 26.4, 24.6, 23.5, 19.0; IR (cmꢀ1, neat)
3259, 2974, 2929, 1639; HRMS (FAB) 293.1501 (calcd for
ꢁ
the mixture was stirred below 15 C for 10 min. The reaction
mixture was poured onto crushed ice and extracted three times
with CH2Cl2. The combined organic layer was extracted three
times with 10% Na2CO3. The aqueous layer was acidied to pH
3 upon concentrated HCl addition, at which time, a precipitate
appeared. The solid was ltered via suction to afford a yellow
solid.
C
15H20N2O4 292.1423).
Kinetics measurements
7d; orange prism crystals (recrystallized from carbon tetra-
chloride); yield 46%; mp 168.0–168.1 ꢁC; 1H NMR (400 MHz,
CDCl3) d 10.3 (s, 1H), 7.69 (s, 1H), 2.80 (t, J ¼ 6.8 Hz, 2H), 1.86
(t, J ¼ 6.8 Hz, 2H), 1.36 (s, 6H); 13C NMR (100 MHz, CDCl3) d
146.6, 141.0, 140.3, 132.9, 125.2, 114.0, 75.7, 30.8, 26.5, 19.3; IR
(cmꢀ1, neat) 3123, 2980, 1530, 1369; HRMS (EI) 268.0695 (calcd
for C11H12N2O6 268.0695).
The kinetics were determined by measuring the disappearance
of absorbance at 428 nm under pseudo-rst-order conditions at
25 ꢁC.31 Substituted 6-chromanols (with the following nal
concentrations: 0–100 mM for compounds 4a, 5a, and 7a;
0–300 mM for compounds 4b, 4c, 5b, 6a, 6b, 7b, and 7c; 0–600
mM for compounds 4d, 5d, 6d, and 7d; and 0–1000 mM for
compounds 5c and 6c) and Gc (nal concentration of 5.0 mM)
were dissolved in argon deaerated with acetonitrile. The two
syringes were loaded with 2 mL of each compound and Gc
Synthesis of 5,7-diamino-2,2-dimethyl-6-chromanol (7a)
7d (20 mg, 0.07 mmol) was rst dissolved in methanol (5 mL), solution. The pneumatic drive accessory initiated mixing aer
and 5% palladium/carbon (19 mg) was then added to the the initiation of data acquisition by the spectrophotometer at
solution. The reaction mixture was stirred under hydrogen gas 300–600 nm and 0.5 s intervals. Half of the starting concen-
for 30 min at room temperature. The reaction mixture was tration of Gc solution and antioxidant was used aer mixing.
ltered through celite, and the lter cake was washed with
The radical scavenging rates were determined by monitoring
deaerated CH2Cl2 under nitrogen gas. The ltrate was blown dry the changes in absorbance due to the galvinoxyl radical at
with argon to afford a red solid.
428 nm. Pseudo-rst-order rate plots of ln(A ꢀ AN) versus time,
7a; red solid; yield 97%; 1H NMR (400 MHz, CDCl3) d 7.36 (s), where A and AN refer to the absorbance at a given time and the
2.55 (br), 2.32 (br), 2.19 (br), 1.81 (br), 1.37 (br), 1.30 (s); HRMS nal absorbance, respectively, were linear until three or more
(FAB) 209.1288 (calcd for C11H16N2O2 208.1212). 13C NMR data half-lives. The AN used was the absorbance 10 min aer each
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reaction started. To avoid the inuence of minor absorption concentration was at more than a 10-fold excess compared to the
from the Gc reduction products at this wavelength, only the rst Gc concentration. The observed pseudo-rst-order rate constant
Gc absorption decay values were used in kinetics analyses. (kobs) was compound concentration-dependent in a linear
Pseudo-rst-order rate constants were determined using the manner. Second-orderrateconstants (k)forthe reactionsbetween
least-squares method. The observed pseudo-rst-order rate 6-chromanols and Gc were obtained from the slopes of the linear
constant (kobs) was compound concentration-dependent. The functions of kobs versus compound concentration (Table 1).
second-order rate constants (k) for the reactions between the
The aromatic ring substituent effects on Gc-scavenging
compounds and Gc were obtained from the slopes of the linear activity showed that the amino 6-chromanols exhibited the
functions of kobs versus various compound concentrations highest radical scavenging activity, followed by acetylamino,
under pseudo-rst order reaction conditions. The data were chloro, and nally nitro 6-chromanols at any of the substituent
collected in at least three different experimental sessions.
positions. In terms of substituent position, the ortho-disubsti-
tuted or ortho-monosubstituted compounds demonstrated
higher radical scavenging activities, whereas meta-substituted
compounds were less efficient.
The data also showed that the electron-donating substitu-
ents (NH2 and NHCOCH3) led to an accelerated Gc-scavenging
reaction rate, whereas the electron-withdrawing substituents
(Cl and NO2) led to a decreased reaction rate.
Results
Chemistry
The lead compound optimized in this manuscript is
2,2-dimethyl-6-chromanol (3). Compounds 1 and 2 are consid-
ered to be derivatives of 3. The substituents were chosen based
on their ability to donate electrons (NH2 and NHCOCH3) or
accept electrons (Cl and NO2). Compounds 4a–d and 5a–d
possess a substituent at position 5 or 7, respectively, which are
ortho to the phenolic OH group. Compounds 6a–d have a
substituent at position 8, which is meta to the phenolic OH
group. Compounds 7a–d have two substituted groups, both in
ortho positions (Fig. 1).
Three monoacetylamino compounds (4b, 5b, 6b), a nitro
compound (6d), and 5,7-diamino, 5,7-diacetylamino, and
5,7-dinitro compounds (7a, 7b, 7d) were newly synthesized.
The nitro compounds were prepared by nitration, reduced by
hydrogen gas in the presence of palladium/carbon to the cor-
responding amino compound. The acetylamino compounds
were prepared using simple catalytic reduction of the corre-
sponding nitro compounds (4d, 5d, 6d, 7d) in the presence of
acetic anhydride to obtain the acetoxy acetylaminochromans for
storage. The acetoxy compounds were hydrolyzed with alkaline
reagents immediately before use (Schemes 1–3).
Correlation of radical scavenging activity with Hammett and
Ta substituent constants for 6-chromanol derivatives
The Hammett sigma constant is one of the most widely used
means for studying and interpreting organic reactions and their
mechanisms. The Hammett sigma constant (sm) for the posi-
tion meta to the phenolic OH group, which has been shown to
interact with radicals, was used.32–34 The Ta sigma constant
(s*) describes the electronic effect, which includes a sub-
stituent's steric effect. In this case, the s* for substituents in
positions ortho to the phenolic OH group were applied.34
To identify the electronic effects of all of the substituents in a
given compound in each reaction with the series of 6-chroma-
nols and Gc, the sum of the sigma constants was plotted against
log k for the radical scavenging activity at each substituent
position. The reaction constants (r) were then obtained from
the slope values.35 For meta-substituted 6-chromanols, a linear
relationship between log k and s was observed (rmeta ¼ ꢀ3.71, r2
¼ 0.91). The ortho-monosubstituted 6-chromanols (r5-ortho
¼
Galvinoxyl radical scavenging activity of the substituted 6-
chromanols
ꢀ0.86, r2 ¼ 0.89; r7-ortho ¼ ꢀ0.87, r2 ¼ 0.89) and the 5,7-disub-
stituted 6-chromanols (r5,7-diortho ¼ ꢀ0.47, r2 ¼ 0.90) also
The ability of a series of 6-chromanols to scavenge Gc was evalu- exhibited linear relationships between their s and Gc scav-
ated in acetonitrile. Gc is a reactive oxygen species with a strong enging activities. In all cases, s versus Gc scavenging activity
absorption band at 428 nm.31 Upon addition of a compound to showed negative linear slopes with good correlation.
deaerated Gc solutions in acetonitrile, the absorption band at
The magnitude of r was compared among substituent posi-
428 nm rapidly decreased. The absorbance decay at 428 nm tions.32,33 The r of meta-substituted 6-chromanols (3.71) was the
obeyed pseudo-rst-order reaction kinetics when the compound greatest, indicating that the Gc scavenging reaction was more
Fig. 1 Structures of a-tocopherol and its derivatives.
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Scheme 1 Synthesis of 5- or 7-subsituted 6-chromanols reagents and conditions: (A) (i) 5% Pd–C, H2 gas, Ac2O, rt, (ii) Ac2O, pyridine, rt; (B) 1 M
NaOMe, MeOH, rt.
Scheme 2 Synthesis of 8-subsituted 6-chromanols Reagents and conditions: (A) Ac2O, pyridine, rt; (B) 1 M NaOMe, MeOH, rt.
Scheme 3 Synthesis of 5- and 7-disubsituted 6-chromanols Reagents and conditions: (A) HNO3, AcOH, 15 ꢁC; (B) 5% Pd–C, H2 gas, rt; (C) (i) 5%
Pd–C, H2 gas, Ac2O, rt, (ii) 0.5 M NaOMe, MeOH, rt.
sensitive to the inductive substituents. The r5-ortho (0.86) and of the substituents and their position on Gc scavenging activity
r7-ortho (0.87) values were similar in magnitude, suggesting that were investigated.
a substituent at either the 5- or the 7-ortho position has the
Phenolic compounds scavenge oxyl radicals via the following
same effect on the radical scavenging reaction. The r5,7-diortho two primary mechanisms: one-step hydrogen atom transfer
(0.47) showed a smaller value (Fig. 2).
(HAT), and electron transfer followed by proton transfer (ET-PT).36
One-step HAT involves the abstraction of a hydrogen atom from
the phenolic hydroxyl group to form a phenoxyl radical. By this
mechanism, the O–H bond dissociation is homolytic, and the
reaction is driven by BDE. In contrast to HAT, ET-PT involves the
loss of an electron followed by the exothermic loss of a proton and
formation of a radical cation. ET-PT is driven by IP.36
Discussion
A series of 6-chromanol derivatives containing amino, acetyla-
mino, chloro, or nitro groups were synthesized, and the effects
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Table
1 The second-order rate constants (k) of the substituted
enhance Gc scavenging activity. These data agree well with our
previous report.30
6-chromanol derivatives with the galvinoxyl radical
Many studies have reported that the hydrogen atom
abstraction rates for a series of meta- or para-substituted
phenols linearly correlate with the BDE or Hammett sigma
constant (s).22,23,25,27,39 In this study, the sums of sm and s* were
used to investigate the relationship between the effects of
substituents in 6-chromanols and the radical scavenging
activity of the compounds. s was plotted against log k. For many
reactions, a series of log k values is linearly related to the
respective s values. By contrast, a number of reactions have
been shown to deviate from this linearity.40,41 Nonlinear Ham-
mett plots are due to a variation in transition state or reaction
mechanism for a series of compounds with different substitu-
ents. In this study, nonlinear relationships between the s value
and log k are possible. However, calculated BDEs in phenols are
linearly related to s values.22,23,25,27,39
The linear slope of s value versus log k for each substituent
position was obtained. The reaction constants for the Gc scav-
enging reactions were extrapolated from the slopes (r).32,33 The r
value magnitudes reveal the susceptibility of a reaction to
substituent effects. The rmeta value was the greatest, indicating
that the radical scavenging reaction was highly sensitive to the
inductive substituent effect at the meta position. Even though
the ortho-substituted 6-chromanols demonstrated high radical
scavenging activity, the r value magnitudes were low. The
magnitude of r depends on several factors, including temper-
ature, solvent, and transition state stability.41–44 The 5- and
7-aminochromanoxyl radicals have been detected by ESR,30
indicating that their intermediates are highly stable at room
Compound
ka (Mꢀ1 sꢀ1
)
Compound
ka (Mꢀ1 sꢀ1
)
4a
4b
4c
4d
5a
5b
5c
5d
50840 ꢂ 0.09
831.0 ꢂ 0.003
100.3 ꢂ 0.001
31.2 ꢂ 0.001
48610 ꢂ 0.02
914.1 ꢂ 0.009
100.5 ꢂ 0.001
33.2 ꢂ 0.001
6a
6b
6c
6d
7a
7b
7c
7d
23970 ꢂ 0.25
396.8 ꢂ 0.002
45.2 ꢂ 0.003
23.3 ꢂ 0.001
61300 ꢂ 0.26
859.4 ꢂ 0.004
181.7 ꢂ 0.001
30.1 ꢂ 0.000
a
Standard error of the regression line for each concentration.
We report that BDE of chlorinated 6-chromanols (4c, 5c, 6c,
7c) correlate with log k in Gc scavenging reactions, indicating
that the hydrogen atom transfer mechanism is the rate-deter-
mining step in these reactions.37,38 Moreover, high radical
scavenging activity of aminochromanols (4a, 5a, 6a) related with
the high stability of the corresponding phenoxyl radicals.30
At any substituent position, all of the 6-chromanols showed
Gc scavenging activity, with increasing k values for substituents
in the following order: amino, acetylamino, chloro, and then
nitro groups. The data indicated that 6-chromanols with elec-
tron-donating substituents signicantly increased Gc scav-
enging activity. Furthermore, the introduction of an electron-
donating substituent at a position ortho to the phenolic OH
group in the chroman ring has been reported to signicantly
Fig. 2 log k/k3 versus calculated s value plots. (A) 5-Substituted 6-chromanols: 4a (C), 4b (:), 4c (-), 4d (A); (B) 7-substituted 6-chromanols:
5a (C), 5b (:), 5c (-), 5d (A); (C) 8-substituted 6-chromanols: 6a (C), 6b (:), 6c (-), 6d (A); (D) 5,7-disubstituted 6-chromanols: 7a (C), 7b
(:), 7c (-), 7d (A). k3 is presented as k (340.3 Mꢀ1 sꢀ1) for compound 3. The sm and the s* value are quoted from ref. 34.
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¨
¨
¨
temperature (half-life of 43 min). These data agreed with our 12 R. Apak, S. Gorinstein, V. Bohm, K. M. Schaich, M. Ozyurek
¨
¨
results and explained that the low magnitude of r was caused by
the stability of the intermediate radical. A relatively small r
and K. Guçlu, Pure Appl. Chem., 2013, 85(5), 957–998, (IUPAC
Technical Report).
value reects high 6-chromanol derivative reactivity. Therefore, 13 W. Brand-Williams, M. E. Cuvelier and C. Berset, LWT–Food
the radical reactions of the ortho-monosubstituted and disub- Sci. Technol., 1994, 28(1), 25–30.
stituted 6-chromanols are largely dependent on the stabilities of 14 M. Lucarini and G. F. Pedulli, Chem. Soc. Rev., 2010, 39(6),
the intermediates to increase radical scavenging activity. 2106–2119.
There is a possibility that radical scavengers can be devel- 15 Y. Kadoma, T. Atsumi, N. Okada, M. Ishihara, I. Yokoe and
oped as anti-inammatory agents and disease chemopreventive S. Fujisawa, Molecules, 2007, 12(2), 130–138.
agents.45 As our 6-chromanols showed positive radical scav- 16 M. C. Foti, C. Daquino, I. D. Mackie, G. A. DiLabio and
enging activities, a protecting group will be introduced into a K. U. Ingold, J. Org. Chem., 2008, 73(23), 9270–9282.
phenolic hydroxyl group and/or amino groups, and then their 17 N. Nenadis, L. F. Wang, M. Z. Tsimidou and H. Y. Zhang, J.
cytotoxicity will be evaluated.
Agric. Food Chem., 2005, 53(2), 295–299.
18 S. Fujisawa, M. Ishihara, Y. Murakami, T. Atsumi, Y. Kadoma
and I. Yokoe, In Vivo, 2007, 21(2), 181–188.
19 P. Mulder, H. G. Korth, D. A. Pratt, G. A. DiLabio,
L. Valgimigli, G. F. Pedulli and K. U. Ingold, J. Phys. Chem.
A, 2005, 109(11), 2647–2655.
Conclusion
For a series of substituted 6-chromanols, amino-6-chromanols
substituted at ortho positions demonstrated the highest radical
scavenging activities. Additionally, Hammett or Ta sigma 20 R. Bosque and J. Sales, J. Chem. Inf. Comput. Sci., 2003, 43(2),
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ties of substituted 6-chromanols to design new antioxidants 21 C. X. Xue, R. S. Zhang, H. X. Liu, X. J. Yao, M. C. Liu, Z. D.Hu
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