Stoichiometric oxidation of quercetin by HAuCl4 accompanied by H-D exchange with the solvent

Article abstract of DOI:10.1016/j.mencom.2013.03.016

The stoichiometric two-electron oxidation of quercetin by HAuCl₄ is accompanied by H-D exchange with D₂O at the 2'-position, which was not observed previously.

Full text of DOI:10.1016/j.mencom.2013.03.016

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 98–100
Stoichiometric oxidation of quercetin by HAuCl4
accompanied by H–D exchange with the solvent
Alexander F. Shestakov,* Alexander V. Chernyak, Nadezhda V. Lariontseva,
Stella A. Golovanova, Anatolii P. Sadkov and Lidiya A. Levchenko
Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka,
Moscow Region, Russian Federation. Fax: +7 496 522 3507; e-mail: a.s@icp.ac.ru
DOI: 10.1016/j.mencom.2013.03.016
The stoichiometric two-electron oxidation of quercetin by HAuCl4 is accompanied by H–D exchange with D2O at the 2'-position,
which was not observed previously.
Recently,1 we found that the interaction of HAuCl4 with bio-
flavonoids in aqueous solutions led to their deep oxidation. To
study the reaction between quercetin C15O7H10 and HAuCl4 at
room temperature (22 2°C), we used NMR spectroscopy.† For
this purpose, a 0.1 m solution of quercetin was prepared in a
mixture of DMSO-d6 and D2O (4:1, by volume); then, HAuCl4
was added to this solution in two steps at regular intervals of four
days to obtain quercetin-to-Au ratios of 1:0.5 and 1:1 after the
first and second steps, respectively.
Slow oxidation of quercetin under the action of Cuii ions was
reported,3 but the reaction products were not identified.
The 1H and 13C NMR spectra of quercetin (Table 1) are con-
sistent with published data.4–6 Signals of O and Cl nuclei were not
revealed because of their significant broadening. When adding
1
HAuCl4, a drift of H6 and H8 quercetin peaks in the H NMR
spectra was no more than 0.02 ppm. Moreover, this shift increases
with time under increasing degree of replacement of H by D in
these positions. Thus, this effect is probably due to the influence
of deuterium, and, most likely gold complexes with quercetin
do not form under experimental conditions. Such complex forma-
tion, for example, in the case of Cuii, leads to the observed shift
of proton signals up to 0.5 ppm towards low fields.5
To obtain the 1H NMR spectra, a standard pulse sequence p/2
free induction decay (FID) was used. For the accumulation of
13C NMR spectra, a standard pulse sequence t p/6-SSI was used
1
with the suppression of H during the entire experiment. The
delay before the pulse t was 1 s, and the number of savings was
500–4000. Standard two-dimensional correlations 1H-1H COSY,
1H-1H NOESY, 13C-1H HSQC, 13C-1H HMBC were studied to
interpret the spectra. Lines due to DMSO at 2.51 ppm (1H) and
39.51 ppm (13C) were used as reference ones. Earlier, in the
investigation of quercetin 1 oxidation by air,2 it was found that
the presence of Feiii or Cuii ions in the system accelerates the
reaction. p-Quinonemethide 2 is formed, which quickly adds water
molecule with the generation of a cyclic semiketal, which occurs
in two forms 3 and 4 (Scheme 1).
We found 15 additional lines in the 13C NMR spectrum after
adding the first portion of HAuCl4 (Figure 1). This indicates the
presence of only two organic compounds in the system: quercetin
and its oxidation product. Thus, the equilibrium in Scheme 1 is
completely shifted to one side. According to a detailed study of the
electrochemical oxidation of quercetin,7 it acts as a two-electron
reducer in an acid medium. Since HAuCl4 is a complementary
two-electron oxidizing agent, the primary redox reaction (1)
C15O7H10 + Au3+ = C15O7H8 + Au+ + 2H+
(1)
5'
OH
proceeds rather quickly, and the degree of conversion h = 46% is
achieved within 10 min (Table 2). The degree of transformation
was monitored by a change of the signal intensities of the original
compound and its oxidation product in the 1H NMR spectra. This
gives a rough estimate of the effective rate constant of reaction (1)
at ~10–2 mol dm–3 s–1. After the second addition of HAuCl4, only
signals from the oxidized form remain in the 13C NMR spectrum.
Thus, the oxidation of quercetin by HAuCl4 is stoichiometric with
the formation of a single product. It is accompanied by a change
in the optical spectrum of the system and can be used to develop
a sensitive analytical procedure for the determination of Au.8
The reliable assignment of signals was carried out taking into
account the two-dimensional 13C–1H correlations HSQC and
HMBC, which indicate that only carbon atom at 105.2 ppm does
not have any interaction, even distant, with hydrogen atoms. That
is, carbon at 105.2 ppm is distant at least by four bonds from any
hydrogen atom. Only form 4 of the two equilibrium forms of the
oxidized quercetin meets this requirement.
4'
6'
8
3'
1'
HO
O
9
2
7
– 2H
OH
2'
O
3
6
4
10
OH
5
HO
O
O
OH
O
OH
1
O
OH
2
OH
OH
H2O
OH
HO
O
O
O
O
8
HO
9
7
6'
O
OH
2
1'
3
5'
4'
3
4
6
OH
10
5
2'
OH
3'
O
OH
OH
4
Scheme 1
On the two-electron oxidation of quercetin, the formation of two
structures is possible, o-quinone one (the oxidation of two ortho
OH groups in ring B), and p-quinone one (shown in Scheme 1).
According to quantum-chemical calculations performed using
The H and 13C NMR spectra were recorded on a Bruker Avance III
†
1
Fourier NMR spectrometer (500 and 126 MHz, respectively).
© 2013 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2013, 23, 98–100
Table 1 Experimental and theoretical shielding constants of 1H and 13C nuclei for quercetin and its oxidation product.
Oxidation product 4
H/ppm
Quercetin 1
(experiment)
1
d
13
Atom C(H)
d C/ppm
1
d
13
d
H/ppm
C/ppm Experiment
Theory Experiment
Theory
2
3
4
5
6
—
—
—
—
146.9
135.8
175.9
160.8
98.3
—
—
—
—
105.2
191.1
191.0
159.2
97.4
169.3
91.3
125.4
196.5
197.4
168.2
97.1
6.16 (4JH –H 2.1 Hz)
5.94 (4JH –H 1.8 Hz)
5.63
5.26
6
8
6
8
7
8
—
164.0
93.5
—
174.7
90.5
6.41 (4JH –H 2.1 Hz)
5.94 (4JH –H 1.8 Hz)
6
8
6
8
9
—
—
—
7.60 (4JH
—
—
6.88 (3JH
7.51 (3JH
156.2
103.1
122.1
115.2
145.1
147.7
115.7
120.1
—
—
—
7.48 (4JH
—
—
6.81 (3JH
7.49 (3JH
172.7
101.2
125.7
117.9
145.4
152.0
115.7
124.8
178.0
105.7
132.5
124.2
151.9
154.4
114.1
125.7
10
1'
2'
3'
4'
5'
6'
2'–H6'
2'–H6'
2.3 Hz)
8.5 Hz)
2.2 Hz)
8.2 Hz)
8.56
5'–H6'
5'–H6'
5'–H6'
5'–H6'
6.35
7.38
8.5 Hz, 4JH
2.3 Hz)
8.2 Hz, 4JH
2'–H6'
2'–H6'
2.2 Hz)
of other signals in the 13C NMR spectrum of 4, except for the C2
atom, was performed taking into account the theoretical chemical
shifts. The mean deviation theory–experiment is similar to the
case of C atoms with C–H bonds.
(a)
In quercetin and its oxidation product 4 H–D exchange with the
solvent occurs mainly in the 8- and 6-positions (Table 2). Earlier
such exchange was observed in quercetin in CF3COOD solutions,10
but the 2'-position was not affected. HAuCl4 is responsible for
these phenomena because in its absence H–D exchange in quercetin
was not detected in six days. The estimated effective exchange rate
constants of the first order are 7×10–6, 4×10–6 and 3×10–6 s–1 for
the 8-, 6- and 2'-positions, respectively. They are much smaller than
those, more or about 10–3 s–1, found for exchange in CF3COOD.8
This difference is justified, since the concentration of protons in
the system, taking into account the formation of HCl, is about
0.15 mol dm–3, which is one order of magnitude lower than that
in CF3COOD. The mechanism of H–D exchange at the 6- and
8-positions seems to comply with keto-enol tautomerism, as sug-
gested previously.10
(b)
190 180 170 160 150 140 130 120 110 100 90
d/ppm
Figure 1 13C NMR spectra of quercetin (a) before adding HAuCl4 and
(b) after the first adding of HAuCl4.
density functional theory with nonempirical PBE functional with
extended basis: H [6s2p/ 2s1p] C, O [10s7p3d/ 3s2p1d],‡ the
energy of the latter structure is lower than that of the o-quinone one
by 7.9 kcal mol–1. The binding of a water molecule with the forma-
tion of structure 4 results in an energy release of 8.1 kcal mol–1.
The energy of isomeric structure 3 is higher by 1.7 kcal mol–1
(DG = 1.9 kcal mol–1). The calculated chemical shifts for 1H and
adjacent 13C nuclei in structure 4 (Figure 2) are in reasonable
agreement with experimental values (Table 1). The assignments
Our calculations show that the energy of the isomeric form of
quercetin with a carbonyl group at the 7-position and an additional
H atom in the 8- or 6-position is higher by 11.2 or 14.4 kcal mol–1,
respectively, than the energy of quercetin. The similar isomeriza-
tion of oxidized product 4 requires 12.0 and 14.3 kcal mol–1,
respectively. This is in qualitative agreement with a faster exchange
at the 8-position of quercetin. However, the degrees of exchange for
Table 2 Kinetics of exchange of quercetin protons with deuterium.
Deuterium exchange
of protons in 1 (%)
Deuterium exchange
of protons in 4 (%)
H
ha
(%)
H
O
Time/h
1.39
C
1.22
1.49
C
H
8
0
6
2' 6' 5'
8
0
6
0
2' 6' 5'
H
C
1.41
1.40
H
1.36
O
C
1.57
C
C
1.41
C
1.37
C
O
C
H
1.47
1.38
0.17
5
46
0
8
7
7
9
0
5
5
7
9
8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
7
6
5
9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1.39
O
O
1.41
H
1.36
H
1.40
1.39
1.41
1.58
C
1.41
C
83 12
100 18
100 22
100 27
17 17
30 30
35 35
49 49
C
C
1.41
2.10
C
1.42
1.23
26
1.36
C
1.39
H
0.98
O
1.35
O
32
O
2.04
H
48
0.99
73
100 37 11
64 64 12
88 88 13
91 91 14
96 96 19
Figure 2 Structure of the product 4 of two-electron oxidation of quercetin
according to the quantum-chemical calculations. Bond lengths are given in Å.
144
168
670
100 62 16 12
100 68 18 13
100 94 29 14
‡
Quantum-chemical calculations have been made using the PRIRODA
program9 at the facilities of the Joint Supercomputer Center of the Russian
Academy of Sciences.
a h is the conversion of quercetin in the reaction with HAuCl4 (the reaction
was completed at the ratio 1:4 = 1:1).
– 99 –

Mendeleev Commun., 2013, 23, 98–100
3 A. Pekal, M. Biesaga and K. Pyrzynska, Biometals, 2011, 24, 41.
the 6- and 8-positions in the product are the same, which indicates
fast intramolecular exchange between the 6- and 8-positions in 4.
The exchange in the 2'-position takes place only in the presence
of Au compounds. One can assume that the activation of a C–H
bond in ring B is responsible for it based on the fact that even
aliphatic C–H bonds are activated in the Au–bioflavonoid (rutin,
quercetin) systems.11,12
The oxidized form of quercetin in the absence of gold is
characterized by exactly the same shielding constants in 1H NMR
spectra; thus, it, like quercetin itself does not formAu-containing
complexes in appreciable quantities. Apparently, this is due to the
acidic medium and the presence of highly coordinating DMSO
molecules. Thus, we can conclude that in the stoichiometric
reaction found the solvent complex of gold(i), like AuCl(DMSO),
is produced.
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6 J. Li, H. Jiang and R. Shi, Nat. Prod. Res., 2009, 23, 1378.
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11 L. A. Levchenko, N. G. Lobanova, V. M. Martynenko, A. P. Sadkov,
A. F. Shestakov, A. K. Shilova and A. E. Shilov, Dokl. Akad. Nauk,
2010, 430, 773 [Dokl. Chem. (Engl. Transl.), 2010, 430, 50].
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Received: 26th October 2012; Com. 12/4004
– 100 –