Hexadentate β-Dicarbonyl(bis-catecholamine) Ligands for Efficient Uranyl Cation Decorporation: Thermodynamic and Antioxidant Activity Studies

Article abstract of DOI:10.1021/acs.inorgchem.9b02306

The special linear dioxo cation structure of the uranyl cation, which relegates ligand coordination to an equatorial plane perpendicular to the O=U=O vector, poses an unusual challenge for the rational design of efficient chelating agents. Therefore, the

Full text of DOI:10.1021/acs.inorgchem.9b02306

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Hexadentate β‑Dicarbonyl(bis-catecholamine) Ligands for Efficient
Uranyl Cation Decorporation: Thermodynamic and Antioxidant
Activity Studies
Qingchun Zhang,*,† Bo Jin,*,† Tian Zheng,† Xingyan Tang,‡ Zhicheng Guo,§ and Rufang Peng*,†
†State Key Laboratory of Environment-friendly Energy Materials, Southwest University of Science and Technology, Mianyang
621010, People’s Republic of China
‡Sichuan Research Center of New Materials, Institute of Chemical Materials, China Academy of Engineering Physics, Chengdu
610200, People’s Republic of China
§School of National Defense Science and Technology, Southwest University of Science and Technology, Mianyang 621010, People’s
Republic of China
S
* Supporting Information
ABSTRACT: The special linear dioxo cation structure of the uranyl cation, which relegates
ligand coordination to an equatorial plane perpendicular to the OUO vector, poses an
unusual challenge for the rational design of efficient chelating agents. Therefore, the planar
hexadentate ligand rational design employed in this work incorporates two bidentate
catecholamine (CAM) chelating moieties and a flexible linker with a β-dicarbonyl chelating
moiety (β-dicarbonyl(CAM)2 ligands). The solution thermodynamics of β-dicarbonyl-
(CAM)2 with a uranyl cation was investigated by potentiometric and spectrophotometric
2+
titrations. The results demonstrated that the pUO2 values are significantly higher than for
the previously reported TMA(2Li-1,2-HOPO)2, and efficient chelation of the uranyl cation
was realized by the planar hexadentate β-dicarbonyl(CAM)2. The efficient chelating ability of
β-dicarbonyl(CAM)2 was attributed to the presence of the more flexible β-dicarbonyl
chelating linker and planar hexadentate structure, which favors the geometric arrangement
between ligand and uranyl coordinative preference. Meanwhile, β-dicarbonyl(CAM)2 also exhibits higher antiradical efficiency
in comparison to butylated hydroxyanisole. These results indicated that β-dicarbonyl(CAM)2 has potential application
prospects as a chelating agent for efficient chelation of a uranyl cation.
oxygen atoms, which relegate ligand coordination to an
equatorial plane perpendicular to the OUO vector;
significant deviations from uranyl linearity9−12 or equatorial
coordinative planarity10,11 occur only in the presence of
unusually sterically demanding ligands. Furthermore, the
terminal oxygen atoms of the uranyl cation universally exhibit
poor Lewis basicity, although they have been typically only
observed to interact with Lewis acids in the solid state13−19
and the purposely designed ligand scaffolds.11,20−25 As a result,
few uranyl ligands attempt targeted interactions with the
terminal oxygen moieties,22−24 with most instead focusing on
optimizing bonding interactions in the equatorial coordinative
plane.26−30 Equatorial pentacoordinative or hexacoordinative
geometry generally occurs between five- and six-membered
chelating rings with bidentate ligands.27,28,31,32 The side-
rophore-inspired bidentate catecholamine (CAM) and hydrox-
ypyridinone (HOPO) chelating moieties with hard Lewis
bases are well-suited for binding the Lewis acidic uranyl cation.
Moreover, previous research has indicated that the incorpo-
rated bis-bidentate ligands more effectively chelate uranyl
1. INTRODUCTION
The development of civilian energy generation and atomic
weapons requires further research on the various environ-
mental and health issues of uranium.1 Uranium is introduced
into the environment via atomic weapon tests and accidents in
nuclear facilities and is then absorbed by humans through
ingestion or inhalation or introduced into the blood through a
wound or abrasion. Unlike organic poisons, which in the body
is able to metabolize, the toxic uranium is either excreted or
immobilized. In the case of the uranium, immobilization in the
body for months to years forms complexes with bone and
tissue constituents. The retention of uranium complexes in
bones and tissues is a potent carcinogen in mammals because
of its long-term α-radiation damage and induces cancer in the
deposition site.2−4 Meanwhile, the highly active α rays can
produce reactive oxide species (ROS) that activate apopto-
sis.5,6 Thus, uranium and ROS should be eliminated from the
body by administration of efficient and antioxidative chelating
agents.
However, uranium is usually present as a stable uranyl cation
(UO22+) form in vivo, which poses an unusual challenge for the
rational design of efficient chelating agents.7,8 These
complications stem partly from the trans orientation of its
Received: July 30, 2019
© XXXX American Chemical Society
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cation in comparison to a solo monobidentate ligand.8,33,34
Therefore, the usual approach for the design of chelating
agents for a uranyl cation has been incorporation of CAM or
HOPO chelating moieties into bis-bidentate planar li-
gands.27,32,35−37 However, the bis-bidentate CAM or HOPO
ligands fail to saturate the equatorial coordinative plane of
uranyl cation, leaving a solvent-accessible area at the trans
orientation of the uranyl center (Figure 1),32,35−37 which
ligands are as yet unexplored. Herein, a detailed character-
ization of the solution thermodynamic stability of β-
dicarbonyl(CAM)2 ligands with the uranyl cation and the
antioxidant activity of β-dicarbonyl(CAM)2 ligands by a 2,2-
diphenyl-1-picrylhydrazyl (DPPH•) antioxidant assay are
discussed.
2. RESULTS AND DISCUSSION
2.1. Synthesis and Characterization. The synthesis of β-
dicarbonyl(CAM)2 ligands 5a−c (L1−3H5) are shown in Figure
2. 2,3-Bis(benzyloxy)benzoic acid 2 was prepared according to
a previously reported method.40 Alkanolamine and 2 were
condensed using 1-hydroxybenzotriazole/dicyclohexylcarbodii-
mide (HOBt/DCC) to obtain the desired benzamides 3a−c
with up to 90% yield.41 Then malonyl chloride was added to
3a−c in the presence of Et3N in anhydrous CH2Cl2. The
reaction generated benzyl-protected intermediates 4a−c with
up to 71% yield. Deprotection of the hydroxyl groups under
typical catalytic hydrogenation conditions with removal of the
benzyl group gave the target product ligands L1−3H5 with up to
99% yield.
Figure 1. (left) Solvent-accessible area in UO2(bis-Me-3,2-HOPO)
complexes, with uranyl oxygen atoms omitted for clarity. (right) Tris-
bidentate ligands with a chelating linker design for coordinative
saturation of a uranyl cation.
Uranyl−L1−3H5 complexes were prepared according to the
reported method.35 A methanol solution of UO2(NO3)2·6H2O
was added dropwise to methanol solutions of ligands L1−3H5
with vigorous stirring, and then a small amount of pyridine was
added to give the product as an orange solid with a yield of up
to 74%.
allows undesired interactions with solvent molecules. In the
environment, the solvent-accessible area is eliminated via
coordination of mono- and bidentate ligands, such as
hydroxide or acetate.38 This gives inspiration that a tris-
bidentate chelating agent might achieve equatorial coordinative
saturation by strategic employment of an appropriately shaped
linker.39 Fortunately, the flexible bidentate β-dicarbonyl has a
strong chelating ability for the uranyl cation, and its
introduction into the structure design can achieve an
appropriately flexible linker with chelating ability.
Therefore, the rational design of planar hexadentate ligands
employed in this work incorporates two bidentate CAM
chelating moieties and a flexible linker with a β-dicarbonyl
chelating moiety (β-dicarbonyl(CAM)2 ligands; Figure 1),
which is expected to better match the equatorial plane
hexacoordinative geometry of uranyl cation, ultimately realiz-
ing the efficient chelation of the uranyl cation. To the best of
our knowledge, the antioxidant activity and steric consequen-
ces of uranyl chelation by synthetic β-dicarbonyl(CAM)2
The ligands L1−3H5 and uranyl−L1−3H5 complexes were
fully characterized by nuclear magnetic resonance (NMR),
Fourier-transform infrared (FTIR) spectroscopy, and mass
spectra (MS). The FTIR spectra of ligands L1−3H5 showed
characteristic peaks at 1745 and 1732 cm−1 for the vibrational
coupling of β-dicarbonyl, 1639 cm−1 for ν(CO) of
benzamide carbonyl, and 1266 cm−1 for ν(C−O) of the
1
phenolic hydroxy group. The H NMR signals of the CAM
aromatic protons of ligands L1−3H5 in (CD3)2CO were
identified as two doublet of doublets at 7.10−7.13 ppm (dd,
J = 7.8, 1.2 Hz, 2H, Ar-H) and 6.82−6.84 ppm (dd, J = 7.8, 1.2
Hz, 2H, Ar-H) and one triplet at 6.65 ppm (t, J = 7.8 Hz, 2H,
Ar-H). The results indicated that the structures of ligands
L1−3H5 were as we expected. However, for the FTIR spectra of
uranyl−L1−3H5 complexes, the peak at 1639 cm−1 for ν(C
O) of benzamide carbonyl shifted to about 1588 cm−1 and the
Figure 2. Synthesis of β-dicarbonyl(CAM)2 ligands. Metal-binding atoms are shown in red and blue.
B
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peak at 1266 cm−1 for ν(C−O) of the phenolic hydroxy group
shifted to about 1258 cm−1 in the corresponding uranyl
complexes. The 1H NMR signals of the CAM aromatic protons
of uranyl−L1−3H5 complexes in DMSO-d6 demonstrated a
small amount of isomers, due to the rapid formation of the
complex in methanol solution. The major isomers were
identified as two peaks at 7.13−7.03 ppm (m, 2H, Ar-H)
and 6.98−6.88 ppm (m, 4H, Ar-H); in comparison with
ligands L1−3H5 they have appreciable changes and downfield
shifts. The results indicated that the oxygen atoms of CAM
have taken part in coordination with the uranyl cation.
2.2. Solution Thermodynamics. In the presence of
dissolved metal ions (Ma+) and protonated ligands (LHh,
where L is a ligand with h removable protons), a pH-
dependent metal−ligand complex with the general formula
MmLlHh forms. The relative amount of each species in solution
was determinated by eq 1, whose rearrangement provides the
standard formation constant notation of log βmlh (eq 2). The
log βmlh values describe a cumulative formation constant, and a
stepwise formation constant (log K) can be calculated from log
βmlh values by using eq 3. When addressing protonation
constants, the stepwise formation constants are commonly
Figure 3. Incremental spectrophotometric titration of ligand L1H5 by
0.01 M KOH. Conditions: [L1H5] = 0.2 mM, I = 0.1 M KCl, T =
298.2 K.
H
reported as log Kh (h = 1, 2, 3, ...).
[MmLlHh] = β [M]m[L]l[H]h
(1)
(2)
mlh
[MmLlHh]
[M] [L] [H]
Figure 4. Representative speciation diagram of ligand L1H5 at [L1H5]
= 10 μM with absorbances at 310, 320, and 330 nm as a function of
pH.
i
y
j
j
z
z
log β = log
j
j
j
z
z
z
mlh
m
l
h
k
{
i
j
j
j
j
j
j
y
z
z
z
z
z
z
i
y
β01h
β01(h−1)
[LHh]
[LHh−1][H]
j
z
and the possible oxidation of the ligand when the pH exceeds
12.0, as observed in other CAM derivatives.45 The values of
the constants are approximately 13.0 for β-diketonate ligands
with electron-donating substitutes.46 Meanwhile, considering
the ineluctable statistical factor and the actual practice, we used
j
z
log K01h = logj
z = log
j
j
z
z
k
{
(3)
k
{
2.2.1. Ligand Protonation. In their neutral form, the β-
dicarbonyl(CAM)2 ligands (also designated as L1−3H5) involve
five dissociable protons, since they contain one active
methylene and two CAM moieties. Prior to study of the
complexation of metal ions by the investigated ligands L1−3H5,
H
an estimated value of log K1H = 12.7. The log K4H and log K5
values of ligands L1−3H5 are ascribed to two consecutive
protonations of the weaker basic oxygen atoms of the CAM
the log Kh values of ligands L1−3H5 should be determined.
dianion moiety; the average values of log K4 and log K5 are
comparable with the corresponding values for N-methyl-2,3-
dihydroxybenzamide (MDHB),47 N,N-dimethyl-2,3-dihydrox-
ybenzamide (DMB),48 and catechol49 (Table 1). The average
values in this work were in good agreement with the value of
H
H
H
H
The log Kh values of ligands L1−3H5 were calculated by the
program HypSpec,42 fitting incremental spectrophotometric
titration data. The initial maximum UV−visible absorption
peaks at 310 nm red-shift to 330 nm with an increase in pH in
the range 4.8−10.0, which was attributed to the deprotonation
of the more acidic phenolic protons. Subsequently, the
intensity gradually decreases with an increase in pH in the
range 10.0−11.5, which was attributed to further deprotona-
tion (Figure 3 and Figure S1). The log KhH values were used to
calculate a speciation diagram by the program HySS,43 and the
formation of six different species between pH 5.5 and 12.5 was
determined (Figure 4 and Figure S4). In order to determine
the accuracy of the results, the log KhH values of ligands L1−3H5
were confirmed by the program Hyperquad,44 fitting
potentiometric titration curves. The curves all show a break
at m = 2 (mol of base/mol of ligand), which is indicative of the
deprotonation of the two more acidic phenolic hydroxyl in
positions ortho to the carbonyl on each of the CAM moieties
H
log K2 = 7.50 for MDHB. At the same time, the values were
about one logarithm unit lower than that for DMB, which was
attributed to an intramolecular hydrogen bond of the
secondary amide with phenolate oxygen in an ortho
position50−53 and the negative inductive effect of the tertiary
amide in the CAM moiety. Meanwhile, the values were about
two logarithm units lower than that of catechol, which was
attributed to not only the intramolecular hydrogen bond50−52
but also the inductive effect of the secondary amide. In fact,
theoretical calculations, an analysis of crystal structures, and
experimental potentiometric data for the series of CAM
derivatives indicated that the presence of amide on the
catechol reduced the second protonation constant of the
nearby oxygen atoms of catechol dianions by about two
logarithm units.54
H
(Figure S2). The log Kh values extrapolated from both
methods were in excellent agreement (Figure S3). The
2.2.2. Uranyl−Ligand Complex Solution Stability Deter-
mination. The affinities of ligands L1−3H5 with uranyl cation
were determined by incremental spectrophotometric titrations
using a 1:1 uranyl to ligand ratio to avoid the decomposition of
the free ligand at high pH values and also to ensure the
H
determined and estimated log Kh values of ligands L1−3H5
are reported in Table 1. The log K1H values of ligands L1−3H5,
corresponding to the first protonation of active methylene,
cannot be directly determined because of their very high values
C
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Table 1. Summary of log Kh Values of L1‑3H5 and Selected Mono(catechol) Ligands
Article
H
f
H
H
H
H
H
ligand
log K1
log K2
log K3
log K4
log K5
average
a
e
L1H5
12.70
12.70
12.70
11.20
12.10
13.00
11.95(4)
12.00(6)
12.04(3)
7.50
8.42
9.24
10.68(3)
10.72(5)
10.78(6)
7.68(5)
7.56(4)
7.87(5)
6.95(3)
7.32(5)
6.87(6)
7.32
7.44
7.37
a
a
e
L2H5
L3H5
e
b
MDHB
c
DHB
d
catechol
a
b
Values were determined from incremental spectrophotometric titrations at [L1−3H5] = 0.2 mM, I = 0.1 M KCl, and T = 298.2 K. Reference 47.
c
d
e
f
Reference 48. Reference 49. Estimated value. Average value: ∑(log K4 + log K5H)/2.
H
formation of mononuclear complexes. The initial maximum
UV−visible absorption peaks at 310 nm red-shift to 330 nm
with an increase in pH in the range 2.2−10.3, which was
attributed to the deprotonation of the phenolic protons. In
comparison to the UV−visible absorption of the free ligands,
the initial absorption band at wavelengths greater than 380 nm
gradually increases with an increase in pH, which was
attributed to the ligand to metal charge transfer (LMCT)
bands of uranyl−L1−3H5 complexes (Figure 5 and Figure S5).
Figure 6. Representative speciation diagram of the uranyl−L1H5
complex at [UO22+] = 1 μM and [L1H5] = 10 μM with absorbances at
310 and 330 nm as a function of pH.
pH the active methylene of β-dicarbonyl moiety is deproto-
nated, allowing slow rotation and displacement of the
coordinated solvent at the uranyl center by the β-dicarbonyl
moiety, forming [UO2(L1−3)] complexes.
The determined thermodynamic parameters of uranyl−
L1−3H5 complexes and corresponding complexes of HOPO
derivatives are reported in Table 2. The thermodynamic
parameters of uranyl−L1−3H5 complexes are significantly
different from reported uranyl−tetradentate ligand complexes
at high pH. The coordinatively saturated [UO2(L1−3)]3−
complexes can form at relatively low pH, and no partial
hydrolysis of the uranyl cation occurs with increasing
hydroxide concentration. In contrast, the uranyl coordinative
plane cannot be saturated by tetradentate ligands. Hence, the
partial hydrolysis of the uranyl cation is predicted to occur at
high pH value.32,35,36 Because log βmlh values are species-
dependent, a species-independent metric is needed to compare
affinities of various ligands with a uranyl cation. In this regard,
Figure 5. Incremental spectrophotometric titration of the uranyl−
L1H5 complex by 0.01 M KOH. Conditions: [L1H5] = [UO22+] = 0.2
mM, I = 0.1 M KCl, T = 298.2 K.
Incremental spectrophotometric titrations were used to
determine the log βmlh values of uranyl−L1−3H5 complexes,
and variations in the UV−visible absorbance at varying pH
were modeled by the formation of four distinguishable species
between pH 2.0 and 10.0. The uranyl−L1−3H5 complexes
routinely form [UO2(L1−3H3)] complexes, which are gen-
erated at pH 2.0; the absorbance peaks at 310 nm gradually
decrease with an increase in pH in the range of about 2.2−4.0,
which indicated the deprotonation of two more acidic protons
of ligands L1−3H5 and complexation with uranyl cation
continuing to generate [UO2(L1−3H3)]. Subsequently, the
absorbance peak at 330 nm, which is attributed to the
characteristic absorption peak of fully coordinated uranyl
complexes, rapidly increased until around pH 10.0, which
indicated the complete deprotonation of the ligands L1−3H5
and complexation with the uranyl cation to generate
[UO2(L1−3)]3− (Figure 6 and Figure S6). We hypothesize
that the kinetic barrier observed in uranyl titrations with β-
dicarbonyl(CAM)2 ligands is associated with β-dicarbonyl
moiety rotation upon complete deprotonation (Figure 7). It is
assumed that both CAM moieties simultaneously deprotonate
at low pH55 to form UO2(L1−3H) complexes in which only
CAM moieties chelate the uranium atom, with the uranyl
coordinative plane possibly completed by a coordinated
solvent molecule. The β-dicarbonyl moiety would most likely
be oriented away from the uranyl cation; upon an increase in
pM is the metric employed, where pM = −log[Mfree]. “Mfree
”
refers to solvated metal ions free of complexation by ligands or
hydroxides, with a high pM value corresponding to low
concentrations of free metal ions in solution. As a reference
2+
index, pUO2 under oceanic conditions is 16.8, which could
be due to the high affinity of carbonate with a uranyl cation. In
2+
this study, pUO2 values are calculated using standard
conditions of [UO22+] = 1 μM and [L] = 10 μM at a typical
pH of 7.4.
The pUO22+ values of ligands L1−3H5 are significantly higher
than those of the tetradentate PEG-4Li-bis-Me-3,2-HOPO
(Figure 8).32 This finding commonly occurs in ligands L1−3H5
because of their greater denticity. However, the pUO22+ values
are slightly higher than those of the hexadentate TMA(2Li-1,2-
HOPO)2 (Figure 8),56 indicating that denticity is not the sole
reason for the high affinity. Meanwhile, the minor changes in
H
log Kh values are an insignificant factor in determining the
affinity of ligands L1−3H5 with a uranyl cation; the higher
D
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Figure 7. Hypothesized complexation behavior of β-dicarbonyl(CAM)2 ligands, with L2H5 shown as an example.
Table 2. Summary of the Thermodynamic Parameters of Uranyl−L1‑3H5 Complexes and Comparison with Corresponding
Complexes of HOPO Derivatives
d
2+
ligand
log β11‑1
log β110
log β111
log β112
log β113
pUO2
a
a
a
L1H5
L2H5
L3H5
30.21(2)
30.05(3)
29.96(3)
21.95
39.01(4)
38.84(4)
38.54(1)
26.86
45.71(5)
45.41(2)
44.91(5)
30.79
49.89(3)
49.59(5)
49.02(4)
18.97(3)
18.69(4)
18.16(4)
18.2
b
TMA(2Li-1,2-HOPO)2
PEG-4Li-bis-Me-3,2-HOPO
c
6.97
13.90
15.39
a
Values were determined from incremental spectrophotometric titrations at [L1−3H5] = [UO22+] = 0.2 mM, I = 0.1 M KCl, and T = 298.2 K.
b
c
d
2+
Reference 56. Reference 32. pUO2 is the negative logarithm of the free uranyl cation concentration in equilibrium with complexed and free
ligand at a fixed pH of 7.4 with 1 μM total uranyl cation concentration and 10 μM total ligand concentration.
Figure 9. Incremental spectrophotometric titration of the Cu2+−L1H5
Figure 8. Tetradentate PEG-4Li-bis-Me-3,2-HOPO and hexadentate
TMA(2Li-1,2-HOPO)2 ligands for a thermodynamic parameter
comparison of the corresponding uranyl complexes.
complex by 0.01 M KOH. Conditions: [L1H5] = [Cu2+] = 0.2 mM, I
= 0.1 M KCl, T = 298.2 K.
affinity is presumably due to a favorable geometric arrange-
ment between ligands L1−3H5 and the uranyl coordinative
preference. The fact is that, as the length of the linker
increases, the affinity of ligands with uranyl cation gradually
decreases. The possible cause of this result is the longer linker
of ligands L2,3H5 leads to two CAM planes in these complexes,
giving a ruffled shape, reducing affinity.
2.2.3. Copper(II)−Ligand Complex Solution Stability
Determination. The affinity of ligands L1−3H5 with Cu2+
were also determined by incremental spectrophotometric
titrations. The initial maximum UV−visible absorption peaks
at 310 nm red-shift to 330 nm with an increase in pH in the
range 2.2−8.3, which was also attributed to the deprotonation
of the phenolic protons (Figure 9 and Figure S7). Incremental
spectrophotometric titrations were used to determine the log
βmlh value of Cu2+−L1−3H5 complexes, and variations in the
UV−visible absorbance at varying pH were modeled by the
formation of three distinguishable species between pH 3.5 and
7.5. The Cu2+−L1−3H5 complexes routinely form [Cu-
(L1−3H3)] complexes at around pH 4.5; the absorbance
peaks at 310 nm gradually decrease with an increase in pH in
the range of about 4.5−5.5, which indicated the deprotonation
of the two more acidic protons of ligands L1−3H5 and
complexation with Cu2+, forming [Cu(L1−3H3)]. Subse-
quently, the absorbance peaks at 330 nm rapidly increased
until around pH 8.0, which indicated the further deprotonation
of the ligands L1−3H5 and complexation with Cu2+ to form
[Cu(L1−3H)]2− (Figure 10 and Figure S8). The determined
thermodynamic parameters of Cu2+−L1−3H5 complexes and
corresponding complexes of 1,3,5-tris[(2,3-dihydroxy-5-
sulfobenzamide)methyl] (MECAMs)57 and ethylenediamine-
tetraacetic acid (EDTA)58 are reported in Table 3. The pCu2+
values of ligands L1−3H5 are slightly lower than those of
MECAMs and EDTA.
2,2,4. Zinc(II)−Ligand Complex Solution Stability Deter-
mination. The affinities of ligands L1−3H5 with Zn2+ were also
determined by incremental spectrophotometric titrations
under the same conditions as above. The initial maximum
E
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ligands,57,60−62 indicating that ligands L1−3H5 with weak Zn2+
affinity exhibited improved selectivity to the uranyl cation.
2.3. Antioxidant Activity. DPPH• is a stable free
radical,63 which has been widely used to monitor the free
radical scavenging ability of various antioxidants.64−66 The
assays were carried out in methanol, and the results are
expressed as EC50, which represents the antioxidant concen-
tration required to decrease the initial DPPH• concentration
by 50%. A low EC50 value indicates a high radical scavenging
capacity. This parameter is widely used to measure antioxidant
capacity but does not consider the reaction time. The time
needed to reach the steady state at the concentration
Figure 10. Representative speciation diagram of the Cu2+−L1H5
complex at [Cu2+] = 1 μM and [L1H5] = 10 μM with absorbances
at 310 and 330 nm as a function of pH.
corresponding to EC50 (TEC ) was calculated, and the
50
antiradical efficiency (AE) was introduced as a parameter to
characterize the antioxidant.64 AE was determined by eq 4.
Table 3. Summary of the Thermodynamic Parameters of
Cu2+−L1‑3H5 Complexes and Comparison with
Corresponding Complexes of MECAMs and EDTA
1
AE =
EC50 × TEC
(4)
50
d
ligand
log β111
log β112
log β113
pCu2+
The percentage of remaining DPPH• was determined from the
kinetic curves of different concentrations n (Figure S11),
where n is the molar ratio of antioxidant to DPPH• (mol of
AH/mol of DPPH•). The EC50 values of lignads L1−3H5 were
obtained from the curves of the percentage of remaining
DPPH• at the steady state as a function of concentration n
(Figure S12). The structures of phenolic derivatives have a
great influence on antioxidant activity.67,68 The phenolic
ligands L1−3H5 exhibit similar antioxidant activities due to
their similar molecular structures. Meanwhile, it is known that
more phenolic hydroxyls are known as having more efficient
antioxidant activity.68 The DPPH• assay results indicated that
the tetraphenolic hydroxyl ligands L1−3H5 exhibited EC50
a
L1H5
L2H5
L3H5
33.63(2)
33.61(3)
34.40(2)
39.71(5)
39.96(4)
40.43(5)
44.69(7)
44.07(5)
41.96(6)
13.45(5)
13.52(4)
14.29(4)
16.9
a
a
b
MECAMs
EDTA
c
16.9
a
Values were determined from incremental spectrophotometric
titrations at [L1−3H5] = [Cu2+] = 0.2 mM, I = 0.1 M KCl, and T =
b
c
d
298.2 K. Reference 57. Reference 58. pCu2+ is the negative
logarithm of the free Cu2+ concentration in equilibrium with
complexed and free ligand at a fixed pH of 7.4 with 1 μM total
Cu2+ concentration and 10 μM total ligand concentration.
UV−visible absorption peaks at 310 nm red-shift to 330 nm
with an increase in pH in the range 2.3−9.3, which was also
attributed to the deprotonation of the phenolic protons
(Figure S9). Incremental spectrophotometric titrations were
used to determine the log βmlh value of Zn2+−L1−3H5
complexes, and variations in the UV−visible absorbance at
varying pH were modeled by the formation of one distinguish-
able species between pH 8.0 and 9.0 (Figure S10). The
determined thermodynamic parameters of Zn2+−L1−3H5
complexes and corresponding complexes of 1,4,7,10-tetraaza-
cyclododecane-N,N′,N″,N′′′-tetraacetic acid (DOTA)59 and
diethylenetriaminepentaacetic acid (DTPA)59 are reported in
Table 4. The pZn2+ values of ligands L1−3H5 are significantly
lower than those of the traditional chelating agents DOTA and
DTPA. The low pZn2+ values are similar to those of catechol
values of the same magnitude and shorter TEC values in
50
comparison to that the diphenolic hydroxyl catechol69 and the
monophenolic hydroxyl butylated hydroxyanisole (BHA),64
which had high AE values (Table 5).
Table 5. EC50 and AE Values of Ligands L1‑3H5 and Other
Antioxidants
a
EC50 (mol of AH /mol of
antioxidant
DPPH•)
TEC (min) AE (×10−3
)
50
L1H5
L2H5
L3H5
0.112
0.120
0.110
0.09
20.0
20.0
20.0
122.1
103.9
228
256 10
220
91
48
5
8
b
catechol
c
BHA
0.203
a
b
c
Antioxidants. Reference 69. Reference 64.
Table 4. Summary of the Thermodynamic Parameters of
Zn2+−L1‑3H5 Complexes and Comparison with
Corresponding Complexes of DOTA and DTPA
3. CONCLUSIONS
c
ligand
log β111
log β113
pZn2+
New planar hexadentate ligands, which contain two CAM
chelating moieties attached to a flexible linker with a β-
dicarbonyl chelating moiety, have been synthesized. The
results of solution thermodynamics demonstrated that the
a
L1H5
23.30(3)
22.96(2)
23.11(4)
37.49(1)
36.75(3)
35.15(4)
6.0
6.0
6.0
17.9
14.8
a
L2H5
a
L3H5
b
DOTA
DTPA
2+
pUO2 values are up to 18.97, which is significantly higher
b
than that for the previously reported TMA(2Li-1,2-HOPO)2,
and efficient chelation of the uranyl cation was realized by the
planar hexadentate β-dicarbonyl(CAM)2. The efficient chelat-
ing ability of β-dicarbonyl(CAM)2 was attributed to the
presence of the more flexible β-dicarbonyl chelating linker and
planar hexadentate structure, which is more suitable for uranyl
cation chelation and achieves coordinative saturation of the
a
Values were determined from incremental spectrophotometric
titrations at [L1−3H5] = [Zn2+] = 0.2 mM, I = 0.1 M KCl, and T =
b
c
298.2 K. Reference 59. pZn2+ is the negative logarithm of the free
Zn2+ concentration in equilibrium with complexed and free ligand at a
fixed pH 7.4 with 1 μM total Zn2+ concentration and 10 μM total
ligand concentration.
F
DOI: 10.1021/acs.inorgchem.9b02306
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
DPPH• at the steady state against the molar ratio of antioxidant to
DPPH•. Moreover, the time needed to reach the steady state to EC50
uranyl cation. Meanwhile, β-dicarbonyl(CAM)2 also exhibits
higher antiradical efficiency in comparison to BHA. These
results indicated that β-dicarbonyl(CAM)2 has potential
application prospects as a chelating agent for efficient chelation
of a uranyl cation.
concentration (TEC ) and the AE values were also calculated.
50
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b02306.
■
S
4. EXPERIMENTAL SECTION
4.1. Ligand and Metal Stock Solutions. Aqueous stock
solutions of ligands L1−3H5 were freshly prepared by direct dissolution
of a weighed portion of ligands in ultrapure water prior to each set of
experiments. A uranyl cation stock solution was prepared by
dissolving a weighed amount of uranyl nitrate (UO2(NO3)2·6H2O,
99%) in standardized 0.1 M HNO3 solution. A Cu2+ stock solution
was prepared by dissolving a weighed amount of copper nitrate
(Cu(NO3)2·3H2O, 99.9%) in ultrapure water. A Zn2+ stock solution
was prepared by dissolving a weighed amount of zinc chloride (ZnCl2,
99.9%) in ultrapure water. All solid reagents were weighed on a
Sartorius BT25S analytical balance that was accurate to 0.01 mg.
4.2. Potentiometric Titrations. Potentiometric titrations were
carried out with a INESA ZDJ-4B automated titrator. The solution
was maintained at 298.2 K by an external thermostated water bath.
The analyte solution was bubbled with N2 gas in each set of
experiments and measurement performed in 0.1 M KCl electrolyte to
correct for the ionic strength. The pH electrode (INESA, equipped
with a Metrohm combination electrode in saturated KCl) was
calibrated to measure p[H] (hydrogen ion concentration) by
standardized pH buffer (Hamilton). Titrations of free ligands used
standardized 0.01 M KOH as the titrant (Aladdin). The
potentiometric titrations data were used in the Hyperquad refine-
ments,44 and titrations were repeated a minimum of three times.
4.3. Spectrophotometric Titrations. Spectrophotometric titra-
tions were also carried out with a INESA ZDJ-4B automated titrator.
The solution was maintained at 298.2 K by an external thermostated
water bath. All analyte solutions were prepared in a 50.0 mL
volumetric flask, and measurements were conducted with a ligand to
metal ratio of 1:1 by careful addition of the ligand stock solution and
metal ion stock solution. Measurements of analyte solutions with
different pHs were made on a Thermo Scientific Evolution 201 UV−
vis spectrophotometer using a 10.0 mm quartz cuvette. The scan
range of spectra was typically 250−450 nm. For each set of analyte
solutions, no precipitation was observed. The stability constants and
spectral deconvolution were refined using the least-squares fitting
program HypSpec.42
4.4. Titration Data Treatment. The potentiometric titrations
and spectrophotometric titration data were respectively analyzed
using the programs Hyperquad44 and HypSpec,42 utilizing nonlinear
least-squares fitting to refine stability constants and protonation
constant. The pM values and speciation diagrams were calculated
using the program HySS43 and the protonation constants of ligands
and formation constants of metal complexes (Figures S13−S15)
determined by potentiometric and spectrophotometric titration
experiments. Errors were determined as t*s/(n)1/2 at the 95%
probability level, where n is the number of samples, s/(n)1/2 is the
standard deviation, and t* is the distribution over n − 1 degrees of
freedom. The errors quoted in Tables 1−4 were used to account for
error propagations, which are the standard deviations of the overall
thermodynamic parameters given directly by the programs HypSpec42
and Hyperquad44 for the input potentiometric titration data and batch
spectrophotometric titration data, which include the experimental
points of all the titration data.
Synthetic process, NMR, FTIR, and potentiometric and
spectrophotometric titration data, speciation diagram,
and antioxidant assay data (PDF)
AUTHOR INFORMATION
Corresponding Authors
*Q.Z.: e-mail, zhangqingchun@swust.edu.cn; tel, +86-816-
2419011.
■
*B.J.: e-mail, jinbo0428@163.com.
*R.P.: e-mail, pengrufang@swust.edu.cn.
ORCID
Qingchun Zhang: 0000-0003-4063-9645
Bo Jin: 0000-0002-6966-2876
Author Contributions
Q.Z. and B.J. conceived and designed the experiments; Q.Z.,
T.Z. and X.T. performed the experiments; Q.Z., Z.G. and R.P.
analyzed the data; Q.Z. and R.P. wrote and edited the
manuscript.
Funding
This research was funded by the National Natural Science
Foundation of China (grant number 51572230), Independent
Research Projects of State Key Laboratory of Environment-
friendly Energy Materials (grant number 19fksy0104), and the
Natural Science Foundation of Southwest University of
Science and Technology (grant number 18zx7136).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. Heyan Huang (Analytical and Testing
Center, Southwest University of Science and Technology) for
nuclear paramagnetic resonance measurements and Prof. Li Su
(Analytical and Testing Center, Southwest University of
Science and Technology) for potentiometric and spectropho-
tometric titrations.
ABBREVIATIONS
CAM = catecholamine
HOPO = hydroxypyridinone
■
DPPH• = 2,2-diphenyl-1-picrylhydrazyl
MDHB = N-methyl-2,3-dihydroxybenzamide
DMB = N,N-dimethyl-2,3-dihydroxybenzamide
LMCT = ligand to metal charge transfer
TMA(2Li-1,2-HOPO)2 = 2,3-dihydroxy-N1,N4-bis[(1,2-hy-
droxypyridinone-6-carboxamide)ethyl]terephthalamide
MECAMs = 1,3,5-tris[(2,3-dihydroxy-5-sulfo-benzamide)-
methyl]
4.5. Antioxidant Assay. An aliquot of methanol (0.1 mL) and
different aliquots of stock methanol solutions of 5 × 10−5
M
antioxidant were added to a 2.5 mL methanol solution of 6 × 10−5 M
DPPH•, and the volume was adjusted to a final value of 3.0 mL with
methanol. Absorbances at 517 nm were measured immediately at 10 s
intervals on a Thermo Scientific Evolution 201 UV−vis spectropho-
tometer until the reaction reached a steady state. Five different
concentrations were measured for each assay. Then the EC50 value
were plotted to obtain from the graph the percentage of remaining
EDTA = ethylenediaminetetraacetic acid
DOTA = 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′′′-tet-
raacetic acid
DTPA = diethylenetriaminepentaacetic acid
AE = antiradical efficiency
G
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Inorganic Chemistry
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DOI: 10.1021/acs.inorgchem.9b02306
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