A Chiral Ligand Assembly That Confers One-Electron O2 Reduction Activity for a Cu2+-Selective Metallohydrogel

Article abstract of DOI:10.1002/anie.201801290

The design of functional metallohydrogels is attractive but challenging. A rational approach is introduced for designing functional metallohydrogels using chiral ligands, a phenylalanine derivative with a pyridyl group (l/d-PF). Intriguingly, the as-prepared metallohydrogel exhibits excellent O₂ binding and activating properties. Insights into the O₂ binding pathway reveals the presence of a novel [(l+d)-PF-Cu³⁺-O₂^?] species, which can efficiently reduce ferric cytochrome c with the reactive O₂^? by receiving an electron from reductant ascorbic acid. This study provides helpful instructions for developing new artificial systems with specific functions through the effective combination of chiral ligands with metal ions.

Full text of DOI:10.1002/anie.201801290

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Chiral Ligands Assembly Confers One-electron O2 Reduction
Activity for a Cu2+-selective Metallohydrogel
Authors: Xiaojuan Wang, Chuanwan Wei, Jihu Su, Bo He, Ge-Bo Wen,
Ying-Wu Lin, and Yi Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801290
Angew. Chem. 10.1002/ange.201801290
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Angewandte Chemie International Edition
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COMMUNICATION
Chiral Ligands Assembly Confers One-electron O Reduction Activity
2
2+
for a Cu -selective Metallohydrogel
1
1*
2
1
3
1,3*
4*
Xiaojuan Wang , Chuanwan Wei , Jihu Su , Bo He , Ge-Bo Wen , Ying-Wu Lin , and Yi Zhang
Abstract: The design of functional metallohydrogels is attractive but
challenging. In this study, we introduce a rational approach for
designing functional metallohydrogels, through the combination of
chiral ligands, a phenylalanine derivative with a pyridyl group (L/D-
PF). Intriguingly, the as-prepared metallohydrogel exhibits excellent
To this end, it is pivotal to design new ligands for creating active
sites within the scaffold of metallohydrogels. Although the basic
component of proteins, amino acids, have been attempted for design of
metallohydrogels, current studies are limited only to natural L-amino
[6c, 6d, 7]
acids and their derivatives.
The knowledge that chirality plays
O
2
binding and activating properties. Insights into the O
2
−
binding
significant roles in biological systems prompted us to introduce both L-
and D-amino acids in design of metallohydrogels. We envisaged that
the combination of chiral ligands such as L/D-amino acids with a
hydrophobic group may construct a microenvironment suitable for
small molecules binding and activation. To test our aganippe, we
synthesized both L- and D-phenylalanine derivatives by introduction of
a metal-binding motif of pyridyl group, namely, L-PF and D-PF (See
the Supporting Information, SI, for details, Scheme S1). As shown in
this study, we found that both gelators exhibit specific responses to
3+
pathway reveals the presence of a novel [(L+D)-PF-Cu -O
which can efficiently reduce ferric cytochrome c with the reactive O
by receiving an electron from reductant ascorbic acid. We believe that
this study provides helpful instructions for developing new artificial
systems with specific functions through the effective combination of
chiral ligands with metal ions.
2
] species,
−
2
Metalloproteins and metalloenzymes are widely used by nature to
perform diverse functions, including O storage and transport, electron-
2
transfer and catalysis, etc. Inspired by natural metalloproteins and
metalloenzymes, artificial systems have been successfully designed to
mimic their natural counterparts, with similar functions or even
CuSO
CuSO
4
, and more interestingly, the assembly of L-PF and D-PF with
generates a novel purple metallohydrogel with one-electron O
4
2
[1]
reduction activity.
[1-2]
beyond.
Moreover, enormous progress has been achieved in
understanding the choice of metal ions by nature for different systems.
For example, heme-copper oxidases (HCOs) prefer copper over iron,
and nitric oxide reductases (NORs) prefer iron over copper for the non-
[3]
heme metal center, respectively. In addition to natural scaffolds (e.g.,
protein and DNA), many synthetic materials (e.g. nanoparticles and
hydrogels) have addressed much attention for design of artificial
[
4]
[5]
systems. Hydrogels have exhibited promising applications. In
particular, metallohydrogels can inherit the redox/catalytic properties
[6]
of metal ions and the biocompatibility of hydrogels, which offers
good opportunities for the design of artificial systems with advanced
functions. Despite the progress of broadening numbers of well-studied
"
universal" metallohydrogels, the pre-design but not post screening of
a unique metal ion-driven metallogel is still limited. Functionalization
of metallohydrogels is usually hampered by difficulties in design of an
open active site, due to the occupation by water molecules forming
stable hydrogen(H)-bonding networks. Therefore, to develop a rational
strategy for designing functional, specific and stimuli-responsive
metallohydrogels is highly desired and full of challenges.
[
1] Dr. X. Wang, Dr. C. Wei, B. He, Prof. Dr. Y.-W. Lin
School of Chemistry and Chemical Engineering, University of South China,
Hengyang 421001, China
Figure 1. Chemical structures of gelators, L-PF (a) and D-PF (b), and the preparation
2+
of Cu -hydrogels using (a) L-PF (0.1 M) or (b) L-PF + D-PF (each of them, 0.05 M)
and CuSO (0.1 M) with a molar ratio of 2:1, by sonication treatment in water, as
4
E-mail: weichw@hotmail.com (Dr. C. Wei)
shown by the SEM images (see Fig. S1 for enlarged images). Complex images of L-
PF (a) or L-PF + D-PF (b) and different metal ions under the same conditions are
shown at the bottom.
E-mail: linlinying@hotmail.com; ywlin@usc.edu.cn (Prof. Y.-W. Lin)
2] Dr. J. Su
[
CAS Key Laboratory of Microscale Magnetic Resonance, Department of
Modern Physics, University of Science and Technology of China, Hefei,
Anhui 230026, China
Both L-PF and D-PF are white powder solids with excellent
solubility in alkaline aqueous solutions. To study the gelling behaviors
of these two gelators, we first tested a series of metal ions, including
[3] Prof. Dr. G.-B. Wen, Prof. Dr. Y.-W. Lin
Laboratory of Protein Structure and Function, University of South China,
Hengyang 421001, China
2
+
2+
3+
2+
2+
2+
3+
2+
2+
2+
Ca , Fe , Bi , Ni , Pb , Cu , La , Zn , Co and Mn , for L-PF
by sonication treatment. The results showed that only CuSO induces
the formation of a metallohydrogel in several seconds with a blue color
termed PF-Cu) (Fig. 1a, and Fig. S1a and S2a for enlarged SEM and
[4] Prof. Dr. Y. Zhang
Hunan Provincial Key Laboratory of Chemical Power Sources, College of
Chemistry and Chemical Engineering, University of Central China, Changsha
4
4
21183, China.
(
E-mail: yzhangcsu@mail.csu.edu.cn
TEM images, respectively), indicating that the metallohydrogel is
Cu -selective, likely due to the preference of the ligands by the nature
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/anie.2014xxxxx.
2+
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Angewandte Chemie International Edition
10.1002/anie.201801290
COMMUNICATION
2
+
of Cu ion, such as the ionic radius and coordination geometry. In the
Cyclic voltammetry (CV) studies showed that both L-PF-Cu and
(L+D)-PF-Cu hydrogels are not stable upon reduction or oxidation by
electrochemistry, as both of them were collapsed after several redox
cycles and produced precipitations, which are not reversible, likely due
to the disruption of both coordination and H-bonding interactions (Fig.
S10). More interestingly, after addition of a small amount of
ascorbic acid (Asc), (L+D)-PF-Cu hydrogel converted into a blue sol,
2
+
2-
absence of Cu ions, the L-PF solution itself or with SO
could not self-assemble to form a gel, showing an indispensable role of
4
anions
2+
Cu in gelation. The effect of anions on gelation was further studied
by using CuCl or Cu(Ac) in replace of CuSO . Meanwhile, neither
CuCl nor Cu(Ac) could induce the formation of a metallohydrogel
2
2
4
2
2
under the same conditions (Fig. S3), which may be attributed to strong
coordination and H-bonding effects of chloride and acetate that tend to
turn off" gelation by competition with the gelator. In addition, two
isomers of L-PF with the nitrogen atom in pyridyl group at position 2
or 3 (termed L-2-PF and L-3-PF, respectively) were found unable to
form metallohydrogels in presence of CuSO
and reformed a purple hydrogel by bubbling O
that O may participate in the formation of (L+D)-PF-Cu hydrogel,
presumably by coordination to the copper center. The other possibility
2
gas, which suggests
[8]
"
2
2
+
+
2+
that the reduction of Cu to Cu by Asc and oxidation back to Cu by
2
O under these conditions could be ruled out by the EPR results in
4
(Fig. S4), suggesting that
a subtle change in coordination position resulted in a distinct gelation
property. These observations indicate that a metal-selective hydrogel is
determined by the nature of both metal ions and anions, as well as the
chemical structure of the gelator.
following sections.
2+
Although D-PF can also form a Cu -hydrogel with a blue color
identical to that of L-PF (Fig. S5), we found that the mixture of L-PF
2
+
and D-PF with a 1:1 ratio selectively induces the formation of a Cu -
hydrogel with a novel purple color (termed (L+D)-PF-Cu) (Fig. 1b and
Fig. S5), which, to the best our knowledge, has not been observed for a
copper-hydrogel. The minimum gelation concentration (MGC) was
determined to be 0.07 M at room temperature when the molar ratio of
(
4
L+D)-PF and CuSO was 2:1, which is similar to that of L-PF-Cu.
Scanning electron microscopy (SEM) revealed that the L-PF-Cu
hydrogel consists of a uniform network with incompact nanofibers
about 10-20 nm in dimension (Fig. 1a and Fig. S1a). Meanwhile, the
morphology of (L+D)-PF-Cu hydrogel showed more dense fibers (Fig.
1
b and Fig. S1b). Similar morphologies were also shown by
transmission electron microscope (TEM) images (Fig. S2). The
mechanical strength of the metallohydrogel was further determined by
rheological experiment. The results showed that (L+D)-PF-Cu
hydrogel exhibits dramatically enhanced values for both the average
value of storage modulus G′ and the loss modulus (G″) compared to
that of L-PF-Cu hydrogel in the entire measurement range (0.1-100 Hz)
(
Fig. S6). These observations indicate that the two chiral ligands may
pack more tightly in the metallohydrogel, leading to an improvement in
the mechanical strength.
The (L+D)-PF-Cu hydrogel can be stable for weeks at room
temperature. To evaluate its response for external stimuli, we tested
multiple physical and chemical treatments. As shown in Fig. S7, the
gel quickly restored after vigorous shaking by hand due to an excellent
Figure 2. (a) EPR spectra of (L+D)-PF-Cu complexes with different ratios of L-PF/D-
PF (see Supporting Information for details), collected at 100 K, 0.595 mW power, and
9
.43 GHz, and (b) the corresponding complex images. (c) Comparisons between
experimental and simulation results of the EPR spectra for L-PF-Cu, D-PF-Cu, and L-
PF/D-PF (5:5)-Cu complexes, respectively.
o
thixotropic nature. When the temperature was increased to 70 C (Tgel),
the gel began to collapse and the sol-to-gel transition occurred within 3
hr, suggesting a thermoreversible property. Note that the Tgel increased
with the increase of gelling concentration (Fig. S8). When titrated with
HCl, the gel appeared as a transparent blue solution, and turned cloudy
To probe the formation pathway of the unique purple (L+D)-PF-
Cu hydrogel, we varied the ratio of L-PF/D-PF, and collected the EPR
spectra for a series of (L+D)-PF-Cu complexes with a concentration
2
+
by addition of excess KOH, likely generating both Cu(OH)
2
and
below MGC. As shown in Fig. 2a, the hyperfine signals of Cu
2
-
[
Cu(OH)
4
] . The pH responsiveness of (L+D)-PF-Cu hydrogel was
decreased gradually by decreasing the ratio of L-PF:D-PF from 9:1 to
5:5, and increased gradually by increasing the ratio of D-PF:L-PF from
5:5 to 9:1. Accompanying the spectral changes, the solution color
changed gradually from blue (L-PF-Cu complex) to purple ((L+D)-PF-
Cu complex), and then changed back to blue (D-PF-Cu complex) (Fig.
2b). Simulation results showed that both L-PF-Cu and D-PF-Cu
also monitored by electron paramagnetic resonance (EPR) studies (Fig.
S9a). As listed in Table S1, the EPR parameters obtained at pH 2.0 and
3
4
.0 are same to those of CuSO control sample, which decrease with
2+
the increasing of pH to 4.0 and 6.0. The Cu signal is hardly resolved
at the pH range of 7-9, in which a new species is formed with a purple
color (Fig. S9b, and following sections for further investigations). At
pH 12 or higher, the Cu signal appears again. EPR simulation
revealed that the signals at pH 6.0 are a superposition of two different
coordinated copper ions. The first signal appears at pH 4.0 and the
complexes have the identical g-values (g
x y z
= 2.046, g = 2.059, g =
2+
2.256) and A-values (A = A = 10 G, A = 173 G), indicating that there
x
y
z
are two equivalent nitrogen ligands in the xy-plane, with a hyperfine
constant of ~12 G (Fig. 2c). The EPR spectrum of (L+D)-PF-Cu
second one is similar to that at pH 12 or higher (Fig. S9c and Table S1). complex with a 5:5 ratio of L-PF/D-PF exhibits no hyperfine signals of
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COMMUNICATION
2
+
−
2+
3+
−
Cu (Fig. 2a), instead, it originates from a superoxide species (O
with the g values (g = 2.047, g = 2.077, g = 2.183, Fig. 3a), in
agreement with the simulation results (Fig. 2c), which are similar to
2
),
[(L+D)-PF-Cu -O
2
] and [(L+D)-PF-Cu -O
2
]. Upon reduction by Asc,
3
+
−
x
y
z
the signal intensity of [(L+D)-PF-Cu -O
and the hyperfine signals of Cu species appeared (Fig. 3d, inset),
which agrees with the resultant blue color of the (L+D)-PF-Cu sol (Fig.
S7). In this process, [(L+D)-PF-Cu -O
from Asc, which is likely to produce [(L+D)-PF-Cu ] complex and
release superoxide O
cytochrome c (Cyt c), we evaluated whether the reduction of Cyt c
2
could be accelerated by reaction with [(L+D)-PF-Cu -O ] upon
addition of Asc. As expected, the kinetic UV-Vis studies showed that
the Soret band (410 nm) of the ferric human Cyt c rapidly increased
and red-shifted to 414 nm, accompanied by an increase of the α-band
(550 nm) (Fig. 4a), indicating the conversion of Cyt c from ferric to
ferrous state. This was further confirmed by circular dichroism (CD)
spectral changes, as shown in Fig. S13. Along with the spectral
changes, the color of the Cyt c solution changed from yellowish to pink
within 10 min (Fig. 4a, inset). In comparison, the catalytic effect of Cyt
2
] species deceased (Fig. 3d),
2
+
−
those observed for O
reported by Bennett et al. in earlier years (g
.175 ; g
suggest that the coordinated O
2
stabilized in solid sodium superoxide (NaO
= 2.002, g = 2.002, g
= 2.188 ). These observations
2
), as
3
+
−
x
y
z
=
2
] may receive one electron
[9]
[10]
2+
2
x
= 1.991, g
y
= 1.991, g
may scramble one electron from Cu ,
z
2
+
−
−
2
2
2
. Since O
is an efficient reductant for
3+
8
[12]
resulting in diamagnetic Cu (d ) and formation of a novel [(L+D)-PF-
3
+
−
2+
3+
3+
−
Cu -O
2
] species. Oxidation of Cu to Cu was also reported for
, producing
Isothermal titration calorimetry (ITC)
hydroxy-salen-copper complexes in reaction with O
oxygen-based free radicals.
studies showed that (L+D)-PF binds Cu with a binding constant (K
2
[11]
2+
a
)
6
-1
2+
a
of 3.6910 M , which is double that of L-PF binding Cu (K =
6
-1
1
.8310 M ), and both of them have a stoichiometry close to 2 (2.13
2+
and 2.14, respectively) (Fig. S11). These results indicate that one Cu
ion is coordinated by two ligands, with the combination of L-PF and
D-PF binding more tightly than that by two L-PF ligands. This was
further supported by mass spectrometry (MS) studies, which identified
several ionized forms of the L-PF-Cu complex, such as [Cu(L-
2
+
c reduction was not observed for the [L-PF-Cu ] complex that showed
an increase of the α-band (550 nm) with a rate similar to the reduction
of Cyt c by Asc alone (Fig. 4b). These observations suggest that the
+
+
PF)
PF)
2
+H
+H
2
O+H] (593 Da), [Cu(L-PF)
2
+K] (612 Da) and [(Cu(L-
+H] (1187 Da) (Fig. S12a). Interestingly, two major
+
3+
−
−
2
2
O)
2
[(L+D)-PF-Cu -O
2 2
] species could produce O for efficient reduction
ionized forms were observed for the (L+D)-PF-Cu complex, which can
of biomolecules such as Cyt c.
+
be attributed to the formation of [Cu(PF)
2 2
+O +H] (604 Da), and its
2-
complex with SO
4
and a water molecule (717 Da) (Fig. S12b).
Figure 4. (a) UV-Vis spectral changes in reduction of ferric human Cyt c (8 μM) by
L+D)-PF-Cu complex (2.5 mM) in presence of Asc (0.25 mM) in air-saturated water
(
for 10 min (Inset: the color change of ferric Cyt c upon reduction); (b) Kinetic traces
showing the reduction of ferric Cyt c (following the intensity at 550 nm). Controls
experiments with L-PF-Cu complex and Asc alone were shown for comparison.
Based on the above observations, we proposed a plausible
2
mechanism for the one-electron O reduction activity of (L+D)-PF-Cu
hydrgel (Scheme 1). Due to the suitable packing of L-PF and D-PF
2
+
chiral ligands with a microenvironment, the (L+D)-PF-Cu hydrgel
efficiently binds O and donates one-election, generating [(L+D)-PF-
] species. By receiving an electron from Asc, this species may
2
3
+
−
Cu -O
convert to [(L+D)-PF-Cu ] and release O
2
2
+
−
2
. In the presence of Cyt c,
2
may efficiently reduce ferric Cyt c, producing ferrous
Figure 3. EPR spectra of L-PF-Cu and (L+D)-PF-Cu hydrogels (a), (L+D)-PF-Cu
complex in solution and (L+D)-PF-Cu powder (b), (L+D)-PF-Cu complex prepared in
anaerobic conditions and that exposed to air (c), and the reduction of (L+D)-PF-Cu
hydrogel (0.1 M) by addition of Asc (3 mM) (d). The inset in (c) shows the color
change upon exposure of anaerobic (L+D)-PF-Cu complex to air. The inset in (d)
shows the hyperfine signals of Asc-reduced (L+D)-PF-Cu complex.
−
the active O
Cyt c and O
center and generate the [(L+D)-PF-Cu -O
2
+
2
2
. The O and that in air, may further bind to the Cu
2
+
2
] complex.
Scheme 1. Proposed mechanism for the one-electron O2 reduction activity of (L+D)-
PF-Cu hydrgel, and the reduction of ferric Cyt c in the presence of reductant Asc.
2
To further provide evidence for the crucial role of O in formation
of the purple (L+D)-PF-Cu hydrogel, we carried out additional EPR
studies. Fig. 3a shows the EPR spectra of L-PF-Cu and (L+D)-PF-Cu
hydrogels. In addition, the EPR spectrum of (L+D)-PF-Cu is similar in
2 2
solution and solid power (Fig. 3b). In the absence of O by N
protection, (L+D)-PF-Cu hydrogel exhibits an EPR spectrum (Fig. 3c,
red) similar to that of L-PF-Cu (Fig. 3a, black). As shown in Fig. 3c,
inset, when the anaerobic (L+D)-PF-Cu complex was exposed to air,
the color changed from blue to purple in 3 min, which further confirms
2+
2
the coordination of O to the Cu ions, resulting in an equilibrium of
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Angewandte Chemie International Edition
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COMMUNICATION
2
+
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J. C. Lewis, T. R. Ward, Chem. Rev. 2018, 118, 142-231.
In conclusion, we have constructed three Cu -selective
metallohydrogels using two chiral phenylalanine derivatives (L/D-PF)
with a pyridyl group as gelators. The combination of L-PF and D-PF
[
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4
resulted in the formation of a
2
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PF-Cu hydrogel. This study presents a novel example that an
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[
[
−
2
the reactive O
assembly can confer one-electron O
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2+
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+
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+
normal Cu gels. With the simple synthesis of the chiral ligands and
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Acknowledgements
[
This work was supported by the National Natural Science Foundation
of China (31370812, 21473257, 21773311, 11227901, 81788104),
National Key Basic Research Program of China (2013CB921800),
Hunan Provincial Education Foundation (15C1168, 15A158) and
Hunan Provincial Science and Technology Plan Project (2017TP1001).
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Angewandte Chemie International Edition
10.1002/anie.201801290
COMMUNICATION
Functional Metallohydrogel
COMMUNICATION
*
Using Both Hands: The
Xiaojuan Wang, Chuanwan Wei ,
combination of chiral ligands, a
phenylalanine derivative with a
pyridyl group (L/D-PF), forms a
Cu -selective metallohydrogel
and exhibits a novel one-electron
Jihu Su, Bo He, Ge-Bo Wen, Ying-
Wu Lin , and Yi Zhang
*
*
2+
Page No. – Page No.
Chiral Ligands Assembly
Confers One-electron O
Reduction Activity for a Cu -
selective Metallohydrogel
2
O reduction activity.
2
2
+
This article is protected by copyright. All rights reserved.