Reactivity of dinuclear copper(II) complexes with N -salicylidene glycine Schiff bases as carboxylesterase models

Article abstract of DOI:10.1002/kin.20904

Two phenoxo-bridged dinuclear copper(II) complexes (Cu2L¹ 2 , Cu₂L² 2 ) with Nsalicylidene glycine Schiff bases were prepared and evaluated their performance for catalyzing the hydrolysis of p-nitrophenyl picolinate (PNPP)

Full text of DOI:10.1002/kin.20904

Reactivity of Dinuclear
Copper(II) Complexes with
N-Salicylidene Glycine
Schiff Bases as
Carboxylesterase Models
BIN XU,1 WEIDONG JIANG, FUAN LIU, YONGDE YU, JUAN DONG
,2
1,2
2
1
1
1School of Chemical and Pharmaceutical Engineering, Sichuan University of Science & Engineering, Sichuan Zigong,
43000, People’s Republic of China
6
2Key Laboratory of Green Catalysis of Sichuan Institute of High Education, Sicuan Zigong, 643000,
People’s Republic of China
Received 3 September 2014; revised 23 November 2014; 13 December 2014; accepted 16 December 2014
DOI 10.1002/kin.20904
Published online 16 January 2015 in Wiley Online Library (wileyonlinelibrary.com).
1
2
ABSTRACT: Two phenoxo-bridged dinuclear copper(II) complexes (Cu2L 2, Cu2L 2) with N -
salicylidene glycine Schiff bases were prepared and evaluated their performance for catalyzing
the hydrolysis of p-nitrophenyl picolinate (PNPP). The observations reveal that the as-prepared
dinuclear copper(II) complexes exhibited better activity by two to three orders of magnitude rate
2
enhancement in comparison with the autohydrolysis rate of PNPP. Chloro-containing Cu2L 2
1
aroused approximately three times kinetic advantage over chloro-free Cu2L 2 at pH 7.0, which
ꢀ
is probably contributed to the electron-withdrawing inductive effect of the 5 -chloride group.
Moreover, it was found that the pH-responded kinetic behavior displayed an enzyme-like
property for the PNPP hydrolysis by the two complexes. ꢁC 2015 Wiley Periodicals, Inc. Int J
Chem Kinet 47: 191–198, 2015
Correspondence to: Weidong Jiang; e-mail: jwdxb@163.com.
Bin Xu; e-mail: xbjwd@163.com.
INTRODUCTION
Contract grant sponsor: China Nature Science Foundation.
Contract grant number: 21243003.
Contract grant sponsor: Key Project of Chinese Ministry of Ed-
ucation.
Schiff bases derived from various amines and aldehy-
des were widely studied for the coordination chemistry
of metal ions [1,2]. In spite of the above-mentioned
Contract grant number: 210191.
Contract grant sponsor: Key Project of the Education Department
of Sichuan Province.
Contract grant number: 12ZA095.
Contract grant numbers: LZJ1201 and LZJ1303.
Contract grant sponsor: Innovation Project for the Undergraduate
Students (Sichuan University of Science & Engineering).
Contract grant numbers: CX20121307 and 2014PY03.
Contract grant sponsor: Key Project of Key Laboratory of Green
Catalysis of Sichuan Institutes of High Education.
ꢀ
C
2015 Wiley Periodicals, Inc.

1
92
XU ET AL.
application, amounts of metal complexes with various
Schiff bases were proved to play vital roles in the fields
of anticancer [3,4] and antimicrobial activity [5,6].
Besides, chemists focused on hydrolytic reactivity of
Schiff base metal complexes toward esters [7–9] as
well on the interaction between DNA and Schiff base
complexes [9–12].
Especially, amino acid Schiff bases and correspond-
ing metal complexes were attracted attention due to the
physiologically activity and compatibility of amino
acids [13–15]. However, it is noteworthy that main
aspects of the relevant researches only concentrated
on the synthesis, structural analysis, as well poten-
tial medicinal values of metal complexes with various
amino acid Schiff bases. To expand the applications
of amino acid Schiff bases metal complexes, some re-
search groups began to evaluate their esterolytic re-
activity [16–19]. These studies not only facilitate the
understanding of the esterolytic mechanism but also
prompt the development of novel cleave reagents to-
ward phosphates [16–18] and carboxylic acid esters
Figure 1 Schemetical illustrations of plane structures and
three-dimensional optimum geometries of the two dinuclear
copper complexes used in the current work.
The ionic strength (I) was maintained a constant value
[19].
(0.1 M) with KCl. To avoid the spontaneous hydrolysis
Despite many reports that are correlative with the
of PNPP, anhydrous acetonitrile was freshly prepared
anhydrous acetonitrile was used for the preparation of
the PNPP stock solution.
Kinetic measurements of the PNPP hydrolysis
were recorded on a GBC960 UV–vis spectrometer
reactivity of metal complexes with amino acid Schiff
bases for the cleavage of DNA or small molecular phos-
phates, to our knowledge, only one paper reported the
reactivity of dinuclear copper(II) with L-threonine-type
Schiff bases toward the hydrolysis of small molecular
carboxylate [19] so far. To probe the catalytic efficiency
of metal complexes with different amino acid Schiff
bases, here we probably report the second case that
involves the hydrolysis performance of p-nitrophenyl
picolinate (PNPP) by two kinds of phenoxo-bridged
(GBC, Braeside, Australia). Elemental analysis was
preformed on a CHNOS elemental analyzer Vario
EL Cube (Elementar, Hanau, Germany). Molecule
weights of complexes were determined on an Agilent
1100 liquid chromatography–mass spectrometer (Agi-
1
2
lent Technologies, Santa Clara, CA). Characterizations
of the two complexes were shown as follows. Deter-
mined data that are accordance with theoretic values
confirm their structures of the two dinuclear complexes
depicted in Fig. 1.
dinuclear copper(II) complexes (Cu2L 2 , Cu2L 2) with
N-salicylidene glycine Schiff base (Fig. 1).
EXPERIMENTAL
Synthesis of Dinuclear Copper(II) Complexes
Instruments and Materials
1
2
(
Cu2L 2 and Cu2L 2) with Glycine –Salicylaldehyde
All reagents were of analytical grade and used as re-
ceived unless otherwise noted. Glycine, salicylalde-
hyde, 5-chlorosalicylaldehyde, and triethylamine were
obtained from Chengdu Kelong Chemical (Chengdu,
P.R. China). Tris (tris(hydroxymethyl) aminomethane)
and potassium chloride were purchased from Sigma-
Aldrich (Shanghai, P.R. China). PNPP was synthesized
according to a previous report [20]. The two copper(II)
complexes, i.e., Cu2L 2 and Cu2L 2, were prepared
by a similar method described [21]. Highly purified
water was obtained using a Waters purification sys-
tems (Nex Power 1000; Human Corporation, Seoul,
South Korea) and used throughout for kinetic runs.
Schiff Base. Appropriate salicylaldehyde or 5-
chlorosalicylaldehyde (7 mmol) in 200 mL of
anhydrous ethanol was added to an ethanol solution
containing 7 mmol of glycine; 1 mL triethylamine
was added synchronously. The mixture was refluxed
at 75°C for 1 h, leading to a yellow-green solution.
And then, anhydrous methanol solution of equimo-
lar copper(II) chloride dihydrate (7 mmol) was drop-
wise added to the above yellow-green solution. The
yellow-green system became to dark green one. The
reaction mixture was kept refluxing at 75°C for an-
other 3 h. The reaction mixture was then cooled to
room temperature and filtered under reduced pressure.
1
2
International Journal of Chemical Kinetics DOI 10.1002/kin.20904

DINUCLEAR COPPER(II) COMPLEXES WITH N -SALICYLIDENE GLYCINE SCHIFF BASES
193
1
1
1
40
20
00
430
pH 6.70
pH 7.00
pH 7.30
1
2.5
pH 6.70
pH 7.30
pH 7.00
pH 7.60
pH 6.70
pH 7.30
pH 7.00
pH 7.60
10.5
380
pH 7.90
pH 7.90
8
6
4
2
.5
.5
.5
.5
3
2
2
30
80
30
1
2
Cu
2
L
2
Cu
L
2
2
8
6
4
2
0
0
0
0
0
0
.2 0.3 0.4
180
130
40.0
pH 6.70
pH 7.00
pH 7.30
3
2
1
0.0
0.0
0.0
8
0
30
–
20
0
–20
0.0
.18
0.28
0.38
0.48
0.18
0.28
0.38
0.48
0
.2 0.3 0.4
3
–1
3
–1
1
0 [PNPP] (mol L )
10 [PNPP] (mol L )
Figure 2 Dependence of rate constant upon the PNPP concentration for the Cu2L2-promoted hydrolysis of PNPP. Conditions:
2
5°C, [complex] = 0.01 mM, I = 0.1 M (KCl). To enhance the visibility of kob–pH plots at different pH values (6.70, 7.00,
7
.30), two partial enlarged profiles from the dashed rectangles are sandwiched between the two full kob–pH profiles.
The filtrate was kept for 1 week at room temperature.
RESULTS AND DISCUSSION
1
Blue-green rod-like crystals of Cu2L 2 or turquoise
2
rod-like crystals of Cu2L 2 were collected after filter-
Apparent First-Order Rate Constants (kob)
of the PNPP Hydrolysis by Cu2L2
1
ing and drying processes under vacuum. Cu2L 2 (blue-
green rod-like crystals): yield 69.8%. mp >260°C
Figure 2 presents the variations of apparent first-order
rate constants (kob) of the PNPP hydrolysis by the
two dinuclear copper(II) complexes used. The rate
constants–[PNPP] profiles are able to give at least
two pieces of information. First, hydrolytic rates of
PNPP positively correlate with systematic pH ranging
from 6.70 to 7.90. At the same time, the marked in-
crease in rate achieved for both catalysts when pH was
above 7.30, which suggests the formation of certain
active species. Second, the saturation curves for the
two catalysts indicate the relationship between the rate
constant and the concentration of substrate, represent-
ing the PNPP hydrolysis by both of the as-prepared
complexes is accordance with Michaelis–Menten
kinetics [22,23].
(dec.). m/z: Anal. calcd. for C18H14Cu2N2O6: 481.41;
found: 482.43 (M + H), 504.42 (M + Na). Anal.
calcd. For C18H14Cu2N2O6 C 44.91, H 2.93, N 5.82
2
found C 44.90, H 2.95, N 5.87. Cu2L 2 (turquoise rod-
like crystals): yield 71.4%. mp >260°C (dec.). m/z:
Anal. calcd. for C18H12Cl2Cu2N2O6: 550.30; found:
5
51.31(M + H), 573.34 (M + Na). Anal. calcd. For
C18H12Cl2Cu2N2O6 C 39.29, H 2.20, N 5.09 found C
9.32, H 2.23, N 5.16.
3
Kinetic Measurements
Kinetics of PNPP hydrolysis was preformed at 25°C
in a pH range 6.70–7.90 ± 0.01. The final substrate
concentration varied from 0.200 to 0.467 mM, i.e.,
2
In addition, Cu L with a 5-chloro-substitued
2
2
1
0
.200, 0.267, 0.333, 0.400, 0.467 mM. In all kinetic
2 2
Schiff base is ca. 1.3–3.6 folds reactive than Cu L
runs, a fixed concentration of the copper(II) complex
without the chloride group in the operated range of the
substrate concentration. As compared with the back-
(
(
0.01 mM) was adopted here. Mole ratios of substrate
PNPP) to the complex were in a range of 20–46.7. Ap-
−
6
−1
ground value (k = 7.8 × 10
0
s ) of the PNPP
parent first-order rate constants (kob) were determined
using the initial rate method. Kinetic measurements
were carried out spectrophotometrically by following
the absorbance with time at λmax (400 nm) correspond-
ing to the absorption maximum of p-nitrophenolate an-
ion. The experimental data are averages of two or three
runs with uncertainty of less than 5%.
spontaneous hydrolysis [20], the hydrolysis reactions
were, respectively, accelerated by a factor of ca. 5.90
2
1
3
2
× 10 for Cu L and 1.77 × 10 for Cu L at
2
2
2
2
pH 7.0. Our previous study [19] reported the reac-
tivity of two copper(II) complexes with L-threonine
Schiff bases. It is found that the current results are
more predominant in comparison with those previous
International Journal of Chemical Kinetics DOI 10.1002/kin.20904

1
94
XU ET AL.
1
observations. For example, at pH 7.0 Cu2L 2 as a cat-
alyst in the present study is about 1.2 times reactive
than the previous dinuclear copper(II) complex. Rel-
evant causes about the distinguishable reactivity of
these complexes are specially elucidated in the later
section.
other free water rapidly displaces the Cu(II)-bound
alpha-picoline acid (PA), arousing the next catalytic
cycle.
In this pathway, the two copper centers play im-
portant roles in the positive effects of Cu2L2 on the
PNPP hydrolysis. Three vital roles of the copper cen-
ters include activating substrate molecules, stabiliz-
ing the negative tetrahedral transition state, and low-
ering the pKa of the Cu(II)-bound H2O. To explore
the hydrolysis mechanism, we carried out the spec-
tral scans under selected conditions (pH 7.0, 25°C,
Proposed Hydrolysis Mechanism of PNPP
by Cu2L2
Nowadays, a few proposed esterolysis mechanisms
probably involve in an acid- or general base–
catalyzed process [24]. In the metal-induced esterol-
ysis, it is popularly accepted that a nucleophilic at-
tack of the metal-coordinated hydroxide anion on
the carbonyl or phosphoryl groups of carboxylic
acid esters or phosphates [25]. As we know, din-
uclear complexes generally possessed much better
hydrolytic reactivity than mononuclear one, which
probably originated from an alternative bimetallic
cooperative route [26–28] concerning the efficient
linkage of substrate and intramolecular nucleophilic
attack.
[
Cu2L2] = 0.01 mM). UV spectra shown in Fig. 3
provide direct evidence for the formation of binary
catalyst–PNPP intermediates and the generation of
PNPO . The inserts of Fig. 3 reveal the distinguish-
−
2
2
able spectra of Cu L in absolute ethanol and buffered
aqueous solution, respectively. As shown in the in-
serts, the introducing of water, respectively, led to a
blueshift of ꢀ3.3 and ꢀ4.2 nm for the UV–vis ab-
sorption spectrum of Cu2L2 (L = L , L ), suggest-
ing the formation of dihydrate species (Cu2L2(H2O)2).
Therefore, the proposed mechanism is believable
and reasonable due to the two facts mentioned
above.
1
2
Scheme 1 presents the possible mechanism of PNPP
hydrolysis by the as-synthesized complexes. Owing to
the formation of the catalyst–substrate binary complex
In the present work, saturation curves of kob–
[PNPP] shown in Fig. 2 are in agreement with the
Michaelis–Menten equation. Classic double reciprocal
plots (Fig. 4), which are based on the Lineweaver–Burk
formula (1/kob = 1/kcat + 1/(kcatKs[S])), are depicted to
determine kinetic parameters (Table I) using the slopes
(
Ks), Cu2L2(H2O)(PNPP), a transformation of the orig-
inal intermolecular reaction to an intramolecular one
leads to a greater acceleration of the PNPP hydroly-
sis. And then, the deprotonated form of H2O bound
to another central copper(II) nucleophilically attacks
the copper-linked PNPP, releasing the UV-responded
−
1
−1
and intercepts of linear kob –[PNPP] plots. Kinetic
parameters in Table I testify that the chloro-containing
2
−
Cu2L 2 indeed exhibited dominated catalytic activity
p-nitrophenolate anion (PNPO ) at 400 nm. This pro-
1
against Cu2L 2, which is a result of their distinguish-
cess was widely considered as a rate-determining step
29] with a catalytic constant (kcat). At the end, an-
able structures.
[
–
Scheme 1 Schemetic pathway of the hydrolysis of PNPP catalyzed by Cu2L2. “PNPO ” means the leaving group, p-
nitrophenolate anion. “PA” is α-picoline acid, which can be replaced by one free H2O.
International Journal of Chemical Kinetics DOI 10.1002/kin.20904

DINUCLEAR COPPER(II) COMPLEXES WITH N -SALICYLIDENE GLYCINE SCHIFF BASES
195
1
2
Figure 3 UV spectral scanning for the hydrolysis of PNPP catalyzed by Cu2L 2 (A) or Cu2L 2 (B). Inserts of Fig. 3 show the
changing spectra of the two complexes in various solvents, i.e., anhydrated ethanol and buffered aqueous solution.
0
0
0
0
0
0
0
.30
.25
.20
.15
.10
.05
.00
0.20
pH 6.70
pH 7.30
pH 7.90
pH 7.00
pH 7.60
pH 6.70
pH 7.30
pH 7.90
pH 7.00
pH 7.60
A
B
0
0
0
0
.15
.10
.05
.00
2.0
2.5
3.0
–3
3.5
4.0
–1
4.5
5.0
2.0
2.5
3.0
3.5
4.0
4.5
5.0
–
3
–1
–1
–1
1
0
[PNPP] (mol L)
10 [PNPP] (mol L)
Figure 4 Plots of kob 1–[PNPP] for the hydrolysis of PNPP catalyzed by Cu2L 2 (A) or Cu2L 2 (B). Conditions: 25°C,
−
−1
1
2
[complex] = 0.01 mM, I = 0.1 M (KCl).
pH Dependence of Catalytic Activity
of Cu2L2
substrate concentration), pH is also an important in-
fluencing factor in the stability of enzymes. Extremely
low or high pH values probably result in complete
or partial deactivation for most enzymes [30]. In our
Generally, natural enzymes display their optimum
activity only under mild conditions. Besides other
factors (e.g., temperature, catalyst concentration,
study, k –pH profiles in Fig. 5 indicate that the rate
ob
constants respond nonlinearly to the changing pH for
Table I Kinetic Parameters for the PNPP Hydrolysis by the Current Dinuclear Copper Complexes at 25°C
Cu2L12 Cu2L22
−
3Ks
3
−3
3
1
0
10 kcat
kcatKs
(M·s
10 Ks
10 kcat
kcatKs
(M·s
kcatKs Ratios of
Cu2L 2/Cu2L 2
k Ratios of
Cu2L 2/Cu2L 2
−
1
−1
−1
−1
2
1
2
1
pH
(M)
(s
)
)
(M)
(s
)
)
6
7
7
7
7
.70
4.33
4.65
6.94
0.60
0.51
9.13
9.30
13.46
252.1
622.3
39.53
43.29
93.46
151.5
315.9
7.85
16.14
9.86
0.39
0.29
10.03
17.70
36.23
1264.2
3325.8
78.74
285.7
357.1
488.3
934.6
1.99
6.60
3.82
3.22
2.96
1.10
1.90
2.69
5.02
5.19
.00
.30
.60
.90
Conditions are the same as in Fig. 2.
International Journal of Chemical Kinetics DOI 10.1002/kin.20904

1
96
XU ET AL.
1
20
00
450
0.200 mM
0.267 mM
0.333 mM
0.400 mM
0.467 mM
0.200 mM
0.267 mM
0.333 mM
0.400 mM
4
00
50
1
3
8
6
4
2
0
0
0
0
0
300
2
50
00
0.467 mM
2
150
00
1
50
0
6
.6 6.8 7.0 7.2 7.4 7.6 7.8 8.0
6.6 6.8 7.0 7.2 7.4 7.6 7.8 8.0
pH
pH
1
Figure 5 Variations of the apparent first-order rate constant with pH for the PNPP hydrolysis catalyzed by Cu2L 2 (left) and
2
Cu2L 2 (right).
the PNPP hydrolysis. When pH is below 7.5, the hy-
1
0
.5
.0
ƸpK
a
drolysis of PNPP by the both complexes is almost pH
independent, indicating a nucleophilic reaction by the
metal-bound H2O. Meanwhile, sharp hydrolysis ac-
celeration was observed when pH was above 7.50,
suggesting certain pH-dependent changes in catalytic
species that is described below.
Cu L
2
2
2
Cu L
2
2
0
–
0.5
Binding constants (Ks) in Table I display an inter-
ested bell-shaped trend for each catalyst used in this
work; the strongest binding strength of PNPP to cata-
–1.0
–1.5
–2.0
1
lyst was, respectively, achieved at pH 7.30 (for Cu2L 2)
2
and 7.00 (for Cu2L 2). In addition, the catalytic con-
stant (kcat) also exhibits a similar nonlinear increase in
the kob–pH profiles. It is noteworthy to point out that
this kind of similarity likely results from the favor-
able conversion of the dehydrated complex to the real
catalytic species in the reaction medium.
6
.6
6.8
7.0
7.2
7.4
7.6
7.8
8.0
pH
Figure 6 pH dependence on logkcat for the hydrolysis of
PNPP induced by the as-prepared catalysts, Cu L and
Cu2L 2. Conditions are the same as in Fig. 1. Swallow-
tail shaped arrows indicate the inflection points (red dots) of
the two sigmodal-shaped curves. Light green zone highlights
1
2
2
2
The sigmoid logkcat–pH curves (see Fig. 6) imply
the first-order deprotonated form of the copper-bound
H2O is the real nucleophiles. Systematic pKa1 values of
1
the pKa1 difference between the Cu-bound H O of both of
copper complexes used.
the two catalysts are determined as ꢀ7.49 for Cu2L 2
2
2
and ꢀ7.45 for Cu2L 2 from the respective inflection
points of logkcat–pH curves. According to the ioniza-
tion equilibrium of the Cu(II)-bound H2O, the Cu-OH
species as real nucleophiles gradually form with the pH
values of reaction media above the pKa1 of the Cu(II)-
coordinate H2O. For this reason, an obvious jump in
the hydrolysis rate was observed as the pH was ad-
justed to above 7.50, which provides evidence for the
sharp increase in the rate shown in Fig. 5. Herein, it
were reported by other groups [31,32] and our labora-
2
tory [19,33]. As a whole, Cu2L 2 still exhibited 1.3–3.6
1
times kinetic advantage over Cu2L 2 even though two
pKa1 values were very close to each other, displaying
only a small difference of 0.04 pKa unit.
2
is emphasized that the smaller pKa1 for Cu2L 2 may
Effects of the Structures of Dinuclear
Copper(II) Complexes
be a result of the electron-withdrawing induced ef-
ꢀ
fect of the 5 -chloride substituent. That is, at the same
pH the efficient concentration of the active interme-
Designing small molecule mimic hydrolases is a ma-
jor challenge, as they must incorporate structural ele-
ments of the enzyme active site as well as accommodat-
ing metal binding. Metal ions, forming the enzyme’s
2
−
diate Cu2L 2(PNPP)(OH ) is relatively higher than
that for another system containing the chloride-free
1
Cu2L 2. Similar substitute effects on the esterolysis
International Journal of Chemical Kinetics DOI 10.1002/kin.20904

DINUCLEAR COPPER(II) COMPLEXES WITH N -SALICYLIDENE GLYCINE SCHIFF BASES
197
catalytic core, are known to catalyze the hydrolysis
of various esters [34,35] and amides [36]. Typically,
these hydrolysis reactions involve the catalytically ac-
tive M (OH ) with the metal ion, serving three possi-
ble purposes (activating substrate and coordinated wa-
ter, activating leaving group, and stabilizing the transi-
tion state) [37].
5
4
.0
.5
0
0
0
0
.200mM
.267mM
.333mM
.400mM
x+
−
4.0
3.5
3
2
2
.0
.5
.0
0.467mM
In this case, both binuclear copper(II) complexes
have higher activity toward the PNPP hydrolysis. The
ꢀ
2
one complex (Cu2L 2) with the 5 -chloride group was
1.5
1
more active than its chloride-free analogue, Cu2L 2.
1
0
.0
Figure 7 presents the variations of the relative data of
.5
6
enzyme efficiency (kcatKs) and kcat values as a function
.80 7.00 7.20 7.40 7.60 7.80 8.00
pH
2
of pH. The enzyme efficiency of Cu2L 2 is about 2.0–
1
6
.6 folds higher than that of Cu2L 2. Meanwhile, the
catalytic constant kcat has a 1.1–5.2 times difference
between the two complexes. Besides, relative values
of kcatKs display bell-shaped change giving a maxi-
mum difference at pH 7.00, and whereas kcat ratios is
sigmoid-shaped pH respondent.
Figure 8 pH-Dependent variations of reactivity ratios of
dinuclear Cu2L 2 (this work) to the dinuclear analogue with
N-salicylidene L-threonine Schiff base in our previous study
1
[19].
We have once studied the catalytic activity of two
dinuclear copper(II) complexes with L-threonine-type
Schiff bases for the hydrolysis of PNPP [19]. In this
report, both of complexes exhibited better reactivity by
Schiff base (pKa = 7.65). Sigmoid-shape curves in
Fig. 8 show that at various concentration levels of
PNPP, the rapidly increased difference in a reaction
rate was achieved within the pH range 7.4–7.6, which
is probably due to the easier deprotonation of H2O
bound to the two dinuclear copper(II) complexes with
N-salicylidene glycine Schiff bases.
2
–3 order of magnitude over the spontaneous hydrol-
ysis of PNPP. Under compared conditions, moreover,
glycine-type Schiff base copper(II) complexes in the
current work were approximately 1.13–4.79 folds ac-
tive than those dinuclear copper(II) complexes with
N-salicylidene L-threonine Schiff base. For dinuclear
In general, metal ions of metalloenzymes play a vi-
tal role in enzyme reactions [38]. On the one hand,
substrates can be nucleophilically activated by the
metal center as Lewis acid, thereby increasing its elec-
trophilicity. Another reason is that the metal-bound
H2O undergoes a further polarization by the metal
ion and readily converts into its conjugated metal-OH
base as the real nucleophiles under near-neutral con-
dition. On the other hand, metal centers can stabilize
negative tetrahedral transition state (TS) during a hy-
drolytic procedure of esters [39]. The positive charge
1
Cu2L 2 with N-salicylidene glycine Schiff base, its
smaller pKa value (7.49) leads to much higher efficient
concentration of active Cu(II)-OH species compared to
its dinuclear analogue with N-salicylidene L-threonine
7
kcatKs
6
5
4
3
2
1
0
kcat
2
density of Cu(II) ions of Cu2L 2, which comes from
ꢀ
the electron-withdrawing effect of 5 -chloro group, is
1
relatively higher than chloro-free Cu2L 2. In compar-
1
ison with Cu2L 2, the strengthened Lewis acidity of
2
the electropositive Cu(II) ions of Cu2L 2 directly led
to the more efficient stabilization of TS, the activation
of PNPP, and the bigger lowering of pKa1 of the bound
2
H2O. Consequently, Cu2L 2 possesses a better activ-
1
6.6
6.8
7.0
7.2
7.4
7.6
7.8
8.0
ity over its chloride-free analogue (Cu2L 2), which is
pH
consistent with its higher Lewis acidity and lower pKa
value (ꢀ7.45). As a result, various constituents perhaps
play a vital role in modulating the hydrolytic reactivity
of artificial hydrolases toward the esterolysis.
Figure 7 pH dependence on the ratios of kcatKs or kcat for
the hydrolysis of the PNPP by the two dinuclear copper(II)
complexes used.
International Journal of Chemical Kinetics DOI 10.1002/kin.20904

1
98
XU ET AL.
CONCLUSIONS
15. Santini, C.; Pellei, M.; Gandin, V.; Porchia, M.; Tisato,
F.; Marzano, C. Chem Rev 2014, 114, 815–862.
16. Reddy, P. A. N.; Nethaji, M.; Chakravarty, A. R. Eur J
Inorg Chem2004, 1440–1446.
17. Thalamuthu, S.; Annaraj, B.; Neelakantan, M. A. Spec-
trochimca Acta, Part A 2014, 118, 120–129.
In summary, two dinuclear copper(II) complexes with
N-salicylidene glycine Schiff base efficiently acceler-
ated the PNPP hydrolysis. Cu2L 2 containing the 5 -
ꢀ
2
chloride group possesses much higher activity than its
ꢀ
1
8. Lu, L. P.; Yue, J. J.; Yuan, C. X.; Zhu, M. L.; Han, H.;
Liu, Z. W.; Guo, M. L. J Inorg Biochem 2011, 105,
analogue without 5 -chloride, denoting a 1.3–3.6 folds
kinetic advantage over the whole concentration range
of PNPP. Also, the pH-dependent catalytic constant
1
323–1328.
1
2
2
9. Jiang, W. D.; Xu, B.; Liu, F. A.; Wang, Y.; Xiang, Z.
Syn React Inorg M 2015. 45, 34–39.
0. Sigman, D. S.; Jorgensen, C. T. J Am Chem Soc 1972,
(kcat) gave two pKa1 value closed to 7.5, which im-
plies the divalent copper ions have a strong ability to
reduce the pKa1 of the Cu(II)-bound H2O. Hence, we
are permitted to predict that much better activity of
dinuclear metal complexes containing highly stronger
electron-withdrawing substituents (e.g., nitro, triflu-
omethyl group) will be achieved for the hydrolysis of
various esters. Moreover, metal complexes with amino
acid Schiff bases likely become a class of potential ar-
tificial enzymes that will help not only the theoretical
researches but also in the development of physiolog-
ically active antimicrobial, antifungal, and anticancer
agents.
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International Journal of Chemical Kinetics DOI 10.1002/kin.20904