Substrate Specificity and Leaving Group Effect in Ester Cleavage by Metal Complexes of an Oximate Nucleophile

Article abstract of DOI:10.1021/acs.inorgchem.6b02739

Deprotonated zinc(II) and cadmium(II) complexes of a tridentate oxime nucleophile (1, OxH) show a very high reactivity, breaking by 2-3 orders of magnitude the previously established limiting reactivity of oximate nucleophiles in the cleavage of substituted phenyl acetates and phosphate triesters, but are unreactive with p-nitrophenyl phosphate di- and monoesters. With reactive substrates, these complexes operate as true catalysts through an acylation-deacylation mechanism. Detailed speciation and kinetic studies in a wide pH interval allowed us to establish as catalytically active forms [Cd(Ox)]⁺, [Zn(Ox)(OH)], and [Zn(Ox)(OH)₂]^? complexes. The formation of an unusual and most reactive zinc(II) oximatodihydroxo complex was confirmed by electrospray ionization mass spectrometry data and supported by density functional theory calculations, which also supported the previously noticed fact that the coordinated water in [Zn(OxH)(H₂O)₂]²⁺ deprotonates before the oxime. Analysis of the leaving group effect on the cleavage of phenyl acetates shows that the rate-determining step in the reaction with the free oximate anion is the nucleophilic attack, while with both zinc(II) and cadmium(II) oximate complexes, it changes to the expulsion of the leaving phenolate anion. The major new features of these complexes are (1) a very high esterolytic activity surpassing that of enzyme hydrolysis of aryl acetate esters and (2) an increased reactivity of coordinated oxime compared to free oxime in phosphate triester cleavage, contrary to the previously observed inhibitory effect of oxime coordination with these substrates.

Full text of DOI:10.1021/acs.inorgchem.6b02739

Article
pubs.acs.org/IC
Substrate Specificity and Leaving Group Effect in Ester Cleavage by
Metal Complexes of an Oximate Nucleophile
Jose Carlos Lugo-Gonzalez, Paola Gomez-Tagle,* Xiaomin Huang, Jorge M. del Campo,
́
́
́
and Anatoly K. Yatsimirsky*
́ ́ ́
Facultad de Química, Universidad Nacional Autonoma de Mexico, 04510 Mexico City, Mexico
S
* Supporting Information
ABSTRACT: Deprotonated zinc(II) and cadmium(II) com-
plexes of a tridentate oxime nucleophile (1, OxH) show a very
high reactivity, breaking by 2−3 orders of magnitude the
previously established limiting reactivity of oximate nucleophiles
in the cleavage of substituted phenyl acetates and phosphate
triesters, but are unreactive with p-nitrophenyl phosphate di- and
monoesters. With reactive substrates, these complexes operate as
true catalysts through an acylation−deacylation mechanism.
Detailed speciation and kinetic studies in a wide pH interval
allowed us to establish as catalytically active forms [Cd(Ox)]+,
[Zn(Ox)(OH)], and [Zn(Ox)(OH)2]− complexes. The for-
mation of an unusual and most reactive zinc(II) oximatodihy-
droxo complex was confirmed by electrospray ionization mass
spectrometry data and supported by density functional theory
calculations, which also supported the previously noticed fact that the coordinated water in [Zn(OxH)(H2O)2]2+ deprotonates
before the oxime. Analysis of the leaving group effect on the cleavage of phenyl acetates shows that the rate-determining step in
the reaction with the free oximate anion is the nucleophilic attack, while with both zinc(II) and cadmium(II) oximate complexes,
it changes to the expulsion of the leaving phenolate anion. The major new features of these complexes are (1) a very high
esterolytic activity surpassing that of enzyme hydrolysis of aryl acetate esters and (2) an increased reactivity of coordinated oxime
compared to free oxime in phosphate triester cleavage, contrary to the previously observed inhibitory effect of oxime
coordination with these substrates.
way that the desolvation free energy starts to compensate
completely for a decrease in the activation free energy due to
higher nucleophile basicity.5a As a result, oximes with increased
basicity reach a reactivity limit that corresponds to that of an
oxime with a pKa of around 8 and more basic oximate anions
do not display their potentially high reactivity in aqueous
solutions.
INTRODUCTION
■
Oximate anions are strong nucleophiles with important
applications in the degradation of toxic organophosphorus
compounds,1 as cholinesterase reactivators2 or drugs as well as
analytical reagents.3 They belong to the type of so-called α-
nucleophiles that possess two adjacent donor atoms and display
an enhanced reactivity in water compared to simple
nucleophiles of similar basicity.4 The kinetics of carboxylic
acid and phosphate ester cleavage by oximates has been
extensively studied both for understanding the nature of the α
effect and for optimization of their applications. A characteristic
feature of the esterase reactivity of oximate anions is a nonlinear
Brønsted plot for rate constants of oximolysis versus the oxime
pKa, demonstrating a leveling off when the pKa of the oxime
reaches approximately 8.4 This behavior has been attributed to
a “solvational imbalance effect”,5a which represents a type of
transition-state imbalance phenomena.5b−e For nucleophilic
substitution, the solvational imbalance in essence reflects the
necessity of desolvation (dehydration in water) of the
nucleophile prior to the nucleophilic attack. Consequently,
the energetic cost for desolvation of more basic oximate anions
becomes gradually higher, and this leads to a decoupling
between the desolvation and bond-formation steps in such a
Recently, we have discovered that the chelating oxime 1,
when complexed to zinc(II) or cadmium(II) cations,6 surpassed
Received: November 16, 2016
© XXXX American Chemical Society
A
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Figure 1. Anion-mode ESI-MS spectrum of a 0.1 mM equimolar mixture of Zn(ClO4)2 and the hydrochloride of 1 at pH 10.5 adjusted with diluted
NaOH. The peaks range between m/z 50 and 1000. Insets: expanded area between m/z 289.5 and 296.5, calculated isotope distribution pattern for
the complex [Zn(Ox)(OH)2]−, C10H16N3O3Zn−, and proposed structure for the complex.
by 2 orders of magnitude the reactivity limit of oximes toward
the 4-nitrophenyl acetate (2a) apparently by removing the
“solvational imbalance” around the nucleophilic site, in addition
to lowering the pKa of the oxime by coordination. However, 2a
is a highly activated ester, and it has been frequently observed
that nucleophilic catalysts, with an exceptionally high reactivity
toward nitrophenyl esters, lose their reactivity with less
activated substrates.7 In view of this, the initial purpose of
this work was to determine the esterolytic reactivity of zinc(II)
and cadmium(II) complexes of 1 toward a series of less
activated esters 2b−2i. The leaving group effect on the reaction
rate provides also valuable mechanistic information. An
unexpected result of this study was the observation that an
even more reactive Zn(1) hydroxo complex in addition to the
previously identified [Zn(Ox)(OH)] (OxH = 1) existed at a
pH above 9. This finding was possible with less reactive
substrates, which allowed us to make measurements in more
basic solutions.
tion with pKa = 8.17 generates the active species of the
composition [Zn(Ox)(OH)].6 This speciation agreed well with
the experimentally observed rate−pH profiles for the catalytic
hydrolysis of 4-nitrophenyl acetate (2a) in the presence of
complexes of both metal ions obtained at pH below 9.
Measurements at higher pH values were hampered by too fast
cleavage of 2a. In the current study with less activated
substrates, we were able to follow the reaction kinetics up to
pH 11 and surprisingly observed that the reaction rate with the
zinc(II) complex did not level off as expected at higher pH
values but continued to grow and started to level off only at pH
above 10 (see below), indicating the occurrence of an
additional deprotonation process and leading to even more
active species. Because the oxime ligand is already deprotonated
at pH 9, the only possible process left for this step is
deprotonation of a second water molecule with formation of
the dihydroxo complex [Zn(Ox)(OH)2]−.
Previous potentiometric titrations did not show such species,
but they were limited by precipitation out from 10 mM
solutions employed in titration experiments already at pH of
about 8.5. Now we repeated titrations with more diluted 1−2
mM zinc-ligand solutions performed up to pH 11 without
precipitation of Zn(OH)2 and from these data were able to
complete our set of formation constants and pKa values6,8
(Supporting Information, Table S1) including formation of the
[Zn(Ox)(OH)2]− complex with pKa = 10.5.
Because oximes possess nucleophilic reactivity toward both
carboxylate and phosphate esters, another issue addressed in
this paper was the substrate specificity of metal complexes of 1,
i.e., their reactivity toward phosphate mono-, di-, and triesters
in addition to carboxylates.
RESULTS AND DISCUSSION
■
Speciation. Previous studies have demonstrated that the
interaction of 1 with cadmium(II) involves the formation of a
simple 1:1 complex with neutral ligand [Cd(OxH)]2+, the
oxime group of which undergoes deprotonation with pKa =
9.37, affording the catalytically active complex [Cd(Ox)]+
(OxH = 1), but the situation with zinc(II) is more complex:
in this case the first deprotonation of the initially formed
[Zn(OxH)]2+ complex involves a water molecule rather than an
oxime group of the ligand, affording the hydroxo complex
[Zn(OxH)(OH)]+, and subsequent oxime group deprotona-
Because titrations of dilute solutions may involve larger
errors especially at high pH, we were looking for additional
proof of the real existence of the dihydroxo complex. The
formation of this complex was confirmed by the electrospray
ionization mass spectrometry (ESI-MS) results in the anionic
mode obtained with solutions above pH 10.0, which clearly
show the presence of a peak centered at m/z 292 with a
characteristic isotope distribution pattern for zinc (64Zn, 66Zn,
and 68Zn) and the mass corresponding to [Zn(Ox)(OH)2]−
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(Figure 1; see the Supporting Information, Figures S1 and S2,
for details).
Thus, the sequence of deprotonation processes of the
Zn(OxH)2+ complex involves [Zn(OxH)]2+ → [Zn(OxH)-
(OH)]+ → [Zn(Ox)(OH)] → [Zn(Ox)(OH)2]−, with the last
two complexes being the catalytically active species. The
deprotonation of water before the deprotonation of a
coordinated oxime group is unusual and was not observed in
speciation studies with other related oxime complexes.9 In
order to prove that such a sequence of deprotonations is really
possible, we complemented the experimental study with density
functional theory (DFT) calculations (see the Computational
Details) of the deprotonation free energies of the zinc(II)
oximate complexes, ΔGaq*.
It was assumed that the zinc(II) complex of 1 is
pentacoordinate and has a distorted bipyramidal geometry, as
was found in several structurally characterized zinc(II)
complexes with tridentate oxime ligands.10,11 At the first step,
we attempted a DFT geometry optimization of the simplest
expected, but surprisingly missing, oximate complex [Zn(Ox)-
(H2O)2]+ in the gas phase using Terachem, but no stable
structure of such a complex was found; instead, optimization
led to the hydroxo complex with a neutral oxime ligand,
[Zn(OxH)(OH)(H2O)]+, in accordance with the speciation
proposed above. An additional molecular dynamics [Born−
Oppenheimer molecular dynamics (BOMD)] on [Zn(Ox)-
(H2O)2]+ conducted in a short simulation time frame of 30 ps
also led to a [Zn(OxH)(OH)(H2O)]+ structure, whereas,
again, no [Zn(Ox)(H2O)2]+ structure with low energy was
found, suggesting that the first deprotonation is more likely to
occur on the coordinated water. Afterward, [Zn(OxH)(OH)-
(H2O)]+ was optimized with Gaussian 09, and this optimized
structure was used as a starting geometry for all other
complexes (the optimized geometries are provided in the
Supporting Information, Figures S3−S7). The structure of the
initial diaqua oxime complex [Zn(OxH)(H2O)2]2+ shown in
Figure 2 was obtained by protonation of the coordinated
hydroxo ligand and a subsequent DFT optimization.
Figure 3. Energy diagram of the deprotonation free energies ΔGaq*
(kcal/mol).
ing Information, Figure 5S), or from the oxime ligand, yielding
[Zn(Ox)(OH)(H2O)] (Supporting Information, Figure 6S).
Theoretical analysis shows that the ligand deprotonation ΔGaq*
is 4.07 kcal/mol lower than the deprotonation of the second
coordinated water molecule; hence, the former is more likely to
occur. Under these considerations, further possible species that
may arise from the deprotonation of [Zn(Ox)(OH)(H2O)] are
[Zn(Ox)(OH)2]− or [Zn(Ox)(O)(H2O)]− complexes. No
stable geometry was found for [Zn(Ox)(O)(H2O)]−, while
the structure that yielded the lowest free energy of
deprotonation was [Zn(Ox)(OH)2]−; therefore, the third acid
dissociation was only calculated for the remaining water
molecule of [Zn(Ox)(OH)(H2O)], giving the anionic species
[Zn(Ox)(OH)2]− (Supporting Information, Figure 7S), with a
ΔGaq* value of 38.51 kcal/mol. The values depicted on Figure
3 suggest that the second deprotonation occurs on the oxime
ligand, and the high ΔGaq* value for the third one suggests that
high pH values are required for such a reaction. These results
are in agreement with our previous assignment of the sequence
of group deprotonation steps for the zinc complex of 16 and the
feasibility of forming the [Zn(Ox)(OH)2]− species in solution.
Reaction Kinetics. The kinetics of the cleavage of phenyl
esters 2 was monitored spectrophotometrically by the
appearance of the respective free-substituted phenol or
phenolate anion, depending on the pH. Simple second-order
kinetics, first-order in both the ester and catalyst, was observed
with all employed substrates. Also, the cleavage of less activated
esters 2 measured in the presence of 1 mM substrate, 0.01 mM
ligand, and metal resulted, at pH 9.0, in the transformation of
up to 80 and 25 mol equiv of the substrate per 1 mol of the
complex in the presence of zinc and cadmium, respectively
(Supporting Information, Figure 8S), showing that the reaction
proceeds catalytically in accordance with Scheme 1, with a rate-
determining acylation step, followed by a fast deacylation step,
to regenerate the active oximate complex, as has been
previously found with 2a.6
Figure 2. DFT-optimized structure of [Zn(OxH)(H2O)2]2+ com-
plexes.
Figure 3 summarizes the ΔGaq* values (kcal/mol) for each
deprotonation step (see also the Supporting Information, Table
S2). In accordance with the results described above, the first
deprotonation of [Zn(OxH)(H2O)2]2+ occurs on one of the
water molecules coordinated with zinc, forming [Zn(OxH)-
(OH)(H2O)]+ (Supporting Information, Figure S4), and it is
associated with a ΔGaq* of 18.48 kcal/mol. The second
deprotonation may arise from a second water molecule
coordinated to the zinc, yielding [Zn(OxH)(OH)2] (Support-
Previous speciation studies demonstrated that at a M:L = 1:1
molar ratio [M = zinc(II), cadmium(II); L = 1] at pH ≥ 7, for
total metal concentrations above 0.1 mM, more than 90% of 1
is bound to the metal, and the active species are metal
complexes of the oximate anion, [M(Ox)]+ for cadmium(II)
and [M(Ox)(OH)] for zinc(II).6 To determine the true rate
constant kM(Ox) corresponding to the acylation step of the
individual [M(Ox)]+ complex (Scheme 1), the first-order
observed rate constants, kobs, were measured at fixed catalyst
C
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Scheme 1. General Reaction Scheme for Ester Hydrolysis by
Oximate Complexes (Nonreactive Aqua and Hydroxo
Ligands Omitted for Clarity)
(kZn(Ox)(OH) ) generated by two consecutive deprotonation
processes with dissociation constants Ka1 and Ka2.
2
kobs = (kZn(Ox)(OH)[H+]/Ka1 + kZn(Ox)(OH)
/(1 + [H+]/Ka1 + [H+]2 /Ka1Ka2)
)
2
(1)
Second-order rate constants corresponding to the reaction
with the [Zn(Ox)(OH)] complex were first estimated from the
kinetic results obtained below pH 9, in the same manner as that
for [Cd(Ox)]+ but using the distribution curve for [Zn(Ox)-
(OH)], as illustrated in the Supporting Information (Figure
S10); see also the inset in Figure 4A. The second-order rate
constants for the [Zn(Ox)(OH)2]− complex were then
estimated by including the equilibria corresponding to the
second water deprotonation with a pKa value of 10.5
(Supporting Information, Table S1), which essentially co-
incided with the “kinetic” pKa2 value obtained from the rate−
pH profiles fitted to eq 1. The final values for the second-order
rate constants of [Zn(Ox)(OH)] and [Zn(Ox)(OH)2]−
complexes were obtained by using multiple linear regressions
on the pH dependence of the whole set of observed rate
constants, kobs, in accordance with eq 2:
concentration and variable pH and superimposed with the
species distribution plot, as illustrated in the Supporting
Information (Figure 9S) for cadmium(II). The values of the
second-order rate constants for the cadmium complex were
calculated from the slope of the linear plots of kobs as a function
of the concentration of active [Cd(Ox)]+ species at each pH
and averaged to find the final kCd(Ox) values, collected in Table
1.
Such treatment for zinc(II) and 2a reported in ref 6 was
limited to pH values below 9 because of the inaccuracy of the
kobs determination at high pH due to a very fast reaction rate.
Figure 4A shows the pH profile for kobs and Zn(1) with the
much less reactive ester 2g, which can be followed up to pH 11.
Evidently, the profile is not saturated at pH above 9, where
formation of the [Zn(Ox)(OH)] species is already complete;
instead, it continues to grow with an inflection point of around
pH 10.5, reflecting the formation of a much more reactive
species at higher pH. The same behavior was observed with all
substrates. At the same time, the profile of kobs as a function of
the pH at pH < 9, shown in the inset in Figure 4A, follows very
well the distribution curve for the [Zn(Ox)(OH)] complex,
indicating that this species is the reactive form at lower pH, as
was concluded in ref 6.
kobs = kZn(Ox)(OH)[Zn(Ox)(OH)] + kZn(Ox)(OH) [Zn(Ox)
2
−
(OH)2 ]
(2)
All second-order rate constants are collected in Table 1
together with rate constants of oximolysis by a free anion of 1
(kOx) and alkaline hydrolysis (kOH). Analysis of the results in
terms of a Bronsted-type relationship considering the reaction
rate as a function of the acidity of the conjugate acid of the
leaving aryloxide ion is illustrated in Figure 5, and the slopes βlg
of the linear portions of the dependencies are collected in Table
1.
For nucleophilic substitution in phenyl esters, the values of
βlg are located within the characteristic ranges associated with
the type of rate-determining step: between −0.2 and −0.4 when
this is the nucleophilic attack and between −0.9 and −1.3 when
this is expulsion of the leaving phenolate anion.12 The reaction
with the free oximate anion of 1 has a low βlg value, indicative
of a rate-determining nucleophilic attack. This fact agrees well
with the detail that the pKa value of the oxime (pKa = 11.74) is
larger than the pKa value of the conjugate acid of the leaving
phenoxide ion for all substrates, the situation when the
nucleophilic attack should be rate-determining. Under such
conditions, the Bronsted slope for nucleophiles, βnuc, should be
small (ca. 0.3).12 As mentioned earlier in the Introduction, the
slope βnuc for highly basic oximes (pKa > 8) to which free 1
Figure 4B shows the whole pH profile for 2g in the
logarithmic scale, clearly demonstrating the existence of two
apparent pKa values, one around pH 8.5, which reflects the
formation of [Zn(Ox)(OH)], and another one around pH 10.5,
reflecting the formation of a second hydroxo complex,
supposedly [Zn(Ox)(OH)2]−. The solid line in Figure 4B is
the fitting to the theoretical equation (1) derived for a
simplified formal mechanism with the two reactive species
[Zn(Ox)(OH)] (kZn(Ox)(OH)) and [Zn(Ox)(OH)2]−
Table 1. Rate Constants of the Cleavage of Esters 2a−2i
substituent
log kOH
1.15
log kOx
1.78
log kCd(Ox)
log kZn(Ox)(OH)
log kZn(Ox)(OH)
2
p-NO2
p-COO−
p-Cl
4.04
3.90
3.95
3.60
4.9
4.18
0.041
0.20
1.17
1.32
3.62
3.15
3.98
p-Ph
−0.018
−0.060
−0.174
−0.20
−0.21
−0.26
1.15
3.58
3.18
3.94
H
1.01
3.28
2.30
3.20
p-Me
p-Isop
p-Tert
p-MeO
βlg
0.87
3.28
2.20
3.18
0.87
3.07
2.15
3.08
0.86
3.05
2.00
3.08
0.79
3.47
2.30
3.15
−0.42 0.03
−0.29 0.03
−0.76 0.06
−1.4 0.2
−1.1 0.1
D
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Figure 4. (A) Rate−pH profile for the cleavage of ester 2g in the presence of a 0.1 mM zinc(II) complex of 1. Inset: expanded profile at pH below 10
superimposed with the distribution curve for the [Zn(Ox)(OH)] complex. (B) Same results in logarithmic coordinates.
in the pKa value of the coordinated oxime down to 9.37 for the
cadmium(II) complex and down to 8.17 in the case of the
corresponding zinc(II) complex, making the pKa value of the
conjugated acid of the nucleophile lower than the pKa value of
the conjugated acids of the leaving groups of substrates.
The increased reactivity of the oximate anion coordinated to
cadmium(II) or zinc(II) was attributed to the removal of the
“solvational imbalance” effect in the coordination sphere of the
metal ion, so that the coordinated oximate anion has the
esterolytic reactivity closely related to its basicity.6 Here, we
provide a logical explanation of this phenomenon by establish-
ing a change in the nature of the rate-determining step
comparing free to coordinated oximates. Indeed, if the
nucleophilic attack is not the rate-determining step anymore,
then the nucleophile solvation becomes irrelevant. An
intriguing point is that coordination of the oximate group to
the metal involves the lone electron pair on the nitrogen atom
responsible for the α effect and, therefore, for the high reactivity
observed for the oximate; nevertheless, the coordinated oximate
can be much more reactive than the free one. Probably the
nature of the M−N bond in these complexes has a large
contribution of the ionic character, and the sharing of the N sp2
orbital containing the lone electron pair with empty orbitals of
the metal ion is relatively small.
Figure 5. Dependence of the rate constants for the cleavage of esters 2
by different nucleophiles on the pKa values of the conjugate acid of the
leaving aryloxide ion.
The increased reactivity of [Zn(Ox)(OH)2]− compared to
[Zn(Ox)(OH)] is generally in line with the hypothesis of a
principal role of the removal of the “solvational imbalance”.
Moreover, the dihydroxy species must have a significantly more
basic oximate anion due to the inductive effect of a second
hydroxide anion coordinated to the metal ion, and
consequently it may possess a higher reactivity in the absence
of the leveling-off effect created by the “solvational imbalance”.
The rate constant estimated for 2a and [Zn(Ox)(OH)2]−
(Table 1) is unprecedentedly large for both model and
biological esterases; e.g., the rate constant for hydrolysis of 2a
by α-chymotrypsin is only 3 × 103 M−1 s−1.13
Recently, a zinc(II) oximato complex with a different
structure was found to possess an unusually high reactivity in
the cleavage of activated phosphodiesters.14 Testing zinc(II)
and cadmium(II) complexes of 1 showed no reactivity with
bis(4-nitrophenyl) phosphate, at pH values ranging from 7.0 to
belongs is essentially zero, but for low basic oximates, it is about
0.7.4 The leveling off effect for highly basic oximates is
attributed to a “solvational imbalance”, but on the basis of the
observed low βlg value, it seems that this effect can be at least
partially attributed to a possible change in the rate-determining
step, which for low basic oximates should be the leaving group
expulsion.
The Bronsted plots for the metal complexes are linear in the
range of pKa above 9 with large slopes indicative of the rate-
determining expulsion of the leaving phenoxide anion. The
point corresponding to substrate 2a deviates downward most
probably due to the change in the rate-determining step to the
nucleophilic attack with the very good 4-nitrophenolate leaving
group. We see therefore that the coordination of oximate 1 to
cadmium(II) or zinc(II) is accompanied by a change in the
rate-determining step from the nucleophile attack to the leaving
group expulsion. The most obvious reason for this is a decrease
E
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Figure 6. (A) First-order rate constants as a function of the pH for the cleavage of paraoxon by 0.5 mM zinc(II) (open squares) and cadmium(II)
(solid squares) complexes of 1. Solid lines are the theoretical fits according to the second-order rate constants provided in Table 2. (B) Logarithm of
the first-order rate constants, log kobs, as a function of the pH for the cleavage of paraoxon by a 0.5 mM oximate anion of 1 (dashed line), hydroxide
(background hydrolysis, dotted line), and 0.5 mM zinc(II) (open squares) and cadmium(II) (solid squares) complexes of 1. Solid lines are the
theoretical fits according to the second-order rate constants provided in Table 2.
a
Table 2. Second-Order Rate Constants and Rate Enhancement for Triester Cleavage by Cadmium(II) and Zinc(II) Complexes
of 1 in Water at 25 °C
b
b
c
paraoxon
parathion
NPDPP
species
k (M−1 s−1
8 × 10−3
)
kM(Ox)/kOx
k (M−1 s−1
)
b
kM(Ox)/kOx
k (M−1 s−1
)
kM(Ox)/kOx
d
kOH
2.5 × 10−4
0.0019
0.95
0.22
0.35
22
kOx
0.028
1.4
kCd(Ox)
50
500
25
63
51
kZn(Ox)(OH)
kZn(Ox)(OH)
0.11
0.4
3.9
14.3
0.048
18
0.127
67
120
350
c
2
a
b
Rate enhancement with respect to the free oximate anion of 1. The solution for kinetic measurements contained 2% acetonitrile in volume. The
solution for kinetic measurements contained 4% dioxane in volume. kOH measured in 0.1−5.0 mM aqueous NaOH solutions.
d
9.5, as well as with the 4-nitrophenyl phosphate monoester. On
the other hand, these complexes were very efficient in the
cleavage of paraoxon, parathion, and 4-nitrophenyldiphenyl
phosphate (NPDPP) triesters. Figure 6 shows the pH profiles
for the cleavage of paraoxon by zinc(II) and cadmium(II)
complexes of 1. Analysis of these observed rate constants was
done by the same approach as above, and the second-order rate
constants toward paraoxon, parathion, and NPDPP for each
complex are summarized in Table 2, together with the
constants for alkaline hydrolysis, kOH, and oximolysis by the
anion of 1, kOx.
From these results, it is clear that all rate constants of the
metal oximato complexes toward parathion, paraoxon, and
NPDPP as substrates are significantly higher than the rate
constant for oximolysis by a free oximate anion of 1. The
enhancement of the reactivity by the oximate metal complexes
(kM(Ox)/kOx) varies from complex to complex, but an average
increase in the reactivity toward these phosphate triesters is
around 50 times. However, a 500 times increase is found for the
[Cd(Ox)]+ complex toward parathion, which may reflect the
affinity of cadmium to the sulfinyl group and a possible metal−
substrate interaction. The reactivity of the [Zn(Ox)(OH)2]−
complex toward phosphate triesters is greater than the
reactivity of the [Zn(Ox)(OH)] species, in line with our
results for carboxylic esters.
It has been previously reported that the complex formation
of pyridineoximate anions with metal ions leads to an inhibitory
effect on the cleavage of phosphate triesters, in contrast to an
acceleration effect with carboxylic acid esters.15 The reason for
this difference is unclear because mechanistically the
nucleophilic substitution in both types of esters is quite similar.
It has been noted previously that the reactivity of the metal
oximate complexes is extremely sensitive to minor variations in
the ligand structure, which is virtually impossible to rationalize
yet.16 The strong promotional effects of zinc(II) and cadmium-
(II) in the oximolysis of both types of substrates by 1 shows
that a possible reason for the contrasting effects of metal
coordination on the reactivity with other oximate ligands
toward phosphate and carboxylate esters as substrates may rely
on some still poorly understood details of the ligand structures.
CONCLUSION
■
This paper is concerned with three aspects of the nucleophilic
reactivity of coordinated oximate anions: substrate specificity,
detailing the mechanism of the cleavage of carboxylic acid
esters, and improvement of the absolute esterase reactivity.
With respect to the substrate selectivity, the major mechanistic
difference between the catalytic cleavage of noncoordinating
neutral carboxylic acid esters or phosphate triesters on the one
side and anionic phosphodiesters or monoesters on the other
F
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Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
perchlorate salts of zinc(II) and cadmiun(II) were standardized against
ethylenediaminetetraacetic acid and zinc chloride using Eriochrome
Black T as a metallochromic indicator; their concentrations were also
confirmed by atomic absorption spectroscopy. pH measurements were
carried out using a Thermo Scientific Orion 4-Star research digital pH
meter equipped with a ROSS Ultra pH glass electrode. Kinetic
measurements were performed on a Hewlett-Packard 8453 diode-array
spectrophotometer with a water-thermostated multicell compartment
( 0.1 °C). Barnstead nanopure distilled and deionized water was used
in all experiments.
side is that the cleavage of the anionic substrates involves metal
coordination of the phosphoryl group. The absence of reactivity
toward the latter group of substrates indicates therefore that the
metal complexes of 1 act via a simple bimolecular attack to the
carbonyl or phosphoryl group without the simultaneous
coordination of these groups to the metal ion. However,
some contribution of such coordination is seen in the cleavage
of parathion by the cadmium(II) complex.
The change in the rate-determining step from the
nucleophilic attack for free oximate to leaving group
dissociation for coordinated oximate explains why the solva-
tional imbalance effect becomes less significant for oximate
complexes, and this allows one to reach the nucleophilic
reactivity much above the limiting value about 50 M−1 s−1 (for
the most common ester substrate 2a), previously reported for
highly basic oximate anions.
An unexpected result of this study is the observation that, at
pH values above 9, Zn(1) is transformed into a bis(hydroxo)-
oximato complex, a much more reactive chemical form than
other previously identified catalytic species. Results for 4-
nitrophenyl acetate (2a), a substrate most widely used for the
assay of esterase catalysts, which allows us to make comparisons
with a large number of reported systems, demonstrate that the
[Zn(Ox)(OH)2]− complex surpasses by its reactivity all known-
so-far chemical and biological esterases. The highest reported
reactivity belongs to the “pseudoenzymatic” cleavage of 2a by
human serum albumin17 with the second-order rate constant
kcat/KS = 3.3 × 104 M−1 s−1, while the second-order rate
constant for the [Zn(Ox)(OH)2]− complex is 7.9 × 104 M−1
s−1.
At the same time, it should be noted that the trends in the
reactivity of coordinated oximates are still not well understood.
For example, the zinc(II) complex of ligand 3, which is
essentially an isomer of 1 with the pyridine group directly
linked to the oximate anion, is 1000 times less reactive than the
complex with 1, although the oximate group in the complex
with 3 has only a slightly smaller basicity (pKa = 7.7);16
however, the zinc(II) complex of the pyridineoxime ligand 4 is
ca. 100 times more reactive than the complex with 3, although
it possesses an even less basic oximate group (pKa = 7.0).18
Another intriguing question is what makes the zinc(II) complex
of tetradentate ligand 5 one of the most reactive catalysts in
phosphodiester hydrolysis,14 while the zinc(II) complex of 1
does not have any phosphodiesterolytic reactivity at all.
Answering these questions may lead to the future discovery
of even more potent artificial esterases and/or phosphoes-
terases on the basis of coordinated oximates.
The ligand HOxAPy was synthesized according to the method that
we previously reported.6 Phenyl esters used as substrates were
prepared by the O-acylation of the corresponding substituted phenols
with acetyl chloride according to literature procedures,21 except for the
4-carboxyphenyl ester, which was prepared using acetic anhydride as
the acylating agent catalyzed by sulfuric acid.22 All of the substrates
were obtained as clear oils or white solids (4-carboxy and 4-phenyl)
and purified by column chromatography in SiO2 (9:1 hexane−ethyl
1
acetate), and their identity was confirmed by H and 13C NMR.
Kinetic Methods. Reaction solutions were prepared by mixing
appropriate amounts of water, metal stock, ligand stock, and buffer
solutions to the desired volume (ca. 2.45 mL); the pH was adjusted by
adding small volumes of an aqueous HCl solution as required and
included in the total volume. Biological nonchelating buffers were used
depending on the desired pH: MES (5.5−6.7), MOPS (6.5−8.2),
CHES (8.3−10.0), and CAPS (9.7−11.2), all of them 50 mM. The pH
of each solution was checked just before the substrate was added and
at the end of each reaction, confirming that it remained constant.
Reactions were initiated by adding 50 μL of a stock solution of the
substrate (2.5 mM freshly prepared in acetonitrile or dioxane), so the
reaction mixture contained 2% in volume of each of these solvents.
The course of the phenyl ester cleavage was monitored spectrophoto-
metrically at the maximum wavelength of absorption of the
corresponding phenol and phenolate anions. These wavelengths, the
extinction molar coefficient, and the pKa value of each substrate were
determined by spectrophotometric titrations under the same
experimental conditions (Supporting Information, Table S3); all of
them agree with the reported values.23 Kinetic measurements used a
50 μM substrate, varying concentrations of metal salts and ligands, and
varying pH in a 50 mM buffer (TRIS, CHES, or CAPS) at 25 °C.
The observed first-order rate constants (kobs) were calculated by
two methods. The integral method was used when at least 90% of
conversion was attained, and the initial rates were used for slow
reactions before 10% of conversion. The second-order rate constants
for the cleavage of substrates by an active cadmium(II) complex were
calculated by linear regression from the plots of kobs versus CdL
species concentration with correlation coefficients better than 0.985. In
the case of zinc(II), the second-order rate constants of individual
species were calculated by means of multiple regression on the pH
dependence of kobs, according to eq 2.
ESI-MS. Aqueous samples of 0.1 mM solutions of 1 and Zn(ClO2)4
at pH values ranging from 9.5 to 11.0 were transferred into a syringe
and introduced into the ESI source of a 6530 QTOF mass
spectrometer (Agilent) with the aid of a syringe pump (PN5190-
1530, Agilent) at a flow rate of 5 μL/min. The spray then passed
through a heated capillary held at 100 °C. The capillary voltage was set
at 3.0 kV, and nitrogen was used as a sheath gas at 30 psig. Data were
collected and analyzed on MassHunter Workstation software.
Computational Details. DFT calculations were realized to clarify
which are the most stable structures of the zinc complexes of 1 in
solution and where the deprotonation processes occur using simple
thermodynamic cycles of the standard-state free energy of each
possible reaction in the aqueous phase. Calculations were performed
using the suites Terachem24 and Gaussian 09.25 An initial gas-phase
DFT geometry optimization for the cation [Zn(Ox)(H2O)2]+ was
performed using Terachem, employing a combination of the PBE/
DZVP26,27 level of theory and the gas-phase BOMD at 300 K with an
integration step of 1 fs; this molecular dynamics simulation was
conducted in a time frame of 30 ps. No [Zn(Ox)(H2O)2]+ structure
with low energy was found, and instead calculations led to a
EXPERIMENTAL AND COMPUTATIONAL SECTION
■
General Methods. 4-X-substituted phenols [X = H, CH3, (CH3)3,
CH(CH3)2, OCH3, Cl, C6H5, and COOH], acetyl chloride, and acetic
anhydride for synthesis purposes, as well as biological buffers and
inorganic salts, were used as purchased from Sigma-Aldrich. Reagent-
grade solvents were used without further purification and dried, and
dioxane was tested as peroxide-free. 4-Nitrophenol and 4-nitrophenyl
acetate were purified by recrystallization from hot water and
dichloromethane19 and ethanol,20 respectively. Stock solutions of
G
DOI: 10.1021/acs.inorgchem.6b02739
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
[ZnHOx(OH)(H2O)]+ structure with lower energy. [Zn(OxH)(OH)-
(H2O)]+ was optimized with Gaussian 09, using the PBE028 level of
theory in the gas phase. Harmonic frequency calculation was
performed to obtain the corresponding thermochemical corrections
and to confirm that the structures used were stationary points on the
potential energy surface. Because the objective of the previous
procedure was to obtain optimized structures for studies that include
solvent effects, subsequent geometry optimizations were conducted
with Gaussian 09 by means of the implicit solvation model based on
the density of Marenich et al.29 (SMD) using the PBE0 exchange-
correlation functional and Def2-TZVP basis set.30 The optimized
structure of [Zn(OxH)(OH)(H2O)]+ was used as a starting point for
all other complexes. Their optimizations and harmonic frequencies
were also calculated with Gaussian 09 at the PBE0 level of theory.
Afterward, a single point using the SMD solvation model was
calculated, yielding the solvation free energy, ΔGsolv*, of each species
in aqueous solution.
complex of 1, spectral data for substituted phenols, and
additional kinetic data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: pao@unam.mx. Tel: +52 55 56223813. Fax: +52 55
56162010.
*E-mail: anatoli@unam.mx. Tel: +52 55 56223813. Fax: +52
55 56162010.
ORCID
Paola Gomez-Tagle: 0000-0002-4713-8774
́
Jorge M. del Campo: 0000-0002-4195-3487
Notes
The authors declare no competing financial interest.
In order to study the sequence of deprotonation, a simple
thermodynamic cycle31 (Figure 7) was employed to obtain free-
energy changes for the reaction in the aqueous phase.
ACKNOWLEDGMENTS
■
Financial support from DGAPA-UNAM-PAPIIT (Project IN
214514) and FQ-UNAM-PAIP is gratefully acknowledged.
J.M.C. thanks DGTIC-UNAM (Project SC16-1-IR-12) for
providing the computational resources and DGAPA-UNAM
(Grant IA-104516). J.C.L.-G. and X.H. also thank the National
Council for Science and Technology of Mexico (CONACyT)
for their graduate fellowships. We thank Dr. R. C. Canas-
̃
Alonso and USIP for ESI-MS analysis.
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Figure 7. Thermodynamic cycle used to predict the pKa values.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.6b02739.
■
S
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Le Guevel, E.; Chatrousse, A. P.; Moutiers, G.; Buncel, E. The
Levelling Effect of Solvational Imbalances in the Reactions of Oximate
Additional spectroscopic data, DFT calculation data,
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