Mechanistic study of carboxylic acid and phosphate ester cleavage by oximate metal complexes surpassing the limiting reactivity of highly basic free oximate anions

Article abstract of DOI:10.1039/c9dt04733f

Two tridentate and one tetradentate new ligands containing the terminal oxime group separated from secondary amino and pyridine groups as additional binding sites by two or three methylene groups have been prepared. Their acid-base properties, as well as the composition and stability of their complexes with Zn(ii) and Cd(ii) ions, were determined by potentiometric and spectrophotometric titrations. The X-ray structure of a Cd(ii) complex of a related tridentate oxime ligand previously studied in solution was determined. All oximate complexes show high reactivity in the cleavage of aryl acetates, paraoxon, parathion and 4-nitrophenyl diphenyl phosphate, with rate constants significantly surpassing the limiting rate constants observed for highly basic free oximate anions. The second-order rate constants for individual oximate complexes in solution are assigned to each ligand, metal cation and substrate. The results of the cleavage of 4-substituted phenyl acetates were analyzed in terms of Br?nsted correlations with the leaving group pK_a, which demonstrated a change in the rate determining step from the nucleophilic attack to the leaving group departure upon an increase in the leaving group basicity. The zero slope of the Br?nsted correlation for the nucleophilic attack indicates transition state stabilization through electrophilic assistance by the metal ion. This interpretation is supported by metal selectivity in the relative efficiency of the cleavage of paraoxon and parathion. The existence of the alpha-effect in ester cleavage by coordinated oximates is confirmed by an analysis of the Br?nsted correlations with the nucleophile basicity for metal bound oximate and alkoxo or hydroxo nucleophiles. The very high reactivity of the oximate complexes of the new ligands is attributed to transition state stabilization and to the removal of the solvational imbalance of oximate anions that impedes the expected increase in the reactivity of highly basic free anions.

Full text of DOI:10.1039/c9dt04733f

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An international journal of inorganic chemistry
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Gonzales, P. Gómez-Tagle, M. Flores-Alamo and A. K. Yatsimirsky, Dalton Trans., 2020, DOI:
10.1039/C9DT04733F.
Volume 46
Number 10
14 March 2017
Pages 3073-3412
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N-Heterocyclic carbene stabilized parent sulfenyl, selenenyl,
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Mechanistic study of carboxylic acid and phosphate esters cleavage by oximate metal complexes
surpassing the limiting reactivity of highly basic free oximate anions
José Carlos Lugo-González, Paola Gómez-Tagle*, Marcos Flores-Alamo, Anatoly K. Yatsimirsky*
Universidad Nacional Autónoma de México, Facultad de Química, 04510, Mexico City, México.
E-mail: pao@unam.mx; iatsimirski46@comunidad.unam.mx
Fax: +52 55 56162010;
Tel: +52 55 56223813
ABSTRACT
Two tridentate and one tetradentate new ligands containing the terminal oxime group separated from a
secondary amino and pyridine groups as additional binding sites by two or three methylene groups have
been prepared. Their acid-base properties, as well as the composition and stability of their complexes with
Zn(II) and Cd(II) ions were determined by potentiometric and spectrophotometric titrations. The X-Ray
structure of a Cd(II) complex of a related tridentate oxime ligand previously studied in solution was
determined. All oximate complexes show high reactivity in the cleavage of aryl acetates, paraoxon,
parathion and 4-nitrophenyl diphenyl phosphate with rate constants significantly surpassing the limiting
rate constants observed for highly basic free oximate anions. The second-order rate constants for individual
oximate complexes in solution are assigned for each ligand, metal cation and substrate. Results for the
cleavage of 4-substituted phenyl acetates were analyzed in terms of Brønsted correlations with leaving
group pKa, which demonstrated a change in the rate determining step from nucleophilic attack to the
leaving group departure on increase in the leaving group basicity. The zero slope of the Brønsted
correlation for the nucleophilic attack indicates the transition state stabilization through electrophilic
assistance by the metal ion. This interpretation is supported by the metal selectivity in the relative
efficiency of the cleavage of paraoxon and parathion. The existence of the alpha-effect in ester cleavage by
coordinated oximates is confirmed by analysis of Brønsted correlations with the nucleophile basicity for
metal bound oximate and alkoxo or hydroxo nucleophiles. The very high reactivity of the oximate
complexes of new ligands is attributed to the transition state stabilization together with the removal of
solvational imbalance of oximate anions impeding the expected increase in reactivity of strongly basic free
anions.
1

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INTRODUCTION
The cleavage of carboxylic acid and phosphate esters have been studied extensively due to their ubiquitous
presence and relevant implications in a diversity of biological and environmental processes.1 Recently,
attention has been focused on catalytic cleavage as well as selectivity to substrates by using molecular
recognition systems that mimic natural systems,2 but the potential of more simple chemical systems in
which the nucleophilicity of the cleavage reagent plays a dominant role still attracts significant attention.3
Among widely studied nucleophiles are the oximate anions,4 a type of so-called alpha nucleophiles
possessing an unshared electron pair next to the nucleophilic atom and exhibiting an increased reactivity
compared to “normal” nucleophiles of the similar basicity. In particular, pyridyl oximes have been used as
detoxificators of cholinestarese poisoning by organophosphorus war or pesticides reagents because they
promote the cleavage of the phosphorylated acetylcholinesterase (AChE) restoring its activity when
inhibited by organophosphates5–7 and more recently also by carbamates.8 1-Methylpyridine-6-carbaldehyde
oxime, also known as 2-PAM or pralidoxime, is the only FDA approved drug to administrate in cases of
organophosphate poisoning.9 Also an FDA approved reactive skin decontamination lotion contains as the
active ingredient Dekon 139 - a potassium salt of 2,3-butanedione monooxime.10
As it is typical for other nucleophiles11 the reactivity of oximates increases on increase in their
basicity, but it levels-off in aqueous solutions when pKa of oximes reach the values between 7 and 8.12 This
effect interpreted in terms of “solvational imbalance”, resulting from the necessity of the nucleophile
desolvation before the nucleophilic attack,13,14 poses a serious limitation on the intrinsic reactivity of the
oximates. For instance, with 4-nitrophenyl acetate (NPA) as a substrate, the limiting value of kNu (the
second-order rate constant of the ester cleavage be the oximate anion) is about 60 M-1s-1,11 but the
extrapolation of the linear part of the Brønsted plot of logkNu vs. pKa to an oxime with e.g. pKa = 12
predicts that it could have much higher kNu value about 4×104 M-1s-1.
Chelating molecules containing oximate function can form metal-nitrogen bound oximate
complexes which display enhanced reactivity relative to free oximes. Initially the favorable effect of metal
coordination was attributed only to the lowering of pKa values of oximes,15 generating higher fraction of
the oximate anion at pH below pKa of oxime, similarly to “activation” of water molecules by converting
them to coordinated hydroxide anions.16 However it was later demonstrated that in contrast to the water
activation when the nucleophilic reactivity of coordinated OH- decreases by 1 to 2 orders of magnitude in
comparison with that of free OH-,17 some metal oximates can surpass the reactivity of the corresponding
free oximate anions.18 Recently Wiliams et al.19 discovered similar superiority of coordinated oximates
2

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over coordinated alkoxides in phosphate diester cleavage and attributed it to the fact that in oximate
complexes the coordination occurs at the donor atom contiguous to the reactive nucleophile while in
alkoxo (and hydroxo) complexes metal is bound directly to it.
Regarding the esterolytic acitivity of the oximate complexes, studied mostly with NPA as a
substrate, Zn(II) oximate complexes 1 with R = H, 2 and 3 (R = H or CH3) have a lower nucleophilic
reactivity than the respective free oximates, while the Zn(II) oximate of 1 with R = CH3 and the Cd(II)
oximate complex 2 surpass by 10 and 4-times respectively the reactivity of free oximates.20
R
R
H
N
N
N
N
M2+
M2+
N
N
N
N
M2+
N
M2+
N
N
H
HO
OH
OH
OH
OH
1, R = CH3 or H
2
3, R = CH3 or H
4, M2+ = Zn(II) or Cd(II)
Particularly strong esterase reactivity was observed with Zn(II) and Cd(II) complexes 4, which
surpassed by 2-3 orders of magnitude the reactivity of the free oximate, reaching the level of enzyme
reactivity, and operating in a true catalytic mode.21,22 Metal complexes 4 were also very eficient catalysts
towards phosphate triesters and parathion. The large reactivity of these complexes was interpreted in terms
of the removal of the solvation imbalance in the oximate nucleophile due to the presence of the metal
cation, thus removing the limiting reactivity of the corresponding oximates with pKa > 8.21–22
Although structures of complexes 1 – 4 have much in common, their esterolytic reactivity in NPA
cleavage with M = Zn(II) varies in a wide range from kNu = 2.5 M-1s-1 for 3 (R=H) to 8.7x103 M-1s-1 for 4
and it seems that rather subtle changes in the ligand structure may cause a substantial change in the
reactivity of the metal-oximate complex. For this reason our primary intention in this work was to test
several systematic structural modifications of the most successful ligand L4 in a hope to get an additional
insight into factors affecting the reactivity of the oximate complexes and possibly to improve the
esterolytic activity of such complexes in general. To this end three new ligands L1-L3 were prepared.
3

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N
H
N
N
H
N
H
H
N
N
N
N
N
N
N
OH
OH
N
OH
OH
NH2
L4
L1
L2
L3
With L1 and L2 the changes from five to six-membered chelate rings are implemented by
increasing the number of carbon atoms between the secondary amino group and pyridine or oxime
expecting to modify the stability and the acidity of the metal-oximate complexes. In L3, an additional
fourth donor amine group is introduced to gain inceased complex stability and to see the effect of
occupation of an additional coordination site on the reactivity. Since previous studies established the
highest reactivity of complexes of L4 with Zn(II) and Cd(II) among other tested divalent metal ions, only
these two cations were employed in the present study.
We report here the reactivity of indivudual species of metal complexes of ligands L1-L3, towards
the cleavage of nine phenyl acetate esters (5a-5i) and three phosphate triesters, paraoxon, parathion, and
NPDPP (6, 7 and 8) based in the speciation and detailed kinetic data involving determination of pH-rate
profiles of the observed rate constants with all ligands, metal ions and substrates. The influence of the
structure of the ligand is discussed and these results are analyzed and compared to get insight into the
reaction mechanism.
NO2
NO2
NO2
X
S
P
O
O
P
O
P
O
O
EtO
PhO
O
O
EtO
Et
OPh
O
Et
O
5
6 (Paraoxon)
7 (Parathion)
8 (NPDPP)
X= NO2(a), COOH(b), Ph(c), Cl(d),
H(e), Me(f), i-Pr(g), t-Bu(h), MeO(i).
4

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RESULTS AND DISCUSSION
Structure and speciation.
Attempts to grow suitable for X-Ray diffraction crystals of the complex were successful only for Cd(II)
complex of L4 of the composition [Cd(LH)2(NO3)]NO3 prepared in ethanol, Fig. 1. Although this complex
is not detected by potentiometric titrations in aqueous solution its structure is helpful for understanding the
coordination mode of an oximate ligand around Cd(II).
Fig. 1 Ortep drawing of [Cd(HL4)2(NO3)]NO3 showing thermal ellipsoids at 50 % probability level for
non-H atoms.
Speciation of ligands L1-L3 and their zinc(II) and cadmium(II) complexes was determined in
aqueous solutions by acid-base potentiometric titrations and was additionally confirmed by
spectrophotometric measurements in more diluted solutions. The obtained set of acidity (pKa) and stability
constants (log KML) is summarized in Table 1, including the values for L4 for comparison.
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Table 1. Stability constants (log K) and pKa values of ligands L1-L4 and their zinc(II) and cadmium(II)
metal complexes in water at 25°C and 0.1 M ionic strength. The number in parentheses is the standard error
in the last significant digit.
logK or pKa
Reaction
L1
L2
L3
L4
HL ⇌ L- + H+
11.73(2)
11.34(4)
12.06(3)
11.74(9)
1
2
3
4
H2L+ ⇌ HL + H+
H3L2+ ⇌ H2L+ + H+
H4L3+ ⇌ H3L2+ + H+
8.00(3)
3.77(3)
8.07(3)
3.63(2)
9.19(3)
7.07(4)
3.15(4)
6.96(5)
2.6(2)
Zn(II) Cd(II) Zn(II) Cd(II
4.3(1) 3.10(1) 5.46(2) 3.96(5) 6.10(2) 5.60(2)
2.9(1)
Zn(II)
Cd(II)
Zn(II) Cd(II)
5.04(5) 4.46(3)
3.94(4)
M + HL ⇌ [M(HL)]
[M(HL)] + HL ⇌ [M(HL)2]
[M(HL)(H2O)2] ⇌
5
6
8.00(3)
7.38(5)
9.37(3)
8.2(1)
7
8
[M(HL)(OH-)(H2O)] + H+
[M(HL)(H2O)2] ⇌
[M(L-)(H2O)2] + H+
7.90(5) 9.2(1) 7.20(2) 8.08(4)
10.20(3)
[M(HL)(OH-)(H2O)] ⇌
[M(L-)(OH-)(H2O)] + H+
[M(L-)(H2O)2] ⇌
[M(L-)(OH-)(H2O)] + H+
[M(L-)(OH-)(H2O)] ⇌
[M(L-)(OH-)2] + H+
8.50(3)
9
8.4(1)
10
10.5(3)
6.3(1)
11
12
[M(HL)2] ⇌ [M(HL)(L-)] + H+
The acid-base and coordination properties of L1-L4 agree well with those reported previously for
similar ligands, in particular for the parent bidentate 2-picolylamine ligand,23 and follow the expected
chelate size effect in stability constants.24,25 A detailed description of trends observed in stability and
acidity constants shown in Table 1 is given in ESI. The pKa values of coordinated oximes correlate very
well with the pKa of free ligands (ESI, Fig. 5S) indicating that the structural changes affecting the
dissociation of the oxime group in free ligands and M(II) complexes are similar.
The basicity of the nucleophile is a very important factor affecting its reactivity therefore, it is
essential to find a reasonable interpretation of the trend in oxime pKa values in a given set of ligands and
complexes. In general terms, the coordination to a metal cation induces a significant decrease in the pKa of
the oxime group by 2 to 4 logarithmic units. The effect of Zn(II) is expectedly larger than that of Cd(II) due
to its stronger Lewis acidity. The oxime moiety of ligands L1-L4 is structurally similar to methyl ethyl
ketoxime, which has a pKa of 12.2 at 25oC and 0.1 M ionic strength,26 above the pKa values of all ligands
L1-L4. The increased acidity of ligands hardly can be attributed to electronic effects because the oxime
fragment is bound to the rest of the molecule via an aliphatic carbon. Thus, an effect of stabilization of the
deprotonated oximate group by intramolecular hydrogen bonding to NH group as illustrated in structure 9
seems more plausible. The strongest acidification observed in L2 can be attributed to a possible gem-
6

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dialkyl effect of the methyl groups at the intermediate carbon atom, known to stabilize cyclic structures,27
see structure 10. In respective metal complexes a similar cycle involves a metal ion (11) and the trend in
pKa values for different ligands is therefore conserved.
R
N
R
R
H
N
H
N
H
N
O
2+
M
N
N
–
O
–
–
O
9
10
11
The next section presents a detailed kinetic study of the esterolytic reactivity of these complexes
towards 4-substituted phenyl acetates 5a-5i and phosphate triesters: paraoxon (6), parathion (7), and
NPDPP (8).
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Kinetics of the Cleavage of the 4-Substituted Phenyl Acetates.
All studied reactions followed simple second-order kinetics, first-order in both the nucleophile and the
substrate. Reactions with free ligands were studied under pseudo-first-order conditions by using a large
excess of L1-L3 over the substrates. In the presence of metal cations an excess of the nucleophile was not
necessary because metal-oximate complexes were operating as catalysts, in accordance with the general
Scheme 1, and their concentration was maintained constant thanks to their highly efficient turnover (see
below).
N
N
H
M2+
O
O
N
NH
O-
O
N
O-
O
M2+
OH-
(
)
n
kML
N
R
OH-
(
)
n
R
X
X
O-
OH-
N
O
N
H
+
M2+
O
N
O
OH-
(
)
n
X
O-
R
Scheme 1. Acylation-deacylation mechanism for the cleavage of phenyl acetates
Rates of catalytic reactions were strongly pH-dependent. The general trends in rate-pH profiles
were similar for all esters. As an example, Figure 2 illustrates the complete pH-rate profiles for the
cleavage of 5h by the zinc(II) and cadmium(II) complexes of L1-L3. The pH-rate profile for background
hydrolysis is also included to show the scale of the catalytic effect, which is up to 104 times in the range of
pH 7-8. For example, at pH 7.4 the half-live of 5h due to the spontaneous hydrolysis is 2.7 months while in
the presence of 0.1 mM zinc(II) oximate complexes it reduces to 18 min for L3 and to 1 min for L2.
8

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-1
-2
-3
-4
-5
-6
-7
-1
-2
-3
-4
-5
-6
-7
Zn(II)
Cd(II)
L2
L1
L3
OH-
OH-
L2
L1
L3
6
7
8
9
10
11
7
8
9
10
11
pH
pH
Fig. 2 pH-Rate profiles in logarithmic coordinates of kobs (s-1) for the cleavage of 4-t-Bu phenyl acetate
(0.05 mM) in the presence of equimolar mixtures of zinc(II) or cadmium(II) nitrate and ligands L1-L3 (0.1
mM) in 0.1 M buffered aqueous solutions. Open circles (○) L1, solid circles (●) L2, solid triangles (▲) L3.
The dotted line is the background alkaline hydrolysis.
Qualitatively the profiles in Fig. 2 behave as expected for a reaction mechanism where the active
form is the oximato complex. As the pH increases so does the reaction rate and levels-off at pH values
above the pKa of coordinated oxime (cf. Table 1). With more acidic Zn(II) complexes the rate increase
occurs at lower pH than with Cd(II) and for this reason Zn(II) complexes are more active at pH around 7.
The limiting values of rate constants at high pH are comparable for different ligands and for both metals;
however the fraction of bound ligands under conditions of Fig. 2 is smaller for Cd(II) than for Zn(II) and
therefore the intrinsic reactivity of Cd(II) oximate complexes should be higher (ESI figures 8S, 10S and
12S). Similar reactivity of fully deprotonated complexes indicates that the structural variations in ligands
L1-L3 are manifested mostly in stability and acid-base properties of the complexes rather than in their
intrinsic reactivity.
The assignment of second-order rate constants for individual reactive species in solution was done
by correlating the species distributions at variable pH with the observed rate constants for each ligand,
metal cation and substrate. At the first step, the corresponding species distribution curves were
superimposed with kinetic data (see ESI for pH profiles with all ligands L1-L3 and substrates). The plots in
figure 3 show, as an example, kinetic and species data for zinc(II) complexes with ligands L1-L3 and 5h as
a substrate. A simple inspection of figure 3a shows that the pH-rate profile does not correlate with the
distribution of only one deprotonated complex within the whole experimental range of pH. From pH 6 to
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7.7, the observed reactivity follows very well the distribution curve for [Zn(L1)]+, a complex were only the
oxime group is deprotonated. As the pH increases above 8, the reaction rate starts to increase noticeably
faster than the concentration of [Zn(L1)]+ complex, which reaches the maximum and decreases above pH
8.6. At the same time, the fraction of the complex [Zn(L1)(OH-)] starts to increase from pH 7.5, and
evidently the trend in observed rate constants follows the distribution curve for this species which acts as
the reactive nucleophilic form of the complex at higher pH values. Hence, the observed reaction rate in the
whole pH range can be presented as the sum of contributions from these two nucleophilic species, Eq. (1).
6.00x10-5
4.50x10-5
3.00x10-5
1.50x10-5
0.00
0.03
0.02
0.01
0.00
0.075
0.050
0.025
0.000
a
b
HN
HN
Zn2+
9.0x10-5
6.0x10-5
3.0x10-5
0.0
N
[Zn(L1-)]+
N
Zn2+
N
N
[Zn(L2-)]+
OH
OH
calculated profile
[Zn(HL2)]2+
[Zn(HL1-)]2+
[Zn(L1-)(OH-)]
6
7
8
pH
9
6
7
8
9
pH
c
N
H2
N
NH
N
9.0x10-5
6.0x10-5
3.0x10-5
0.0
0.075
0.050
0.025
0.000
Zn2+
[Zn(L3-)(OH-)]
OH
[Zn(HL3)]2+
[Zn(HL3)(OH-)]+
7
8
9
10
11
pH
Fig 3. pH-rate profiles (left Y-axis) of zinc complexes with ligands L1-L3 towards 5h in the presence of
equimolar mixtures 0.1 mM of zinc(II) perchlorate and ligand in buffered aqueous solutions at 25°C,
superimposed with the species distributions for zinc complexes at the same conditions (right Y-axis).
(1)
푘표푏푠 = 푘Zn(퐋ퟏ)[Zn(퐋ퟏ)] + 푘Zn(퐋ퟏ)(OH)[Zn(퐋ퟏ)(OH)]
The numerical values of individual second-order rate constants kZn(L1) and kZn(L1)(OH) were calculated
as the coefficients of the multiple linear regression applied to the set of kobs values as a function of pairs of
10

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concentrations of the reactive species calculated at each experimental pH for given total concentrations of
Zn(II) and ligand. Similar analysis of the results for Zn(II) complex with L2 illustrated in Fig. 3b shows a
more simple behavior. In this case a single oximate complex [Zn(L2)]+ is formed and the kobs vs. pH profile
follows exactly the distribution curve for this complex. The respective second-order rate constant can be
calculated now from a linear regression according to equation (2). The similar situation is observed for L3.
In this case a single reactive species correlating with the reaction rate is [Zn(L3-)(OH-)], Fig. 3c.
(2)
푘표푏푠 = 푘Zn(퐋ퟐ)[Zn(퐋ퟐ)]
In respect of the ligand L1, it is worth noting that the potentiometric titration does not allow one to
discriminate between formation of [Zn(L1-)]+ or [Zn(HL1)(OH-)]+ species because thay differ just by the
presence of one water molecule, but correspond to deprotonation of either coordinated oxime or water in
the [Zn(HL1)]2+ complex. The assignment of the first deprotonation to the oxime group rather than to a
coordinated water molecule is based on the fact that zinc(II) coordinated hydroxide anions posses very low
nucleophilic reactivity towards phenyl acetates; even considering the largest reported rate constant so far,
about 1 M-1s-1 for NPA cleavage by a Zn(II) hydroxocomplex,28 the kobs value under the conditions of Fig.
3a would be less than 310-5 s-1 becoming undetectably small in comparison with observed values about
0.01 s-1. A similar anbiguity exists also for L3: the species [Zn(HL3)(OH)]+ in fact could be [Zn(L3)]+, but
the absence of noticeable reactivity associated with formation of this species (Fig. 3c) indicates that this is
a hydroxo rather than an oximate complex. Subsequent deprotonation of the coordinated oxime affording
the hydroxo-oximate complex [Zn(L3-)(OH-)] is accompanied by a strong increase in the reaction rate
correlating very well with the concentration of this single species.
The pH-rate profiles for Cd(II) complexes with ligands L1 to L3 towards 5h are shown in figure 4.
Evidently in all the cases, the observed reactivity correlates with only one species, which is considered to
be [CdL]+. In fact, as in the case of Zn(II), this species is indistinguishable with [Cd(HL)(OH)]+, but high
esterolytic reactivity confirms that the deprotonation of [CdHL]+ must be assigned to the oxime group.
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0.045
1.2x10-5
9.0x10-5
6.0x10-5
b
a
0.02
0.01
0.00
N
H
HN
Cd2+
Cd2+
N
N
N
OH
N
0.030
0.015
0.000
8.0x10-6
4.0x10-6
0.0
OH
[Cd(HL1-)]+
[Cd(L1-)]+
[Cd(L2-)]+
[Cd(HL2-)]+
3.0x10-5
0.0
10
7
8
9
7
8
9
pH
pH
0.12
0.08
0.04
0.00
c
1.2x10-4
8.0x10-5
4.0x10-5
0.0
N
H2N
N
H
Cd2+
[Cd(HL3)]2+
[Cd(L3-)]+
N
OH
7
8
9
10
pH
Fig 4. pH-rate profiles (left Y-axis) of cadmium(II) complexes with ligands L1-L3 towards 5h in the
presence of equimolar mixtures 0.01 mM of cadmium(II) nitrate and ligand in buffered aqueous solutions
at 25°C, superimposed with the species distributions for cadmium(II) complexes at the same conditions
(right Y-axis).
Table 2 collects the complete set of calculated rate constants for L1-L3 systems and Fig. 5 shows
the results in the coordinates of a Brønsted correlation, as plots of logarithms of rate constants vs. the pKa
values of the conjugate acids of the leaving aryloxide anions; these plots also allow one a better
visualization of the reactivity trends. Figure 5 includes the previously reported results with L4 (Fig. 5d) for
comparative purposes.
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Table 2. Logarithms of the Second Order Rate Constants (M-1s-1) for the Cleavage of 4-Substituted Phenyl
Acetates. The number in parentheses is the standard error in the last significant digit.
Specie
OH-
L1-
p-NO2
1.15(1)
1.83(3)
3.58(10)
4.30(4)
4.37(1)
1.68(4)
3.34(1)
3.72(1)
1.81(9)
3.90(1)
3.93(1)
p-COO-
0.041(4)
1.19(1)
3.55(20)
4.23(1)
4.34(1)
1.08(7)
3.29(1)
3.68(1)
1.18(3)
3.77(1)
3.79(1)
p-Cl
p-Ph
-0.018(1)
1.16(3)
3.33(2)
3.91(1)
3.93(1)
1.02(4)
2.93(1)
3.28(1)
1.16(8)
3.41(1)
3.44(1)
H
p-Me
-0.174(1)
0.70(2)
2.62(2)
3.06(1)
3.41(2)
0.83(6)
2.51(1)
2.89(1)
0.94(9)
3.18(1)
3.24(1)
p-Iso
-0.20(1)
0.67(2)
2.81(14)
3.05(8)
3.34(1)
0.82(6)
2.46(1)
2.77(1)
0.93(4)
2.99(1)
3.06(1)
p-Tert
-0.21(3)
0.57(6)
2.61(11)
3.17(3)
3.28(1)
0.79(7)
2.40(1)
2.66(1)
0.90(5)
2.92(1)
3.0(1)
p-MeO
-0.26(2)
0.56(2)
2.65(3)
3.053(3)
3.20(3)
0.77(7)
2.42(1)
2.59(1)
0.85(6)
2.89(1)
2.99(1)
0.20(1)
1.23(8)
3.18(11)
3.87(4)
3.99(1)
1.11(7)
3.12(1)
3.48(1)
1.31(6)
3.57(1)
3.60(2)
-0.06(1)
0.72(9)
2.60(4)
3.18(1)
3.43(2)
0.85(6)
2.69(1)
3.02(1)
1.02(9)
3.21(1)
3.25(1)
[Zn(L1-)]+
[Zn(L1-)(OH-)]
-
[Cd(L1 )]+
L2-
[Zn(L2-)]
[Cd(L2-)]+
L3-
[Zn(L3-)(OH-)]
[Cd(L3-)]+
L = L1
a
L = L2
b
4
3
[Cd(L)]
[Zn(L)(OH)]
[Cd(L)]
[Zn(L)]
4
[Zn(L)]
3
2
1
0
L-
L-
OH-
1
7.0
7.5
8.0
8.5
9.0
9.5
10.0
1
7.0
7.5
8.0
8.5
9.0
pKa
9.5
10.0 10.5
pKa
L = L3
c
d
4
3
L = L4
[Zn(L)(OH)2]
[Cd(L)]
[Cd(L)]
4
[Zn(L)(OH)]
3
2
1
[Zn(L)(OH)]
L-
L-
1
7.0
7.5
8.0
8.5
9.0
9.5
10.0
7.0
7.5
8.0
8.5
9.0
pKa
9.5
10.0
10.5
pKa
Fig 5. Brønsted-type plots for L1-L4 systems, logk (M-1s-1) vs pKa of 4-substituted phenols (the leaving
groups in the cleavage of 5a-5i). The second-order constants k (M-1s-1) are from table 2.
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The slopes of Brønsted correlations (lg values) obtained with aryl carboxylates have characteristic
values for a particular rate-determinant step (r.d.s.).29 When the r.d.s. is the nucleophilic attack, the lg
values are in the interval -0.2 > lg > -0.4, while values of -0.9 > lg > -1.3 are found when the r.d.s. is the
leaving group departure; the intermediate lg values are typical for reactions proceeding through a
concerted mechanism. The alkaline hydrolysis (Fig 5a, open circles) demonstrates a simple linear
dependence of logkNu vs. pKa of the leaving group with the slope of -0.42 ± 0.03 typical for the rate-
determining nucleophilic attack. A negative deviation for the point for the negatively charged substrate 5b
can be explained by the electrostatic repulsion with the anionic nucleophile. The leaving group effects in
oximolysis of aryl carboxylates were studied previously for reactions of substituted phenyl benzoates,30
carbonates31 and cinnamates32 with butane-2,3-dione monoximate. The results were analyzed in terms of
Hammett and Brønsted correlations and it was concluded that in all cases the oximolysis proceeded
through a concerted mechanism. We observe, however, with free oximate anions L1-L4 non-linear plots of
logkNu vs. pKa of the leaving group with the slope increasing for more basic leaving groups (Fig. 5a-d,
black symbols). The Brønsted plots of this type are interpreted as an indication of a change of r.d.s. from
nucleophilic attack for “good” low basic leaving groups to the leaving group departure for “poor” highly
basic leaving groups in terms of Scheme 2.
O-
O-
Nu
O
O
O
k1
k2
Nu:-
O
X
Nu
k-1
X
X
Scheme 2. Addition-elimination mechanism for the ester cleavage. The nucleophilic addition to the
carbonyl occurs with a rate constant k1 to yield the tetrahedral intermediate which undergoes dissociation to
products or reactants with rate constants k2 or k-1 respectively.
It follows from Scheme 2 that under steady-state conditions the expression for the observed second-
order rate constant kNu is given by equation (3).
kNu = k1k2/(k-1 + k2)
(3)
The type of r.d.s. depends on the relative values of k2 and k-1: when k2 >> k-1 the observed rate constant kNu
= k1 and the rate-determining is the nucleophilic attack; when k2 << k-1 the first step is a fast equilibrium,
kNu = k2(k1/k-1) and the rate-determining is the leaving group departure.
The Brønsted profiles for all four ligands have similar shape and their quantitative analysis has been
performed by using the empirical equation (4) originally derived for the variation of the nucleophile,33 but
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equally applicable also for the leaving group variation.34 In equation (4) the slope 1 corresponds to the
rate-determining nucleophilic attack and the slope 2 to the rate-determining leaving group departure while
0
kNu and pKa0 refer to a hypothetical situation when k2 = k-1. This situation should be expected when
entering nucleophile and the leaving group have similar pKa values, i.e. when both have similar tendency to
leave from the tetrahedral intermediate with the respective rate constants k-1 and k2.
― 훽 )(푝퐾 ― 푝퐾 °)
1 + 10(훽
2
1
푎
푎
(
)
(4)
log 푘푁푢/푘° = 훽2 푝퐾푎 ― 푝퐾푎° ― 푙표푔
[
]
2
As an example, the fitting of the results for L1 to equation (4) is illustrated in Fig. 6a which gives
the following parameters: 1 = -0.23, 2 = -1.39, pKao = 10.03 and logko = 0.86. Both 1 and 2 have the
typical values for the respective r.d.s., but pKa0 is significantly below the pKa 11.73 of L1. The calculated
1 values for all four oxime ligands are within the range from -0.23 to -0.25; 2 values are from -1.2 to -2.1
and pKa0 from 10.0 to 11.0. Thus in all cases the change in the r.d.s. takes place with the leaving group still
less basic than the nucleophile. In fact all leaving groups in 5 are at least one order of magnitude less basic
than the attacking nucleophile and the change of r.d.s. to the rate-determining leaving group expulsion
should not occur. The Hammett plots for all four oximates were too scattered for a meaningful analysis.
2.0
b
a
1.8
NPA
1.8
1.5
1.6
1.4
1.2
PA
1.2
0.9
1.0
0.8
0.6
0.6
0.3
0.4
7.0
7.5
8.0
8.5
9.0
pKa
9.5
10.0 10.5
7
8
9
10
pKa
11
12
13
Fig. 6. (a) Brønsted plot (logkNu vs pKa) for the cleavage of 5a-5i by L1 and its fitting to equation (4).
(b) Brønsted plot for the oxymolisis of 5a (NPA) and 5e (PA) and their fitting to equation (4).
If non-linear plots in Fig. 5 and 6a really reflect the change in r.d.s., the corresponding Brønsted
plots for logkNu vs. pKa of the nucleophile also should be non-linear changing the slope at pKa close to pKao.
Figure 6b shows such plots for two esters: 5a and 5e with leaving group pKa values 7.14 and 10.04
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respectively. They are non-linear and the fitting to the equation (4) predicts pKao values of 7.9 and 11.3
respectively. Thus we again observe the r.d.s. change when the basicity of the nucleophile is ca. one order
of magnitude larger than that of the leaving group. However, the non-linearity of the plots like that in Fig.
6b is attributed to a solvational imbalance effect rather than to the change in r.d.s. and this interpretation
has been convincingly supported by a thorough study of solvent effects on the oximate reactivity.13,35
Importantly, our study of the leaving group effect is performed with strongly basic oximate anions, the
least basic of which is L2 (pKa 11.34), while reported kinetic studies employ mostly much less basic anions
as 2,3-butanedione monoximate (pKa 9.32). The degree of solvational imbalance must be higher for more
basic nucleophiles and this is the most probable reason of the described above inconsistency in the values
of pKao and actual pKa values for oximate nucleophiles. Going in details of this aspect is beyond the scope
of this study however.
As is evident from Table 2 and Fig. 5, the coordination of oximate ligands to Zn(II) or Cd(II)
cations enhances their esterase reactivity by one to three orders of magnitude. The behavior of Zn(II)
complexes is complicated by concomitant deprotonation of coordinated water molecules. It occurs both
before and after deprotonation of the oxime group and when the oximate complex undergoes subsequent
water deprotonation ([Zn(HL1)]2+ to [Zn(HL1)(OH-)]+ and [Zn(L4-)(OH-)] to [Zn(L4)(OH)2]-) the
appearance of an additional hydroxo ligand enhances the reactivity by up to one order of magnitude. It is
impossible to estimate the effect of the hydroxo ligand which already is present in the complex before
deprotonation of the oxime group, but probably it also induces an increased reactivity. In favor of this
speaks the fact that complexes [Zn(L3-)(OH-)] and [Zn(L4-)(OH-)] are significantly more reactive than
those lacking the hydroxo ligand [Zn(L1-)]+ and [Zn(L2-)]+. Similar effect was observed in esterolytic
reactivity of a dizinc complex with an alcohol-pendant macrocycle36 and it was attributed to a weakening
of the metal-alkoxide bond and making the coordinated alkoxide a stronger base and a stronger
nucleophile. Similar explanation can be valid also in our case. To prove that increased basicity enhances
the reactivity of coordinated oximates, we analyzed the kNu values for oximate complexes of both metals in
which the hydroxo ligand is absent as a function of pKa of the oxime group, Fig. 7. Evidently the reactivity
grows linearly with the basicity for all ligands besides L3 with both the most and the least reactive esters
5a and 5i. It follows from Fig. 7 that the structural variations in ligands L1, L2 and L4 affect the reactivity
of their metal complexes mostly by changing basicity of coordinated oximate. The presence of an
additional amino group in L3 has a negative effect indicating the necessity of a sufficient number of free
coordination sites for high reactivity.
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4.5
4.0
3.5
3.0
2.5
5a
5i
L4
L1
L3
L1
L2
L2
7.0
7.5
8.0
8.5
9.0
9.5
10.0
10.5
pKa ML
Fig. 7. Brønsted plots (logkNu vs pKa ML) for the cleavage of 5a and 5i by [Cd(L-)]+ (blue symbols) and
[Zn(L-)]+ without hydroxo ligand (red symbols).
The Brønsted plots for metal complexes have much more pronounced curvature than those for free
ligands (Fig. 5). The fitting of these plots to equation (4), illustrated with results for the complex [Cd(L1)]+
in Fig. 8A, gives very small 1 values, close to zero in limits of uncertainty; 2 values are in the range from
-1.0 to -1.5, and pKao are in the range 9.1-9.7. The pKa values of coordinated oximes are much lower than
those of free ligands and are within the range of pKa of conjugated acids of the leaving groups. Therefore
the change in r.d.s. seems more reasonable in this case. Using the procedure described in Ref. 34 we
calculated from plots of the type shown in Fig. 8a the individual values of k1 and k2/k-1 for each ester and
for all complexes. An example of the plots of logk1 and log(k2/k-1) vs leaving group pKa for [Cd(L1-)]+ is
shown in Fig. 8b. Similar plots were obtained for other complexes. In all cases the ratio k2/k-1 logically
decreases for more basic leaving groups due to an increase in the activation barrier for the departure of the
leaving group, but the k1 is completely independent of the leaving group basicity in agreement with very
small 1 value. This means that the energetically unfavorable repulsion of the negative charge on the
carbonyl group of the substrate developed during the nucleophilic attack (see Scheme 2) by progressively
more basic leaving groups, which should give 1 about -0.4, is compensated by a favorable interaction with
an electrophilic center, apparently the coordinated metal ion. Thus, the transition state of the nucleophilic
attack by the metal complex can be represented schematically by the structure 12. This electrophilic
assistance to the nucleophilic attack by the oximate obviously contributes to the overall “activation” of
oximate making it more reactive than the free anion.
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a
5
4
b
4.4
4.2
4.0
3.8
3.6
3.4
3.2
logk1
3
2
1
log(k2/k-1)
0
-1
-2
7.0
7.5
8.0
8.5
9.0
pKa
9.5
10.0
10.5
7.0
7.5
8.0
8.5
9.0
pKa
9.5
10.0 10.5
Fig. 8. (a) Brønsted plot (log kNu vs pKa) for the cleavage of 5a-i by [Cd(L1-)]+ and its fitting to equation
(4). (b) Plot of log k1 and log (k2/k-1) vs leaving group pKa showing the kinetic contributions to log kNu.
-
OR
O
N
R'
2+
M
O
-
OR
O
R'
2+
M
OR"
12
13
To place this effect in a more general context let us compare the Brønsted plots for the cleavage of
5a (NPA) (the only substrate for which extensive data are available in the literature) by free (Ox-) and
metal-bound (M(Ox)) oximates including all present and majority of previously reported relevant results,
Fig. 9. The points for mixed oximato-hydroxo complexes of [Zn(L1-)(OH-)] and [Zn(L4-)(OH-)2]-, in which
water deprotonation occurs after oxime deprotonation (green circles), are placed at pKa 8.40 and 10.5
corresponding to water deprotonation in order to reflect the fact that the real basicity of oximate groups in
these species should be higher than that corresponding to their respective pKa 7.90 and 8.17 determined in
the absence of hydroxo ligands.
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5
4
M(Ox)
3
RO-
Ox-
2
1
M(OH)
0
Zn2(OR)
Zn(OR)
-1
-2
-3
3
4
5
6
7
8
9
10 11 12 13 14
pKa (Nu)
Fig. 9. Brønsted plots for the cleavage of 5a (NPA) by free oximates Ox- (black open circles),12a substituted
phenolates and alkoxides RO- (black open squares),12a metal hydroxo complexes M(OH) (black solid
squares),11,12a,37 zinc alkoxide complexes Zn(OR) (purple solid squares),38 Zn2(OR) (orange solid
squares).36 Metal-oximate complexes M(Ox): taken from literature (gray circles),18,20 zinc and cadmium
complexes of L1-L4 (red and blue circles respectively), [Zn(L1-)(OH-)] and [Zn(L4-)(OH)2]- (green
circles) this work
It seems that the profile for M(Ox) tends to level-off at kNu between 104 - 105 M-1s-1 for highly basic
complexes as it is observed for free oximates at kNu about 102 M-1s-1 (cf. solid and open circles). However,
this fact needs to be clarified in the future because of uncertainty in pKa of oxime groups in mixed hydroxo
complexes and possible inhibitory effect of the amino group in the complexes [M(L3-)]. Independently of
this, it is clear that the effect of metal coordination on the oximate reactivity is significantly smaller for
oximes with pKa values below 8 than for more basic oximates which suffer from solvational imbalance
effect. We believe that for low basic oximates the activation effect by metal cations consists only in the
stabilization of the transition state illustrated in the structure 12, but for highly basic oximates the metal
cation additionally plays its role inducing a change in solvation of the coordinated group removing the
solvational imbalance effect.
An interesting point is whether metal oximate complexes demonstrate the alpha-effect. For free
oximates the alpha-effect is evident as a positive deviation of their reactivity from the Brønsted plot of
logkNu vs. pKa for a series of related normal nucleophiles, i.e. RO- anions: see Fig. 9, open squares (RO-)
vs. open circles (Ox-). For the respective comparison in the case of coordinated oximates one needs to
construct the Brønsted plot for coordinated RO- anions. Respective data are scarce and cover only a narrow
range of pKa. Available results for Zn(II) complexes are shown in Fig. 9 as purple squares for mononuclear
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and orange squares for dinuclear complexes. Results for more extensively studied metal hydroxo
complexes are shown as black squares. Evidently the reactivity of coordinated hydroxide and alkoxide
anions is very close and is only slightly above the reactivity of free alkoxide anions. The small activation
effect of metal ions for alkoxide and hydroxide anions may be attributed to an inefficient transition state
stabilization in strained four-membered cycle 13. It is worth noting that the activation effect is higher in
binuclear complexes (orange squares) where the electrophilic assistance can be provided by a second metal
ion without necessity of formation of a strained cyclic structure. Thus one may conclude that coordinated
oximates indeed demonstrate large alpha-effect in comparison with coordinated alkoxide or hydroxide
anions and the nature of this effect is reminiscent of that established for hydrazine or hydroxylamine
nucleophiles consisting in stabilization of a five-membered cyclic transition state by electrophilic
assistance from NH group.39
Turnover numbers.
An important characteristic of the L1-L4 oximate metal complexes is that they operate in a catalytic mode,
which means the acylated nucleophile is regenerated to reenter the catalytic cycle, Scheme 1. The turnover
numbers (TON) of cleavage of esters 5a-5i by zinc(II) and cadmium(II) complexes of L1-L4 were
measured with a 100-fold substrate excess over the oximate ligand as the maximum number of equivalents
of the product released per one mole of the catalyst until it stops working.40 Kinetic curves for the cleavage
of 1 mM 4-MeO phenyl acetate (5i) by 0.01 mM L1-L4 in the presence of 0.01 mM zinc(II) perchlorate at
pH 9 used for estimation of TON are shown in Fig. 10 (results at various pH are shown in ESI figures 13S-
21S).
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100
80
Zn(L3)
Zn(L4)
60
40
20
Zn(L1)
Zn(L2)
8
6
4
2
0
0
200
400
600
800
1000
t, s
Fig. 10. Equivalents of 4-MeO-phenol released during the cleavage of 5i (1 mM) in the presence of
equimolar mixtures of zinc(II) perchlorate and ligands L1-L4 (0.01 mM) in buffered aqueous solutions at
25°C. Continue curves are the fittings to the integral first order kinetics.
The highest TON of 97 corresponding to practically complete conversion of the substrate is
observed with Zn(L3), the complex possessing the highest stability. Lower, but still large TON of 65 is
observed with Zn(L4), but complexes Zn(L1) and Zn(L2) have low TON values between 7 and 9. The
incomplete hydrolysis of the ester obviously reflexes the catalyst degradation during the catalytic cycles,
which occurs rather rapidly in just 5 min for Zn(L1) and Zn(L2). We did not observe however any
degradation of these complexes in titration experiments for much longer periods of time. A possible
explanation of instability of these complexes in the presence of the large excess of a substrate is a strongly
reduced stability of the complex with O-acylated ligand losing the negative charge on the oxime group. As
a result, the acylation induces the complex dissociation and free Zn2+ cation suffers irreversible
transformation into a polymeric hydroxide.41 In line with this explanation, the highest TON is observed
with tetradentate L3, which forms the most stable complex with Zn(II).
Kinetics of the Cleavage of Phosphate Triesters.
In general, phosphate triesters are more resistant to alkaline hydrolysis in water than phenyl acetates, unless
they are activated by strong electron accepting groups. Previously, we reported the catalytic effect of
zinc(II) and cadmium(II) complexes of L4, [Zn(L4)(OH)] and [Cd(L4)], in the hydrolysis of
environmentally important triesters paraoxon, parathion and a model substrate NPDPP.21 The second order
rate constants for the cleavage of these substrates by the oximate anions of L1-L4 as well as their zinc(II)
and cadmium(II) complexes are shown in Table 3. All rate constants for individual species were calculated
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from the pH-rate profiles in combination with species distribution diagrams in the same way as described
above for phenyl acetates 5a-5i.
a
Table 3. Second-Order Rate Constants (k M-1s-1) and Rate Enhancements kML/kL for the Cleavage of
Triester Phosphates by Zinc(II) and Cadmium(II) complexes of L1-L4b. The number in parentheses is the
standard error in the last significant digit
Specie
Paraoxonc
k (M-1 s-1) kML/kL
0.008(2)
Parathionc
NPDPPd
k (M-1 s-1)
kML/kL
k (M-1 s-1)
kML/kL
OH-
L1-
0.000250(3)
0.0017(2)
0.89(1)
0.22(2)
0.31(3)
28(1)
0.025(2)
[Cd(L1-)]+
[Zn(L1)]+
[Zn(L1-)(OH-)]
L2-
[Cd(L2-)]+
[Zn(L2-)]+
L3-
[Cd(L3-)]+
[Zn(L3-)(OH-)]
L4-
[Cd(L4-)]+
[Zn(L4-)(OH-)]
0.64(1)
0.35(3)
0.45(2)
0.026(1)
1.62(3)
0.43(1)
0.032(3)
1.51(3)
1.44(1)
0.028(1)
1.4(1)
26
14
18
524
28
90
0.047(2)
0.062(1)
0.0018(2)
0.93(1)
46(3)
145
220
36
68(2)
0.33(1)
25(1)
62
17
517
39
76
0.071(1)
0.0023(2)
1.02(1)
92(1)
280
0.40(2)
26(0.5)
84(1)
47
45
443
110
65
0.253(1)
0.0019(2)
0.95(2)
210
0.35(3)
22(1)
50
4
500
25
63
50
0.11(2)
0.048(3)
0.13(1)
18(2)
[Zn(L4-)(OH-)2]- 0.4(1)
14
67
120(10)
340
a Rate enhancements refer to the ratio of second-order constants of metal oximates and free oximates L1-
L4. bkOH values and data for L4 and their zinc(II) and cadmium(II) complexes were taken from Ref. 23.
d
cSolutions for kinetic measurements contained 2% acetonitrile v/v in water. Solutions for kinetic
measurements contained 4% of 1,4-dioxane v/v in water.
The oximolysis of phosphate triesters also displays a non-linear Brønsted plot of logkNu vs. pKa of
the nucleophile with leveling-off at large pKa values attributed to solvational imbalance.42 In particular for
paraoxon, kNu becomes independent of the basicity of the oxime when pKa surpasses 8 with a limiting value
about 0.01 M-1s-1 at 25oC.43 Thus, the oxime ligands L1-L4 belong to the group of nucleophiles with
limiting reactivity. They have about 4-fold and 8-fold enhanced reactivity as compared with hydroxide ion
for paraoxon and parathion respectively, Table 3. The existence of the alpha-effect for free ligands can be
deduced from their ca. 80 times higher reactivity in comparison with phenolate anions of similar basicity.44
The coordination of L1-L4 with Zn(II) and Cd(II) further enhances kNu by 10 – 500 times and a part of this
effect should be due to removal of solvational imbalance. However, the metal selectivity of the
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enhancement effects for paraoxon and parathion indicates that the principal role of the metal ion should be
the transition state stabilization analogous to 12.
Figure 11 shows the rate enhancement induced by the metal coordination (kML/kL) for paraoxon and
parathion as a function of pKa of the complex. One can see that in contrast to acetates as substrates, the
reactivity of the complexes with phosphate esters is independent of their basicity (cf. Fig. 7 and Fig. 11). In
general, Cd(II) produces a slightly larger acceleration effect with paraoxon than Zn(II), but with parathion
the effect of Cd(II) is much higher than that of Zn(II), and for both cations the effect with parathion is
larger than with paraoxon.
600
500
Parathion
400
Cd(L)
Zn(L)
300
200
100
0
Parathion
Paraoxon
Paraoxon
7.5
7.0
8.0
8.5
8.0
8.5
9.0
9.5 10.0 10.5
pKa
pKa
Fig. 11 Catalytic effects kML/kL for the cleavage of paraoxon (6) and parathion (7) as a function of the pKa
of the zinc and cadmium oximate complexes.
These tendencies correlate very well with stabilities of Zn(II) and Cd(II) complexes with methyl
phosphate and methyl thiophosphate,45 which could be considered as crude transition state models for the
hydrolytic reactions.46,47 Chart 1 shows the reported stability constants together with postulated transition
state structures and observed enhancement effects, which demonstrate clear parallels between equilibrium
and rate data and the feasibility of the cyclic transition state for metal promoted reactions.
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O
P
O
P
S
-
-
O
O
Me
O
O
Me
-
-
O
Zn2+
Cd2+
logKa) =
logKa) =
2.22
2.52
2.34
4.50
EtO
EtO
OEt
OEt
O
P
O
O
P
S
O
NO2
NO2
N
N
-
-
O
2+
2+
M
M
Zn2+
Cd2+
kML/kL =
kML/kL =
4 - 45
26 - 62
25 - 110
440 – 520
a) Logarithms of stability constants from reference 45.
Chart 1
The behavior of NPDPP should be similar to that of paraoxon besides the higher total reactivity of
NPDPP due to the presence of electron accepting phenyl groups. We observe with this substrate similar
enhancement effect of Cd(II) in the range of 60-90 times as in case of paraoxon, but significantly improved
efficiency of Zn(II) which induces the enhancement effects in the range 50-300 times (Table 3).
Determination of TON for paraoxon cleavage gave the value about unity with all complexes
demonstrating that in contrast to the cleavage of ester substrates it is not catalytic. This is not surprising
because the chemical transformation of O-phosphorylated oximes is a complex process sometimes
accompanied by degradation of the oxime molecule and the catalytic mode of paraoxon cleavage is rarely
observed with oximates.48 At the same time, as stoichiometric cleavage agents complexes of L1-L4 are
among the most effective detoxificants. For instance, the less basic [Zn(L2-)]+ complex cleaves paraoxon at
pH 8 and 25oC with the second-order observed rate constant 0.37 M-1s-1, that is 100 times larger than the
rate constant reported for commercial detoxicant Dekon-139 (0.0037 M-1s-1) at pH 10.5 and 37oC.10 In an
extensive compilation of kinetic data for the paraoxon cleavage by nucleophilic reactants,48 authors cite as
the most powerful system at pH 8 the 0.02 M iodozobenzoate in the presence of 0.02 M cationic surfactant,
which reduces the paraoxon half-life to 180 s. At the same concentration and pH [Zn(L2-)]+reduces the
Paraoxon half-life to 95 s and it does not need a surfactant additive. The same iodozobenzoate system but
at pH 9 reduces the half-life of Parathion to 230 s.49 At the same concentration and pH [Cd(L2-)]+ reduces
it to 40 s.
From these comparisons it is evident that from the practical standpoint Zn(II) and Cd(II) complexes
of the oximate ligands L1-L4, which can be easily prepared from commercially available reagents,
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deserves consideration as potentially effective reactants for the remediation of paraoxon or parathion
contamination.
CONCLUSIONS
A family of oximate complexes of Zn(II) and Cd(II) with polydentate ligands bearing the oxime group in
the terminal position with general sequence of the coordination sites pyridine – aliphatic amine – oxime
shows very high cleavage activity towards aryl acetate and phosphate esters. Detailed kinetic studies of the
cleavage reactions at variable pH together with the speciation studies allowed us to identify the reactive
oximate species and to determine the second-order rate constants of the cleavage reactions for individual
species. Structural variations in the ligands such as the size of chelate cycles and total number of donor
atoms affect stability and basicity of the complexes but to a lesser degree their reactivity. The cleavage of
acetate esters proceeds as a true catalytic process with turnover numbers up to 100 but the cleavage of
phosphate esters is a stoichiometric process.
Results for para-substituted phenyl acetates were analyzed in terms of the Brønsted correlation with
the leaving group basicity. The plots of logkNu vs. pKa of the conjugated acids of leaving group anions are
non-linear indicating the change in the rate determining step from nucleophilic attack to the leaving group
expulsion on increase in the leaving group basicity in the range of pKa 9.1 - 9.7 close to pKa values of the
coordinated oximes. The dissection of the rate constants kNu into individual contributions of nucleophilic
attack (k1) and leaving group departure (k2/k-1) shows that k1 is independent of the leaving group basicity.
This can be explained by electrophilic assistance from the metal ion, which stabilizes the growing negative
charge on the carbonyl oxygen in the tetrahedral intermediate / transition state via five-membered cyclic
structure.
The cleavage of both carboxylate and phosphate esters by coordinated oximate ligands L1-L4
proceeds much faster than the cleavage of these substrates by free oximate anions. Importantly, the
reactivity of the coordinated oximates surpass by ca. two orders of magnitude the limiting reactivity of
highly basic oximates attributed to solvation imbalance effect. The removal of this effect owing to strongly
reduced pKa of the coordinated oxime group together with electrophilic transition state stabilization by the
metal ion is responsible for the outstanding reactivity of these complexes.
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EXPERIMENTAL SECTION
General Methods. Reagents employed for synthesis of ligands and reagent grade solvents were used as
purchased from Sigma Aldrich; 2,3-butanodione monoxime was recrystallized from water. Substituted
esters 4-XC6H4OAc (X = Cl, C6H5, CH(CH3)2, COOH, C(CH3)3 and OCH3) were synthesized as previously
reported22,50,51 and those containing X = H, CH3, NO2 as well as phosphate esters were purchased from
Aldrich. Non-coordinating buffers (MES, MOPS, CHES, and CAPS) were used in all kinetic
measurements in appropriate pH intervals. Solutions of Zn(ClO4)2 and Cd(ClO4)2 were standardized by
complexometric titrations using EDTA and Eriochrome black T as an indicator, and the concentrations
were later checked by atomic absorption spectroscopy. The stock solutions of metal salts and ligands were
prepared in deionized water (Barnstead nanopure distiller and deionizer) while those of substrates were
prepared in acetonitrile; pH measurements for potentiometric titrations and reaction kinetics were carried
out using a digital pH meter (Thermo Scientific Orion 4-Star Plus) connected to a ROSS Ultra 8103BN pH
glass electrode. Reactions kinetics and titrations were followed by UV spectroscopy in a spectrophotometer
Hewlett-Packard 8453 diode-array with a thermostated multicell sample compartment (±0.1 °C). The
methodology for the synthesis of the ligands L1 (3-((2-(pyridin-2-yl)ethyl)amino)butan-2-one oxime), L2
(3,3-dimethyl-4-((pyridin-2-ylmethyl)amino)pentan-2-one oxime) and L3 (3-(((6-(aminomethyl)pyridin-2-
yl)methyl)amino)butan-2-one oxime) is provided in ESI, p.S25.
Stability and acidity constants in aqueous solution
All the acid-base potentiometric titrations were performed in aqueous solutions under nitrogen and constant
ionic strength 0.1 M (NaClO4) in a thermostated glass cell at 25 °C. The initial volumes were 10.0 mL, and
in all cases, the amount of standardized HCl was added sufficient to completely protonate all basic groups
of the ligand. Potentiometric titrations by standardized NaOH were carried out in 1-10 mM range of
concentrations of either free ligands or their mixtures with Zn(II) or Cd(II) perchlorates containing a small
excess of the ligand to avoid early precipitation of metal hydroxides. All the data were analyzed by using
the HyperQuad program and the species distribution plots for each system were calculated with the Hyss
program.52
Kinetic measurements
The cleavage reactions were initialized by adding 50 L of a substrate stock solution in acetonitrile into the
UV-cuvette to get initial concentrations of substrates of 5×10-5 M and monitored spectrophotometrically by
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the increase in the absorbance at max of the corresponding 4-substituted phenol (the leaving group). Initial
volumes were always 2500 L, pH values were kept constant with 0.1 M of MES (pH 5.5-6.7), MOPS (pH
6.5-8.2), CHES (pH 8.3-10) or CAPS (pH 9.7-11.2), all solutions contained 2% vol. of acetonitrile. The
values of pH were measured before and after the kinetic run and experiments with pH changing more than
0.05 units were discarded. The observed first-order rate constants (kobs) were calculated either by the
integral method or by initial rates for slower reactions.
Crystallography
A suitable single crystal of compound (nitrato)-bis[N-(3-{[(pyridin-2-yl)methyl]amino}butan-2-
ylidene)hydroxylamine]cadmium nitrate [Cd(HL4)2(NO3)]NO3 was mounted on a glass fiber and
crystallographic data were collected with an Oxford Diffraction Gemini "A" diffractometer with a CCD
area detector with monochromator of graphite for λMoKα = 0.71073 Å. CrysAlisPro and CrysAlis RED
software packages were used for data collection and integration.53 The double pass method of scanning was
used to exclude any noise. The collected frames were integrated by using an orientation matrix determined
from the narrow frame scans. Final cell constants were determined by a global refinement; collected data
were corrected for absorbance by using analytical numeric absorption correction using a multifaceted
crystal model based on expressions upon the Laue symmetry with equivalent reflections.54 Structure
solution and refinement were carried out with the SHELXS-201455 and SHELXL-201456 packages.
WinGX v2018.357 software was used to prepare material for publication. Full-matrix least-squares
refinement was carried out by minimizing (Fo2 – Fc2)2. All non-hydrogen atoms were refined
anisotropically. H atoms of the hydroxy (O-H) and amine (N-H) groups were located in a difference map
and refined isotropically with Uiso(H) = 1.5 Ueq for H-O and Uiso(H) = 1.2 Ueq for H-N. H atoms
attached to C atoms were placed in geometrically idealized positions and refined as riding on their parent
atoms, with C–H = 0.95–1.00 Å and with Uiso(H) = 1.2Ueq(C) for aromatic, methylene and methine groups
and Uiso(H) = 1.5Ueq(C) for methyl groups.. Summary of crystallographic data are presented in Table S1X
in the Supporting Information. The crystallographic data for the structure reported in this paper has been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC
1971433. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: (+44) 1223-336-033, e-mail: deposit@ccdc.cam.ac.uk).
Hazardous materials
The following chemicals are hazardous and should be handled carefully: paraoxon and parathion.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: pao@unam.mx. Tel: +52 55 56223813. Fax: +52 5556162010.
*E-mail: iatsimirski46@comunidad.unam.mx. Tel: +52 55 56223813. Fax: +52 55 56162010.
Author’s contributions
José Carlos Lugo-González: investigation, data curation, formal analysis, writing manuscript.
Paola Gómez-Tagle: conceptualization, investigation, methodology, data curation, formal analysis, writing,
review & editing manuscript, validation, visualization, funding acquisition.
Marcos Flores-Alamo: X-ray single crystal analysis and structure elucidation of compound [Cd(H
L4)2(NO3)](NO3).
Anatoly K. Yatsimirsky: conceptualization, data curation, methodology, supervision, writing, review &
editing manuscript, funding acquisition, visualization.
CONFLICTS OF INTEREST
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from Dirección General de Asuntos del Personal Académico (DGAPA, UNAM) project
PAPIIT IN 219718 and Programa de Apoyo a la Investigación y el Posgrado (Facultad de Química,
UNAM, projects PAIP 5000-9161 and 5000-9042 is gratefully acknowledged.
J.C.L.-G thanks the National Council for Science and Technology of Mexico (CONACyT) for the
Graduate Fellowship.
REFERENCES
1
2
K. A. McCall, C. Huang and C. A. Fierke, J. Nutr., 2000, 130, 1437S-1446S.
F. Schwizer, Y. Okamoto, T. Heinisch, Y. Gu, M. M. Pellizzoni, V. Lebrun, R. Reuter, V. Köhler, J.
C. Lewis and T. R. Ward, Chem. Rev., 2018, 118, 142–231.
3
a) V. E. Anderson, M. W. Ruszczycky and M. E. Harris, Chem. Rev., 2006, 106, 3236–3251.
b) M. Diez-Castellnou, A. Martinez and F. Mancin, in Advances in Physical Organic Chemistry,
28

Page 29 of 32
Dalton Transactions
View Article Online
DOI: 10.1039/C9DT04733F
Academic Press Inc., 2017, 51,129–186.
4
5
P. Politzer, and J.S. Rappoport, in The Chemistry of Hydroxylamines, Oximes and Hydroxamic
Acids, ed. Z. Rappoport and J.F. Liebman, Wiley & Sons, England, 1st edn, 2009, ch.1, pp. 1−29.
G. Saint-André, M. Kliachyna, S. Kodepelly, L. Louise-Leriche, E. Gillon, P. Y. Renard, F. Nachon,
R. Baati and A. Wagner, Tetrahedron, 2011, 67, 6352–6361.
6
7
D. Kiderlen, F. Worek, R. Klimmek and P. Eyer, Arch. Toxicol., 2000, 74, 27–32.
G. Mercey, T. Verdelet, J. Renou, M. Kliachyna, R. Baati, F. Nachon, L. Jean and P.-Y. Renard,
Acc. Chem. Res., 2012, 756, 756–766.
8
9
T. Wille, L. Kaltenbach, H. Thiermann and F. Worek, Chem. Biol. Interact., 2013, 206, 569–572.
Products Approved for Chemical Emergencies, FDA, https://www.fda.gov/drugs/bioterrorism-and-
drug-preparedness/products-approved-chemical-emergencies, (accessed 27 November 2019).
P. T. Wong, S. Bhattacharjee, J. Cannon, S. Tang, K. Yang, S. Bowden, V. Varnau, J. J. O’Konek
and S. K. Choi, Org. Biomol. Chem., 2019, 17, 3951–3963.
10
11
12
W. P. Jencks and M. Gilchrist, J. Am. Chem. Soc., 1968, 90, 2622–2637.
a) F. Terrier, P. MacCormack, E. Kiziliana, J. Halle, D. F. Guirc and C. Lion, J. Chem. Soc. Perkin
Trans. 2, 1991, 153–158. b) F. Terrier, E. Le Guével, A. P. Chatrousse, G. Moutiers and E. Buncel,
Chem. Commun., 2003, 600–601.
13
14
15
16
E. Buncel, C. Cannes, A. P. Chatrousse and F. Terrier, J. Am. Chem. Soc., 2002, 124, 8766–8767.
C. F. Bernasconi, Acc. Chem. Res., 1992, 25, 9–16.
D. Breslow, R.ꢀ; Chipman, J. Am. Chem. Soc., 1965, 87, 4196.
L. M. Berreau, in Activation of Small Molecules, ed. W.B. Tolman, Wiley-VCH Verlag GmbH &
Co. KGaA, Weinheim, Germany, 1st edn, 2006, ch.8, pp. 287–317.
17
18
R. C. diTargiani, S. Chang, M. H. Salter, R. D. Hancock and D. P. Goldberg, Inorg. Chem., 2003,
42, 5825–5836.
A. Yatsimirsky, P. Gomez-Tagle, S. Escalante-Tovar and L. Ruiz Ramirez, Inorganica Chim. Acta,
1998, 273, 167–174.
19
20
21
E. Y. Tirel and N. H. Williams, Chem., Eur. J., 2015, 21, 7053–7056.
F. Mancin, P. Tecilla and U. Tonellato, European J. Org. Chem., 2000, 1045–1050.
P. Gómez-Tagle, J. C. Lugo-González and A. K. Yatsimirsky, Chem. Commun., 2013, 49, 7717–
7719.
22
J. C. Lugo-González, P. Gómez-Tagle, X. Huang, J. M. del Campo and A. K. Yatsimirsky, Inorg.
Chem., 2017, 56, 2060–2069.
29