Buffer-Induced Acceleration and Inhibition in Polyoxometalate-Catalyzed Organophosphorus Ester Hydrolysis

Article abstract of DOI:10.1021/acscatal.8b00394

The Zr-containing polyoxometalates (POMs), including (Et₂NH₂)₈{[α-PW₁₁O₃₉Zr(μ-OH)(H₂O)]₂}·7H₂O (1), effectively catalyze the hydrolysis of nerve agent simulants at near-neutral pH. Analogous Zr-containing heterogeneous systems are much-studied and effective nerve-agent hydrolysis catalysts, but due to their heterogeneous nature, it is very challenging to know the exact structure of the catalytic sites during turnover and to clarify at the molecular level the elementary mechanistic processes. Here, under homogeneous conditions, hydrolysis rates of the nerve-agent simulant methyl paraoxon catalyzed by 1 are examined as a function of pH, ionic strength, catalyst, and substrate concentrations. In addition, the specific effect of three commonly used buffers is examined, revealing that acetate functions as a co-catalyst, phosphate inhibits hydrolytic activity, and 2-(N-morpholino)ethanesulfonic acid (MES) has no effect on the hydrolysis rate. Spectroscopic (³¹P nuclear magnetic resonance) and computational studies demonstrate how each of these buffers interacts with the catalyst and offer explanations of their impacts on the hydrolysis rates. The impact of the nerve-agent hydrolysis product, methyl phosphonic acid, is also examined, and it is shown to inhibit hydrolysis. These results will aid in the design of future Zr-based hydrolysis catalysts.

Full text of DOI:10.1021/acscatal.8b00394

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Article
Buffer-Induced Acceleration and Inhibition in Polyoxometalate-
Catalyzed Organophosphorus Ester Hydrolysis
Daniel Collins-Wildman, Mooeung Kim, Kevin P. Sullivan, Anna M.
Plonka, Anatoly I Frenkel, Djamaladdin G Musaev, and Craig L Hill
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 18 Jun 2018
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Buffer-Induced Acceleration and Inhibition in
Polyoxometalate-Catalyzed Organophosphorus Ester
Hydrolysis
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a
a
a
b
Daniel L. Collins-Wildman, Mooeung Kim, Kevin P. Sullivan, Anna M. Plonka, Anatoly I.
b
,a,c
,a
Frenkel, Djamaladdin G. Musaev,* Craig L. Hill*
a
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322
b
Department of Material Science and Chemical Engineering, Stony Brook University, Stony
Brook, New York 11794, United States
c
Cherry L. Emerson Center for Scientific Computation, Emory University, 1515 Dickey Drive,
Atlanta, Georgia 30322
KEYWORDS
Polyoxometalate, hydrolysis, chemical warfare agents, buffer effects, co-catalysis, inhibition.
ABSTRACT
The Zr-containing polyoxometalates (POMs), including (Et
2
NH
2
)
8
[{α-PW11O39Zr(μ-
OH)(H
2
O)} ]·7H O (1), effectively catalyze the hydrolysis of nerve agent simulants at near neutral
2
2
pH. Analogous Zr-containing heterogeneous systems, are much-studied and effective nerve agent
hydrolysis catalysts, but due to their heterogeneous nature, it is very challenging to know the exact
structure of the catalytic sites during turnover and to clarify at the molecular level the elementary
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mechanistic processes. Here, under homogeneous conditions, hydrolysis rates of the nerve agent
simulant methyl paraoxon catalyzed by 1 are examined as a function of pH, ionic strength, catalyst,
and substrate concentrations. In addition, the specific effect of three commonly used buffers is
examined revealing that acetate functions as a co-catalyst, phosphate inhibits of hydrolytic activity,
and 2-(N-morpholino)ethanesulfonic acid (MES) has no effect on the hydrolysis rate.
0
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1
Spectroscopic ( P NMR) and computational studies demonstrate how each of these buffers
interacts with the catalyst and offer explanations of their impacts on the hydrolysis rates. The
impact of the nerve agent hydrolysis product, methyl phosphonic acid, is also examined, and it is
shown to inhibit hydrolysis. These results will aid in the design of future Zr-based hydrolysis
catalysts.
INTRODUCTION
The removal of toxic organophosphorus nerve agents and pesticides remains a significant
and general goal. Ideally, this would be accomplished by materials that can either sequester or
1
-3
catalytically transform OP substances into non-toxic forms.
The primary route for
4
decomposition of OP chemical warfare agents (CWAs) is hydrolysis. While strong bases can be
used to hydrolyze and destroy large stockpiles of these nerve agents, the development of personal
protective equipment requires a material, preferably a catalytic one, that can be integrated into
2
, 5
masks and garments.
Metal oxides, metal hydroxides, and metal organic frameworks (MOFs) have been studied
3
, 6-14
extensively as potential actives for such protective equipment.
The Lewis acidic sites of these
materials coordinate the phosphoryl (P=O) oxygen of the nerve agent and activate the phosphorus
oxygen bond making it more susceptible to nucleophilic attack thereby accelerating the hydrolysis
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rate. Recent studies have further interrogated the reactions of CWAs and simulants with MOF
systems using synchrotron-based spectroscopic techniques (XANES, EXAFS, XPS, XRD,
1
5-17
Raman) along with complementary computation.
Despite the use of these advanced methods,
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the heterogeneous nature of these materials continues to generate challenges in determining the
exact mechanism of the reactions, including the nature of substrate/product interactions with the
active site.
An in-depth understanding of the mechanism and governing factors of metal-catalyzed
CWA decomposition is vital for optimizing catalyst performance. Therefore, the study of a
molecular metal-based Lewis acid catalyst, would directly complement the existing body of
research on heterogeneous hydrolysis catalysts. Techniques amenable to molecular systems, such
as solution-phase nuclear magnetic resonance (NMR), would help facilitate the elucidation of
mechanistic details of the CWA decontamination. One such compound is the zirconium
1
8
containing polyoxometalate (POM), (Et
2
2
NH )
8
[{α-PW11
O
39Zr(μ-OH)(H
2
O)}
2
]·7H O (1), which
2
19-24
is known to be an effective peptide and RNA hydrolysis catalyst.
POMs are a class of highly modifiable, molecular transition-metal oxygen-anions that can
2
5-33
function as oxidation, reduction, and hydrolysis catalysts.
They are capable of forming
34
complexes with many elements across the periodic table, and can act as ligands for the strongly
18, 35-37
38
Lewis acidic metal ions including Zr(IV)
and Ce(IV). Over the last decade, Parac-Vogt
and coworkers have studied the POM-catalyzed hydrolysis of a number of compounds including
39-44
polypeptides and organophosphate RNA analogues.
They have demonstrated that Lewis acidic
metal centers, including Zr(IV), activate phosphorus-oxygen bonds and enhance the rate of
4
1
phosphate hydrolysis. In addition, they have thoroughly examined several factors that affect the
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hydrolysis of organophosphorus compounds including ionic strength, pH, temperature, and
1
9-21, 41-42, 45-47
catalyst concentration.
Given that most nerve agent hydrolysis products, such as methylphosphonic acid (MPA),
are acidic, and that hydrolysis is an inherently pH-dependent process, it is vital to have a buffer to
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, 48-49
maintain constant pH.
Furthermore, an analysis of the existing literature shows that the
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impact of buffers on the reaction outcome can be significant.
Herein, we report the considerable
and diverse impact of common buffers on hydrolysis of the OP ester nerve agent simulant, methyl-
paraoxon or O,O-dimethyl O-(4-nitrophenyl) phosphate (DMNP) catalyzed by the Zr-POM, 1,
(
Scheme 1) and suggest a possible mechanism for the observed effects. This compound, 1, was
chosen as its speciation in solution has been well characterized and it is one of the most active Zr-
substituted POM hydrolysis catalysts. We report the specific effects of different buffer anions on
Lewis acid-catalyzed OP ester hydrolysis while carefully controlling the pH, ionic strength,
catalyst concentration, and substrate concentration. Together these results mark significant
progress toward a full mechanistic understanding of homogeneous CWA hydrolysis by
electrophilic zirconium centers and serve as insightful homogeneous models for heterogeneous Zr-
based catalysts.
O
P
O
P
1
+
+
O
O
NO2 H O
O
OH HO
NO2
2
O
O
Scheme 1. The hydrolysis of O,O-dimethyl O-(4-nitrophenyl) phosphate (DMNP) in the presence
of the POM catalyst 1.
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EXPERIMENTAL SECTION
Synthesis and Materials
The Zr-containing POM, (Et
2
NH
2
)
10[Zr(α-PW11
O
39
)
2
]·7H
2
O (2), was prepared by reacting
CO solution, followed by
Cl as described in published procedures (detailed
1
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3−
a 2:1 molar ratio of [α-PW12
O40] with ZrCl
2
O·8H
NH
procedure described in the Supporting Information). Similarly, (Et
OH)(H O)} ]·7H O (1) was prepared by reacting a 1:1 molar ratio of the in situ-generated 2 with
ZrCl O in an aqueous HCl solution, followed by the addition of excess amounts of solid
Et NH
2
O in an aqueous Na
2
3
the addition of excess amounts of solid Et
2
2
3
5
2
NH ) [{α-PW11O39Zr(μ-
2
8
2
2
2
2
O·8H
2
1
8-19
2
2
Cl as described in the literature.
The monolacunary phosphotungstate, K [α-
7
PW11
O
39]·14H O, was prepared via a modified version of literature procedures (detailed procedure
2
5
3-54
described in the Supporting Information).
All chemicals were of commercial quality unless
otherwise specified.
Buffers were made by dissolving the desired concentration of acid in water, followed by
adjustment to the desired pH by concentrated sodium hydroxide. This was done using volumetric
glassware conducting the pH adjustment with most of the desired volume present before filling to
the mark once the desired pH was reached. All pH measurements were done using an Orion 230A
pH meter.
Characterization
Fourier transform infrared spectra (FTIR) spectra were collected on a Nicolet 6700 FT-IR
spectrometer for samples 1 and 2 (Figures S1, S2). Samples were prepared as KBr pellets using
3
1
FTIR-grade KBr and 1-2 % sample by weight. P NMR spectra of 1 and 2 were collected on a
Bruker 600 (Figures S3, S4). Instead of running experiments in a deuterated solvent such as D
2
O,
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NMR tube inserts filled with D
2
O were added to each tube to maintain the lock throughout data
acquisition and allow the pH of the solution to be precisely controlled. For speciation studies,
POMs were dissolved, pH adjusted, and then immediately taken to the NMR instrument for
characterization. For each spectrum, 1024 scans were taken with a delay time of 2s. Determination
of phase purity of solid samples of 1 was done using powder X-ray diffraction. The data were
collected using a Rigaku Ultima-IV diffractometer equipped with Cu Kα radiation within a range
of 5° ≤ 2θ ≤ 40° (scanning rate: 1°/min). The unit cell parameters of ZrPOM were refined with
LeBail fitting using the Jana2006 software, where peak shapes were refined with pseudo-Voigt
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function and peak asymmetry corrected with a Simpson function (Figure S7, Table S1). The
background was modeled manually using 50 points.
Hydrolysis Studies
The pK
a
of p-nitrophenol is 6.7, and when deprotonated it exhibits a strong absorption
-1
-1
band at 401 nm with an extinction coefficient of 18,390 M ·cm ; in contrast, the protonated form
5
6
is colorless. Product formation during DMNP hydrolysis was therefore followed by measuring
the strong absorption band of the hydrolysis product p-nitrophenolate on an Agilent 8453 UV-
visible spectrophotometer. The initial rates were then determined from the slope of p-
nitrophenolate formation vs. time. Given that the reactions were conducted at pH values well
below the pK
mL of pH 10, 0.45 M sodium borate buffer (greater detail in Supporting Information). This gave
an appropriate concentration for absorption measurements and ensured the product p-nitrophenol
a
of p-nitrophenol, small aliquots of the reaction solution were diluted by addition of
3
was well above its pK
a
, yielding quantitative results. Full reaction conversion was confirmed by
3
1
P NMR (Figure S8).
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For all hydrolysis experiments, separate solutions of POM and DMNP were prepared and
then combined to start the reaction. Reported concentrations are based on the combined volume
of the two starting solutions. DMNP solutions were prepared at least 20 min prior to the start of
the reaction because DMNP does not dissolve immediately in aqueous solution. During this time,
negligible hydrolysis occurs as seen in the control reaction (Figure 1). The pH was adjusted after
the dissolution of the POM but before the addition of DMNP to the solution, preventing product
formation during pH adjustment. The timer was started upon addition of DMNP. The pH was
measured again after the last absorption measurement was taken.
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RESULTS AND DISCUSSION
Extensive studies by Parac-Vogt and co-workers on RNA analogue hydrolysis catalyzed
by 1, established that there is a complex set of equilibria that govern the speciation of 1 in solution.
This speciation is influenced by temperature, pH, ionic strength, catalyst concentration, and
19-24
substrate concentration.
At high temperature, ionic strength, catalyst and substrate
concentrations, 1 converts to 2 (Scheme 2 eq. (1)). In a second equilibrium process, 1 hydrolyzes
4
−
to form two equivalents of the monomeric form [α-PW11
2)).
O
39Zr(OH)(H
2
O)
2
] (3) (Scheme 2 eq.
(
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Scheme 2. Speciation of 1: 1) loss of bridging hydroxides and one zirconium center to form the
8
-coordinate complex, 2. 2) hydrolysis of 1 to form 3. This process is favorable at lower pH.
WO , grey octahedra; PO , purple tetrahedra; Zr, green; O, red.
6
4
3
1
The pH dependence of this reaction can be monitored by P NMR (Figure 1). Under acidic
conditions a single resonance is observed at -13.06 ppm while at pH 7 there is a distinct chemical
shift further downfield (-12.90). At pH 8 the POMs become unstable, and compounds 1, 2 and 3
decompose. At middle pH values (4-6), there are broadened peaks between these two resonances
5
7
consistent with rates for equilibration that are comparable to the NMR timescale. Previous
diffusion-ordered spectroscopy (DOSY) NMR studies confirmed the existence of 3 below pH 4
2
2
and assigned 1 to the peak further downfield. Given that 3 has multiple aqua ligands and is less
sterically encumbered, it is expected to be more active than 1. Compound 2 is coordinatively
2
4
saturated, and it is therefore completely inactive. Herein, knowledge of this speciation is used to
inform experimental design. When 1 is used for subsequent experiments, the majority of which
are at pH 4.8, it is assumed that the more active form, 3, is both present and responsible for the
majority of the catalytic activity. For pH values where both 1 and 3 are present in solution, only
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one broadened peak at ~-13 ppm is observed preventing quantification of the relative amounts of
both species. Thus for simplicity, apart from Figure 1 where the speciation is specifically
3
1
examined, the P NMR resonance at ~-13 ppm is labeled as the more catalytically active species,
1
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Figure 1. P NMR of 2.5 mM 1 at varying pH values in deionized water. At pH 8 the lack of
peaks for both 1 and 2 indicates they are unstable at this pH and have decomposed into other
complexes not identified here. Solutions were pH adjusted with NaOH or HClO
4
(600 MHz NMR,
internal standard). Polyhedral representations 1 and 2 are based on known
while 3 is a cartoon of the likely structure present in solution.
1
024 scans, 85% H
3
PO
4
1
8, 35
crystal structures,
The activity of 1 was established by measuring the rate of hydrolysis of DMNP as a
function of the concentration of 1 (Figure S9). The initial rates are close to linearly proportional
to the starting concentration of 1 indicating the reaction is first order in 1. Any deviation likely
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results from the formation of 2 at higher concentrations of 1. Additionally, the acetic acid/acetate
buffered solution containing 6 mM of 1 hydrolyzes DMNP 96 times faster than the control (no
catalyst in this buffer), indicating that 1, as expected, is a DMNP hydrolysis catalyst. Full catalytic
conversion of four equivalents of DMNP is achieved at pH 4.8 using a 0.5 M acetic acid/acetate
buffer (Figure 2). Unbuffered control reactions show that equivalent concentrations of aqueous
zirconium exhibit some activity, although substantially less than 1, while, the mono-lacunary
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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0
1
2
3
4
5
6
7
8
9
0
Keggin, K
7
[α-PW11
O
39]·14H
2
O, and counter cation, Et
2
NH , both independently evaluated, show
2
negligible activity above the baseline hydrolysis rate (Table 1). Varying the concentration of
DMNP also shows that the hydrolysis is first order in this substrate (Figure S9).
1
2
0
8
6
4
2
0
0.5 M Acetate
M Acetate
Control
0
1
0
20
40
60
80
100
120
Time (hours)
Figure 2. Product formation as a function of time for the full conversion of 10.3 mM DMNP.
Conditions: pH 4.8, 10.3 mM DMNP, 2.5 mM 1 in the case of blue and black curves and 0 mM in
1
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the case of the red no-catalyst curve. An ionic strength was maintained at 0.3 M with 0.5 M acetic
acid/acetate buffer (blue), or 0.3 M NaClO4 (black, red), pH adjusted with NaOH.
Table 1. Initial rates of unbuffered hydrolysis of 10.3 mM DMNP at pH 4.8 with no additional
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
1
2
3
4
5
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7
8
9
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
electrolyte added, pH adjusted with HClO or NaOH.
4
Conditions
Initial Rate (nM/s)
2
.5 mM 1
286
0.54
15
DI water only
2
5
.5 mM 2
mM K
7
[α-PW11
O39]·14H
2
O
1.2
20 mM Et
2
NH
2
Cl
1.8
5
mM ZrOCl
2
119
Previous studies of organophosphate RNA analogue hydrolysis catalyzed by 1 have shown
1
9-21
an initial rate dependence on the pH of the solution.
This pH dependence is particularly
important because the hydrolysis product of DMNP, and nerve agent hydrolysis products more
broadly, are acidic. The solution pH drops in conjunction with reaction conversion, and the effect
is more pronounced in non-buffered media near neutral pH. To test this dependence, the initial
rates of DMNP hydrolysis were assessed over a range of pH values from 3 to 7 (Figure 3). This
study was done without the use of a buffer because no buffer can operate over such a broad range.
For measurements of the initial rate, the pH drop from generation of acidic product is minimal.
Figure 3 shows that the initial rate maximizes at around pH 5, hence further studies were
conducted in this pH range. The decrease in rate at lower pH values can be attributed to the lack
of a terminal hydroxide ligand on the zirconium center. Previous studies have shown that at lower
4
−
pH, the predicted monomeric structure [α-PW11
O
39Zr(OH)(H
2
O) ] becomes protonated, leaving
2
22
only aqua ligands on the zirconium atom. Because hydroxide is a better nucleophile, the reaction
3
will proceed slower with water under the proposed mechanism for a single site catalyst. At higher
1
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pH, the rate very likely decreases due to formation of the dimeric species, 1, in solution, which
2
2
also lacks a terminal hydroxide ligand and is more sterically hindered.
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1
0
.5
2
.5
1
.5
0
2
3
4
5
6
7
8
pH
Figure 3. Initial rate dependence of DMNP hydrolysis on pH. Conditions: 2.5 mM 1, 10.3 mM DMNP,
pH adjusted with HClO or NaOH.
4
Based on the pH dependence shown above and acidic nature of the hydrolysis product of
DMNP, acetic acid/acetate at pH 4.8 was used to buffer many reactions in this study. Acetic acid
has a pK of 4.76 which matches the pH window where 1 has the highest activity. While buffering
a
the solution is not essential for initial rate measurements, using a properly buffered solution allows
a single system to be studied both at early times and under high turnover conditions.
58
A 0.5 M solution of acetate buffer at pH 4.8 has a calculated ionic strength of 0.3 M.
Before examining catalysis under buffered conditions, the effect of ionic strength was also
evaluated using sodium perchlorate, which does not interact with the POM. While maintaining a
constant pH, increasing the concentration of NaClO decreases the rate of catalytic hydrolysis
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(
Figure 4). There are multiple explanations for this observed slowing of the reaction: first, high
ionic strength favors the formation of the inactive species 2; second, there will be a decreased
interaction between the partial negative charge on the oxygen of DMNP and the Zr(IV) center in
1
1
1
1
1
1
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2
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2
3
4
5
6
7
8
9
0
3
; and third, the increased ionic strength appears to shift the monomer/dimer equilibrium in favor
31
of the dimer, 1, as indicated by the downfield shift of the P NMR peak at ~-13 ppm with
increasing ionic strength (Figure S10). The NMR spectra also show that as the concentration of
NaClO
4
increases from 0 to 0.3 M, the percentage of 2 increases from 12% at 0 M NaClO
4
to 20%
at 0.3 M NaClO
4
, which represents an 8% decrease in the active species. Interestingly however,
-4
-4
-1
the initial rates drop from 2.9 x 10 to 1.0 x 10 M*s , which represents a 64% rate decrease. This
indicates that formation of 2 is not the sole cause of this rate loss. Instead, the weakened attractive
force between the Zr-active site and DMNP or changes to the monomer/dimer equilibrium
contribute to the rate decrease.
1
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.5
1
0
.5
0
0
0.1
0.2
0.3
0.4
0.5
0.6
Ionic Strength (M)
Figure 4. Initial rate dependence of DMNP hydrolysis on ionic strength. Higher ionic strength
lowers the coulombic attraction between the Zr(IV) center and partial negative on the phosphoryl
oxygen resulting in lower reactivity. Conditions: Varied [NaClO
4
], 2.5 mM 1, 10.3 mM DMNP,
pH 4.8, pH adjusted with NaOH.
To account for effect of ionic strength, buffered and unbuffered catalytic reactions were
compared while maintaining a constant ionic strength by adding the appropriate amount of
NaClO . After 115 hours, when the 0.5 M acetate buffered solution had reached 99% conversion
4
of DMNP, the pH was recorded (Figure S11). As expected, the solution with the highest buffer
concentration showed almost no change in pH, while the unbuffered solution dropped appreciably
from pH 4.86 to 2.80. Significantly, however, the initial rates were not equal, with the initial rate
increasing as a function of buffer concentration (Figure 5). To understand this phenomenon
further, the impact of varying concentrations of acetate buffer in the reactions catalyzed by 1 was
3
1
examined by P NMR.
1
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1.6
1.4
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1.2
1
0.8
0.6
0.4
0.2
0
0
0.1
0.2
0.3
0.4
0.5
[
Acetate] (M)
Figure 5. Initial rate dependence of DMNP hydrolysis on acetic acid/acetate buffer concentration.
Conditions: buffer and NaClO concentration varied; ionic strength, 0.3 M (combined effect of
4
acetate and perchlorate ions), 2.5 mM 1, 10.3 mM DMNP, pH 4.8, pH adjusted with NaOH.
31
The P NMR spectra of 1 show a clear dependence on the acetate buffer concentration
present in the solution (Figure 6). As the concentration of acetate increases, a new peak grows in
upfield of the original peak at -13.0 ppm, and the original peak begins to diminish. Both peaks
shift upfield concomitant with the increase in acetate concentration. The new peak eventually
moves to -13.5 ppm. The formation of this peak is consistent with an acetate ion coordinating to
the POM, either by displacing an aqua ligand coordinated to the Zr(IV) center creating a new Zr-
acetate species or via hydrogen bonding with one of the zirconium bound water molecules.
1
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9
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3
1
Figure 6. P NMR spectra of 2.5 mM 1 at pH 4.8 with varying concentrations of acetate buffer.
Solutions were pH adjusted with NaOH and maintained at an ionic strength of 0.3 M with NaClO
600 MHz NMR, 1024 scans, 85% H PO internal standard). Polyhedral representation 2 is based
4
(
3
4
35
on a known crystal structure while 3 and 4 are cartoons of the likely structures present in solution.
Two additional lines of evidence indicate that there is coordination between the POM and
31
acetate. First, temperature dependent P NMR spectra were collected in 0.2 M acetic acid/acetate
where both peaks are present in similar quantities (Figure 7). At elevated temperatures the two
peaks coalesce into a single peak indicative of a dynamic exchange process occurring at an
57
intermediate rate relative to the NMR timescale. Upon lowering the temperature the two peaks
return to their original positions, demonstrating that the reversible change results from a dynamic
equilibria rather than a physical change to the material. Second, POM-acetate coordination is
13
further supported by changes to the C NMR spectrum of an acetic acid/acetate buffer solution in
1
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presence of 1 (Figure S12). The carboxylic acid carbon resonance observed at 178.52 in the
absence of 1 shifts downfield to 178.64 and broadens from 1.8 to 5.4 Hz, again consistent with a
dynamic exchange process. In contrast, the methyl carbon does not shift or broaden appreciably
indicating the POM interaction is through the carboxylic acid group.
1
1
1
1
1
1
1
1
1
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2
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5
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6
0
1
2
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5
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7
8
9
0
1
2
3
4
5
6
7
8
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0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
31
Figure 7. P NMR spectra of a single solution of 2.5 mM 1 in 0.2 M acetic acid/acetate buffer at
different temperatures (600 MHz NMR, 1024 scans, 85% H
3
PO internal standard). Spectra are
4
presented in chronological order going from top to bottom. Note the increase in 2 in the last
spectrum resulting from prolonged exposure to elevated temperatures used in the previous
3
5
experiment. Polyhedral representation 2 is based on a known crystal structure while 3 and 4 are
cartoons of the likely structures present in solution.
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In contrast to the NMR resonances corresponding to 3, the peaks at -14 ppm associated
with catalytically-inactive 2 do not shift as a function of acetate concentration. With eight bonds,
the Zr center in 2 is coordinatively saturated leaving no open site for binding of an acetate ligand,
nor does it have aqua ligands to facilitate hydrogen bonding. Accordingly, there is no chemical
shift associated with increasing acetate concentration. To assess catalyst stability in the presence
0
1
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1
2
3
4
5
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1
2
3
4
5
6
7
8
9
0
3
1
of acetate, P NMR spectra were taken of samples aged in acetate buffer both with and without
substrate (Figure S13). After two weeks, additional 2 forms, however, 3 remains the predominant
species. In both the presence and absence of DMNP, 3 shows a similar decrease in concentration,
suggesting that of the presence of DMNP does not affect the speciation or stability of 3
appreciably.
Based on the interactions between the buffer anion and POM, the observed dependence on
the buffer concentration is more easily interpreted. This effect can be attributed to the acetate
5
9
anion acting as a proximal base making water a more potent nucleophile, or by helping facilitate
proton transfer from water to the product in the transition state. In both cases this would lower the
barrier for product formation, increasing the reaction rate. To test this hypothesis, the pH
dependence was re-examined while under buffered conditions. Given that the buffer capacity
decreases to less than 10% of its maximum at 1 pH unit above or below the pK of the buffer, the
a
effect of pH on the reaction rate was examined within this range: pH 3.8 to 5.8. Unlike the
unbuffered reaction, here the reaction rate increased with increasing pH (Figure S14). This is
likely because at the same concentration of buffer there is a higher proportion of acetate anion
present at higher pH that can act as a local base. In addition, the presence of acetate bound to
zirconium could also affect the pH-dependent dimerization equilibrium, leading to an increased
concentration of 3 at higher pH.
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With these key findings for the effect of acetate buffer on catalytic hydrolysis by 1, another
buffer, phosphate, was examined as it is a common buffer for POM reactions in aqueous media
and for hydrolysis reactions in general. While phosphate does not buffer at pH 4.8, experiments
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
1
2
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9
0
31
were carried out at this pH nonetheless to keep POM speciation constant. The P NMR spectra
show that as with acetate, there is a chemical shift of the POM resonance upfield in the presence
of phosphate indicating the formation of a complex with 3 (Figures S15, S16). Additional evidence
of complexation exists in the phosphate region of the spectrum where a new peak grows in upfield
of free phosphate as the POM concentration is increased. The peak is attributed to the phosphate
molecules bound to the POM (Figure S17). In stark contrast with the acetate-buffered reactions,
a solution with 0.3 M phosphate reduced the activity of the catalyst by a factor of 13 relative to 0.5
M acetic acid/acetate (Figures 8, S18, Table 2). A concentration of 0.3 M phosphate was used, as
opposed to the 0.5 M used in the case of acetate, so that an ionic strength of 0.3 M would be
maintained. This finding is consistent with a significantly different interaction mode of phosphate
versus acetate with Zr(IV). It is likely that monobasic sodium phosphate competes with DMNP
for binding to the zirconium center thus slowing reactivity, whereas acetate does not.
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0.7
0
.5 M Acetate
0.3 M Perchlorate
0
.6
.5
0.3 M Phosphate
0
0
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6
7
8
9
0
0.4
0
.3
.2
0
0.1
0
0
20
40
60
80
Time (minutes)
Figure 8. Product formation as a function of time in the presence of different anions. Acetate
blue) shows an enhancement over perchlorate (non-coordinating), whereas phosphate (red)
(
exhibits inhibition. Conditions: Ionic strength of 0.3 M, 2.5 mM 1, 10.3 mM DMNP, pH 4.8, pH
adjusted with NaOH.
Table 2. Initial rates of hydrolysis of 10.3 mM DMNP at pH 4.8 with an ionic strength of 0.3 M
(
buffer or electrolyte), pH adjusted with HClO or NaOH.
4
Conditions
Initial Rate (nM/s)
0
0
.3 M NaClO
4
, 2.5 mM 1
102
144
3.2
.5 M Acetate Buffer, 2.5 mM 1
0.5 M Acetate Buffer
-
0
0
.3 M NaH
2
PO
4
, 2.5 mM 1
11
.3 M MPA, 2.5 mM 1
19.7
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To support these experimental findings, density functional theory (DFT) computational
studies were conducted. DFT studies (see Supporting Information for details) provide clear insight
into distinct binding modes and associated energetics of these two widely used buffers for
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
4
4
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4
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4
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4
4
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0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
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0
1
2
3
4
5
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1
2
3
4
5
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0
1
2
3
4
5
6
7
8
9
0
-
hydrolysis reactions (Figure 9). The calculations predict that H
2
PO
4
indeed does bind directly to
-
the Zr center which explains the loss of activity relative to non-nucleophilic and non-basic ClO
4
,
which NMR spectra confirm does not interact strongly with the POM (Figure S10). In the case of
acetate, the zirconium center remains open to substrate binding as acetate is predicted to bind in a
non-competitive mode to the POM by hydrogen bonding to a Zr-based aqua ligand. For
comparison, direct coordination with the Zr center is higher in energy and thus less favorable
(Figure S19).
The indirect binding mode of acetate to the catalytically active zirconium likely provides
the hydrolysis rate enhancement via both proposed mechanisms described above: acting as a local
base and/or shifting the dimerization equilibrium in favor of the more active monomer. Figure 9a
shows an increase in the O-H bond length of the aqua ligand hydrogen bonded to acetate. For this
water molecule one O-H bond distance is 0.969 Å, matching the typical length for a water O-H
bond, while the second O-H bond has increased to 1.023 Å. This provides evidence that acetate,
through hydrogen bonding with water, can act as a local base by pulling the hydrogen atom away
from water making it more hydroxide like, and thus a better nucleophile. Calculations suggest this
occurs when the zirconium center in 3 has both a free coordination position and an aqua ligand
(
Figure S20).
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Figure 9. Comparison of the complexation energies and geometries between the POM monomer,
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, and the anions acetate (a), and phosphate (b). W, blue; O, red; Zr, blue-green; Na, purple; C,
grey; P, orange; H, white.
-
Based on the above understanding of the interaction between 3 and NaH
2
PO , a logical
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next step was to look at catalyst poisoning by the nerve agent hydrolysis product, MPA. By P
NMR we see that as with both acetate and phosphate, the POM resonance shifts upfield in the
presence of MPA (Figure S21). The initial rates of hydrolysis as a function of MPA show that,
similar to phosphate, there is inhibition of the reaction (Figure S22). This suggests that the binding
of MPA happens in competition with DMNP, significantly slowing the reaction.
In light of the large number of CWA hydrolysis studies involving N-ethylmorpholine
7
, 9-10, 13, 49, 60
(
NEM) as a buffer,
The compound 2-(N-morpholino)ethanesulfonic acid (MES) was chosen as it is very similar in
structure than NEM, but it has a lower pK of 6.16 allowing it to buffer at pH values where both 1
and 3 will be present in solution. A pH of 5.8 was chosen to maximize both the concentration of
and deprotonated MES as a means to probe the effect of a local nucleophile/base in solution.
the effect of a morpholine based buffer was also examined here.
a
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Interestingly, the initial rate of hydrolysis was effectively independent of MES concentration while
3
1
maintaining a constant ionic strength (Figure 10). The P NMR shows that in the presence and
absence of MES there is no change in the chemical shift of the POM indicating there is little or no
interaction with MES (Figure S23). Thus, the MES is not involved in the rate limiting step. Future
studies will continue to examine other buffer molecules to further develop the relationship between
buffer-catalyst interaction and observed hydrolysis chemistry.
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Concentration of MES (M)
Figure 10. Initial rate dependence of DMNP hydrolysis as a function of MES concentration.
Conditions: MES and NaClO concentration varied; ionic strength, 0.3 M (combined effect of
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MES and perchlorate ions), 2.5 mM 1, 10.3 mM DMNP, pH 5.8, pH adjusted with NaOH.
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CONCLUSIONS
This is the first report of an electrophilic Zr-substituted POM catalytically hydrolyzing a
CWA simulant at near-neutral pH. This study also reveals that buffer anions, often thought to be
relatively innocent in CWA hydrolyses, can play key roles in such reactions either accelerating
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(
co-catalyzing) or inhibiting the rate. This effect results from their direct interaction with the
catalyst in solution. Other buffers ions, such as MES, that are non-coordinating have no effect on
the rate of hydrolysis. Future work will expand on this relationship between buffer-catalyst
coordination and its impact on catalyzed hydrolysis rates. Lastly, the nerve agent hydrolysis
product, methyl phosphonic acid (MPA), shows inhibition of 1-catalyzed hydrolyses. As this
POM has structural similarities to many of the Zr-based heterogeneous systems, which also
experience similar product inhibition, this system provides a nice means of probing and potentially
studying the reversal of such inhibition. This will have important implications on the poisoning
and long-term use of all Zr-based CWA hydrolysis catalysts.
ASSOCIATED CONTENT
Supporting Information
Additional experimental parameters/data: Experimental procedures, FTIR spectra, NMR spectra,
powder X-ray diffraction data, initial rates data, reaction conversion profiles, calculated cartesian
coordinates.
AUTHOR INFORMATION
Corresponding Author
*Email for Craig L. Hill: chill@emory.edu
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Funding Sources
We thank DTRA (ARO Award # W911NF-15-2-0107) for support. The authors gratefully
acknowledge NSF MRI-R2 grant (CHE-0958205 for D.G.M.) and the use of the resources of the
Cherry Emerson Center for Scientific Computation.
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ACKNOWLEDGMENTS
The Bruker 600 NMR was funded by NSF grant CHE-1531620. We thank Natalie Uhlikova for
calculating atom positions.
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