Heterogeneous Organophosphate Ethanolysis: Degradation of Phosphonothioate Neurotoxin by a Supported Molybdenum Peroxo Polymer

Article abstract of DOI:10.1021/acs.inorgchem.7b01545

A polystyrene-supported molybdenum peroxo material [Mo-Y(s)] was applied toward the oxidative degradation of the organophosphate neurotoxin O,S-diethylphenyl phosphonothioate (1) through ethanolysis. In addition to the operational advantages of the heterogeneous reactivity, oxidative ethanolysis with a 10-fold excess of hydrogen peroxide yields only P-S bond scission to produce diethylphenyl phosphonate and ethyl sulfate. This is the first report of a molybdenum solid support that promotes the degradation of sulfur-containing organophosphate with the turnover benefits of heterogeneous catalysis. The activation parameters of 1 ethanolysis by Mo-Y(s) (E_a = 57 ± 6 kJ/mol and ΔS^? = -124 ± 21 J/mol·K) and by the model compound oxodiperoxo(pyridine-2-carboxylato)molybdate(VI) bis(pyridine-2-carboxylic acid) monohydrate (3; E_a = 55 ± 5 kJ/mol and ΔS^? = -154 ± 15 J/mol·K) are almost identical for the oxidation of thioanisole by 3. This suggests that the rate-determining step for 1 ethanolysis is sulfur oxidation to form an intermediate phosphonothioate S-oxide, which subsequently undergoes nucleophilic attack by the ethanol solvent to form diethylphenyl phosphonate and ethyl sulfate. Evidence for the formation of this S-oxide intermediate and the postulated ethanolysis mechanism is provided.

Full text of DOI:10.1021/acs.inorgchem.7b01545

Article
pubs.acs.org/IC
Heterogeneous Organophosphate Ethanolysis: Degradation of
Phosphonothioate Neurotoxin by a Supported Molybdenum Peroxo
Polymer
Louis Y. Kuo,* Andrew Bennett, and Qianli Miao
Department of Chemistry, Lewis & Clark College, Portland, Oregon 97219, United States
S
* Supporting Information
ABSTRACT: A polystyrene-supported molybdenum peroxo material
[Mo−Y(s)] was applied toward the oxidative degradation of the
organophosphate neurotoxin O,S-diethylphenyl phosphonothioate
(1) through ethanolysis. In addition to the operational advantages of
the heterogeneous reactivity, oxidative ethanolysis with a 10-fold
excess of hydrogen peroxide yields only P−S bond scission to produce
diethylphenyl phosphonate and ethyl sulfate. This is the first report
of a molybdenum solid support that promotes the degradation
of sulfur-containing organophosphate with the turnover benefits of
heterogeneous catalysis. The activation parameters of 1 ethanolysis
by Mo−Y(s) (Ea = 57 6 kJ/mol and ΔS⧧ = −124 21 J/mol·K)
and by the model compound oxodiperoxo(pyridine-2-carboxylato)-
molybdate(VI) bis(pyridine-2-carboxylic acid) monohydrate (3; Ea =
55 5 kJ/mol and ΔS⧧ = −154 15 J/mol·K) are almost identical
for the oxidation of thioanisole by 3. This suggests that the rate-determining step for 1 ethanolysis is sulfur oxidation to form an
intermediate phosphonothioate S-oxide, which subsequently undergoes nucleophilic attack by the ethanol solvent to form
diethylphenyl phosphonate and ethyl sulfate. Evidence for the formation of this S-oxide intermediate and the postulated
ethanolysis mechanism is provided.
to yield the corresponding S-oxide that subsequently under-
went nucleophilic substitution to yield the phosphonate
[EtOP(O)(Nu)CH3] and ethylsulfenic acid; the latter quickly
oxidized to ethyl sulfonate.
INTRODUCTION
■
This is the first report of a heterogeneous system for the
oxidative degradation of a phosphonothioate neurotoxin.
Phosphonothioates of the form RP(O)(SR1)(OR2)1 are
acetylcholine esterase inhibitors that have applications as
pesticides2 and, most notoriously, as chemical warfare agents.3
As one of the most dangerous toxins, the nerve agent VX
In this case, exclusive P−S scission was always seen, which is
the desired degradation pathway for phosphonothioates; P−O
scission yields another phosphonothioate that sometimes is as
toxic as the original compound.14 The S-oxide of phosphono-
thioate was further investigated by Segall and Casida,15 who
found it to be extremely reactive and even implicated it as a
potential intermediate in the biological oxidation of phospho-
nothioates.16 These homogeneous investigations prompted us
to look at heterogeneous systems that accomplish the same
oxidative degradation of phosphonothioate neurotoxins. To that
end, we chose a molybdenum peroxide complex17 immobilized
on a polystyrene support via a triethylenetetramine linker. This
immobilized molybdenum system is easily made from
molybdenum powder/hydrogen peroxide (H2O2) and com-
mercially available CR20 Diaion beads (Mistubushi Chemical
Co.); that molybdenum is an abundant metal further adds to
the utility of this oxygenation system. The CR20 Diaion beads
are polystyrene chelating resins with polyamine functional
groups, as drawn in the Table of Contents figure; they have
[R = CH3, R1 = CH2CH2N(iPr)2, and R2 = Et] has an LD50
=
0.015 mg/kg;4 just 2 drops would kill an average 70 kg adult.
Even phosphorothioate pesticides such as parathion5 [ArOP(S)-
(OEt)2] undergo tautomerization (eq 1)6 to form phosphono-
thiolate with the same P−S and P−O ligation as VX.7,8
Several prior reports9,10 highlight the use of the peroxy
functionality for oxidative degradation of phosphonothioates.
Given the prior literature11,12 on sulfide oxidation by
molybdenum peroxo catalysts, the plausible strategy for
degrading phosphonothioate neurotoxins entails sulfur oxida-
tion, followed by the decomposition of phosphonothioate
S-oxide. Specifically (Scheme 1), Yang and co-workers13
oxidized O,S-diethylmethyl phosphonothioate (30 mM) with
excess aqueous m-chloroperoxybenzoic acid (m-CPBA; 240 mM)
Received: June 18, 2017
© XXXX American Chemical Society
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Scheme 1. Oxidative Degradation of Phosphonothioate via S-Oxide
Figure 1. Organophosphate structures including the phosphonothioate chemical warfare agent VX and its analogue 1.
The title phosphonothioate, O,S-diethylphenyl phosphonothioate
(1), was made according to prior literature preparations21 with
reagents that were purchased from TCI (Portland, OR). The synthesis
of 13C-enriched phosphonothioate O-ethyl-S-methyl(13CH3)phenyl
phosphonothioate (2), an analogue of 1 for 13C NMR studies, was
done according to prior literature reports.22 The solution analogues
oxodiperoxo(pyridine-2-carboxylato)molybdate(VI) bis(pyridine-2-
carboxylic acid) monohydrate (3) and oxoperoxo(pyridine-2,6-dicar-
boxylato)aquomolybdate(VI) (4) were made according to the procedure
of Mares and co-workers.23 Characterization was done with 13C NMR
and, in the case with the diperoxomolybdate (3), SC-XRD (Supporting
Information S1); this compound was previously characterized with
single-crystal X-ray crystallography.
The supported molybdenum peroxo catalyst, abbreviated as Mo−Y(s),
was synthesized according to the procedure of Kurusu and co-workers.17
Molybdenum powder (0.75 g, 7.8 mmol) was gradually added to
10 mL of aqueous 30% H2O2 (327 mmol) over the course of 20 min.
The addition process took place over an ice bath to avoid rapid heating
or boiling of the solution. The solution initially became opaque with a
dark-green hue but transitioned to translucent (bright) yellow over the
course of the molybdenum addition, thus the reason for the Mo−Y(s)
naming by the original authors. Diaion CR20 polymeric beads (2.15 g)
were slowly added to the stirring yellow suspension over the course of
20 min. The suspension was stirred slowly (to avoid damage of the
beads) overnight. After ∼18 h of light stirring, the bright-yellow beads
were filtered on a fritted funnel and washed with deionized water
(100 mL) followed by diethyl ether. Elem anal. Calcd for Mo−Y(s):
C, 56.66; H, 5.80; N, 3.67; Mo, 11.68. Elem anal. Calcd for CR20
(no molybdenum added): C, 72.70; H, 8.95; N, 8.35.
Kinetic Runs and Oxygen Species Analyses. The title reaction
was carried out in 1 dram vials with 100 mg of the Mo−Y(s) support
(0.12 mmol of molybdenum). The ethanol (EtOH) solvent (900 μL)
and deuterated methanol (MeOH; 50 μL for a lock source) were
added to Mo−Y(s), followed by the addition of 15 μL of aqueous 30%
H2O2 (0.15 mmol), which turned the solution above the beads slightly
yellow. This suspension was allowed to sit for ∼30 min until the mild
bubbling ceased before the addition of 1. Kinetics commenced with
the addition of 1 (3 μL, 0.014 mmol). At specific time intervals, the
solution above the Mo−Y(s) beads/support was pipetted from the vial
and into a 5 mm NMR tube without collection of any of the 0.5 mm
beads. Following a 31P or 13C NMR spectrum, this solution was
pipetted back to the 1 dram reaction vial containing the Mo−Y(s)
beads/support. This process was repeated at various time points for
kinetic runs.
been used to selectively chelate heavy-metal ions. This
molybdenum peroxide support successfully epoxidized alkenes
with the addition of tert-butyl peroxide and demonstrated
recyclability in the epoxidation chemistry, which makes this
system catalytic. An exhaustive literature search on supported
molybdenum peroxide polymers18,19 did not find their use in
the oxidative degradation of phosphonothioate neurotoxins.
As such, this is the first report of a polymer-supported
molybdenum material that effectively carries out ethanolysis of
a phosphonothioate neurotoxin. The title compound of this
report is O,S-diethylphenyl phosphonothioate (1),20 which
was used to discern the chemistry of phosphonothioates.
In addition, 1 serves as an analogue for the chemical warfare
agent VX (Figure 1).3
This report describes the polymer-supported molybdenum
[abbreviated as Mo−Y(s)] material, followed by its use for
heterogeneous 1 ethanolysis; the original reason for calling this
support Mo−Y is spelled out in the Materials and Methods
section. We conclude with several thermodynamic and NMR
studies on a discrete solution model that seeks to elucidate a
possible mechanism for this successful neurotoxin oxidation.
MATERIALS AND METHODS
■
1
Equipment and Materials. All 31P, H, and 13C NMR spectra
were taken on a Bruker Avance-300 spectrometer at 121.495, 300.130,
and 75.468 MHz, respectively. IR spectra of the molybdenum
compounds were obtained with a Nicolet 380 FT-IR spectrometer
as a KBr pellet. Reactions for Arrhenius plots were run either in a
Fischer Scientific Isotemp Refrigerated Circulator (model 9000) or on
an IKA RCT hot plate/stirrer. All UV−vis spectra were obtained
with an Agilent 8453 UV−vis spectrometer, and fluorescence was done
on a PerkinElmer LS 55 fluorimeter. Single-crystal X-ray diffraction
(SC-XRD) characterization was carried out on a Bruker Smart X2S
diffractometer. Molybdenum powder was from Alfa Aesar (99.999%),
and aqueous H2O2 (27−30%) was from Sigma-Aldrich. The Diaion
CR20 polystyrene beads were a gift from Mitsubishi Chemical Co.,
and the Singlet Oxygen Sensor Green (SOSG) detection kit was from
Molecular Probe (Eugene, OR). Elemental analyses were conducted
by ALS Environmental (Tuscon, AZ), and energy-dispersive X-ray
(EDX) spectroscopy was carried out at the Center for Electron
Microscopy and Nanofabrication facility at Portland State University.
Gas chromatography/mass spectrometry (GC/MS) analysis was
performed at the Pankow Group Mass Spectrometry Facility at
Portland State University.
The singlet oxygen sensing experiment followed the same
procedure as that of Hwang and co-workers,24 which began with a
stock solution of fluorescent SOSG made up of 100 mg of SOSG in
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330 μL of MeOH for a final concentration of 5.0 mM. From this stock
solution, 0.1 or 1 mM SOSG was added to the aforementioned
Mo−Y(s)/MeOH/H2O2 suspension (no 1). The liquid above the
Mo−Y beads was transferred to the fluorimeter, and the 525 nm
emission was recorded with both 382 and 505 nm excitation.
authentic addition (Supporting Information S5). Throughout
this study, these were the main two signals, and at 30 °C, the
reaction was complete in ∼3 h with 30 μL of 30% H2O2(aq),
as shown in Figure 2. That only the phosphonate is produced
RESULTS AND DISCUSSION
■
Immobilized Molybdenum Support. The immobilized
molybdenum polymer, Mo−Y(s),17 was characterized by
elemental analysis and IR spectroscopy. The oxidation of
Mo(s) with H2O2 initially generated a canary-yellow solution
referred to as Mo−Y(l). This yellow solution was postulated by
Kurusu and co-workers to be a polyoxomolybdate consisting of
a chain of Mo−O−Mo (μ-oxo) linkages that carried out
homogeneous alkene oxidation chemistry with H2O2 addi-
tion.25 This polyoxomolybdate [Mo−Y(l)] was immobilized
on the CR20 Diaion polyamine support (0.5 mm beads).17 Our
analysis results were consistent with the previous report
wherein the molybdenum elemental analyses gave 11.68%
vis-a-
̀
vis the 10%17 reported previously. In addition, the IR
Figure 2. Heterogeneous 1 ethanolysis (0.014 mmol) by Mo−Y(s)
support (100 mg, 0.12 mmol) in 900 μL of EtOH (+50 μL MeOH-d4
for the deuterium lock) with the addition of 30 μL of 30% H2O2
(0.30 mmol) at 30 °C. This demonstrates only the production of
diethylphenyl phosphonothioate at 19.5 ppm; only P−S scission.
Actual kinetic runs were done at room temperature and with 15 μL of
H2O2 for a reasonable sampling over the course of a 18 h reaction time.
spectrum of crushed Mo−Y(s) beads revealed a prominent
MoO 943 cm−1 stretch with weaker peroxo stretches at
850 and 580 cm−1. In addition, there is a broad OH stretch
at 3450 cm−1, but this prominent stretch was already present in
the CR20 Diaion polymer prior to Mo(s)/H2O2(aq) addition
(Supporting Information S2). There is a strong 906 cm−1
stretch in Mo−Y(s), and a prior report on a dried solution of
Mo−Y(l) attributed this stretch to a μ-oxo functional group.26
Furthermore, EDX spectroscopy on Mo−Y(s) showed that
modification of the CR20 Diaion beads resulted in the surface
attachment of molybdenum that was previously absent
(Supporting Information S3A). To this end, we were interested
in calculating the ratio of oxygen to molybdenum through both
elemental and EDX analyses. The actual calculations are
detailed in the Supporting Information S4; from the elemental
analysis results, the O/Mo ratio comes out as 5.3:1. This is
close to the EDX data, which give an O/Mo ratio of ∼3:1.
It should be noted that the molybdenum content in the
Mo−Y(s) beads does vary from batch to batch, as determined
from EDX, and Supporting Information S3B gives a represen-
tative variation in the weight percent of molybdenum from a
different batch preparation. The oxygen atoms on Mo−Y(s) are
a combination of MoO, Mo(OO), and Mo−O−Mo func-
tionalities that originate from the added H2O2(aq).
Heterogeneous Ethanolysis Reaction. The title reaction
was 1 ethanolysis (0.014 mmol) by excess Mo−Y(s) (0.12 mmol
of molybdenum, 100 mg of Mo−Y beads) in EtOH (900 μL of
EtOH and 50 μL of MeOH-d4) in excess H2O2 (0.15 mmol,
15 μL of a 30% aqueous solution). Ethanolysis was chosen
based on prior reports27 for the heterogeneous sulfur oxidation
by a silica-immobilized oxovanadium(IV) salicylidene complex;
EtOH was one of the optimal solvents found in the oxidation of
sulfides. In addition, the product of ethanolysis was a neutrally
charged phosphonate (vide infra); hydrolysis under alkaline
conditions yielded an anionic phosphonate that was resistant to
further nucleophilic attack. In that connection, an alcohol media
allowed further degradation of the product(s) by hydrolysis or
incineration. Finally, ethanolysis was chosen because the
phosphonothioate 1 was very soluble in EtOH. Ethanolysis
was tracked with 31P NMR in solution by monitoring the
disappearance of the starting material 1 (47 ppm) with
concomitant growth of the product signal (19.5 ppm).28 This
product was identified as diethylphenyl phosphonate through
means that ethanolysis proceeds via selective P−S scission,
which is the desired pathway for phosphonothioate degradation.3
Therefore, the overall fate of the phosphorus for phospho-
nothioate 1 is shown in eq 2. Mo−Y(s) failed to promote the
degradation of 1 in acetonitrile or acetone (with 30 μL of
H2O2), which underscores the value of ethanolysis29 by
Mo−Y(s) in a nucleophilic alcohol solvent; the same reaction
occurs in MeOH to yield ethylmethylphenyl phosphonate.
In addition, di-tert-butyl peroxide did not promote any ethanol-
ysis under the same conditions.
In this connection, we do see an intermediate 26.7 ppm 31P
(broad) singlet when the reaction medium is switched to a
less nucleophilic 7:3 EtOH/acetone medium (Supporting
Information S6). Upon completion of this slower ethanolysis,
this singlet goes away. Prior reports13 have attributed this
singlet as the S → O oxide upon oxidation of O,S-diethylmethyl
phosphonothioate by m-CPBA (Scheme 1) in a non-
nucleophilic solvent (tert-butyl alcohol). Given the oxidative
conditions of this work, this phosphonothioate S-oxide of 1 is a
plausible intermediate in ethanolysis, which will be addressed at
the end of this discussion.
Actual kinetic (quantitative) runs in this heterogeneous
investigation employed conditions with slower ethanolysis (see
the Materials and Methods section) to accurately track the
reaction over a longer (∼18 h) time period. An initial lag/delay
was observed in the first hour, which corresponded to the time
for mild bubbling from the Mo−Y(s) beads (in EtOH and
H2O2) to cease. As such, all ethanolysis allowed a half-hour
“wait time” for this bubbling to diminish, wherein the reaction
medium consisted of only the Mo−Y(s) beads in EtOH/
MeOH-d4 and 15 μL of 30% H2O2. Headspace GC of the gas
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Table 1. Control Reactions for 1 Ethanolysis (900 μL) by Mo−Y(s) with 50 μL of MeOH-d4 for the NMR Lock
control no.
conditions
result
1
2
3
4
5
6
EtOH + H2O2(aq) + Mo−Y(s); for conditions for kinetic runs, see the Materials and Methods section
EtOH + H2O2(aq)
completion of 1 ethanolysis in 18 h
no ethanolysis seen for up to 3 days
no ethanolysis seen for up to 3 days
no ethanolysis seen for up to 3 days
no ethanolysis seen for up to 3 days
no ethanolysis seen for up to 3 days
EtOH + Mo−Y(s); no H2O2
solution/filtrate of the EtOH + H2O2(aq) + Mo−Y(s) reaction
EtOH + H2O2(aq) + CR20 Diaion (no Mo/H2O2) beads
filtration of control no. 1 to remove EtOH/H2O2(aq), followed by replacement with just EtOH
generated in the bubbling revealed it to be only air; no
enrichment of oxygen was detected. The allowance of this wait
time resulted in first-order kinetics for the fraction of the 1
signal versus time. Ethanolysis has a first-order dependence in
the H2O2 concentration [15−30 μL of H2O2(aq)] and in the
Mo−Y(s) polymer (25−100 mg). The upper limit of 100 mg
(0.12 mmol of molybdenum) of Mo−Y(s) was used because
this was the saturation point; any further increase in the
amount of Mo−Y(s) did not yield increased 1 ethanolysis rates
by the solid support.
A few critical controls were run to confirm that ethanolysis
was indeed carried out by the supported molybdenum polymer.
The controls sought to address possible leaching of the
molybdenum active species from the support and that 1
ethanolysis was done by H2O2 + EtOH solvent alone. The
conditions of ethanolysis by Mo−Y(s) in EtOH/H2O2 resulted
in the complete degradation of 1 overnight (∼18 h) at room
temperature. The negative controls set out in Table 1 are the
result of at least 3 days of monitoring (in 50 μL of MeOH-d4
for the NMR lock) that revealed no ethanolysis (i.e., no
product peak at 19.5 ppm).
These controls clearly show that (1) H2O2 is necessary for
any ethanolysis to take place, (2) the unmodified CR20 Diaion
beads are incapable of ethanolysis without the bound
molybdenum, and (3) whatever material that leaches from
the Mo−Y(s) beads is incapable of ethanolysis. Taken together,
they reveal that the molybdenum complex on the CR20 Diaion
support is responsible for ethanolysis. The H2O2 requirement is
further underscored by the last control (no. 6) in Table 1. This
control is identical with the general format of the reaction
where H2O2 (15 μL) is incubated with Mo−Y(s) in EtOH for
half an hour prior to the addition of 1. However, when the
ethanolic solvent (including 15 μL of H2O2) is removed and
replaced with only EtOH, no reaction takes place, which shows the
necessity of having H2O2 around at all times during ethanolysis.
The question of regenerating the support lies at the heart of
heterogeneous reactions, and this was addressed by Kurusu
and co-workers17 for the epoxidation of alkenes by the
Mo−Y(s) polymer. As such, we found that 100 mg of
Mo−Y(s) (0.12 mmol of bulk molybdenum) degrades almost
an equimolar amount of phosphonothioate (30 μL of 1,
0.14 mmol) through ethanolysis (15 μL of 30% H2O2) at 40 °C
(∼24 h) twice. Upon the third addition of 30 μL of 1 to
Mo−Y(s) (0.28 mmol of 1 was already degraded), ethanolysis
went to 50% completion when H2O2 was present.
“depleted” Mo−Y(s) was tested for activity on 1, and no
ethanolysis was observed. This indicates the observed activity is
indeed a function of the supported molybdenum species;
whatever material that leaches from Mo−Y(s) in these turnover
attempts is decomposed molybdenum that is incapable of
1 ethanolysis.
After the second equiv of 1 was added to Mo−Y(s), we
employed the protocol set by Kurusu in regenerating the
support by washing away the reaction products, followed by
incubation of the 100 mg of Mo−Y(s) beads in 10 mL of 30%
H2O2(aq) at 40 °C for 3 h. Mo−Y(s) was filtered and then
dried in vacuo. These regenerated Mo−Y(s) beads were used
for another three complete cycles of 1 ethanolysis. Altogether,
regeneration of the beads with this protocol achieves five
complete cycles of 1 ethanolysis. This result demonstrates a
proof-of-concept feature for the regenerative utility of the Mo−
Y(s) beads.
Product and Singlet Oxygen Species Analysis. Given
the oxidative conditions of the ethanolysis, we examined
the fate of the alkylthiolate leaving group with 13C NMR
for methanolysis of O-ethyl-S-methyl(13CH3)phenylpho-
sphonothioate (2)22 in a MeOH-d4 solvent. Compound 2
differs from 1 by just one carbon on the alkylthiolate leaving
group, and prior synthetic protocols22 placed a 13C-labeled
methylthiolate leaving group for 13C NMR tracking. Consis-
tent with prior reports9,30 on the oxidative degradation of
phosphonothioates, 13C NMR reveals the alkylthioate leaving
group becomes alkylsulfate; in the case for methanolysis of 2,
methanesulfonic acid is formed (i.e., 13C NMR singlet at 38 ppm),
as shown in Figure 3.
The additional minor peak at 35.5 ppm is from esterification
of the methanesulfonic acid with CD3OD (solvent) to form
methyl-d3-methanesulfonate, which displaces the methyl signal
upfield by ∼3 ppm.31
The CD3 carbon signal (not 13C-enriched) of methyl-d3-
methanesulfonate is not visible because of the absence of the
1H−13C NOE. These 13C chemical shifts were also found for
phosphonothioate oxidation by m-CPBA.13 Possible mecha-
nistic pathways for oxidative ethanolysis will be discussed later.
Prior results32 show that MoO42− catalyzes the disproportio-
nation of H2O2 to water and singlet oxygen in micelles.33 This
prompted an investigation of singlet oxygen formation by
Mo−Y(s) that could oxidize the sulfur34 of 1. As such, we used
the commercially available SOSG35 reagent to detect the
presence of 1O2 when Mo−Y(s) is treated with H2O2 in EtOH.
An EDX analysis of the Mo−Y(s) polymer after the second
round of 1 ethanolysis revealed no significant drop in the
molybdenum content with the depleted Mo−Y(s). The
Mo−Y(s) sample started with 36.1 10.5 wt % molybdenum,
and after the second run, it was measured to be 32.3 3.1 wt %
(Supporting Information 3C), a small but statistically
insignificant drop in the molybdenum content after the second
round of 1 ethanolysis. Nevertheless, the solution from this
1
SOSG is specific for O2, does not fluoresce with radicals
or hydroxyl radicals, and has a picomole detection level.
The results clearly show no fluorescence (525 nm emission) in
D
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and H2O2 contents) be comparable between the homogeneous
Mo−Y(l) and the heterogeneous Mo−Y(s) ethanolysis of 1.
The additional water actually slows the Mo−Y(s)-mediated
reactions relative to the NMR in Figure 2.
To a first approximation, 1 ethanolysis in the homogeneous
liquid phase [Mo−Y(l)] is slower by 2-fold compared to the
heterogeneous reaction with the Mo−Y(s) beads under the
same molar amount of H2O2 and molybdenum (Figure 4).
While this is not a dramatic difference, the operational and
regenerative advantages with heterogeneous Mo−Y(s) for 1
ethanolysis make these beads superior to the solution polymeric
Mo−Y(l) homogeneous system.
We were interested in a discrete EtOH-soluble molybdenum
oxo complex that could test the role of key functional groups
in sulfur oxidation chemistry.37 Specifically, this solution model
seeks to examine the role of a molybdenum peroxo
functionality with known sulfide oxidization chemistry.11,12
To that end, Di Furia and co-workers used oxodiperoxo-
(pyridine-2-carboxylato)molydate(VI) (3) to oxidize thioani-
sole to the corresponding sulfide (eq 5).38 The hypothesis
seeks to test whether this sulfur oxidation could be employed in
the oxidative degradation of phosphonothioate 1.
Figure 3. 13C NMR spectrum of 2 methanolysis in CD3OD by
Mo−Y(s) that has the 13C-enriched methylthiolate leaving group.
Starting 2 has a doublet (2JCP = 6.7 Hz) at 11 ppm that completely
disappears after 18 h (30 °C in CD3OD) to yield only two prominent
product singlets at 38 and 35.5 ppm described in eq 3.
the presence of SOSG that is above the background when excited
at both 382 and 505 nm. The possibility of a radical reaction
mechanism was also addressed, and the rate of 1 ethanolysis by
Mo−Y(s) was examined with an equimolar amount of 2,2,6,6-
tetramethylpiperdine-1-oxyl,36 a known radical scavenger. Under
the identical conditions set in Figure 3, the radical scavenger
had no effect on 1 ethanolysis into diethylphenyl phosphonate.
A similar observation was made by Ren and co-workers12 in
their thioanisole oxidation by a polyoxomolybdate, and it suggests
that while radical intermediates may be present, they do not affect
the oxidative degradation reaction (eq 2).
Solution Model with a Discrete Coordination Com-
plex. Early work by Kurusu examined homogeneous alkene
oxidation by a homogeneous solution of molybdenum powder in
H2O2(aq),25,26 which was called Mo−Y(l). It was postulated
that this Mo−Y(l) liquid has the Mo−O−Mo (μ-oxo) array that
was disrupted by H2O2 to form a molybdenum perhydroxyl
group (eq 4); the molybdenum-bound hydroperoxide was the
active species in the homogeneous oxidation of alkenes.25
Compound 3, a diperoxo anion, was soluble in EtOH, and its
chemistry was compared to Mo−Y(s). There were minor
differences in the IR spectrum (Supporting Information S7) of
3 and Mo−Y(s) with regard to the intensity of the peroxo
stretches. Nevertheless, 0.10 mmol of 3 successfully degraded 1
(0.014 mmol) in a homogeneous solution. Specifically,
hydrolysis of 1 in water was rapid (∼3 h) with excess
(7 fold) 3 (no H2O2). Ethanolysis of 1 by 3 was 3 times as
slow as the heterogeneous [Mo−Y(s)] system under the same
conditions. The relatively slower rate of 1 ethanolysis by this
solution model (3) underscores that the active species in the
heterogeneous reaction [by Mo−Y(s)] is the supported
molybdenum oxoperoxo complex. Had the active species in
the heterogeneous ethanolysis been a leached complex like the
model solution complex, then 3 would have exhibited a much
faster reaction than Mo−Y(s). Ethanolysis of 1 by 3 in EtOH
yielded only the 19.5 ppm product 31P NMR signal (Figure 2),
which demonstrated specific P−S scission. In addition, the 13C
NMR spectrum (Supporting Information S8) for methanolysis
(CD3OD) of 13C-enriched 2 by 3 gave the same spectral
features as Figure 4 for the Mo−Y(s) heterogeneous system.
Ethanolysis of 1 was first-order in 3 and H2O2 within the
concentrations used in the study; similar to the case with Mo−Y(s).
It should be noted that the monoperoxo complex 4 was totally
inactive in degrading 1 through either hydrolysis or ethanolysis.
Complex 3 is a convenient discrete solution model for the
chemistry Mo−Y(s) in terms of the thermodynamics of ethanolysis
Therefore, we were interested in seeing how the solution form
of the Mo−Y(s) beads functions in carrying out 1 ethanolysis
under identical conditions. Thus, prior to adding the Diaion
support to the canary-yellow molybdenum powder/H2O2(aq)
solution, a fraction of Mo−Y(l) was used to carry out 1
ethanolysis. The amount of Mo−Y(l) used corresponded to the
molar amount of molybdenum in Mo−Y(s) employed in a
heterogeneous 1 ethanolysis reaction. Specifically, 167 μL of a
0.79 M molybdenum solution in 30% H2O2(aq) [0.375 g of
Mo(s) in 5 mL of 30% H2O2(aq)] gives 0.13 mmol of
molybdenum and 1.5 mmol of H2O2. This is similar in the
molybdenum content (Figure 2) for the Mo−Y(s) heteroge-
neous reactions, but there is 5 times more H2O2. As such, the
heterogeneous Mo−Y(s) reactions employed 150 μL of 30%
H2O2(aq) in order to have all conditions (i.e., the molybdenum
E
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Figure 4. Comparison of 1 ethanolysis (30 °C) by Mo−Y(l) in the homogeneous liquid phase versus the Mo−Y(s) heterogeneous reaction under
comparable conditions where the molar amounts of molybdenum (0.13 mmol) and H2O2 (15 mmol) are equal. For the homogeneous Mo−Y(l)
reactions, 167 μL of the molybdenum/H2O2(aq) solution (0.375 g of molybdenum powder in 5 mL of 30% H2O2) was used to degrade 3 μL of 1
(0.014 mmol) in 1 mL of EtOH. In order to keep the same H2O2, it entailed using more (150 μL) H2O2(aq) than the usual kinetic runs (15 μL) for
the heterogeneous Mo−Y(s) reactions. The additional signal at 26 ppm for both cases is the intermediate S → O oxide (Supporting Information S6).
The small upfield 17 ppm signal is possibly the result of hydrolysis of 1.
against phosphonothioate 1. Arrhenius plots (30−70 °C) for 1
ethanolysis by 3 and by Mo−Y(s) (Supporting Information S9)
gave activation parameters set in Table 2.
activation parameters in Table 2. These thermodynamic results
suggest 3 serves as a solution model for ethanolysis of phospho-
nothioate 1 by the Mo−Y(s) polymer through the assumption
that sulfur oxidation is the rate-determining step in the ethanol-
ysis reaction.
In terms of presenting a hypothesis for the ethanolysis
mechanism, a critical clue is the fact that H2O2 needs to be
present in 1 ethanolysis by Mo−Y(s) at all times (Table 1,
Table 2. Activation Parameters of 1 Ethanolysis by Mo−Y(s)
and Solution Model 3
3 solution model
55
−154 15
Mo−Y(s)
57
−124 21
Ea(EtOH) (kJ/mol)
ΔS⧧(EtOH) (J/mol·K)
5
6
Interestingly, the two systems have almost identical
activation energies and the large negative entropies of activation
for both Mo−Y(s) and 3 are reasonably close to one another.
A similar thermodynamic observation was noted in hydrolysis
of the pesticide disulfoton in homogeneous and heterogeneous
(iron oxide) media;39 the respective ΔS⧧ were −42 and
−43 J/mol·K. The large negative ΔS⧧ in Table 2 indicates
a bimolecular process or one that goes through an ordered
transition state. Prior 17O NMR studies40 showed the peroxo
oxygen atoms in 3 to be electrophilic, and this has a useful
purpose in sulfur oxidation.40 Therefore, molybdenum peroxide
3 oxidizes sulfides, phosphines, and alkenes, wherein the
electrophilc peroxo group undergoes nucleophilic attack.40
Indeed, our activation parameters in Table 2 for 1 ethanolysis
by both Mo−Y(s) and 3 are similar to those of the thioanisole
oxidation (eq 5) reported by Di Furia and co-workers.41 In
their study, they used 3 and obtained ΔH⧧ = 53 kJ/mol and
ΔS⧧ = −125 J/mol·K, which are close to our ethanolysis
control no. 6). This implies that the first step is formation of
the active molybdenum peroxo functionality with the addi-
tion of H2O2. This could either occur from conversion of
the MoO group (prominent IR stretch at 943 cm−1) to a
Mo(OO) peroxo42 (eq 6) or scission of a Mo−O−Mo group
(prominent IR stretch at 910 cm−1) to a molybdenum-bound
perhydroxy group, as described earlier (eq 4).
Both proposed Mo−Y(s) activations have prior literature
precedence. In the case of eq 5, Kurusu correlated the active
oxygen content with the IR signature of this key functional
group for alkene oxidation by Mo−Y(l) in a homogeneous
system.25,26
Another precedence for this work lies with VX oxidation by
MoO4 in H2O2 in microemulsions.43 It was discovered that,
2−
2−
above 0.10 M H2O2, MoO4 exists as an equilibrium mixture
of the molybdate triperoxo and molybdate tetraperoxo species.
Scheme 2
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The latter complex, Mo(OO)42−, was mainly responsible for
the oxidative degradation of VX through direct oxygen transfer
to the sulfur; the triperoxo MoO(OO)32− reacts much slower.43
At the bare minimum, a diperoxo functionality is necessary,
which is consistent with solution work by Woo and co-workers,
who used oxazine complexes of molybdenum diperoxo
functionalities for sulfide oxidation.44
of chiral organophosphorus (OP) compounds for delayed polyneur-
opathy in a regulatory setting. Food Chem. Toxicol. 2004, 42, 1279−
1285. (b) Larson, R. A.; Weber, E. J. Reaction Mechanisms in
Environmental Organic Chemistry; Lewis Press: Birzebbuga, Malta,
̇
̇
1994; pp 122−125. (c) Gordon, J. J.; Leadbeater, L. The prophylactic
use of 1-methyl, 2-hydroxyiminomethyl- pyridiunium methanesulfo-
nate (P2S) in the treatment of organophosphate poisoning. Toxicol.
Appl. Pharmacol. 1977, 40, 109−114.
These two observations suggest that the first step is the
conversion of MoO and/or Mo−O−Mo functionalities of
Mo−Y(s) to oxygenated molybdenum complexes with H2O2.
Following the formation of “activated” species, the nucleophilic
sulfur of 1 attacks the electrophilic oxygen atoms of the
molybdenum peroxo functional group to yield the phospho-
nothioate S-oxide (Scheme 2). It is proposed that this sulfur
oxidation is the rate-determining step based on the measured
activation parameters (Table 2) for 1 ethanolysis by 3.
Indeed, a similar phosphonothioate S-oxide has been
postulated in the oxidative detoxification of O,S-diethylmethyl
phosphonothioate (Scheme 1),13 which we see by 31P NMR
spectroscopy in a 7:3 EtOH/acetone mixture. This unstable
phosphonothioate S-oxide then undergoes rapid ethanolysis
with the solvent to form diethylphenyl phosphonate and
ethylsulfenic acid. The sulfenic acids are known to oxidize
readily to the sulfate,45 which is evident in our 13C NMR
spectrum of the final product when both 1 and 13C-enriched 2
undergo ethanolysis with Mo−Y(s).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.inorgchem.7b01545.
■
S
Detailed crystallographic data, IR spectra, EDX, calcu-
lations for determining the oxygen-to-molybdenum
atomic ratio, authentic addition of ethylmethylphenyl
phosphate and diethylphenyl phosphate, 31P and 13C
NMR spectra, and Arrhenius plots (PDF)
Accession Codes
CCDC 1557943 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
(12) Thompson, D.; Cao, Z.; Judkins, E.; Fanwick, P.; Ren, T.
Peroxo-dimolybdate catalyst for the oxygenation of organic sulfides by
hydrogen peroxide. Inorg. Chim. Acta 2015, 437, 103−109.
(13) Yang, Y.-C.; Szafraniec, L.; Beaudry, W.; Rohrbaugh, D.
Oxidative detoxification of phosphonothiolates. J. Am. Chem. Soc.
1990, 112 (18), 6621−6627.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kuo@lclark.edu.
■
(14) Yang, Y.-C. Chemical detoxification of nerve agent VX. Acc.
Chem. Res. 1999, 32 (2), 109−115.
(15) (a) Segall, Y.; Casida, J. E. Oxidative conversion of
phosphorothioates to phosphinyloxysulfonates probably via phosphor-
othiolate S-oxides. Tetrahedron Lett. 1982, 23 (2), 139−142.
(b) Bielawski, J.; Casida, J. E. Phosphorylating intermediates in the
peracid oxidation of phosphorothionates, phosphorothiolates, and
phosphorodithioates. J. Agric. Food Chem. 1988, 36 (3), 610−615.
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organothiophosphorus compounds. J. Agric. Food Chem. 1974, 22 (2),
207−211. (b) Segall, Y.; Casida, J. E. Reaction of proposed
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the NSF-RUI (Award CHE-
1413090), and crystallographic data collection was done on
an SC-XRD funded from NSF-TUES (Grant DUE-1140940).
We acknowledge crystallographic advice from Dr. Edward
Valente (University of Portland).
(17) Kurusu, Y.; Masuyama, Y.; Saito, M.; Saito, S. Epoxidation with
t-butyl hydroperoxide in the presence of molybdenum peroxide and
polymer-immobilized molybdenum peroxide. J. Mol. Catal. 1986, 37
(2), 235−242.
(18) Ambroziak, K.; Mbeleck, R.; He, Y.; Saha, B.; Sherrington, D. C.
Investigation of Batch Alkene Epoxidations Catalyzed by Polymer-
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