Oxidation of phenylphosphonites with aqueous hydrogen peroxide

Article abstract of DOI:10.1134/S1070363212080087

An effective route to the oxidation of organic derivatives of trivalent phosphorus with an aqueous solution of hydrogen peroxide was considered. Phenylphosphonites, including those having a hydrolytically unstable phosphorus-nitrogen bond were involved into the oxidation. The identification of oxidation products, the phenylphosphonates, was carried out using the method of ion cyclotron resonance mass spectrometry with Fourier transform combined with electrospray ionization, and by 31P and 1H NMR spectroscopy. The influence of an effective antioxidant of natural origin, quercetin, on the oxidation was demonstrated. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070363212080087

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 8, pp. 1374–1381. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.T. Teleshev, E.N. Mishina, D.A. Ganin, V.Yu. Mishina, I.V. Abrashina, E.E. Nifant’ev, A.S. Kononihin, I.A. Popov, E.N. Nikolaev,
2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 8, pp. 1294–1301.
Oxidation of Phenylphosphonites
with Aqueous Hydrogen Peroxide
A. T. Telesheva, E. N. Mishinaa, D. A. Ganina, V. Yu. Mishinaa, I. V. Abrashinaa,
E. E. Nifant’eva, A. S. Kononihinb,c, I. A. Popovb,c, and E. N. Nikolaevb,c
a Moscow Pedagogical State University, Department of Chemistry, Nesvizhskii per. 3, Moscow, 119021 Russia
e-mail: teleshevat@rambler.ru
b Institute of Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia
c Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, Russia
Received June 20, 2011
Abstract—An effective route to the oxidation of organic derivatives of trivalent phosphorus with an aqueous
solution of hydrogen peroxide was considered. Phenylphosphonites, including those having a hydrolytically
unstable phosphorus–nitrogen bond were involved into the oxidation. The identification of oxidation products,
the phenylphosphonates, was carried out using the method of ion cyclotron resonance mass spectrometry with
Fourier transform combined with electrospray ionization, and by 31P and 1H NMR spectroscopy. The influence
of an effective antioxidant of natural origin, quercetin, on the oxidation was demonstrated.
DOI: 10.1134/S1070363212080087
The hydroxy radical is extremely reactive and can
oxidize almost all low molecular weight organic
compounds [1–3]. A well-known source of the
hydroxy radicals is hydrogen peroxide which is
capable of effective oxidation of organic compounds
including trivalent phosphorus derivatives [4]. The use
of hydrogen peroxide for the selective oxidation of the
organic compounds of phosphorus(III) is of practical
interest, because organophosphorus substances contain-
ing pentavalent phosphorus are used in common
practice. The use of free hydrogen peroxide, in contrast
to the bound one, for example, hyperol [5], does not
affect the purity of the oxidation products. However, it
should be noted that in preparative practice of
organophosphorus chemistry aqueous solution of
hydrogen peroxide is commonly used, which not
always leads to successful results since the majority of
phosphorus(III) organic compounds are insoluble in
water and some are readily hydrolyzed [6, 7].
In this paper we discuss the possibilities and
conditions for oxidation using an aqueous solution of
hydrogen peroxide of a class of phosphorus(III) or-
ganic compounds, phosphonites I–III, including those
containing hydrolytically unstable phosphorus–
nitrogen bond (I, II), (Scheme 1).
Scheme 1.
O
H2O2
dioxane
X
X
PhP
PhP
I_III
Y
Y
IV_VI
X
Et2N_P_NEt2 (I),
(III).
PhP
=
O_P_NEt2 (II),
O_P_O
Y
1374

OXIDATION OF PHENYLPHOSPHONITES
1375
For the identification of the oxidation products, we
suggested to use, along with NMR spectroscopy, the
method of mass spectrometry of ion cyclotron
resonance with Fourier transform (FTICR-MS) in
combination with electrospray ionization. The
implementation of the FTICR-MS method for the
analysis of organophosphorus compounds is less
known than NMR spectroscopy. However, as shown,
for example, in [8], the FTICR-MS method can be
used effectively for the identification of both
individual organophosphorus compounds and in com-
plex mixtures. The main advantages of this method are
the ultra-high resolution and accuracy of the mass
measurement [9, 10]. On the basis of modern FTICR
mass spectrometer with an accuracy in mass measuring
of 1 ppm it is possible to identify exactly the empirical
formula of a low molecular weight (≤500 Da)
phosphorus-containing compound [11].
According to the 31P NMR spectra, the oxidation of 1.1
mmol of a phosphonite I–III in these conditions was
completed in 1–2.5 h. The oxidation of diester III
proceeds faster than that of compounds containing a
phosphorus–nitrogen bond.
The reaction products IV–VI were identified after
separation by the accurate measurement of their
masses with the FTICR-MS using electrospray for the
ionization of the sample. Additional structural
information about the phosphonates IV–VI was
obtained from 31P and 1H NMR spectroscopy.
In the ICR mass spectrum of compound [Et2NP(O)·
(Ph)NEt2] IV of the molecular weight 268.3 there is a
series of peaks corresponding to the solvated,
protonated, and sodium-containing mono-, di-, and
trimolecular cations (Fig. 1 and table).
In the ICR mass spectrum of the product PhOP(O)·
(Ph)NEt2 V (molecular weight 289.3) there are peaks
that characterize the protonated and cationized
(sodium) forms of monomer and dimer of compound
Preparative oxidation of compounds 1–3 was
carried out using 36% aqueous solution of hydrogen
peroxide dissolved in dioxane at 8–12°C [12].
Irel, %
(2 M + Na)+
(M + DMSO + Na)+
(3 M + Na)+
(M + Na)+
(M + H)+
(2M + H)+
m/z
Fig. 1. ICR mass spectrum of compound IV.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 8 2012

1376
TELESHEV et al.
Ions characterizing the ICR mass spectra of oxidized products IV–VI
Compound
Ion
m/z
Calculated mass, Da
269.17773
291.15967
369.17361
537.34818
559.33013
827.50058
290.13044
312.11239
368.14438
390.12633
580.25361
601.23556
333.06510
411.07904
489.09298
643.14099
953.21687
Error, ppm
0.38
Et2NP(O)(Ph)NEt2+H+
269.17783
291.15979
369.17351
37.34854
559.32972
827.50106
290.13046
312.11252
368.14447
390.12628
79.25385
601.23566
333.06573
411.07867
489.09277
643.14020
953.21619
IV
Et2NP(O)(Ph)NEt2+Na+
Et2NP(O)(Ph)NEt2+DMSO+Na+
2Et2NP(O)(Ph)NEt2+Н+
2Et2NP(O)(Ph)NEt2+Na+
3Et2NP(O)(Ph)NEt2+Na+
PhOP(O)(Ph)NEt2+H+
PhOP(O)(Ph)NEt2+Na+
PhOP(O)(Ph)NEt2+ДMСO+H+
PhOP(O)(Ph)NEt2+DMSO+Na+
2PhOP(O)(Ph)NEt2+H+
2PhOP(O)(Ph)NEt2+Na+
PhOP(O)(Ph)OPh+Na+
0.42
–0.27
0.69
–0.72
0.58
0.06
V
0.42
0.24
–0.11
0.40
0.17
1.89
VI
PhOP(O)(Ph)OPh+DMSO+Na+
PhOP(O)(Ph)OPh+2DMSO+Na+
2PhOP(O)(Ph)OPh+Na+
3PhOP(O)(Ph)OPh+Na+
–0.89
–0.42
–1.23
–0.71
V, and the corresponding solvated ions of the mono-
product (Fig. 2, table). The presence in the spectrum of
an unidentified peak with m/z 363.2 should be noted
that corresponds to the ion, which at the fragmentation
gives the signal of the starting material V.
To determine the characteristics of oxidation of
phenylphosphonites with hydrogen peroxide, and
especially those of the compounds containing a
hydrolytically unstable phosphorus–nitrogen bond, we
used quercetin, a well-known antioxidant of natural
origin [13]. The studies with this compound were
performed in the tube of the 31P NMR spectrometer,
containing dioxane solution of 36% aqueous hydrogen
peroxide. Nature of the effect of quercetin on the
process confirms the radical chain mechanism of
oxidation of the phosphorus(III) organic compounds
by hydrogen peroxide [4]. Thus, we found that the rate
of oxidation of hydrolytically stable triphenyl-
phosphine is reduced by about half with the
introduction of an antioxidant in the reaction mixture,
taken in equimolar amounts relative to the organo-
phosphorus compound. In contrast, the oxidation of the
phenylphosphonous amide in the presence of quercetin
has a pronounced feature. Compared with the control
experiment (Fig. 5, curve 1), quercetin actually slows
down the process of the phosphonite I oxidation at the
initial stage of the reaction (Fig. 5, section AB of the
curve 2). However, then occurs a more intense
conversion of phenylphosphonite (Fig. 5, section BC,
curve 2).
Molecular mass of [PhOP(O)(Ph)OPh] VI is 310.3.
In the ICR mass spectrum of this compound in contrast
to the spectra of IV and V, there are only two distinct
groups of signals corresponding to the solvated and
sodium-containing mono- and bimolecular cations and
there is no series of the ions of a protonated form
(Fig. 3, table).
The selectivity of the phenylphosphonites oxida-
tion was monitored involving NMR spectroscopy on
the 31P nuclei. We found that under the used condi-
tions the aqueous solution of hydrogen peroxide oxi-
dizes
phenylphosphonites
selectively,
without
affecting the hydrolytically unstable phosphorus–nitro-
31
gen bond. Figure 4a shows the P NMR spectrum of
the dioxane solution of phenylphosphonous
tetraethyldiamide III and aqueous hydrogen peroxide
after 1.5 h keeping the reaction mixture. The spectrum
contains the signal of only one reaction product, the
phenylphosphonate IV.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 8 2012

OXIDATION OF PHENYLPHOSPHONITES
1377
Irel, %
(2 M + Na)+
(2 M + H)+
(M + DMSO + H)+
(M + DMSO + Na)+
(M + Na)+
(M + H)+
m/z
Fig. 2. ICR mass spectrum of compound V.
Irel, %
(2 M + Na)+
(M + DMSO + Na)+
(M + Na)+
(3 M + Na)+
(M + 2DMSO + Na)+
m/z
Fig. 3. ICR mass spectrum of compound VI.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 8 2012

1378
TELESHEV et al.
(a)
(b)
δ, ppm
Fig. 4. 31P NMR spectra of the reaction mixtures: (a) phosphonite–hydrogen peroxide and (b) phosphonite–hydrogen peroxide–
quercetin.
We assume that the quercetin in the initial stage of
the reaction quenches the phosphonite I oxidation due
to the formation of quercetinyl radicals (Scheme 2).
The quercetinyl radicals are resonace stabilized
structures and are unable to continue the chain of free
radical reactions [14]. Note that to date the actual
Scheme 2.
H2O2
2HO
HOPPh(NEt2)2
+ PPh(NEt2)2
HO
(HO)2PPh(NEt2)2
HO
HOPPh(NEt2)2
+
H2O2
+
H2O
H2O
(HO)2PPh(NEt2)2
[Qu (OH)
OPPh(NEt2)2
+
[Qu (OH) O
]
+
OH
]
+
4
5
OH
3'
OH
2'
4'
5'
B
1
1'
8
HO
O
8a
7
2
3
6'
A
[Qu (OH)
.
]
=
5
6
4
4a
OH
5
O
OH
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 8 2012

OXIDATION OF PHENYLPHOSPHONITES
1379
source of radical species among the hydroxy groups of
quercetin molecule has not been established. There is
an evidence of the greatest contribution to the
antiradical activity of flavonoid of hydroxy groups of
the catehol group of ring B, but simultaneously a
significant effect on the antiradical activity of quercetin
hydroxy group in C3 position is noted [14, 15].
The intensification of conversion of phenylphos-
phonite I (Fig. 5, section BC in the curve 2) is
probably due to blocking the phosphorylation of the
quercetin hydroxy groups responsible for the
generation of radical species and subsequent
unimpeded oxidation of phosphorus(III)-containing
quercetin into the corresponding oxide (Scheme 3).
Scheme 3.
[Qu (OH) OPPh(NEt )
_
[Qu (OH)
_
]
PPh(NEt2)2
nHNEt2
+
+
]
5 n
4
2 2 n
_
_
PPh(NEt )
2 2 n
[Qu (OH) OP(O)Ph(NEt )
[Qu (OH) O
+ H2O2
H2O
]
+
]
4
2 2 n
4
n = 1, 2.
Comparative spectral characteristics of the reaction
mixtures phosphonite–hydrogen peroxide (Fig. 4a) and
phosphonite–hydrogen peroxide–quercetin (Fig. 4b)
Finnigan LTQ FT (Thermo Electron, Bremen, Germany),
which consists of a linear quadrupole ion trap and the
FT-ICR mass spectrometer with a 7 T superconducting
solenoid. The exact mass values of the objects were
measured on the FT-ICR mass spectrometer in positive
mode with an error of ~2 ppm. External calibration
was carried out using a standard mixture for mass spectro-
meter setup and calibration (caffeine, MRFA, Ultramark).
The electrospray initial parameters are as follows:
capillary voltage 3 kV, the feed rate of the solvent in
the capillary 1.5 ml min–1. The test samples were
prepared as solutions in DMSO.
31
indicate just this course of the process. The P NMR
spectrum of the reaction mixture phosphonite–
hydrogen peroxide–quercetin after 1.5-h of keeping
contains the signals of initial phosphonite I, phos-
phonate IV, the product of quercetin phosphorylation,
and its oxidized forms at 97, 28, 132, 23, and 10 ppm,
respectively.
Thus, the possibility of selective oxidation of the
phosphorus(III) organic compounds, including those
containing hydrolytically unstable phosphorus–
nitrogen bond, with an aqueous solution of hydrogen
peroxide was demonstrated. To identify the oxidation
products we suggest to apply the FTICR method of
mass spectrometry in combination with electrospray
ionization. The effect of quercetin on the oxidation of
phosphorus(III) organic compounds with hydrogen
peroxide is shown to be consistent with the concept of
the radical chain mechanism of the process. It is
established that the specific effect of quercetin on the
system of phenylphosphonous amide–hydrogen
peroxide is due to the blocking phosphorylation of
quercetin. The last note should be taken into account at
the functionalization of antioxidants of natural origin.
W, %
EXPERIMENTAL
1
31
The H and P NMR spectra were recorded on a
JNM-ECX400 spectrometer (Jeol) with internal tetra-
methylsilane as well as relatively to the residual proton
signals of the solvent (CDCl3, 7.27 ppm), or with
external 85% phosphoric acid. The mass spectra were
obtained on the ICR hybrid mass spectrometer
τ, h
Fig. 5. Dependence of the oxidation rate of phosphonite I
on the introduction of quercetin.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 8 2012

1380
TELESHEV et al.
Phenylphosphonous tetraethyldiamide I was
IV. The duration of the mixture exposure was 1.5 h.
The product was isolated by column chromatography
on silica gel eluting with dioxane (Rf = 0,8). After
distilling off the solvent, the residue was kept in a
vacuum (1 mm Hg) at 50°C for 4 h. Yield 97%. The
reaction product is a transparent yellow viscous liquid.
1H NMR spectrum (CDCl3), δ, ppm: 0.92 t (6H, CH3,
synthesized by reacting dichlorophenylphosphine with
excess diethylamine [10]. The product is clear,
1
colorless mobile liquid, bp 137°C (4 mm Hg). H
NMR spectrum (CDCl3), δ, ppm: 1.14 t (12H, CH3,
3
3JHH 7.25 Hz), 3.11 m (8H, CH2 JPH 9.87 Hz), 7.25 m
3
3
(1H, CHarom., JHH 6.63 Hz), 7.36 m (2H, CHarom., JHH
1.82 Hz), 7.46 m (2H, CHarom., 3JPH 4.75 Hz). 31P NMR
spectrum (hexane), δ 97 ppm.
3
3JHH 7.12 Hz), 3.12 m (4H, CH2, JPH 11.33 Hz), 6.78
3
m (1H, CHarom.), 6.84 m (2H, CHarom., JHH 8.04 Hz),
7.11 m (2H, CHarom.), 7.45 m (3H, CHarom.), 7.85 d.d
Phenyl diethylamidophosphonite II was prepared
by reacting equimolar amounts of phenol and
compound I (method a) [16], as well as by aminolysis
of diphenyl phenylphosphonite III (method b) [12].
The product is a clear, slightly yellowish, mobile
liquid. The 31P NMR spectrum (dioxane), δP 131 ppm.
(2H, CHarom.,
3JPH 12.79 Hz). 31P NMR spectrum
(dioxane), δP 23 ppm.
Diphenyl phenylphosphonate VI was prepared
from diphenyl phenylphosphonite III along the
method of preparing compound IV. The exposure
duration was 1 h. After distillation of the solvent, the
residue was kept in a vacuum (1 mm Hg) at 50°C for
4 h. Yield 98.7%. The reaction product is a transparent
Diphenyl phenylphosphonite III. To 2.05 g (8
mmol) of phenylphosphonous tetraethyldiamide I was
gradually added 1.52 g (16 mmol) of phenol. The
mixture was stirred for 30 min in an argon atmosphere,
then heated to 110°C until complete homogenization.
With the continuous stirring, the reaction mixture was
left under these conditions for 2 h. Then the reaction
vessel was connected to a vacuum line and the reaction
mixture was kept successively: (a) 2 h at 110°C and
2 h at 170°C (15 mm Hg), (b) 2 h at 110°C and 4 h at
140°C (1 mm Hg). The reaction product is a clear,
colorless mobile liquid. 1H NMR spectrum (CDCl3), δ,
ppm: 7.19 m (6H, CHarom.), 7.32 m (4H, CHarom.), 7.54
m (2H, CHarom. ) 7.64 m (1H, CHarom.), 7.98 m (2H,
1
yellow viscous liquid. H NMR spectrum (CDCl33), δ,
ppm: 7.16 m (6H, CHarom.), 7.29 m (4H, CHarom., JHH
8 Hz), 7.51 m (2H, CHarom.), 7.61 m (1H, CHarom., 3JHH
3
3
7.31 Hz), 7.97 d.d (2H, CHarom., J PH 13,52 Hz, JHH
8 Hz). 31P NMR spectrum (dioxane), δP 11 ppm.
General procedure of the oxidation of
phenylphosphonites with hydrogen peroxide in the
presence of quercetin. The tube of NMR spectrometer
was filled with the solution of phenylphosphonite
(0.22 mmol) in dioxane (0.6 ml). Then to the solution
was added an equimolar amount of quercetin and 36%
aqueous solution of hydrogen peroxide in 30% deficit.
The 31P NMR spectra were recorded at the initial
moment of the reaction and after 15, 45, 60, and
90 min. Parallel to this experiment, with the same
intervals were recorded spectra of the phenyl-
phosphonite dioxane solution of the same con-
centration with 36% aqueous hydrogen peroxide solu-
tion taken in 30% deficit, without quercetin.
3
3
CHarom., JPH 14 Hz, JHH 8 Hz). 31P NMR spectrum
(dioxane), δP 158 ppm.
Phenylphosphonic tetraethyldiamide IV. To 0.28 g
(1.1 mmol) of phenylphosphonous tetraethyldiamide 1
dissolved in 5 ml of dioxane at cooling to 8–12°C
while stirring was added dropwise 1.1 mmol of 36%
solution of H2O2. The reaction mixture was kept for
2.5 h. The reaction product was isolated by column
chromatography on silica gel eluting with dioxane (Rf
0.8). After removing the solvent in a film evaporator
the residue was kept in a vacuum (1 mmHg) at 50°C
for 4 h. Yield 96%. The reaction product is a
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