Synthesis of alkyl methylphosphonic acid esters

Article abstract of DOI:10.1080/104265090889602

A synthesis and isolation scheme is described for producing mono alkyl esters of methylphosphonic acid based upon stoichiometric addition of alcohol to methylphosphonic dichloride. Solvent extraction is applied to the reaction mixture to separate the mono

Full text of DOI:10.1080/104265090889602

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Phosphorus, Sulfur, and Silicon
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Synthesis of Alkyl
Methylphosphonic Acid Esters
a
a
a
G. M. Mong , S. D. Harvey & J. A. Campbell
a
Pacific Northwest National Laboratory , Richland,
Washington, USA
Published online: 18 Aug 2006.
To cite this article: G. M. Mong , S. D. Harvey & J. A. Campbell (2005) Synthesis of
Alkyl Methylphosphonic Acid Esters, Phosphorus, Sulfur, and Silicon and the Related
Elements, 180:8, 1885-1891, DOI: 10.1080/104265090889602
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Phosphorus, Sulfur, and Silicon, 180:1885–1891, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090889602
Synthesis of Alkyl Methylphosphonic Acid Esters
G. M. Mong
S. D. Harvey
J. A. Campbell
Pacific Northwest National Laboratory, Richland, Washington, USA
A synthesis and isolation scheme is described for producing mono alkyl esters
of methylphosphonic acid based upon stoichiometric addition of alcohol to
methylphosphonic dichloride. Solvent extraction is applied to the reaction mixture
to separate the monoalkyl esters in reasonable yield from dialkyl methylphospho-
nate and unsubstituted methylphosphonic acid. The single-alkylated materials are
important hydrolysis products of the G-series nerve agents, and are not generally
available from chemical suppliers.
Keywords Cyclohexyl methylphosphonic acid; isopropyl methyphosphonic acid; methyl-
phosphonic dichloride
INTRODUCTION
The development of analytical techniques for the detection and analy-
sis of G-series nerve agent hydrolysis products (alkyl methylphospho-
nic acid esters) is hampered by the lack of available reference ma-
terials. With the exception of pinocolyl methylphosphonic acid ester,
1
these materials are not commercially available. The rapid environ-
mental hydrolysis of the G-series nerve agents produces a relatively
persistent alkyl methylphosphonic acid ester as the primary product.2
Further hydrolysis affords methylphosphonic acid. The goal of this
work is to devise a simple synthesis and separation for G-series nerve
agent hydrolysis products that can be performed in most research
Received June 1, 2004; accepted September 7, 2004.
This work was partially funded by the Laboratory Directed Research and Development
program at Pacific Northwest National Laboratory. Additional funds were provided by
the U.S. Department of Energy, National Nuclear Security Administration, Office of Non-
proliferation and Engineering, NA-22. Pacific Northwest National Laboratory is a multi-
program national laboratory operated by Battelle Memorial Institute for the Department
of Energy under Contract DE-AC06-76RLO 1830.
Address correspondence to G. M. Mong, Pacific Northwest National Laboratory,
Richland, WA 99352, USA. E-mail: g.mong@pnl.gov
1885

1
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G. M. Mong et al.
laboratories, which results in material suitable for use in chemical
warfare analysis methodologies.
Several published reports describe the synthesis of alkyl methylphos-
phonic acid esters. Chittenden et al. described a synthetic path to these
3
compounds through methyl phosphonothioic acids. This procedure is
complex and requires the synthesis of starting materials. Timperly et al.
4
detailed their production through an Arbuzov synthesis. A direct route
from partial hydrolysis of methylphosphonic dichloride has been suc-
cessfully employed,5 with overall yields in the 12% to 47% range. This
latter procedure requires the reaction of methylphosphonic dichloride
with water resulting in a hydrolytically unstable, glassy anhydride that
is used as a starting material for esterification. This method, as well
as that of Timperly et al., apparently requires vacuum distillation to
obtain pure product.
,6
5
The synthesis and extraction techniques developed in this study
can be applied using commonly available equipment and materials to
rapidly produce high purity (98+%) alkyl methylphosphonic acid esters.
An additional advantage of the method described here is that vacuum
distillation is not required to obtain a pure product.
Our approach is based on the direct reaction of alcohols (isopropanol
and cyclohexanol) with methylphosphonic dichloride (Figure 1) in
toluene solvent, followed by hydrolysis of monochloride to produce the
desired alkyl methylphosphonic acids. The desired product is isolated
from other products by solvent extraction. The overall synthetic ap-
proach, combined with solvent extraction-based purification, results in
gram quantities (typical yield of >30%) of high-purity (98+%) product.
Inherent to the reaction is the production of transient pyrophosphonate
species (Figure 2) which are easily hydrolyzed to the suite of idealized
products shown in Figure 1.
Since the alkyl methylphosphonic acids were not amenable to direct
Gas Chromatographic (GC) analysis, reaction aliquots and samples
from extractions were treated with ethereal diazomethane to create
7
methyl derivatives prior to analysis by Gas Chromatography-Mass
Spectrometry (GC-MS). This technique has been applied to acidic
8
phosphate-related components in nuclear defense wastes. Many of
FIGURE 1 Reaction between methylphosphonic dichloride and alcohol result-
ing in a statistical production of products.

Alkyl Methylphosphonic Acid Esters
1887
FIGURE 2 Pyrophosphonate artifacts.
the alkyl organophosphous compounds have relatively straightforward
8
mass spectral fragmentation patterns. As analytical methylation and
silylation are likely to be used by other researchers for analysis of
monoalkyl methylphosphonic acid esters, GC and MS data for the com-
pounds synthesized in this work are provided in Tables I and II.
RESULTS AND DISCUSSION
Attempting to form monoalkyl phosphonic esters from direct reaction of
alcohols with methylphosphonic dichloride creates a mixture of prod-
ucts. Upon hydrolysis of these mixtures, depending upon conditions,
a statistical mixture of methylphosphonic acid, dialkyl methylphos-
phonate, and the desired monoalkyl methylphosphonic ester results
(
Figure 1). Linear alkyl pyrophosphonates of the type shown in Figure 2
were found when hydrolysis was done at ambient temperature. The lin-
ear pyrophosphonates either form during hydrolysis of the phosphoryl
chlorides or result from in situ side reactions involving the alcohols,
which generate water. Pienaar and Petrov report that the reaction
of water with methylphosphonic dichloride initially results in a cyclic
dimer. In our approach, the alkyl ester is formed first, allowing alky-
lated linear species to form upon hydrolysis. The pyrophosphonate
dimers are readily hydrolyzed by quenching the reaction with water
at toluene reflux temperature.
5
6
The mixture of products (Figure 1) is purified by first partition-
ing the highly acidic aqueous phase from the toluene. The dialkyl
TABLE I GC and GC-MS Data for Derivatives of Cyclohexyl and
Isopropyl Methylphosphonic Acids
Compound
(
R1O)(R2O)P(O)CH3
GC Index
EI-MS m/z (Relative intensity)
MW (CI)
152
R1 = CH3 , R2 = isopropyl
R1 = TMS, R2 = isopropyl
R1 = CH3, R2 = cyclohexyl
R1 = TMS, R2 = cyclohexyl
982
1107
1383
1492
93(100), 111(97), 137(38), 79(21)
153(100), 169(20), 75(18), 195(8)
111(100), 93(27), 79(9)
192
153(100), 169(43),75(11)

1
888
G. M. Mong et al.
methylphosphonate ester, as well as most of the unreacted alcohol, is
extracted into the toluene layer. The desired product and methylphos-
phonic acid form a separate layer.
9
An approach fashioned after the work of Hardy and Seargill was
used to remove methylphosphonic acid. These authors found that
dibutyl phosphate could be isolated from technical butyl phosphate mix-
tures by extracting with carbon tetrachloride. We have found that the
difference in polarity between methylphosphonic acid and monoalkyl
methylphosphonic acid esters can be exploited in a similar fashion.
Extracting the aqueous mixture with chloroform, and subjecting it
to successive partitions with water, affords a clean separation of the
monoalkylester. The extracted monoalkylated materials were nearly
colorless and displayed GC traces in which >98% of the peak area was
product, suggesting that further purification of these materials for use
as analytical or experimental standards was not necessary. The over-
all levels of by-products found in the extracts were comparable to that
1
found in samples of previously available commercial isopropyl methy-
phosphonic acid (<2%). Examination of the GC-MS trace for the cyclo-
hexyl analogue afforded similar impurity levels; however, no standard
material was available for comparison. Finally, distillation under vac-
uum afforded only one fraction, with very little residue left in the distil-
lation pot. GC-MS traces of this distillate were not markedly different
from the extracts.
The solvent extraction efficiency was investigated by diazomethane
derivatization and GC-MS analysis of each step. Initial removal of di-
alkyl methylphosphonates by toluene was found to be very efficient.
Nearly all of the methylphosphonic acid remains in the aqueous phase
upon partitioning with chloroform. Residual traces of methylphospho-
nic acid were removed by back-extracting the chloroform with water.
Isopropyl methylphosphonate has a moderate extraction distribution
from chloroform to water, so only two back extractions with water
were performed. The cyclohexyl compound did not exhibit significant
loss during this step and three back extractions were done to remove
methylphosphonic acid from the chloroform. In both cases, the end prod-
ucts were found to be 98+% monoalkyl methylphosphonates in terms of
the total peak area in the GC-MS traces. It is recognized, however, that
ion production mechanisms in the mass spectrometer are very differ-
ent for the components; therefore, TIC areas cannot be used for precise
quantification. The isopropyl methylphosphonate obtained from this
procedure, when derivatized, exhibited a GC trace virtually identical
to that obtained from the commercial sample.
Table 1 exhibits the GC, electron ionization (70 eV) mass spec-
trometry (EI-MS) data, and chemical ionization mass spectrometry

Alkyl Methylphosphonic Acid Esters
1889
TABLE II GC and GC-MS Data for Pyrophosphonate Methyl
Derivatives
Pyrophosphonate
Compounds
(
R1O)P(O)(CH3)
OP(O)(CH3)(OR2)
EI-MS m/z (Relative Intensity)
MW (CI)
R1 = R2 = CH3
157(100), 93(52), 172(22), 89(11), 202(9), 187(8)
202
230
258
R1 = CH3, R2 = isopropyl 171(100), 189(84), 111(88), 93(80),157(44), 79(30)
R1 = R2 = isopropyl
175(100), 157(95), 97(44), 79(33), 143(22), 201(16)
R1 = CH3, R2 = cyclohexyl 189(100), 111(80), 93(31), 157(28),171(16), 211(8)
(
CI-MS) data for the methyl and trimethylsilyl derivatives of isopropyl
and cyclohexyl methylphosphonates. Table 2 addresses the EI-MS and
CI-MS data obtained for selected pyrophosphonates. The MS ions
are listed in relative abundance to the base ion. Authentic isopropyl
methylphosphonate, was used for GC-MS comparisons. We noted a
discrepancy between previously reported data for isopropyl methyl
1
5
methylphosphonate and that which we obtained using diazomethane
for derivatizing our isopropyl methylphosphonate product. In light of
our experience in interpreting mass spectra of these types of com-
pounds, the presence of readily interpretable fragment ions, and the
verification of molecular weight by CI-MS, we believe the data reported
in Table 1 and Table 2 to be correct.
Based on our studies of isopropyl methylphosphonic acid and
cyclohexyl methylphosphonic acids, we believe this synthesis would be
generally applicable for producing alkyl methylphosphonic acid esters
from other unhindered alcohols in the C4–C7 range.
EXPERIMENTAL
Alkyl methylphosphonic acid esters were prepared as follows. Alcohol
(
16.5 mmol of either cylcohexanol [1.64 g] or isopropanol [0.992 g]) was
dissolved in 2.0 mL of dry toluene and placed in an additional funnel
that had been swept with dry nitrogen. Methylphosphonic dichloride
(
2.18 g, 16.5 mmol), dissolved in 2.0 mL of dry toluene, placed into
a dried 100-mL round-bottomed flask maintained under dry nitrogen,
and equipped with a reflux condenser. Alcohol was added dropwise to
the round-bottomed flask at ambient temperature. The reaction was
◦
stirred for 15 min before bringing to reflux at 105 C for 2 h.
◦
The reaction mixture was quenched while still warm (ca. 80 C) with
two equivalents of water (0.60 mL), and then refluxed for an additional

1
890
G. M. Mong et al.
1
0 min. The reaction was cooled and the organic phase (approximately
4.0 mL of yellow liquid) was separated from the denser aqueous layer.
Methylphosphonic acid was removed by adding 5.0 mL of chloro-
form to the acidic extract and back-extracting the chloroform two times
isopropyl synthesis) or three times (cyclohexyl synthesis) with 3.0 mL
(
portions of water. The chloroform extracts were dried over sodium sul-
fate followed by quantitative removal of the chloroform under vacuum.
Overall yields of purified extracted product were 38% for isopropyl
methylphosphonic acid and 31% for cyclohexyl methylphosphonic acid
(
based on the weight of purified product remaining after removal of
chloroform).
The temperature-programmed GC retention indices for methyl
derivatives and trimethylsilyl (TMS) derivatives were determined
by a linear interpolation between bracketing n-alkanes on a capil-
lary column coated with a 1.0 µm film of poly (5% diphenyl/95%
dimethylsiloxane). Trimethylsilyl derivatives were created using bis-
1
0
(
trimethylsilyl)trifluoroacetamide (BSTFA). GC-EI-MS data (70 eV)
were collected using a Hewlett-Packard Model 5890 GC (Agilent, Palo
Alto, CA, USA) interfaced with a Hewlett-Packard 5972 mass spectrom-
◦
eter through a heated transfer line (280 C). Splitless sample introduc-
◦
tion (injection port at 250 C) was followed by separation on a Restek
(
Bellefonte, PA, USA) Rtx-5 capillary column [30-m × 0.25-mm i.d., df =
0
.25 µm film of bonded poly (5% diphenyl/95% dimethylsiloxane) sta-
◦
tionary phase]. After an initial hold at 45 C for 2 min, the column was
◦
◦
programmed to 250 C at 8 C/min and held at this final temperature
for 5 min. This program was adequate to elute all expected products
and dimers from the chromatographic system. GC-CI-MS data were
determined using a Hewlett-Packard Model 5890 GC interfaced with
a JEOL SX102/SX102 mass spectrometer (Peabody, MA, USA) oper-
◦
ated in the CI mode (source temperature 190 C, source pressure 2 ×
−
4
1
0
torr) using isobutane reagent gas to observe M+1 ions. The JEOL
instrument used a column identical to that used to collect EI-MS data.
REFERENCES
[
[
[
[
1] Isopropyl methylphosphonic acid was, at one time, available as Aldrich Chemical
Company product number 45,874-0. This product has since been discontinued.
2] N. B. Munro, S. S. Talmage, G. D. Griffin, L. C. Waters, A. P. Watson, J. F. King, et al.
Environmental Health Perspectives, 107, 933 (1999).
3] R. A. Chittenden, C. R. Hall, T. D. Inch, N. H. Nicholson, and C. Pottage, Tetrahedron
Letters, 37, 3557 (1979).
4] C. M. Timperley, M. Bird, I. Holden, and R. M. Black, J. Chem. Soc. Perkin Trans.
1, 1, 26 (2001).

Alkyl Methylphosphonic Acid Esters
1891
[
[
[
5] A. Pienaar, C. M. Erasmus, M. Wentzel, and E. H. Cowley, Phosphorus, Sulfur, and
Silicon, 148, 149 (1999).
6] K. A. Petrov, R. A. Baksova, L. V. Korkhoyanu, L. P. Sinogeikina, and T. V. Skudina,
Journal of General Chemistry of the USSR, 35, 723 (1965).
7] The method of Fieser using N-methyl-N-nitrosourea was employed (L. F. Fieser
and M. Fieser, Reagents for Organic Synthesis, Vol .1, p. 192 (New York: John Wiley
and Sons, 1967). Solutions of diazomethane are prepared by simply decanting the
ethereal reagent from an aqueous base.
[
[
8] G. M. Mong and J. A. Campbell, J. Radioanalytical and Nuclear Chemistry, 241,
297 (1999).
9] C. J. Hardy and D. Seargill, J. Inorg. Nuclear Chem., 10, 323 (1959).
[
10] Use of BSTFA can be found in: D. R. Knapp, Handbook of Analytical Derivatization
Reactions (New York: John Wiley and Sons, 1979).