Preparation, derivatization with trimethylsilyldiazomethane, and GC/MS analysis of a "pool" of alkyl methylphosphonic acids for use as qualitative standards in support of counterterrorism and the chemical weapons convention

Article abstract of DOI:10.1080/10426500490459632

There are hundreds of nerve agents in the class of alkyl methylphosphonofluoridates covered by Schedule 1 of the CWC (Chemical Weapons Convention). Hydrolysis of these sarin-like nerve agents results in an equal number of alkyl methylphosphonic acids. These alkyl methylphosphonic acids are persistent and provide good evidence of specific agent production or use. In order to support the CWC and counterterrorism activities, it is desirable to have ready access to each of these hydrolysis products for use as qualitative standards. A means for simultaneously producing multiple alkyl methylphosphonates from methylphosphonic acid and the corresponding alcohols was developed. Derivatization of these alkyl methylphosphonic acids with trimethylsilyldiazomethane yields the corresponding methyl esters which are suitable for GC/MS analysis.

Full text of DOI:10.1080/10426500490459632

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Phosphorus, Sulfur, and Silicon and the Related
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PREPARATION, DERIVATIZATION WITH
TRIMETHYLSILYLDIAZOMETHANE, AND GC/MS ANALYSIS
OF A “POOL” OF ALKYL METHYLPHOSPHONIC ACIDS
FOR USE AS QUALITATIVE STANDARDS IN SUPPORT OF
COUNTERTERRORISM AND THE CHEMICAL WEAPONS
CONVENTION
Michael D. Crenshaw a & David B. Cummings a
a Battelle Memorial Institute , Columbus, Ohio, USA
Published online: 16 Aug 2010.
To cite this article: Michael D. Crenshaw & David B. Cummings (2004) PREPARATION, DERIVATIZATION WITH
TRIMETHYLSILYLDIAZOMETHANE, AND GC/MS ANALYSIS OF A “POOL” OF ALKYL METHYLPHOSPHONIC ACIDS FOR USE AS
QUALITATIVE STANDARDS IN SUPPORT OF COUNTERTERRORISM AND THE CHEMICAL WEAPONS CONVENTION, Phosphorus, Sulfur,
and Silicon and the Related Elements, 179:6, 1009-1018, DOI: 10.1080/10426500490459632
To link to this article: http://dx.doi.org/10.1080/10426500490459632
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Phosphorus, Sulfur, and Silicon, 179:1009–1018, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490459632
PREPARATION, DERIVATIZATION WITH
TRIMETHYLSILYLDIAZOMETHANE, AND GC/MS
ANALYSIS OF A “POOL” OF ALKYL
METHYLPHOSPHONIC ACIDS FOR USE AS
QUALITATIVE STANDARDS IN SUPPORT OF
COUNTERTERRORISM AND THE CHEMICAL
WEAPONS CONVENTION
Michael D. Crenshaw and David B. Cummings
Battelle Memorial Institute, Columbus, Ohio, USA
(Received July 10, 2002; accepted September 30, 2003)
There are hundreds of nerve agents in the class of alkyl methylphos-
phonofluoridates covered by Schedule 1 of the CWC (Chemical Weapons
Convention). Hydrolysis of these sarin-like nerve agents results in an
equal number of alkyl methylphosphonic acids. These alkyl methylphos-
phonic acids are persistent and provide good evidence of specific agent
production or use. In order to support the CWC and counterterrorism
activities, it is desirable to have ready access to each of these hydrolysis
products for use as qualitative standards. A means for simultaneously
producing multiple alkyl methylphosphonates from methylphosphonic
acid and the corresponding alcohols was developed. Derivatization of
these alkyl methylphosphonic acids with trimethylsilyldiazomethane
yields the corresponding methyl esters which are suitable for GC/MS
analysis.
Keywords: Alkyl methylphosphonic acid; chemical warfare agents;
counterterrorism; esterification; mass spectra; trimethylsilyldiazo-
methane
The ability to detect a greater variety of chemical weapons and related
chemicals has become more urgent as information that was once privy
to the military becomes increasingly available. The large number of
potential chemical warfare agents as described in the CWC (Chemical
Weapons Convention) adds to the complexity of this problem.
∗Current address: Southwest Research Institute, PO Box 237, Johnston Atoll, APO,
AP 96558.
Address correspondence to Michael D. Crenshaw, Battelle Memorial Institute, 505
King Avenue, Columbus, OH 43201, USA. E-mail: crenshaw@battelle.org
1009

1010
M. D. Crenshaw and D. B. Cummings
The CWC prohibits the production, storage, and use of chemical
weapons.∗ Signatory countries that possess chemical weapons also
agree to dispose of their stockpiles. Schedule 1 of the CWC lists specific
as well as classes of highly toxic chemicals that are highly toxic with
no known licit use. Included in Schedule 1 are the neurotoxic chem-
icals of the type RP(O)F(OR’) where R may be C1−3 and Rꢁ may be
C1−10. Sarin (isopropyl methylphosphonofluoridate) and soman (pina-
colyl methylphosphonofluoridate) are two specific examples of this class
of compounds of which there are 3652 possibilities.1 Verification of com-
pliance with the CWC allows for on-site inspections and the use of
chemical analyses, including gas chromatography-mass spectrometry
for definitive identification as required by the OPCW (Organization for
the Prohibition of Chemical Weapons).∗∗ However, terrorist may pro-
duce and use one or more of these nerve agents. Such an event occurred
in the Tokyo subway on March 20, 1995.
Sarin, 1a, and soman, 1b, are known to hydrolyze to isopropyl
methylphosphonic acid, 2a, and pinacolyl methylphosphonic acid, 2b
respectively (Scheme 1).2 The remaining alkyl methylphosphonofluo-
ridates covered by the CWC are expected to hydrolyze in the same
manner. These alkyl methylphosphonic acids are persistent and provide
good evidence of specific agent production or use. Reported here are sim-
ple and convenient methods for preparing a “pool” of alkyl methylphos-
phonic acid standards that would be necessary to identify specific nerve
agent hydrolysis products.∗∗∗
SCHEME 1 Hydrolysis reaction of alkyl methylphosphonofluoridate nerve
agents.
For the preparation of monoesters of methylphosphonic acid, a
method was sought that would be applicable to the simultaneous
∗Convention on the Prohibition of the Development, Stockpiling, and Use of Chemical
Weapons and on their Destruction, United States Arms Control and Disarmament Agency,
Washington, D.C., 1993. As of December 31, 2001 there were 145 State Parties to the CWC,
www.opc.org.
∗∗The OPCW is responsible for monitoring the CWC.
∗∗∗Prof. Hoffmann, while suggesting alternatives for the term “library,” noted that
“pool” was initially used by combinatorial chemists.3

Alkyl Methylphosphonic Acids
1011
preparation of a large number of these monoesters such as a reaction
analogous to the acid-catalyzed esterification of carboxylic acids with
alcohols. Such a method would provide a means for obtaining the mass
spectra of a large number of hydrolysis products from sarin-like chem-
ical warfare agents. However, no such method for the esterification of
methylphosphonic acid has been reported. Previously reported methods
for synthesizing alkyl methylphosphonic acids include the reaction of an
alcohol with methylphosphonic anhydride,4,5 partial hydrolysis of the
dialkyl ester of methylphosphonic acid,6,7 hydrolysis of the monochloro
monoester8,9 and hydrogenation of the benzyl alkyl ester.10
Derivatization of alkyl methylphosphonic acids prior to analysis
by gas chromatography has been used for forensic analyses from the
sarin attack at the Tokyo subway.8,11,12 The methods for derivatizing
alkyl methylphosphonic acids include silylation,13−17 methylation with
diazomethane18−20 or trimethylphenylammonium hydroxide,21,22 and
other alkylations.23−25
RESULTS AND DISCUSSION
Reported here is a new method for preparing alkyl methylphosphonic
acids. Heating a mixture of methylphosphonic acid (3), 1-butanol, and
an aqueous solution of arsenic(V) acid in toluene for 48 h with azeotropic
removal of the water gave the dibutyl ester of methylphosphonic acid
as indicated by analysis of the reaction mixture. Further analysis of the
reaction mixture showed that dibutyl methylphosphonate was present
only in very small amounts and that the predominant product was the
monoester, butyl methylphosphonic acid.
Subsequently, phenylarsonic acid was substituted for arsenic acid to
reduce the loss of lower boiling alcohols through azeotropic distillation.
This method for preparing monoalkyl esters of methylphosphonic acid
was found to be successful with primary and secondary alcohols, includ-
ing cyclic alcohols and alcohols containing an ether group (Scheme 2).
The alcohols used, in order of increasing number of carbons, are:
ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, 2-butanol, 2-
methyl-1-propanol, cyclopropanemethanol, 2-ethoxyethanol, pentanol,
SCHEME 2 Preparation of alkyl methylphosphonates, 2.

1012
M. D. Crenshaw and D. B. Cummings
cyclobutanemethanol, 3-methylbutanol, 2-isopropoxyethanol, hexanol,
pinacolyl alcohol, cyclohexanol, 2-methylcyclohexanol, octanol, 2-
ethylhexanol, decanol, and (−)-borneol. With cyclopentanol, the prod-
uct initially was formed during the reaction but decomposed prior to
completion.
Substitution of p-toluenesulfonic acid for phenylarsonic acid did not
result in the esterification of methylphosphonic acid. This observation
has led us to speculate that the mechanism involves the formation of an
arsonic acid ester followed by transesterification to produce the phos-
phonic acid ester.
Trimethylsilyldiazomethane, a stable and commercially-available
reagent, has been shown to readily form the methyl esters of carboxylic
acids.26 The suitability of trimethylsilyldiazomethane for the methyla-
tion of alkyl methylphosphonic acids was demonstrated by us.27 Addi-
tion of a 2.0 M solution of trimethylsilyldiazomethane in THF to a mix-
ture of benzene, chloroform, or MTBE with methanol (or other alcohol)
containing a portion of the reaction mixture of alkyl methylphosphonic
acids provides the corresponding alkyl methyl methylphosphonates, 4
(Scheme 3). These alkyl methyl methylphosphonates are readily ana-
lyzed by GC/MS. In this way, an alkyl methylphosphonic acid or a group
of isomeric alkyl methylphosphonic acids suspected of being present in
a sample can be readily prepared and used as qualitative standards.
Other techniques, such as the retention index method28,29and a com-
puter algorithm for determining the type of phosphorus ester1 also can
be used to assist in this determination.
SCHEME 3 Derivatization of 2 to yield the methyl esters, 4.
During the derivatization, the methanol acts as a hydrogen source
and other alcohols (e.g., ethanol and 1-hexanol) may be substituted
for it and still provide the methyl ester with no apparent impact on
efficiency. Omission of an alcohol or addition of the trimethylsilyldia-
zomethane to the phosphonic acid prior to the addition of the alcohol
results in a mixture of esters being formed, specifically the methyl ester,
the (trimethylsilyl)methyl ester, and the trimethylsilyl ester.27
Figure 1 shows the chromatogram from derivatization and GC/MS
analysis of the reaction mixture when methylphosphonic acid was
simultaneously esterified with seven straight-chain alcohols. Figure 2

Alkyl Methylphosphonic Acids
1013
FIGURE 1 Total ion current chromatogram from derivatization and GC/MS
analysis of a reaction mixture containing: (a) ethyl methylphosphonic acid;
(b) propyl methylphosphonic acid; (c) butyl methylphosphonic acid; (d) pentyl
methylphosphonic acid; (e) hexyl methylphosphonic acid; (f) octyl methylphos-
phonic acid; (g) decyl methylphosphonic acid.
shows the chromatogram from derivatization and GC/MS analysis
of the reaction mixture when methylphosphonic acid was esteri-
fied with 11 additional alcohols, including secondary alcohols and
branched-chain alcohols. Methylphosphonic acid appears to react
less readily with the sterically hindered alcohols, pinacolyl alcohol,
2-methylcyclohexanol, (−)-borneol, based on the relative chromato-
graphic peak intensities. It is not known if the efficiency of the deriva-
tization is affected by the presence of bulky ester groups. Alcohols with
an asymmetric center give rise to diastereomers that can be separated
on the GC column. In most cases this resolution is complete, but it is
less than 20% for the diastereomers of sec-butyl methyl methylphos-
phonate and less than 5% for the diastereomers of 2-ethylhexyl methyl
methylphosphonate.

1014
M. D. Crenshaw and D. B. Cummings
FIGURE 2 Total ion current chromatogram from derivatization and GC/MS
analysis of a reaction mixture containing: (a) isopropyl methylphosphonic acid;
(b) sec-butyl methylphosphonic acid; (c) isobutyl methylphosphonic acid; (d) cy-
clopropanemethyl methylphosphonic acid; (e) isoamyl methylphosphonic acid;
(f) pinacolyl methylphosphonic acid; (g) cyclobutanemethyl methylphosphonic
acid; (h) cyclohexyl methylphosphonic acid; (i) 2-methylcyclohexyl methylphos-
phonic acid; (j) 2-ethylhexyl methylphosphonic acid; (k) bornyl methylphospho-
nic acid.
For each alkyl methyl methylphosphonate listed in the text, a tabu-
lar listing of those ions with a relative abundance equal to or greater
than three per cent are presented in Tables I–III. For those that give
diastereomers, relative abundances for both are listed. Because an ion
trap was used to acquire the spectra, an ion corresponding to m/z M +
1 is generally observed, resulting from self-chemical ionization within
the ion trap.30 Often the most abundant ion in each of the spectra is
that with m/z 111 resulting from loss of the alkyl ester group (Figure 3).
Continuing studies involve the application of these methods to the
preparation of multigram quantities of alkyl esters of phosphorus acids

Alkyl Methylphosphonic Acids
1015
TABLE I Relative Ion Abundances of Derivatized n-Alkyl Methylphosphonic
Acid Monoesters shown in Figure 1
Phosphonate
m/z (relative abundance)
Ethyl methyl
methylphosphonate (MW 138)
63 (11.2), 65 (8.0), 79 (18.8), 80 (6.6), 93 (39.4),
94 (12.1), 95 (9.8), 111 (76.0), 112 (18.4), 113 (3.9),
139 (100.0)
Methyl n-propyl
methylphosphonate (MW 152)
63 (18.9), 65 (5.0), 66 (3.3), 79 (15.2), 81 (4.2),
93 (38.2), 94 (71.5), 111 (100.0), 112 (47.0),
123 (9.1), 137 (8.8), 151 (3.0), 153 (78.0)
63 (8.6), 79 (5.4), 93 (32.0), 94 (26.7), 111 (100.0),
112 (4.0), 137 (9.4), 167 (24.6)
63 (6.6), 79 (4.8), 93 (43.4), 94 (6.2), 95 (6.7),
111 (100.0), 112 (3.2), 137 (6.0), 181 (14.4)
63 (5.2), 79 (4.1), 93 (35.1), 94 (9.8), 95 (4.4),
111 (100.0), 112 (3.5), 137 (3.3), 195 (11.4)
63 (3.3), 79 (3.2), 93 (25.2), 94 (14.1), 111 (100.0),
112 (3.7), 223 (6.1)
n-Butyl methyl
methylphosphonate (MW 166)
Methyl n-pentyl
methylphosphonate (MW 180)
n-Hexyl methyl
methylphosphonate (MW 194)
Methyl n-octyl
methylphosphonate (MW 222)
n-Decyl methyl
93 (20.7), 94 (10.5), 111 (100.0), 112 (3.9), 251 (4.0)
methylphosphonate (MW 250)
and to the analysis of monoesters of alkylphosphonic acids in matrices
relevant to the support of the CWC and counterterrorism activities.
EXPERIMENTAL
All chemicals were purchased from Aldrich, Pfaltz & Baur, or Lancaster.
Typical procedure for the esterification of methylphosphonic
acid with multiple alcohols: methylphosphonic acid (1.6 g), ethanol
(1.5 mL), propanol (0.61 mL), butanol (0.22 mL), pentanol (0.26 mL),
hexanol (0.31 mL), octanol (0.38 mL), decanol (0.47 mL), phenylarsonic
acid (0.13 g) were heated under an atmosphere of dry nitrogen in 80 mL
of toluene for 28 h with continuous azeotropic removal of the water
formed. Upon cooling, a portion of the reaction mixture is derivatized
as described below.
Typical procedure for the methylation of alkyl methylphos-
phonic acids: 20 µL of 2.0 M trimethylsilyldiazomethane in THF is
added to a mixture of 800 µL of benzene, 200 µL of methanol, and 40 µL
FIGURE 3 Representation of characteristic ion m/z 111.

1016
M. D. Crenshaw and D. B. Cummings
TABLE II Relative Ion Abundances of Derivatized Iso- and Cyclo-alkyl
Methylphosphonic Acid Monoesters shown in Figure 2
Phosphonate
m/z (relative abundance)
Isopropyl methyl
methylphosphonate
(MW 152)
63 (15.9), 65 (5.2), 79 (9.7), 80 (5.1), 93 (79.3), 94 (8.4),
95 (7.9), 111 (91.9), 112 (9.6), 137 (36.8), 138 (3.7),
151 (3.3), 153 (100.0)
sec-Butyl
methyl methylphosphonate
(MW 166)
63 (14.7, 16.1), 79 (5.5, 7.0), 93 (67.2, 83.9), 94 (26.4, 8.2),
111 (100.0, 94.5), 112 (17.2, 18.6), 137 (66.3, 57.4),
138 (9.6, 5.2), 151 (19.9, 14.2), 167 (71.6, 100.0)
63 (9.1), 79 (17.9), 93 (43.8), 94 (23.9), 111 (100.0),
112 (9.5), 124 (4.1), 151 (8.2), 167 (58.0)
54 (7.0), 55 (3.8), 63 (22.3), 79 (4.9), 93 (78.6), 94 (12.1),
111 (100.0), 112 (6.4), 123 (11.8), 165 (29.5)
63 (5.8), 79 (4.7), 93 (40.8), 94 (8.4), 111 (100.0), 112 (3.2),
137 (11.7), 181 (27.4)
63 (7.4, 6.7), 79 (11.5, 15.0), 93 (35.8, 29.6), 94 (9.1, 12.7),
111 (100.0, 100.0), 137 (20.1, 21.2), 138 (19.8, 26.9)
63 (7.8), 67 (3.4), 79 (16.0), 93 (34.7), 94 (12.8), 96 (8.1),
97 (4.8), 111 (100.0), 149 (5.9), 150 (13.8), 179 (20.5)
63 (5.2), 79 (8.3), 93 (32.2), 94 (13.3), 110 (3.7),
111 (100.0), 163 (4.3), 193 (10.4)
Isobutyl methyl
methylphosphonate (MW 166)
Cyclopropanemethyl methyl
methylphosphonate (MW 164)
Isoamyl methyl
methylphosphonate (MW 180)
Methyl pinacolyl
methylphosphonate (MW 194)
Cyclobutanemethyl methyl
methylphosphonate (MW 178)
Cyclohexyl methyl
methylphosphonate (MW 192)
Methyl 2-methylcyclohexyl
methylphosphonate (MW 206)
2-Ethylhexyl methyl
63 (5.3, 4.9), 79 (7.1, 7.0), 81 (4.4, 4.6), 93 (27.9, 27.7),
111 (100.0, 100.0)
55 (3.6, 3.8), 63 (3.1, 3.0), 79 (10.1, 9.7), 93 (23.8, 20.2),
94 (20.4, 17.2), 111 (100.0, 100.0), 124 (10.0, 7.3),
223 (6.4, 7.9)
methylphosphonate (MW 222)
Bornyl methyl
methylphosphonate (MW 246)
63 (7.6, 7.3), 65 (5.3, 4.8), 67 (8.7, 8.5), 77 (14.3, 13.8),
78 (6.8, 6.1), 79 (18.3, 18.4), 80 (6.5, 7.5), 91 (34.2, 33.4),
92 (27.7, 28.5), 93 (100.0, 100.0), 94 (9.2, 9.8),
95 (11.9, 11.6), 105 (6.6, 6.3), 107 (9.0, 8.7),
108 (12.0, 12.9), 111 (60.3, 57.2), 121 (33.7, 32.5), 122
(3.3, 3.0), 136 (33.9, 35.3), 137 (40.8, 42.8)
TABLE III Relative Ion Abundances of Derivatized Alkoxyalkyl
Methylphosphonic Acid Monoesters
Phosphonate
m/z (relative abundance)
2-Methoxyethyl methyl
methylphosphonate
(MW 168)
58 (5.6), 63 (16.7), 79 (4.7), 93 (52.4), 94 (8.4),
108 (7.4), 111 (100.0), 125 (9.6), 137 (4.1),
138 (16.6), 169 (17.9)
2-Ethoxyethyl methyl
methylphosphonate
(MW 182)
2-Isopropoxyethyl methyl
methylphosphonate
(MW 196)
63 (11.5), 79 (24.2), 93 (42.0), 94 (26.1), 108 (3.3),
111 (100.0), 124 (3.1), 125 (18.4), 137 (14.5),
138 (15.0), 139 (3.5), 169 (4.2), 183 (22.2)
58 (11.9), 63 (12.0), 79 (44.8), 93 (55.0), 94 (81.4),
111 (100.0), 112 (3.4), 124 (42.6), 125 (10.4), 137
(55.6), 138 (12.0), 155 (4.8), 183 (5.7), 197 (46.7)

Alkyl Methylphosphonic Acids
TABLE IV GC/MS Parameters
1017
Instrument: Finnigan GCQ (ion trap)
GC Injector Temp: 260◦C
Injection Volume: 1 µL, splitless
Carrier Gas: He, 1 mL/min
GC Column: Restek Rtx-200, 30 m × 0.25 mm, 25 µm film thickness
Oven Temp.: 45◦C for 4.3 min; 12◦C/min to 270◦C; hold 270◦C 5 min.
Transfer Line: 270◦C
MS: + EI, scan 50–440 amu
of the reaction mixture containing the alkyl methylphosphonic acid in
toluene at ambient temperature. The esterification is complete in less
than 30 min and this derivatized mixture is injected directly into the
gas chromatograph-mass spectrometer without any further work-up.
GC/MS instrument conditions are described in Table IV.
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