Microwave induced synthesis of O,O-dialkyl dialkylpyrophosphonates under solvent free conditions: Markers of nerve agents

Article abstract of DOI:10.1071/CH07375

This article describes a one pot, solvent free, microwave assisted synthesis of O,O-dialkyl dialkylpyrophosphonates (DADAPP) from O-alkyl alkylphosphonic chlorides 2a?j with 4-dimethylaminopyridine (DMAP) in the presence of water under microwave irradiation. The reaction takes place by the phosphonium salts, which are converted into the DADAPPs 4a?j. These DADAPPs are important markers of chemical warfare agents sarin, soman, and VX and their analogues. The method has several advantages over the conventional methods such as operational simplicity, high yield, and reduced reaction time. CSIRO 2008.

Full text of DOI:10.1071/CH07375

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 476–480
www.publish.csiro.au/journals/ajc
Microwave Induced Synthesis of O,O-Dialkyl
Dialkylpyrophosphonates under Solvent Free
Conditions: Markers of Nerve Agents
A
A
A
A
Rajesh Kumar, Deepak Pardasani, Avik Mazumder, Devendra K. Dubey,
A,B
and Arvind K. Gupta
A
Vertox Laboratory Defence R & D Establishment, Jhansi Road, Gwalior-474002 (MP), India.
Corresponding author. Email: arvindkumargupta2@rediffmail.com
B
This article describes a one pot, solvent free, microwave assisted synthesis of O,O-dialkyl dialkylpyrophosphonates
DADAPP) from O-alkyl alkylphosphonic chlorides 2a–j with 4-dimethylaminopyridine (DMAP) in the presence of
(
water under microwave irradiation. The reaction takes place by the phosphonium salts, which are converted into the
DADAPPs 4a–j. These DADAPPs are important markers of chemical warfare agents sarin, soman, and VX and their
analogues. The method has several advantages over the conventional methods such as operational simplicity, high yield,
and reduced reaction time.
Manuscript received: 25 October 2007.
Final version: 16 April 2008.
O
Introduction
OR1
O
O
P
R
P
OR1
The development of new efficient synthetic procedures for
the verification analysis of chemical warfare agents (CWAs)
and related compounds is a prominent area of contemporary
R
[
1–6]
research.
This field of synthesis and analysis has attracted
Fig. 1. General structure of O,O-dialkyl dialkylpyrophosphonates.
the attention of several workers because of a strict verification
program of the Chemical Weapons Convention (CWC). The
CWC prohibits the production, storage, and use of chemical
weapons and is administered by an international organization
known as the Organization for Prohibition of ChemicalWeapons
tabun, and VX) but also their precursors and degradation prod-
ucts. The CRCs that have been identified for the application of
verification measures are listed in three schedules based on their
past uses.[
[
7–11]
(
OPCW).
The verification of CWC related chemicals (CRCs) involves
7,10]
chemical analysis of samples collected during inspections con-
ducted under supervision of OPCW. The analysis is performed
O,O-Dialkyl dialkylpyrophosphonates (DADAPPs) are often
produced when highly toxic chemical warfare agents such as
sarin, soman, VX, and their analogues are prepared in any lab-
oratoryorplant.ThusDADAPPsmaybeconsideredasimportant
either on-site by the inspectors or, if deemed necessary, off-site
by at least two laboratories designated by the OPCW.[
11–13]
The
status of a designated laboratory can be achieved by successful
performance in international official proficiency tests (OPTs)
conducted by the OPCW. The OPTs are conducted according to
forensic markers for the verification of these agents and are
covered in the list of CWC text under schedule 2B4.[
8,22]
How-
ever, the spectroscopic data of only a handful of DADAPPs are
available in the literature. These compounds have been recently
standard procedures and performance of participants is judged
as per the norms set by the OPCW.[
14,15]
The prerequisites for
spiked in official proficiency tests as markers of nerve agents.
[23]
successful performance in OPTs depend on the availability of
spectroscopic databases of CRCs. Consequently, a great deal
of work has been devoted to the building up of spectroscopic
Thus, the generation of a spectroscopic database of DADAPPs
is an important goal of the verification regime of the CWC. The
general structure of such DADAPPs is shown in Fig. 1.
[
16–21]
libraries of CRCs.
In such analyses, final structures of ana-
There are several methods for the synthesis of DADAPPs.The
precedent literature revealed that the synthesis of DADAPPs is
associated with several drawbacks such as prolonged reaction
time, use of carcinogenic solvents, harsh reaction conditions,
and tedious workup, and chromatographic techniques are often
lytes are confirmed by synthesizing the reference chemicals and
matching the spectra (mostly gas chromatography/mass spec-
trometry (GC/MS) and 31P NMR). Because OPTs are a time
bound activity, i.e., the analysis results have to be submitted
[12–14]
[24–27]
within a stipulated period of 15 days,
there is dire need to
used to afford the compounds with desired purity.
develop an efficient synthetic procedure that can be used to pre-
pareseveralcompoundssimultaneouslyforscreeningbyGC/MS
and other spectroscopic techniques.
The chemicals relevant to the convention (CRCs) not only
include the infamous chemical warfare agents (like sarin, soman,
Recently, there has been considerable interest in the
microwave induced synthesis of a variety of organic compounds
because of the selective absorption of microwave energy by polar
molecules.[ Microwave assisted organic synthesis is known
for the spectacular accelerations produced in many reactions as
28]
©
CSIRO 2008
10.1071/CH07375
0004-9425/08/060476

Microwave Induced Synthesis of O,O-Dialkyl Dialkylpyrophosphonates
477
O
P
Cl
Cl
O
P
Table 1. Optimization of reaction conditions by performing the model
reaction of O-ethyl methylphosphonic chloride with dimethyl amino
pyridine (DMAP) under microwave irradiation
OR1
Cl
R OH
1
R
R
N(C H )
5 3
2
Reactions were monitored by TLC and 31P NMR spectroscopy in CDCl3 at
2a–j
1
MW
162 MHz
1
80W, 4min 4-Dimethylaminopyridine
Entry
DMAP
Moisture
[%]
Microwave
power
W]
Time
[min]
Conversion
[%]
H O
2
[
mol-%]
O
P
OR1
[
O
P
OR1
R
O
P
OR1
1
2
3
4
5
6
7
8
9
10
30
50
20
20
20
20
20
20
40
40
15
20
100
180
180
180
180
180
180
360
180
100
4
4
4
4
4
5
5
5
5
5
15
37
45
68
80
O
R
ϩ
Ϫ
Cl
R
H C
N
N
3
4a–j
75
H C
3
100
100
100
100
100
100
3a–j
100
74
63
i
R ϭ CH , C H
3
3
7
i
R1 ϭ C H , C H , C H , C H , C H
A
2
5
3
7
4
9
4
9
5
11
90
50
Scheme 1.
1
0
AOther un-desired products were observed by TLC.
compared with literature values and found to be within range.[33]
It is worth noting that the signal of the O-alkyl alkylphospho-
nochloridates 2a–j disappeared with the appearance of a new
signal in the range of 22–31 ppm for 4a–j. These compounds
have shown two signals in the 31P NMR spectra as a result of two
stereogenic centres (Table 2). The results of the other analyses
of 4a–j are compiled in the experimental section.
a consequence of the heating rate and cannot be easily repro-
duced by classical heating. It results in higher yields of products
with easy workup and shorter reaction times.[29]
Results and Discussion
Experimental
Inspired by the concept of microwave heating, it was thought that
DADAPPscouldbepreparedfromO-alkylalkylphosphonochlo-
ridates 2a–j.To address this possibility, we began the preparation
of alkyl phosphonic dichloride 1 by the reported method.[ The
intermediate 1 was reacted with various alcohols in the presence
General
A domestic microwave oven (LG, Model MG-555F, New Delhi)
with variable irradiating powers was used.
30]
Boiling points are uncorrected. IR spectra were recorded on
a Bruker FT-IR spectrometer model Tensor 27 using KBr disks.
◦
◦
of triethylamine at 0 C followed by heating at 50 C, to give rise
1
13
31
[31]
H, C, and P NMR spectra were recorded in CDCl3 on a
to O-alkyl alkylphosphonic chlorides 2a–h.
Bruker DPXAvance FT-NMR at 400, 200, and 162 MHz, respec-
After having the intermediate (O-alkyl alkylphosphonochlo-
ridates 2a–j) in hand, we optimized the reaction conditions to
obtain DADAPPs. In this regard, several reactions of O-ethyl
methylphosphonic chloride with various bases such as dimethyl
amino pyridine (DMAP), pyridine, triethylamine, diethyl ani-
line, N-methyl imidazole, and diisopropyl ethylamine were
performed as a model reaction in the presence or absence of
water under identical microwave power.The maximum yield was
obtained when DMAP was used in the presence of water. Fur-
thermore, to optimize the molar ratio of DMAP, various reactions
of O-ethyl methylphosphonic chloride were also performed by
changing the amount of DMAP, reaction time, amount of water,
and microwave power. These reactions were monitored by TLC
1
tively, using tetramethylsilane as an internal standard for H and
13
31
C, and 85% H3PO4 as an external standard for P. A Chemito
GC model 1000 instrument was used with a flame ionization
detector (FID). A capillary column (30 m × 0.25 mm I.D-BP5)
packed with 5% phenyl and 95% dimethyl polysiloxane (SGE)
coated on fused silica was employed. The injection port and
detector block were maintained at 280 and 260 C, respectively,
and the column oven was at a programmed temperature pro-
◦
◦
◦
file which started at 50 C, and was ramped up to 280 C at
◦ −1
5 C min . Nitrogen was used as a carrier gas (at a flow rate
2
−
1
−1
of 30 mL min ).Air for the FID was supplied at 300 mL min
−
1
and hydrogen at 30 mL min . In all analyses, 0.1 µL of sample
was injected and peaks were recorded on an Iris32 data acqui-
sition station. The GC-MS analyses were performed by electron
ionization (EI, 70 eV) in full scan mode with an Agilent 6890
GC equipped with a model 5973 mass selective detector (Agilent
Technologies, USA).An SGE BPX5 capillary column with 30 m
length × 0.32 mm internal diameter × 0.25 µm film thickness
3
1
and P NMR spectroscopy. The results obtained from this study
Table 1) revealed that the best results were obtained when the
(
model reaction was performed with DMAP and water in a mole
ratio of 1:1:0.2 at 180W for 5 min (entry 6, Table 1). The results
3
1
of P NMR analysis also showed that DADAPP is formed by the
formation of the corresponding phosphonium salt (Scheme 1).
After optimization, the general applicability of the method
was tested with a diversity of structures (2a–j) and the results of
the reactions are summarized in Table 2. The compounds 4a–j
were characterized by spectroscopic techniques such as infrared
spectroscopy (FT-IR), NMR, GC/MS, and elemental analysis.
The results of FT-IR analysis showed the characteristic strong
◦
was used with a temperature program of 80 C for 2 min and heat-
◦
−1
◦
ing at 20 C min to 280 C for 3 min. Helium was used as the
carrier gas at a constant flow rate of 1.2 mL min . The samples
were analyzed in split less mode at injection temperature.
−
1
General Procedure for the Preparation of Diethyl
Dimethylpyrophosphonate 4a
−
1
and broad bands in the range of 975–969 cm , attributable to
[32]
the antisymmetric stretching of the P–O–P linkage. The other
4-DMAP (1.22 g, 0.01 mol) was placed in a conical flask and O-
frequencies assigned to the P–O–C, P–C, and P=O linkage were
ethyl methylphosphonic chloride (1.32 g, 0.01 mol) was added

4
78
R. Kumar et al.
Table 2. Synthesis of O,O-dialkyl dialkylpyrophosphonates 4a–j using microwave irradiation
YieldA
%]
Boiling
point
C mmHg
31
P NMR
Entry
Substrate
Product
B
[
[δ ppm]
◦
−1
]
[
O
P
OC H5
2
O
P
2
OC H5
CH3
O
OC H5
2
4
4
4
a
b
c
86.2
90.5
92.4
115/2
22.49, 22.18
26.32, 26.01
26.26, 25.94
CH3
O
P
Cl
CH3
O
P
OC H7
3
O
OC H7
3
O
CH3
OC3H7
CH3
120/2
CH3
P
O P
Cl
O
P
OC H9
4
O
P
OC H9
4
CH3
O
O
OC H9
4
135/1.5
CH3
P
Cl
CH3
O
OC H
5
11
O
OC H
5
11
CH3
P
O
OC H
5
11
4
4
4
d
e
f
90.3
87.6
88.7
145/1.5
160/1.5
132/1
26.26, 25.94
22.61–20.96
28.25, 28.19
CH3
P
O
P
Cl
CH3
O
P
OCH(CH )C(CH )
3 3 3
O
P
OCH(CH )C(CH )
O
3
3
3
OCH(CH )C(CH )
3
3
3
CH3
CH3
O
P
Cl
CH3
O
OC H5
2
O
P
i
7
OC H5
C H
P
O
OC H5
2
3
2
i
7
C H
O
P
3
i
C H
7
Cl
3
O
P
OC H7
3
O
OC3H7
i
C H
O
OC H7
4
4
g
3
7
3
85.4
93.1
149/1
158/1
28.59, 28.53
28.59, 28.53
i
C H
P
3
7
O P
i
C H
7
Cl
3
O OC H9
O
P
OC H9
4
4
i
O
P
h
C H
OC H9
i
7
3
7
4
C H
3
O
P
i
C H
Cl
3
7
O
P
i
OC H
i
4
9
O
P
OC H
4
9
i
7
i
O
C H
OC H
4
4
i
3
4
9
88.4
93.7
160/1
165/1
28.30, 28.23
31.70, 31.64
i
C H
3
7
O P
i
C H
7
Cl
3
O
OC H
5
11
O
P
OC H
i
7
5
11
C H
O
OC H
P
3
5
11
j
i
7
C H
O P
3
i
C H
7
Cl
3
A
Isolated yield.
B 31
P NMR Spectra were recorded in CDCl3 at 162 MHz; all the reactions were completed within 5–6 min at 180W.
and mixed well. After microwave irradiation at 180W for 4 min
the formation of a salt was observed, this was dissolved by the
addition of one drop of water. The reaction mixture was fur-
ther irradiated at 180W for 1 min. The reaction mixture was
monitored by P NMR spectroscopy until the signal of O-ethyl
methylphosphonic chloride disappeared. The reaction mass was
washed and extracted into n-pentane (4 × 25 mL) and the solvent
was evaporated to afford pure diethyl dimethylpyrophosphonate
−
1
without use of column chromatography. νmax (liquid film)/cm
2885 (C–H), 1230 (P=O), 1095 (P–O–C), 972 (P–O–P), 690 (P–
C). δH 4.17 (m, J 7.36, 4H, CH2), 1.35 (d, J 7.54, 6H, CH3), 0.92
(t, J 6.35, 6H, CH3). δC 46.50 (CH2), 21.06 (CH3), 10.53 (CH3).
3
1

Microwave Induced Synthesis of O,O-Dialkyl Dialkylpyrophosphonates
m/z (EI) 230 (4.06%), 203 (74.19), 186 (15.20), 175 (72.14),
479
315 (M+H, 13.63%), 273 (24.27), 243 (5.45), 231 (100), 213
(28.15), 187 (45.63), 171 (30.09), 145 (17.47), 125 (70.87),
65 (11.65), 43 (25.24). (Found: C 45.84, H 8.96. C12H28O5P2
requires C 45.86, H 8.98%.)
1
57 (75.10), 143 (87.43), 97 (61.70), 79 (100), 65 (10.07), 47
(
32.10). (Found: C 31.30, H 7.02. C6H16O5P2 requires C 31.31,
H 7.01%.)
Dibutyl Diisopropylpyrophosphonate 4h
Dipropyl Dimethylpyrophosphonate 4b
νmax (liquid film)/cm 1 2881 (C–H), 1236 (P=O), 1092 (P–O–
−
νmax (liquid film)/cm 1 2889 (C–H), 1235 (P=O), 1080 (P–O–
−
P), 980 (P–O–P), 690 (P–C). δH 4.20 (m, J 7.83, 4H, CH2), 2.12
C), 970 (P–O–P), 698 (P–C). δH 4.17 (m, J 7.45, 4H, CH2), 1.60
(
m, J 6.75, 2H, CH), 1.67 (m, J 7.03, 4H, CH2), 1.40 (m, J 6.75,
H, CH2), 1.22 (m, J 6.70, 12H, CH2), 0.92 (t, J 7.24, 6H, CH3).
δC 66.33 (CH2), 27.74 (CH), 26.14 (CH2), 18.83 (CH2), 16.15
CH3), 15.98 (CH3). m/z (EI) 343 (M+H, 13.63%), 287 (20.38),
43 (8.95), 231 (100), 213 (25.24), 187 (29.12), 171 (23.30), 145
13.10), 125 (56.31), 65 (10.05), 43 (19.13). (Found: C 49.10, H
.43. C14H32O5P2 requires C 49.12, H 9.42%.)
(
m, J 7.23, 4H, CH2), 1.40 (d, J 7.50, 6H, CH3), 0.88 (t, J 6.39,
4
6
H, CH3). δC 44.67 (CH2), 20.09 (CH3), 18.95 (CH2), 10.35
+
(
CH3). m/z (EI) 259 (M+H , 5.03%), 217 (9.85), 187 (4.52),
(
2
(
9
1
75 (100), 157 (72.15), 143 (23.25), 97 (50.11), 79 (30.13), 41
(
11.10). (Found: C 37.23, H 7.80. C8H20O5P2 requires C 37.22,
H 7.81%.)
Dibutyl Dimethylpyrophosphonate 4c
Diisobutyl Diisopropylpyrophosphonate 4i
νmax (liquid film)/cm 1 2888 (C–H), 1237 (P=O), 1088 (P–O–
−
νmax (liquid film)/cm 1 2889 (C–H), 1238 (P=O), 1085 (P–
−
C), 975 (P–O–P), 696 (P–C). δH 4.10 (m, J 6.88, 4H, CH2),
O–P), 969 (P–O–P), 690 (P–C). δH 3.93 (m, J 6.96, 4H, CH2),
1
.62–1.70 (m, J 7.31, 8H, CH2), 1.40 (d, J 6.59, 6H, CH3), 0.93
2
7
2
3
.05 (m, J 7.05, 2H, CH), 1.88 (m, J 7.43, 2H, CH), 1.05 (d, J
.39, 12H, CH3), 0.81 (d, J 7.39, 12H, CH3). δC 66.20 (CH2),
7.74 (CH), 26.05 (CH), 18.83 (CH3), 18.72 (CH3). m/z (EI)
43 (M+H, 13.63%), 287 (8.03), 243 (10.05), 231 (100), 213
(
t, J 6.75, 6H, CH3). δC 44.56 (CH2), 21.05 (CH2), 18.45 (CH2),
15.97 (CH3), 10.23 (CH3). m/z (EI) 286 (4.85%), 231 (9.98),
201 (8.78), 175 (100), 157 (50.25), 143 (14.15), 97 (40.78),
79 (19.05), 41 (10.85). (Found: C 41.95, H 8.47. C10H24O5P2
(24.27), 187 (24.85), 171 (25.13), 145 (58.25), 125 (56.31),
requires C 41.96, H 8.45%.)
57 (11.33), 43 (30.15). (Found: C 49.10, H 9.43. C14H32O5P2
requires C 49.12, H 9.42%.)
Dipentyl Dimethylpyrophosphonate 4d
νmax (liquid film)/cm 1 2887 (C–H), 1235 (P=O), 1090 (P–O–
−
Dipentyl Diisopropylpyrophosphonate 4j
C), 978 (P–O–P), 705 (P–C). δH 4.10 (m, J 6.97, 4H, CH2), 1.70
νmax (liquid film)/cm 1 2890 (C–H), 1236 (P=O), 1089 (P–O–
−
(
m, J 7.09, 8H, CH2), 1.40 (d, J 7.16, 6H, CH3), 1.32 (m, J 7.57,
H, CH2), 0.90 (t, J 7.06, 6H, CH3). δC 46.50 (CH2), 23.06
CH2), 21.05 (CH3), 18.36 (CH2), 14.36 (CH2), 9.98 (CH3).
m/z (EI) 315 (5.29%), 245 (14.12), 175 (100), 157 (30.15), 143
11.10), 97 (31.03), 79 (17.45), 41 (5.45). (Found: C 45.85,
P), 974 (P–O–P), 698 (P–C). δH 4.21 (m, J 8.16, 4H, CH2), 2.10
4
(
(m, J 6.75, 2H, CH), 1.70 (m, J 7.03, 4H, CH2), 1.34 (m, J 6.75,
4
0
H, CH2), 1.26 (m, J 6.75, 4H, CH2), 1.20 (m, J 6.70, 12H, CH3),
.90 (t, J 7.15, 6H, CH3). δC 66.33 (CH2), 27.74 (CH), 26.14
(
(CH2), 18.83 (CH2), 16.15 (CH3), 15.16 (CH3), 10.98 (CH3).
H 8.99. C12H28O5P2 requires C 45.86, H 8.98%.)
m/z (EI) 370 (13.63%), 301 (38.38), 259 (11.23), 243 (25.92),
2
1
31 (100), 213 (25.24), 187 (32.40), 171 (24.83), 145 (11.15),
25 (78.70), 43 (23.10). (Found: C 51.85, H 9.81. C16H36O5P2
Dipinacolyl Dimethylpyrophosphonate 4e
νmax (liquid film)/cm 1 2885 (C–H), 1240 (P=O), 1095 (P–O–
−
requires C 51.88, H 9.80%.)
C), 980 (P–O–P), 698 (P–C). δH 4.10 (m, J 7.35, 2H, CH2),
1
6
.40 (d, J 7.16, 6H, CH3), 1.22 (dd, J 7.45, 6H, CH3), 0.83 (s, J
.58, 18H, CH3). δC 62.16 (CH), 23.15 (C), 19.56 (CH3), 14.36
Conclusion
In conclusion, we have developed a rapid and efficient method
for the synthesis of O,O-dialkyl dialkylpyrophosphonates 4a–j
with excellent yields. The main advantage of this method is that
reactions were clean and had operational simplicity. Because
column chromatography was not required to purify the pure
products, this method is more attractive for organic chemists.
(
1
(
CH3), 9.98(CH3). m/z (EI)452(7.23%), 202(14.12), 175(100),
57 (47.09), 143 (18.20), 97 (20.15), 85 (15.78), 69 (16.17), 57
20), 41 (37.10). (Found: C 49.10, H 9.40. C14H32O5P2 requires
C 49.12, H 9.42%.)
Diethyl Diisopropylpyrophosphonate 4f
νmax (liquid film)/cm 1 2888 (C–H), 1240 (P=O), 1085 (P–O–
−
Acknowledgements
The authors thank Ms. Mamta Sharma for NMR analysis.
C), 973 (P–O–P), 695 (P–C). δH 4.19 (m, J 7.18, 4H, CH2), 2.08
(
1
m, J 6.85, 2H, CH), 1.13 (t, J 6.73, 6H, CH3), 0.98 (d, J 6.95,
2H, CH3). δC 67.98 (CH2), 27.70 (CH), 18.19 (CH3), 12.30
References
(
(
(
CH3). m/z (EI) 286 (13.63%), 259 (8.75), 244 (72.72), 231
18.18), 215 (40.90), 202 (30.90), 187 (100), 171 (54.50), 152
63.63), 125 (68.18), 65 (48.18), 43 (59.09). (Found: C 41.97,
[
[
[
[
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Dipropyl Diisopropylpyrophosphonate 4g
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