Investigation on the acylation of heterocyclic alcoholate anions with O,O-dialkyl phosphorochloridothioate in water solvent

Article abstract of DOI:10.1080/10426507.2012.702824

The acylation of some heterocyclic alcoholate anions with O,O-dialkyl phosphorochloridothioate has been investigated. Higher yields and fewer byproducts were achieved in water at 50 °C by employing an effective phase-transfer catalyst (PTC) (benzyl triethylammonium chloride [BTEAC]), acylation catalyst (AC) (4-dimethylaminopyridine), and surfactant (sodium dodecyl sulfate), under weakly basic (pH 9.5～10) conditions. This reaction can also be applied to synthesize other insecticides with excellent yields.

Full text of DOI:10.1080/10426507.2012.702824

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Investigation on the Acylation of
Heterocyclic Alcoholate Anions with
O,O-Dialkyl Phosphorochloridothioate in
Water Solvent
Xin Ge a , Chao Qian a & Xinzhi Chen a
a Key Laboratory of Biomass Chemical Engineering of Ministry of
Education , Zhejiang University , Hangzhou , China
Accepted author version posted online: 22 Jun 2012.Published
online: 31 May 2013.
To cite this article: Xin Ge , Chao Qian & Xinzhi Chen (2013) Investigation on the Acylation
of Heterocyclic Alcoholate Anions with O,O-Dialkyl Phosphorochloridothioate in Water
Solvent, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:6, 739-744, DOI:
10.1080/10426507.2012.702824
To link to this article: http://dx.doi.org/10.1080/10426507.2012.702824
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Phosphorus, Sulfur, and Silicon, 188:739–744, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.702824
INVESTIGATION ON THE ACYLATION OF HETEROCYCLIC
ALCOHOLATE ANIONS WITH O,O-DIALKYL
PHOSPHOROCHLORIDOTHIOATE IN WATER SOLVENT
Xin Ge, Chao Qian, and Xinzhi Chen
Key Laboratory of Biomass Chemical Engineering of Ministry of Education,
Zhejiang University, Hangzhou, China
GRAPHICAL ABSTRACT
Abstract The acylation of some heterocyclic alcoholate anions with O,O-dialkyl phospho-
rochloridothioate has been investigated. Higher yields and fewer byproducts were achieved in
water at 50 ◦C by employing an effective phase-transfer catalyst (PTC) (benzyl triethylammo-
nium chloride [BTEAC]), acylation catalyst (AC) (4-dimethylaminopyridine), and surfactant
(sodium dodecyl sulfate), under weakly basic (pH 9.5∼10) conditions. This reaction can also
be applied to synthesize other insecticides with excellent yields.
Keywords Acylation; heterocyclic alcoholate anion; O,O-dialkyl phosphorochloridothioate
INTRODUCTION
Phosphorothionate esters such as Chlorpyrifos (O,O-diethyl O-3,5,6-trichloro-2-
pyridyl phosphorothioate), Quinalphos (O,O-diethyl O-quinoxalin-2-yl phosphorothioate),
and Triazophos (O,O-diethyl O-1-phenyl-1H-imidazol-4-yl phosphorothioate) are known
as powerful organophosphorus insecticides.1–3 The major synthetic route to these products
is the acylation of heterocyclic alcoholate anions with O,O-dialkyl phosphorochloridoth-
ioate.2–12
This reaction was performed in a single-phase4–8 or two-phase solvent system3,9–12
using several types of catalysts. To inhibit the hydrolysis of O,O-dialkyl phosphorochlo-
ridothioate, especially O,O-diethyl phosphorochloridothioate, whose hydrolyzate is the
Received 18 April 2012; accepted 19 May 2012.
This work was supported by the National Natural Science Foundation of China (21076183, 21006087) and
the Key Innovation Group of Zhejiang Province (2009R50002).
Address correspondence to Xinzhi Chen, Key Laboratory of Biomass Chemical Engineering of Ministry of
Education, Zhejiang University, Hangzhou 310027, China. E-mail: chemtec@163.com
739

740
X. GE ET AL.
Figure 1 The structure of sulfotep.
highly toxic sulfotep (O,O,O’,O’-tetraethyl dithiopyrophosphate, Figure 1), a two-phase
solvent (water and a water-immiscible organic solvent) was extensively used.3 O,O-dialkyl
phosphorochloridothioate dissolves in the water-immiscible organic solvent to prevent
hydrolysis in alkaline solution. However, it makes the process complex in that the water-
immiscible organic solvent, e.g., toluene, must be distilled away and the product needs to
be furnished by recrystallization. The single-phase solvent method (water) did not have
these problems.4–8 The focus on the single-phase solvent method was the inhibition of the
O,O-dialkyl phosphorochloridothioate hydrolysis.
Efforts have been made to gain higher yields for this reaction through variations of
solvent, catalyst, and concentration.3–12 An acylation catalyst (AC) and a phase transfer
catalyst (PTC) were used in combination to give a high yield in this acylation. AC in-
creased the reaction rate to inhibit the hydrolysis of O,O-dialkyl phosphorochloridothioate.
4-Dimethylaminopyridine (DMAP) has been in a large range of applications as an AC
for the acylation reaction of sterically hindered heterocyclic alcoholate anions.13 Benzyl
triethylammonium chloride (BTEAC) and benzyl trimethylammonium chloride (BTMAC)
were the main compounds used as the PTC in this synthesis.3–6,9,10,12 PEG26-2, both as
PTC and surfactant, was used to increase the yield.5
Although the water solvent method has been reported in chlorpyrifos synthesis,4–6,8
many factors of the process have not been discussed in detail. Sulfotep, which has been
forbidden as an insecticide and affected the quality of the target product, was not studied
further. On the other hand, the catalyst systems have not been systematically explored,
even though several types of catalysts are used in the reaction. Except for chlorpyrifos
synthesis, the water solvent method was not performed in the acylation between heterocyclic
alcoholate anions and O,O-dialkyl phosphorochloridothioate.
In this article, we report a water solvent method to complete the acylation of hete-
rocyclic alcoholate anions with O,O-dialkyl phosphorochloridothioate (Scheme 1), which
can simplify the procedures. The experimental parameters are optimized for the yield and
purity of the product.
Scheme 1 The acylation of some heterocyclic alcoholate anions with O,O-dialkyl phosphorochloridothioate in
water.

ACYLATION OF HETEROCYCLIC ALCOHOLATE ANIONS
741
Table 1 Effects of pH on the yield and puritya
Entry
pH
Sulfotepb/%
Yieldc/%
Purityd/%
1
2
3
4
5
8.5–9
9–9.5
9.5–10
10–10.5
10.5–11
2.5
92.1
93.3
97.5
96.1
95.2
91.5
94.7
97.8
96.5
95.2
0.89
0.06
0.47
1.21
aConditions: NaTCP (0.2 mol), O,O-diethyl phosphorochloridothioate (0.21 mol), DMAP (4 mmol), BTEAC
(4 mmol), and SDS (1 mmol). All reactions were carried out in water at 50 ◦C for 2 h.
bDetermined by GC using capillary column.
cIsolated yield.
dDetermined by HPLC using a reverse-phase C18 column with a mobile phase: acetonitrile/water/
aceticacid = 750/245/5 (V) at 1.0 mL/min.
RESULTS AND DISCUSSION
Initially, we studied the synthesis of chlorpyrifos in water solvent as the model
reaction. This reaction between the sodium salt of 3,5,6-trichloropyridin-2-ol (NaTCP) and
O,O-diethyl phosphorochloridothioate depended on some main factors such as PTC, AC,
surfactant, and their respective concentrations, pH, temperature, and the reaction time.
Control of the pH was the first task for the present study. The heterocyclic alcoholate
anion was synthesized from a mineral base (such as NaOH) and the necessary heterocyclic
alcohol.14 Weak base reduced the reactivity of heterocyclic alcoholate anion (entries 1–2,
Table 1), which decreased the main reaction rate resulting in lower yield and purity. Strong
base could lead to the hydrolyzation of O,O-diethyl phosphorochloridothioate (entries 4–5,
Table 1). Finally, the pH was controlled at 9.5–10, which was identified to be the best for
the reactivity of heterocyclic alcoholate anion and the purity of the product.
Generally, steric hindrance of the heterocyclic alcohol determined the difficulty of the
reactions. High steric hindrance led to weak nucleophilic ability of the heterocyclic alcohol.
Table 2 The acylation of NaTCP with O,O-diethyl phosphorochloridothioate in water under different conditionsa
Entry AC (mol %) PTC (mol %) Surfactant (mol %) Time/h Temp/oC Sulfotepb/% Yieldc/% Purityd/%
1
2
3
4
5
6
7
8
9
TMA(4)
TEA(4)
–
–
–
–
–
–
–
–
4
4
4
2
2
2
2
1
1
2
60
60
60
50
50
50
60
60
50
50
–
–
Trace
Trace
81.2
91.7
93.0
92.1
94.9
95.5
93.4
97.5
–
–
DMAP(4)
DMAP(2)
DMAP(2)
DMAP(2)
DMAP(2)
DMAP(2)
DMAP(2)
DMAP(2)
6.5
3.5
2.4
2.6
0.57
0.21
0.11
0.06
76.3
92.7
93.5
93.2
95.7
96.1
94.6
97.8
BTMAC(2)
TBAB(2)
BTEAC(2)
BTEAC(2)
BTEAC(2)
BTEAC(2)
BTEAC(2)
–
PEG-400(0.5)
SDS(0.5)
SDS(0.5)
SDS(0.5)
10
aConditions: NaTCP (0.2 mol), O,O-diethyl phosphorochloridothioate (0.21 mol).
bDetermined by GC using capillary column.
cIsolated yield.
dDetermined by HPLC using
aceticacid = 750/245/5 (V) at 1.0 mL/min.
a reverse-phase C18 column with mobile phase: acetonitrile/water/

742
X. GE ET AL.
Table 3 The acylation of heterocyclic alcoholate anions with O,O-dialkyl phosphorochloridothioate in watera
Sulfotepb
/%
Yieldc
/%
Purityd
/%
Entry
1
Substrate 1
Substrate 2
Product
0.06
97.5
97.8
2
3
4
0.12
0.09
0.03
94.1
93.1
98.4
95.7
95.3
97.6
5
6
—
—
93.4
94.1
94.6
95.2
aAll reactions were run with substrate 1 (0.2 mol), substrate 2 (0.21 mol), DMAP(4 mmol), BTEAC(4 mmol),
and SDS(1 mmol) in the solution of pH 9.5–10 at 50 ◦C for 2 h.
bDetermined by GC using capillary column.
cIsolated yield.
dDetermined by HPLC using
a reverse-phase C18 column with mobile phase: acetonitrile/water/
aceticacid = 750/245/5 (V) at 1.0 mL/min.
Further, the difficulty occurred in the reaction because O,O-diethyl phosphorochloridoth-
ioate is water insoluble. For sterically hindered heterocyclic alcohols, acylation is so difficult
that AC is required. It was reported that tertiary amines such as trimethylamine (TMA),
triethylamine (TEA), and DMAP gave the best performance for this reaction.3 Therefore
TMA, TEA, and DMAP as AC were employed early in this work. In the absence of PTC
and surfactant, DMAP proved to be the most efficient AC for this reaction. Other ACs,
such as TMA and TEA, could not promote the product formation (entries 1–2, Table 2). It
was consistent with the previous report.3 It made little difference when BTMAC, tetrabutyl
ammonium bromide (TBAB), or BTEAC was used, respectively, in this reaction as the
PTC (entries 4–6, Table 2). Taking the cost into account, BTEAC was chosen as the PTC.
The amount of sulfotep, which was an unexpected byproduct, was significantly reduced
to less than 1% in the presence of surfactant (entries 7–8, Table 2). Due to enhancement
of the mass transfer of O,O-diethyl phosphorochloridothioate and NaTCP, the surfactant
accelerated the reaction rate. Based on the diminution of sulfotep, sodium dodecyl sulfate

ACYLATION OF HETEROCYCLIC ALCOHOLATE ANIONS
743
(SDS) was found to be better than PEG-400 in this reaction. Next, the temperature and the
time were studied, and the optimal conditions were screened (entries 8–10, Table 2). 2 mol
% DMAP, 2 mol % BTEAC, and 0.5 mol % SDS gave a satisfactory yield and a minimum
of sulfotep at 50 ◦C for 2 h using water as the solvent in the chlorpyrifos synthesis.
After the optimal reaction conditions were identified, some insecticides were exam-
ined as shown in Table 3, including quinalphos, triazophos, diazinon (O,O-diethyl O-2-
isopropyl-6-methylpyrimidin-4-yl phosphorothioate), chlorpyrifos-methyl (O,O-dimethyl
O-3,5,6-trichloro-2-pyridyl phosphorothioate), and etrimfos (O,O-dimethyl O-6-ethoxy-2-
ethylpyrimidin-4-yl phosphorothioate), which were synthesized from heterocyclic alcoho-
late ions with O,O-dialkyl phosphorochloridothioate. It was confirmed that this protocol
could be extended to some different heterocyclic alcoholate anions. The nitrogen atom with
a large electronegativity character caused the electron density of the carbon atoms in the
heterocycle to decrease. It decreased the nucleophilicity of alcoholate ions. An increased
number of nitrogen atoms resulted in a lower yield (entries 2–3, Table 3). The heterocy-
cle possessing electron-donating functional groups was found to give better yields than
those with electron-withdrawing (entries 1–4, Table 3). It is notable that O,O-diethyl phos-
phorochloridothioate is more highly reactive than O,O-dimethyl phosphorochloridothioate
(entries 5 vs. 1, 6, Table 3). To our delight, the reaction preceeded smoothly with these
heterocyclic alcoholate anions and afforded the products in good yields. The byproduct
was successfully inhibited.
CONCLUSION
In summary, good yields and purity make the water solvent method attractive for
the acylation of heterocyclic alcoholate anions with O,O-dialkyl phosphorochloridothioate.
The focus on this reaction was how to accelerate the reaction rate leading to inhibition
of the O,O-dialkyl phosphorochloridothioate hydrolysis. As the most efficient AC against
sterical hindrance, DMAP was introduced to this reaction. The PTC and surfactant were
used in combination to enhance the mass transfer of O,O-dialkyl phosphorochloridothioate
and the heterocyclic alcoholate anions. Thus, in the presence of DMAP, TEBAC, and SDS,
the formation of sulfotep was almost prevented.
EXPERIMENTAL
General methods. Melting points were determined by using the capillary method
on WRR mp apparatus. GC analyses were performed on GC Agilent 1790F series. HPLC
analyses were executed on HPLC Agilent 1100 series charged with C18 column. 1H NMR
and 13C NMR were recorded in CDCl3 on a Bruker NMR spectrometer (400 MHz for
1H NMR; 100 MHz for 13C NMR)
General procedure for the synthesis of chlorpyrifos. To a stirred solution of NaTCP
44.1 g (0.2 mol) and water 200 g at 50 ◦C was added DMAP 0.49 g (4 mmol), BTEAC 0.91 g
(4 mmol), and SDS 0.29 g (1 mmol). Then 98 wt% O,O-diethyl phosphorochloridothioate
33.8 ml (0.21 mol) was added dropwise during 30 min. The pH of this solution was
adjusted to 9.5–10 at 50 ◦C by adding 30 wt % K2CO3 dropwise. With continuous stirring,
the reaction mixture changed to a light yellow emulsion from white suspension.◦Stirring
was maintained for 2 h. The organic and aqueous layers were separated at 70 C. The
organic layer was washed with water (150 mL) at 70 ◦C. After vacuum recovery of water

744
X. GE ET AL.
◦
(70 C, 18 mmHg), the organic phase was crystallized by cooling to afford a colorless
solid.
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