Synthesis and Development of Parathion and Related Compounds J. T. CASSADAY, JOHN H. FLETCHER, J. C. HAMILTON , INGENUIN HECHENBLEIKNER, Ε. I. HOEGBERG, B. J. SERTL, and J. T. THURSTON 1
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American Cyanamid Company, Stamford, Conn.
The investigations carried out and the many problems solved in the synthesis and development of parathion and related compounds are reviewed. Equations are given to illustrate the procedures used in this work.
P a r a t h i o n is the generic name of a compound that was first prepared b y German chem ists and designated as E-605. I n this country many trade names have been used. I n 1946 a report b y the British technical investigators M a r t i n and Shaw (6) was released i n the United States, disclosing among other insecticides a compound called p-nitrophenoxy thiophosphoric acid diethyl ester. A s a result of a publication b y M a s t i n , Norman, and Weilmuenster (7) i n 1945, i n which the name diethyl chlorothionophosphate was used, the compound as first prepared b y United States chemists was designated as diethyl pnitrophenyl thionophosphate. S
(C H Q) P—QNQ
2
(1)
Whether an arrow or a double bond is used between the phosphorus and sulfur is a much-discussed question. B o t h are probably correct. In view of the large amount of field testing that was being carried out during 1947 and the possibilities of publications, i t was desirable to have a common name as well as an approved chemical name for this product. A s a result of meetings with members of the AMERICAN CHEMICAL SOCIETY'S Committee on Nomenclature, Spelling, and P r o nunciation the chemical name 0,0-diethyl O-p-nitrophenyl thiophosphate was adopted. B y a series of similar conferences with members of the U . S. Department of Agriculture (in particular Haller and Rohwer), the name " p a r a t h i o n " was approved. Those par ticipating i n the selection of this common name proposed by Rohwer and concurring i n its suitability included committees representing many scientific societies.
Physical Properties Physical Properties of Parathion Color Melting point, C. Boiling point, ° C. n ' ° d °
Pale yellow 6 . 1 ° ± 0 . 1 ° corrected 157-162° at 0.6 mm. 1.53668 1.263
0
2
D
5
2
27
The technical material has a brown color, a refractive index that may differ slightly i n the third place, and a density that is approximately the same as that of the pure material. Parathion is soluble i n water to the extent of about 20 to 25 p.p.m. I t is completely 1
Present address, Yale University, New Haven, Conn.
143
In AGRICULTURAL CONTROL CHEMICALS; Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
144
ADVANCES IN CHEMISTRY SERIES
miscible with many organic solvents, including esters, alcohols, ketones, ethers, aromatic and alkylated aromatic hydrocarbons, and animal and vegetable oils. I t is very slightly soluble i n paraffinic hydrocarbons such as petroleum ether, kerosene, and refined spray oils. The compound is very slowly hydrolyzed i n water. Hydrolysis rates were re ported i n August 1948 by Peck and co-workers (9), who stated that 5 0 % hydrolysis occurs at 25° C . after 120 days i n saturated distilled water solutions or i n 1 Ν sulfuric acid. The time required to reach 5 0 % hydrolysis i n a saturated lime solution is reduced to 8 hours. Hence parathion appears to be very stable to hydrolysis except under alkaline conditions.
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Toxicology Studies on the pharmacological effect of parathion i n animals have been i n progress for almost 2 years at the Hazleton Laboratory, Falls Church, V a . (4). Some phases of the work, such as long-range feeding tests, are continuing. Tests have been carried out on toxicity by dermal application, inhalation of dust, exposure to aerosol mists, exposure to vapors, and chronic toxicity. Test animals have included rabbits, guinea pigs, rats, mice, and dogs. Acute Oral Toxicity of Parathion
Albino rats Albino mice Guinea pigs
Form of Administration
Mean Lethal Dose, Mg./Kg.
Propylene glycol solution Wettable powder in water Propylene glycol solution Wettable powder in water Propylene glycol solution
5.0 12.5 6.0 21.0 9.3
Schrader (12) stated that i n its pure form, Bladan is ten times as toxic to mammals as E-605 (parathion). ' ' B l a d a n " is the name given by the Germans to a material which they thought to be hexaethyl tetraphosphate. Actually, this material is a mixture, the insecticidally active ingredient of which is tetraethyl pyrophosphate. Tests to determine the long-range effect on animals that ingest a sublethal dose of parathion have been i n progress for more than 18 months. Although definite conclusions cannot be drawn at this time, average food consumption and weight gains are comparable to the controls. I n all these tests the amount of material remaining on the food was over 50 times that anticipated i n residual quantities on food for consumption by humans. Experimental and commercial experience with formulations containing parathion applied as sprays or dusts has covered two seasons. I n a few cases where protective measures were not taken, temporary nausea, headache, or other effects were experienced when individuals were sub jected to unusual exposure to vapors, dusts, or mists. I t is believed that chronic toxicity hazards are greater from D D T than from parathion, even though the acute oral mean lethal dose of D D T is 250 mg. per k g .
Preparation of Parathion and Its Intermediates PC1 + S — > PSCI3
(2)
3
S
II 2 C H O N a + PSC1 — > ( C H 0 ) P — C l + 2NaCl 2
5
3
2
6
(3)
2
S
S
(C H 0) P—Cl + NaOC H N0 — > (C H 0) P—OC H N0 + NaCl (4) Equations 2, 3, and 4 summarize the method proposed by the Germans for preparing parathion (compound E-605). Schrader (18) has reported that thiophosphoryl chloride was synthesized from phosphorus trichloride and sulfur by heating at 130° i n a lead-lined autoclave. Woodstock and Adler (14) carried out a similar reaction at 150° to 160° C . 2
5
2
6
4
2
2
5
2
6
4
2
In AGRICULTURAL CONTROL CHEMICALS; Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
145
CASSADAY et α/.—PARATHION AND RELATED COMPOUNDS
using alkali metal sulfides as catalysts, and were able to reduce the pressures that were normally necessary for the reaction. A s shown i n Equation 3, the alcoholic sodium ethoxide was combined with thiophosphoryl chloride at temperatures of —5° to —10° C , followed by removal of the sodium chloride b y filtration. The final step was carried out i n chlorobenzene during a 15-hour heating period. If this method of preparing diethyl chlorothiophosphate is used, other by-products may be formed which will enter into the final reaction unless the desired chloro ester is very carefully fractionated. Other methods of preparing thiophosphoryl chloride have been reported (10). PC1 + H S — > PSC1 + 2HC1 5
2
(5)
3
P C l . 2 F e C l + 5S — > 2FeCl + 2S C1 + PSC1
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5
3
2
2
2
(6)
3
F e P + 7SC1 — > 2FeCl + PSC1 + 6S 2
2
(7)
3
In E q u a t i o n 6, a method is shown b y which, Woodstock and M c D o n a l d (15) report, thiophosphoryl chloride can be obtained. E q u a t i o n 7 shows a related method (16) for the preparation of this intermediate. Glatzel (8) has reacted iron and antimony chlorides with phosphorus pentasulfide to obtain the desired compound. 6FeCl
3
+ 2P S — > 2
5
3FeCl
2
+ 4PSC1 + 3FeS 3
(8)
2
SbCl + P2S5 — > SbPS + PSCls 3
(9)
4
> 5PSC1
3PCU + P2S5
(10)
3
Weber (8) states that the intermediate thiophosphoryl chloride can be obtained from phosphorus pentachloride, as shown i n E q u a t i o n 10. 5P0C1 + P S — > P 0 + 5 P S a 3
2
6SOCI2 + 2P2S5
6
2
6
— > 4PSC1 + 3 S 0 + 9S 3
2
(12)
2
3CC1 + 2P S — > 4PSC1 + 3CS 4
(11)
3
5
3
( 13)
2
Carius (8) replaced the oxygen i n phosphoryl chloride b y sulfur. This m a y be somewhat analogous to the replacement of oxygen i n a carbonyl group b y sulfur using phosphorus pentasulfide. Prinz (8) used thionyl chloride i n his reaction with phos phorus sulfide and D e F a z i (2) used carbon tetrachloride i n a very interesting preparation of this important intermediate. Methods of Synthesizing Diethyl Chlorothiophosphate. I n 1861 Carius (1) re ported Equations 14 to 17. /PS Oi/PS 0 l ( C H ) 3 + PCU — > C1\(C H ) + 3
2
5
2
5
CI3PO
2
+ C1C H 2
(14)
5
S ( C H 0 ) P S + PCU — > ( C H 0 ) P — C l + 2
5
3
2
6
2
POCI3
+ C H C1 2
5
TPS 0 /PS 0 t ( C H ) M e + PC1 — > C1\(C H )2 + CIMe + C l P O 2
3
2
5
2
6
2
3
5
S ] 5
2
(16)
s
_ ( C H 0 ) P — O J M e + PCI5 — > ( C H 0 ) P - -Cl + M e C l + 2
(15)
2
5
2
POCI3
(17)
The authors' interpretation of the reactions which he carried out is given immediately under the equation taken from the original article. I n 1945, M a s t i n , Norman, and W e i l muenster (7) reported the preparation of the compound as shown i n E q u a t i o n 18. S 2C H OH + 2
5
2 C 5 H 5 N + PSCI3
— > (C H 0) P—CI + 2C H N.HC1 2
5
2
6
6
In AGRICULTURAL CONTROL CHEMICALS; Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
(18)
146
ADVANCES IN CHEMISTRY SERIES
T h e yield obtained was approximately 2 4 % . M u c h higher yields were probably obtained by Schrader's process (12) and b y Equations 19 to 27. S
S
Il
II
2 ( C H 0 ) P — S N a + 3C1 — > 2 ( C H 0 ) P — C l + 2NaCl + S C1 2
5
2
2
2
5
2
S
2
2
S
( C H 0 ) P — S N a + PC1 — > ( C H 0 ) P — C l + PSC1 (?) + N a C l 2
5
2
5
2
5
2
3
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S 5
(20)
S
2 ( C H 0 ) P — S H + 3C1 — > 2 ( C H 0 ) P — C l + 2HC1 + S C1 2
(19)
2
2
2
5
2
2
2
(21)
When chlorine reacted with sodium diethyl dithiophosphate i n the presence of an organic solvent, the desired compound was obtained in good yield. T h e reaction of phosphorus pentachloride on the sodium salt resulted i n the same product. Thiophos phoryl chloride is a probable by-product of this reaction. It was later found that diethyl dithiophosphoric acid could be chlorinated in an organic solvent without the intermediate preparation of the sodium salt. T h e purity and identity of diethyl chlorothiophosphate prepared b y new methods were checked b y reaction with phenylhydrazine according to the directions of M a s t i n , Norman, and Weilmuenster (7). S
S
(C H 0) P—Cl + H NNH — > ( C H Q ) P — H N N H < ^
2
2
5
^> + HC1
2
(22)
A general equation for the chlorination of certain dithiophosphoric acids and their salts can be written as follows: S
S
2 ( R O ) P — S M + 3C1 — > 2 ( R O ) P — C l + 2MC1 + S C1 2
2
2
2
R = C H , C H , C H , iso-C H , C H , iso-C H , C H 3
M
2
5
3
7
3
7
4
9
4
9
6
2
(23)
5
= H , Κ, N a
Using this general method, the chloro esters shown i n E q u a t i o n 23 were made. This method of preparation is a rather important discovery and the reaction is not a simple one. There are numerous methods of preparing the desired intermediate, which can be combined with sodium nitrophenoxide. S
S
(C H 0) P—Cl + NaOC H N0 — > (C H 0) P—OC H N0
2
+ NaCl
(24)
S S I! Base || (C H 0) P—Cl + HOC H N0 — > (C H 0) P—OC H N0
2
+ HC1
(25)
2
5
2
2
5
6
2
6
4
2
4
2
2
5
2
2
5
6
2
4
6
4
T h e reaction shown in Equation 24 gives good yields, using both aqueous and non aqueous media, in a much shorter time than that reported b y Schrader (13). T h e inter mediate chloro ester can be combined directly with paranitrophenol using alkali metal salts in order to prepare sodium nitrophenoxide, which is used in situ. Another method which has been proposed for the preparation of parathion is shown in Equations 26 to 28. PC1 + N a O C H N 0 — > C 1 P — O C H N 0 + N a C l 3
6
C1 P—OC H N0 2
6
4
2
4
2
2
6
4
2
+ 2NaOC H — > (C H 0) P—OC H N0 2
6
2
5
2
6
4
2
+ 2NaCl
In AGRICULTURAL CONTROL CHEMICALS; Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
(26) (27)
CASSADAY et al.—PARATHION
147
AND RELATED C O M P O U N D S
S (C H 0) P—OC H N0 2
5
2
6
4
I
+ S
2
> (C H 0) P—OC H N0 2
5
2
6
4
(28)
2
It has been reported that the compound resulting from Equation 26 may be hazardous to distill (12). However, the compound resulting from Equation 27 has been prepared and attempts have been made to add sulfur to this phosphite i n order to obtain the desired thiophosphate. Similar reactions have been reported in the literature (3). A very vigorous reaction takes place. Another method is shown in Equations 29 and 30. S PSC1 + N a O C H N 0
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3
6
4
^ C 1 P — O C H N 0 + NaCl
2
2
6
's
4
(29)
2
S
C1 P—OC H N0 2
6
4
2
+ 2NaOC H 2
>~ ( C H 0 ) P — O C H N 0
5
2
5
2
6
+ 2NaCl
(30)
+ NaOC H
(31)
4
2
S (C H 0) PS + N a O C H N 0 2
5
3
6
4
>- ( C H 0 ) P — O C H N 0
2
2
5
2
6
4
2
2
5
Still another method was reported b y Schrader (12) (Equation 31). Compounds prepared b y the general method of reaction of the chloro esters with the nitrophenol, either in the presence of base or b y using a salt of the phenol, are shown in Formula 32. S (RO ) P—OC H N0 -p 2
6
4
( 32 )
2
R = C H , C H , n - C H , i s o - C H , n - C H , iso-C H , C H 3
2
5
3
7
3
7
4
9
4
9
6
6
A l l these compounds could be prepared by this method. C H 0 2
S
5
^P^-OCeH.NO,-?
(33)
S (C H;0) P—OC H 2
2
6
(34)
5
S (C H 0) P—OC H CH -p (35) In Formula 33 is pictured a completely mixed ester of a thiophosphate in which all groups are different. T h e thiophosphoryl chloride method was used for preparing such compounds. It was of interest to see whether or not other compounds could be prepared b y the condensation of a dialkyl chlorothiophosphate with a phenol to give products such as shown in Formulas 34 to 36. S 2
5
2
6
4
3
(C H 0 ) P—OR 2
R =
—
