Ind. Eng. Chem. Res. 1996, 35, 4389-4393
4389
KINETICS, CATALYSIS, AND REACTION ENGINEERING Yield and Purity Comparison of Dimethoate Manufacturing Processes: Homogeneous Reaction, Two-Phase Uncatalyzed Reaction, and Phase Transfer Catalysis Juan R. Gonza´ lez-Velasco,* Jose´ A. Gonza´ lez-Marcos, Julia´ n Celaya, and Miguel A. Gutie´ rrez-Ortiz Departamento de Ingenierı´a Quı´mica, Facultad de Ciencias, Universidad del Paı´s Vasco/Euskal Herriko Unibertsitatea, P.O. Box 644, E-48080-Bilbao, Spain
The process for manufacturing dimethoate (O,O-dimethyl S-methylcarbamoylmethyl phosphorodithioate) should provide high yields of highly pure product which requires no further purification steps. A comparison of dimethoate yield and purity obtained by different manufacturing processes is presented. Ethanol, isopropanol, acetone, ethyl methyl ketone, and isobutyl methyl ketone were the solvents used when the reaction was carried out in one single homogeneous phase. In heterogeneous aqueous-organic solvent medium, an analysis by linear regression techniques has revealed temperature, reaction time, and organic solvent volume as the operational variables with statistical significance above 95% on the dimethoate purity, while only temperature was significant on gross and net yields. The phase transfer catalysis did not improve purity and yield obtained in heterogeneous solvent medium with any of the studied catalysts, namely methyltrioctylammonium chloride, tetrabutylammonium bromide, tetraoctylammonium bromide, tetraphenylphosphonium bromide, and tetrabutylphosphonium bromide. Introduction The dimethoate (O,O-dimethyl S-methylcarbamoylmethyl phosphorodithioate) is an organophosphorus compound with high parasiticidal activity against animal parasites in all stages of their growth and, at the same time, a surprisingly low toxicity to warm blooded animals. Most of the methods for preparing dimethoate yield a product with some impurities of similar physical characteristics which makes the separation difficult and increases the toxicity of the desired product. Thus, a good manufacturing process should provide high yields of highly pure dimethoate which requires no further purification steps. The typical process consists of reacting an alkali metal salt of O,O-dimethyl phosphorodithioate with N-methylchloroacetamide (Sisti and Lowell, 1964; March, 1992): OMe S
P
OMe
SNa + ClCH2CONHMe
OMe (nucleophile)
S
P
SCH2CONHMe + NaCl
mixtures containing large amounts of the trimethyl ester impurity is difficult. The whole reaction may be carried out in a ketone solvent, such as acetone, whereby large amounts of the trimethyl ester are formed. The use of a heterogeneous solvent medium allows the obtaining of better yields of purified product. This heterogeneous process comprises bringing the nucleophile and the substrate into reactive contact in a mutual solvent (e.g. water) in the presence of a second organic solvent immiscible with the first and capable of dissolving the reaction product. Thus, the reaction occurs in the aqueous phase, and afterward the dimethoate is transferred to the organic phase, preventing the impurity from being formed. The technique of phase transfer catalysis (PTC) is another possibility for this reaction to occur selectively by the use of a phase transfer agent whose function is to transfer the nucleophile to the organic phase, in which the reaction takes place (Starks and Owens, 1973; Wang et al., 1995) aqueous phase
R1S– + Q+X–
Q+R1S– + X–
OMe (substrate)
(2)
(dimethoate) (1)
Unfortunately, some secondary reactions of the formed dimethoate produce O,O,S-trimethyl phosphorodithioate as an impurity, which decreases the melting temperature of the product (Young et al., 1965). This physical property is used as indicative of the purity grade of the dimethoate. Isolation of the product from crude reaction * Author to whom correspondence should be addressed. Fax: +34-4-4648500. E-mail:
[email protected].
S0888-5885(96)00347-8 CCC: $12.00
organic phase
R1SR2
+
Q+X–
Q+R1S–
+
R2X
where Q+X- represents a quaternary salt containing sufficiently long alkyl groups or other organic structures as to make Q+R1S- predominantly soluble in the organic phase. In the study case R1 is SdP(OMe)2S- and R2 is MeNHCOCH2-. The purpose of this paper, spawned by industrial interest, is to compare yield and purity of dimethoate obtained in one single homogeneous phase, two-phase uncatalyzed reaction, and two-phase transfer catalysis. Once the heterogeneous water-chloroform reaction is © 1996 American Chemical Society
4390 Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996
revealed as the most efficient dimethoate synthesis procedure, we shall optimize the process by looking for a possible optimum in the response surface representing the relationship between the yield of dimethoate and the most influential operational variables, namely the volume of chloroform, the addition time of the sodium salt aqueous solution, the temperature, and the reaction time. Experimental Section Materials. The following are the procedures used to synthesize the sodium and ammonium salts of O,Odimethyl dithiophosphoric acid and N-methylchloroacetamide. The sodium salt was prepared from a mixture of 100 mL of O,O-dimethyl dithiophosphoric acid in 25 mL of pure water at 0 °C, which was neutralized by slow addition of a 20% NaOH solution until the pH reached 5. The ammonium salt was prepared in an anhydrous medium by saturation with dry ammonia of a solution of 250 mL (2 mol) of O,O-dimethyl dithiophosphoric acid and 500 mL of diethyl ether continuously stirred at 40 °C. The salt is insoluble in the ether. The resulting mixture was cooled to room temperature and filtered, and 255 g of the ammonium salt was obtained. The N-methylchloroacetamide was synthesized from a solution of 480 g of N-methylchloroacetate in 200 mL of methanol which was mixed at -5 °C with 360 g of commercial methylamine (40%) and stirred for 30 min. The excess of amine was neutralized with a 10% HCl aqueous solution. The mixture was heated under vacuum to remove the methanol, and the aqueous layer was separated and extracted with 3 × 200 mL portions of dichloromethane. The organic extracts were dried over anhydrous sodium sulfate, concentrated under vacuum, and solidified at 10 °C. The crystals were recrystallized from an acetone solution. Reactions. The synthesis of dimethoate in homogeneous medium was carried out as follows: a solution of 40 g of N-methylchloroacetmide in 400 mL of the chosen solvent (ethanol, isopropanol, acetone, ethyl methyl ketone, or isobutyl methyl ketone) was mixed with 125 mL of the aqueous solution of sodium O,O-dimethyl phosphorodithioate (ammonium O,O-dimethyl phosphorodithioate in the case of anhydrous medium) and allowed to stand at 25 °C for 20 h. The precipitated chloride was filtered off and the filtrate heated under vacuum to remove the solvent. The residual product was cooled down and washed with water, separated from the oil phase and neutralized with a sodium bicarbonate solution, and finally filtered to obtain the reaction product, dimethoate. The standard uncatalyzed heterogeneous experiment was achieved as follows: 200 mL of aqueous solution of N-methylchloroacetamide (0.75 mol) was mixed with 350 mL of toluene (or chloroform, chlorobenzene, or dichloromethane), stirred, and warmed up to the reaction temperature. The prepared sodium salt aqueous solution (125 mL) was added to this mixture with stirring over 3 h. The agitation was continued for two additional hours, and afterward the reaction mixture was cooled down to room temperature and decanted. The aqueous layer was separated, and the toluene solution was washed with 5% NaOH solution and subsequently with aqueous solution saturated with sodium hydroxide to pH ) 7.0. The toluene solution was dried over anhydrous sodium sulfate and then concen-
trated under vacuum, and the product was obtained by cooling the residual oil in ice. In the phase transfer catalysis experiments, some ammonium and phosphonium quaternary salts have been used (Herriott and Picker, 1975; Landini et al., 1977, 1978; Ravikumar, 1996), namely methyltrioctylammonium chloride (MTOAC), tetrabutylammonium bromide (TBAB), tetraoctylammonium bromide (TOAB), tetraphenylphosphonium bromide (TPPB), and tetrabutylphosphonium bromide (TBPB). The catalyst concentrations comprised between 1.3 and 16.7 mmol of catalyst per mol of SdP(OMe)2SNa. The reaction procedure was similar to the above described for heterogeneous medium. Analysis Methods. The dimethoate is separated from its impurities by gas chromatography. Although a glass column packed with silicone OV17 on Chromosorb G-AW-DMCS 80-100 US mesh is suggested by the World Health Organization (1985), better results were obtained with a fused silica capillar column 25 m long, with 0.22 mm internal diameter, with 0.25 µm of BP5 (code 25QC2BP5-0.25). The samples for analysis were dissolved in acetone. Di-n-butyl phthalate was used as internal standard. Following are the operational conditions: injector and detector temperature, 300 °C; oven temperature, isothermal at 110 °C for 4 min, increasing 25 °C/min until 290 °C, and isothermal at 290 °C for 10 min; split 60:1. Under these conditions the retention times resulted in toluene N-methylchloroacetamide O,O,S-trimethyl phosphorodithioate dimethoate di-n-butyl phthalate
1 min 2 min 5 min 9.5 min 10.5 min
The identification of the products was also done by mass spectrometry (GC-MS). Although the same conditions as those in GC were used, different retention times resulted due to the flow increase in the column caused by the detector working in vacuum (e.g. O,O,Strimethyl phosphorodithioate ) 2 min and dimethoate ) 7.66 min). The melting temperature of the dimethoate is closely related to the purity of the product. Thus, this physical property was determined by differential scanning calorimetry after the samples were carefully dried under vacuum (0.3 mmHg) for 200 min. The resulting melting point for the standard dimethoate was 50.8 °C. The percentage yields and purity were then calculated as gross yield ) grams of the obtained product (unpurified) maximum obtainable grams of dimethoate at total conversion × 100 purity )
grams of the obtained dimethoate (pure) × 100 grams of the obtained product (unpurified)
(3)
(4)
net yield ) grams of the obtained dimethoate (pure) maximum obtainable grams of dimethoate at total conversion × 100
(5)
Results and Discussion Homogeneous Reaction. The yields and purity of the product obtained in experiments carried out in
Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996 4391 Table 1. Dimethoate Purity and Yields Obtained in Aqueous and Anhydrous Media with Different Solvents solvent
expt
gross yield, %
purity, %
net yield, %
Sodium O,O-Dimethyl Phosphorodithioate Aqueous Solution ethanol 1 44.7 65.0 26.1 isopropanol 2 59.2 62.0 37.2 acetone 3 51.3 68.4 35.1 ethyl methyl ketone 4 87.4 60.0 52.4 isobutyl methyl ketone 5 53.1 73.7 39.1 Anhydrous Medium: Ammonium O,O-Dimethyl Phosphorodithioate ethanol 6 51.3 52.0 isopropanol 7 51.7 57.4 acetone 8 57.2 55.9 ethyl methyl ketone 9 65.7 59.8 isobutyl methyl ketone 10 87.6 46.2
26.7 29.7 32.0 39.3 40.5
Table 2. Dimethoate Yield and Purity Obtained in Heterogeneous Medium with Different Solvents (V ) 350 cm3, ta ) 3 h, tr ) 2 h) solvent
temp, °C
dichloromethane chlorobenzene toluene chloroform
35 60 60 55
Table 3. Effect of Reactant Excess on the Reaction Yield and Dimethoate Purity
expt
gross yield, %
purity, %
net yield, %
11 12 13 14 15 16 17
43.6 68.9 69.8 82.4 81.4 79.1 78.1
72.6 83.3 81.8 80.8 81.9 78.2 80.5
31.7 57.4 57.2 66.6 66.7 61.8 62.9
homogeneous aqueous and anhydrous media and with the five solvents are presented in Table 1. The reaction carried out using the aqueous sodium salt solution can be observed to produce higher purity of dimethoate but lower gross yield. There is no big difference in the obtained net yield when the same solvent was used with the sodium or ammonium salts as reactants. Uncatalyzed Heterogeneous Reaction. As water is a completely satisfactory solvent for both the amine halide and salt of the acid, it was used as one component of the system. Organic solvents with boiling point below 90 °C are preferred to ease the recovery of the product; thus, toluene, chlorobenzene, chloroform, and dichloromethane (Berkelhammer et al., 1961; Young et al., 1965) were chosen for this study. The reactions were carried out at temperatures close to the boiling point of the reactive mixture. The experimental results of yields and purity are presented in Table 2. From the results in Table 2 one can discard the chloromethane, as very low net yield was obtained with this solvent. On the contrary, chloroform was revealed to be the most appropriate solvent, as it allows high yield in the reaction and highly pure dimethoate. Also, this solvent presents high polarity so that it will be adequate for phase transfer catalysis. A series of experiments was carried out with the aim of studying the impurity formation by mixing of excess of reactantsssodium salt or chloroacetamidesof known technical purity. After 3 h at the reaction conditions in water-toluene medium, the dimethoate was isolated and its amount and purity were determined. The obtained results are presented in Table 3. When an excess of the sodium salt was used, an important decrease in the purity of the obtained product was observed, which did not occur with an excess of chloroacetamide. This indicates that the O,O,S-trimethyl phosphorodithioate, considered as the main impurity, is formed by a series reaction of dimethoate with the sodium salt. On the other hand, when an excess of chloroacetamide was used, it reacts with
reactant in excessa sodium salt (46%) acetamide (100%)
introduced isolated technical technical dimethoate dimethoate purity, % amount, g purity, % amount, g 96.0 96.0
22.0 22.0
83.3 94.0
11.0 7.0
a The excess of reactant is based on the stoichiometric amount needed to produce the initially introduced dimethoate.
Table 4. Yield and Dimethoate Purity Obtained in Heterogeneous Experiments with Chloroform at Different Conditions expt
studied variable gross yield, % purity, % net yield, %
Temperature (T, °C) (V ) 350 cm3, ta ) 3 h, tr ) 2 h) 18 61 (reflux) 78.3 86.7 67.9 14-17 55 80.3 80.4 64.5 19 50 73.9 77.5 57.3 20 45 59.4 72.0 42.8 Chloroform Volume (V, cm3) (T ) 55 °C, ta ) 3 h, tr ) 2 h) 21 200 78.2 82.8 67.4 14-17 350 80.3 80.4 64.5 22 500 80.3 72.3 58.1 Addition Time (ta, h) (V ) 350 cm3, T ) 55 °C, tr ) 2 h) 23 2.5 76.1 81.6 62.1 14-17 3.0 80.3 80.4 64.5 24 3.5 85.1 76.0 64.7 25 4.0 77.8 77.2 60.1 Reaction Time (tr, h) (V ) 350 cm3, ta ) 3 h, T ) 55 °C) 26 0.5 82.5 73.2 60.4 27 1.0 76.7 77.3 59.3 14-17 2.0 80.3 80.4 64.5
dimethoate (the significant decrease in the amount may be noted in Table 3) to give some unidentified products soluble in water as the purity of the dimethoate remains practically constant. The chromatographic analysis of the aqueous phase confirmed the existence of new products (new chromatographic peaks) when the reaction was carried out with excess of chloroacetamide. Thus, the fact that excess of any reactant is pernicious for production of pure dimethoate suggests the convenience of introducing the salt into the reaction mixture by successive small doses (or continuously by pumping) in such a way that an excess of the salt in the reactor never occurs. The next experiments were carried out feeding the salt solution by continuous pumping. Optimization of the Process. In order to find the optimal operational conditions for industrial practice of the heterogeneous water-chloroform process, revealed as the most productive of those studied, a series of experiments was planned to analyze the trends of yield and purity with temperature (T), volume of chloroform (V), addition time of the sodium salt (ta), and reaction time after addition of the salt (tr). The results obtained are presented in Table 4. The repeated experiments 14-17 (Table 2) have been used to determine the variance of experimental error, which is assumed to be constant for all operational conditions. The statistical analysis of the results has been obtained by linear regression techniques with the aim of determining the operational variables which present significant effects on the yields and/or the purity of the product. The variance analysis for the fit corresponding to the three response variables was performed considering separately the sum of squares corresponding to the lack of fit and to the experimental error. The latter was determined from the results obtained in the four experiments carried out at the same conditions.
4392 Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996
Figure 2. Influence of the reaction time and chloroform volume on the obtained dimethoate purity. Table 6. Results of Experiments Carried Out in Phase Transfer Catalysis with Different Organic Solvents
Figure 1. Gross yield, purity, and net yield obtained at different temperatures in chloroform-water medium. Table 5. Statistical Results by Linear Regression for Experiments Shown in Table 4 response
variable
slope
confidence significance
gross yield
temperature 1.28 CHCl3 volume 7.00 × 10-3 addition time 1.69 reaction time -0.17
0.52 2.99 × 10-2 5.43 4.26
Y N N N
purity
temperature 0.867 CHCl3 volume -3.5 × 10-2 addition time -3.73 reaction time 4.31
0.40 2.33 × 10-2 4.24 3.33
Y Y N Y
temperature 1.61 CHCl3 volume -2.2 × 10-2 addition time -1.59 reaction time 3.38
0.66 3.78 × 10-2 6.89 5.40
Y N N N
net yield
CI )
Syx Sxx tS
xSxx
catalyst
14-17 28 29 30 31 32 33 34 35 36
without MTOAC
13 37 38 39 40 41 42 43
without MTOAC TBAB
(6) (7)
where Sxx and Syx represent the corresponding variance and covariance, respectively, S is the typical deviation of the experimental error, and t is the tabulated value of the t-student function. Table 5 shows the values obtained for the correlation coefficients as well as their confidence limits for a probability of 95%. The linear effects which result to be significant above a probability level of 95% have been typed with Yes in the last column of Table 5. To make these effects clearer, the experimental values of the response have been represented graphically against the significant variables, including the response
Ra
gross yield, % purity, % net yield, %
Solvent: Chloroform 80.3 1.6 75.3 16.7 83.0 2.15 87.2 16.7 78.9 1.36 75.0 16.7 78.5 1.9 92.0 16.7 73.7 2.0 72.0
80.4 80.0 58.8 78.0 50.9 81.7 49.4 70.8 46.0 78.0
64.5 60.2 48.8 67.8 40.2 61.3 38.8 65.0 33.9 56.2
TOAB TPPB TBPB
1.5 2.0 2.2 2.4 1.3 2.0 2.0
81.8 88.9 81.0 84.0 81.8 76.0 80.0 78.0
57.2 60.9 58.9 54.6 56.8 53.2 51.2 56.2
12 44 45 46 47
without MTOAC TBAB TPPB TBPB
Solvent: Chlorobenzene 68.9 83.3 1.5 74.0 81.0 2.1 56.0 84.3 2.0 71.0 70.0 2.0 79.0 65.0
57.4 59.9 47.2 49.7 51.4
11 48
without MTOAC
Solvent: Dichloromethane 43.6 72.6 1.75 47.8 84.0
31.7 40.2
a
The correlation coefficient and the confidence interval were determined as
b)
expt
TBAB TOAB TPPB TBPB
Solvent: Toluene 69.8 68.5 72.0 65.0 69.5 70.0 64.0 72.0
R ) mmol of catalyst/mol of SdP(OMe)2SNa.
mean for the repeated experimental point and its confidence interval for a probability of 95%. The temperature presents a positive influence on the purity of the obtained dimethoate and on both gross and net yields as can be seen in Figure 1. The experimental error is marked with a bar for the conditions at which the experiment was replicated, i.e. 55 °C. The effect on the yield presents a slight curvature but does not overcome the significance level. The purity of the obtained dimethoate is also affected by the solvent volume and the reaction time, increasing with low solvent volume and high reaction time as shown in Figure 2. The rest of response vs variable regressions do not overcome the significance level for a probability of 95%, so that no definitive quantitative conclusions can be drawn as to their effect on the reaction system. Phase Transfer Catalysis. In PTC, the use of a small amount of phase transfer agent makes the system catalytic, since the phase transfer agent can repeatedly transfer active salt ions into the organic phase for reaction with chloroacetamide, making short the contact time between nucleophile and dimethoate in the aque-
Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996 4393
ous phase which potentially would minimize formation of the trimethyl ester impurity. In order to analyze the convenience of the PTC process for production of dimethoate, several experiments were carried out with different organic solventsstoluene, chloroform, dichloromethane, and chlorobenzenesand catalytic transfer agentssMTOAC, TBAB, TOAB, TPPB, and TBPB. The obtained results can be seen in Table 6, where the values previously obtained without catalyst have also been included. The analysis of results in Table 6 indicates that phase transfer catalysis with low concentrations of the transfer agent allows the obtaining of similar yields and purity compared to those obtained in uncatalyzed two-phase media; i.e., the secondary reaction forming the trimethyl ester impurity occurs at similar extension in both reaction systems. PTC with high catalyst concentrations produced a notable decrease (about 30%) in the purity of the obtained dimethoate which also reduces appreciably the net yield. Conclusions A comparison of different processesshomogeneous in single phase, heterogeneous in two-phases, and heterogeneous with phase transfer catalysissto obtain dimethoate has been discussed from the view of process yields and product purity. The most efficient process for obtaining high yields of highly pure dimethoate has resulted to be the uncatalyzed heterogeneous two-phase reaction, especially when chloroform was used as the organic solvent. The O,O,S-trimethyl phosphorodithioate impurifying the dimethoate was formed by a series reaction between the formed dimethoate and the sodium salt reactant. A statistical analysis of experiments by linear regression allowed the discerning of the variables with significance above a probability level of 95% resulting in a positive influence of temperature on the gross yield, purity, and net yield and a positive influence of reaction time and a negative influence of chloroform amount on the dimethoate purity.
Acknowledgment We gratefully acknowledge support by General Quı´mica S.A. (Lantaro´n, Alava), especially to J. Pinacho and J. M. Rituerto. Literature Cited Berkelhammer, G.; Dubreuil, S.; Young, R. W. O,O-dialkyl S(carbamoylalkyl) Phosphorodithioates. J. Org. Chem. 1961, 26, 2281. Herriott, A. W.; Picker, D. Phase Transfer Catalysis. An Evaluation of Catalysts. J. Am. Chem. Soc. 1975, 97, 2345. Landini, D.; Maia, A.; Montanari, F. Mechanisms of PhaseTransfer Catalysis. J. Chem. Soc., Chem. Commun. 1977, 4, 112. Landini, D.; Maia, A.; Montanari, F. Phase-Transfer Catalysis. Nucleophilicity of Anions in Aqueous Organic Two Phases Reactions Catalyzed by Onium Salts. A Comparison with Homogeneous Organic Systems. J. Am. Chem. Soc. 1978, 100, 2796. March, J. Advanced Organic Chemistry: Reaction, Mechanisms and Structure, 4th ed.; John Wiley & Sons: New York, 1992; p 339. Ravikumar, V. T. A Convenient Synthesis of Aryl Phosphorodichloridothioates Using Phase Transfer Catalyst. Synth. Commun. 1996, 26, 1821. Sisti, A. J.; Lowell, S. Mechanism of the Bimolecular Nucleophilic Displacement Reaction on R-Halocarbonyl Compounds. Can. J. Chem. 1964, 42, 1896. Starks, C. M.; Owens, R. M. Phase-Transfer Catalysis. 2. Kinetic Details of Cyanide Displacement on 1-Haloctanes. J. Am. Chem. Soc. 1973, 95, 3613. Wang, M. L.; Ou, C. C.; Jwo, J. J. Study of the Reaction of Benzoylchloride and Sodium Dicarboxylate under Inverse Phase Transfer Catalysis. Bull. Chem. Soc. Jpn. 1995, 68, 2165. Young, R. W.; Cob, C.; Clarck, L. Systemic Insecticidal Alkylcarbamoyl-methyl Dimethyl Phosphorodithioates. U.S. Patent 3,210,242, 1965.
Received for review June 17, 1996 Revised manuscript received September 11, 1996 Accepted September 19, 1996X IE9603474
X Abstract published in Advance ACS Abstracts, November 15, 1996.
