Chemical Papers 65 (4) 510518 (2011) DOI: 10.

2478/s11696-011-0026-1

ORIGINAL PAPER

An alternative synthetic process of -acetaminobenzenesulfonyl chloride through combined chlorosulfonation by HClSO3 and PCl5
a

Shiyu Tan,

a,b

Yang Yang, a Ziping Luo, a Shuo Zhao, a,b Dafu Huang*, c Jun Zhang, a,b Lichun Dong, a Gang Wang
of Chemistry and Chemical Engineering, Chongqing University, 400044 Chongqing, China

a School b Chongqing

Key laboratory of the Three Gorges Reservoir Regions Eco-Environment, Ministry of Education, 400044 Chongqing, China Environmental Protection Bureau of Wansheng District, 400800 Chongqing, China Received 21 July 2010; Revised 8 January 2011; Accepted 27 January 2011

c The

p-Aminobenzene sulfonamide (sulfanilamide, SN) is the simplest and most-used sulfonamide medicine. The key step of SN production via the commonly used chlorosulfonic acid routine is the synthesis of p-acetaminobenzenesulfonyl chloride (P-ASC). A large amount of HSO3 Cl has to be used in the traditional process, which results in serious environmental problems. In this study, an alternative chlorosulfonic acid process to synthesize P-ASC was investigated by partially substituting HSO3 Cl by PCl5 as the chlorination agent. Compared with the traditional process, the molar ratio of HSO3 Cl to acetanilide (the main raw material) can be decreased from 4.96 to 2.1 using CCl4 as the diluent; also, addition of a small amount of NH4 Cl was found to signicantly increase the P-ASC yield. Operating conditions of the reaction were studied rst by single-factor experiments and later by orthogonal experiments to obtain optimum operating conditions under which the P-ASC yield can reach as high as 86.3 %. c 2011 Institute of Chemistry, Slovak Academy of Sciences Keywords: p-aminobenzene sulfone chloride, chlorosulfonation process, HSO3 Cl, PCl5 , p-aminobenzene sulfonamide

Introduction
Sulfonamides are the second most-used antibacterial medicine just after antibiotics. They are stable, cheap and have a very broad antimicrobial spectrum (Fidock et al., 2004; Huang et al., 2001; Zhao et al., 2008). Among the sulfonamide medicines, paminobenzene sulfonamide (sulfanilamide, SN) has the simplest molecular structure and the highest annual production. There are two main routines for the production of SN: chlorobenzene and chlorosulfonic acid (Martin et al., 1943; Martin & Hirt, 1947; Galat, 1944). In the chlorobenzene process (Gao et al., 2002), raw material, chlorobenzene, is rst sulfonated and chlorinated to chlorobenzene sulfonyl chloride using
*Corresponding author, e-mail: lcdong72@gmail.com

liquid SO3 as the sulfonation agent and liquid SOCl2 as the chlorination agent, the intermediate is further ammoniated to give SN under high temperature and high pressure using Cu2 O as the catalyst. This process has the advantage of generating a lower amount of waste acid. However, it requires severe operating conditions and the large amount of exhaust gas generated in the process is non-recyclable making its industrial application very limited. In the chlorosulfonic acid process (Gao et al., 2002; Meng, 1995; Zhang, 1991; Zeng, 1981; Fan et al., 2005), SN is prepared from acetanilide which is rst sulfonated and chlorinated to pacetaminobenzenesulfonyl chloride (P-ASC) using an excess of chlorosulfonation acid as a combined chlorination and sulfonation agent. Afterwards, P-ASC is

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Fig. 1. Scheme of the experimental set-up. 1 heater; 2 four-neck ask; 3 water/ice bath; 4 feed inlet; 5 thermometer; 6 stirrer; 7 condenser.

ammoniated and hydrolyzed to produce SN. Raw materials for this process are easy to obtain and the operating conditions are fairy mild, which is why it is the most used industrial process for SN production. However, during the production of P-ASC, an excess of HSO3 Cl with the molar ratio of HSO3 Cl to acetanilide as high as 5.0 has to be used in order to obtain the required product yield. After the reaction, the reaction mixture is treated with water which reacts with HSO3 Cl to generate mixed H2 SO4 /HCl acidic solution and HCl gas. P-ASC is obtained as a crystal precipitate. In this process, HCl gas can be recovered by water-scrubbing producing pure HCl while the mixed acidic solution, after being ltered to obtain crude product, can only be sold as a low value byproduct since it contains a signicant amount of impurities. Finally, the crude product is washed with water to obtain the nal product, which generates a signicant amount of waste acidic water resulting in serious environment problem (Li, 2002). With the aim to decrease the amount of HSO3 Cl, an alternative chlorosulfonic acid process for the synthesis of P-ASC, in which PCl5 is used to partially replace HSO3 Cl as the chlorination agent, is proposed. A diluent, CCl4 , is introduced to reduce the viscosity of the reaction system, and a small amount of NH4 Cl is added into the chlorination process to increase the P-ASC yield. The results show that the alternative routine not only decreases the amount of HSO3 Cl but also signicantly increases the product yield.

Experimental
Acetanilide (Analytical Grade, AR) was purchased from Sinopharm Chemical Reagent Co. Ltd. (Shanghai, China); PCl5 (AR) was from Tingxin Chemical Reagent Co. Ltd. (Shanghai, China); CCl4 (AR) from Chuandong Chemical Co. Ltd. (Chongqing, China);

HSO3 Cl (Industrial Grade) from Changshou Chemical Co. Ltd. (Chongqing, China); and the standard PASC sample was obtained from Changshou Chemical Plant (> 99 %, Chongqing, China). All the reagents were used without further purication. In a 250 mL four-neck ask (Fig. 1), 7.3 mL of HSO3 Cl were mixed with CCl4 at a volume ratio of HSO3 Cl : CCl4 = 1 : 3.4 at room temperature. Then, 7.00 g of acetanilide were added in seven batches under stirring; the interval between each batch was 3 min during which the temperature was maintained at (15 2) C by an ice bath. After the addition was completed, the system was stirred for another 10 min at (15 2) C. Afterwards, the reaction system was heated up to 60 C to perform the sulfonation reaction. After 60 min, when the reaction was close to the end, 0.277 g of NH4 Cl was added. Subsequently, 11.9 g PCl5 were added into the system in three batches, the interval between each batch was 10 min. Then, the temperature was increased to 72 C at which the chlorination reaction proceeded for 3 h. After the synthesis reaction, most CCl4 was removed under vacuum and ice water was added to remove POCl3 , HSO3 Cl, and PCl5 , which also makes P-ASC crystalling out from the water ((5 0.2) C). The reaction mixture was then kept still for liquid-liquid separation of the remaining CCl4 for recycling. The crude product, obtained by ltration, was washed several times using deionized water until the pH of the washing water was neutral (pH > 6), and dried in a vacuum oven for 3 h at 50 C to obtain the nal product (10.4 g, white crystals). Purity of the P-ASC product was determined to be 98.2 % by the argentometric method whose basic principle is to measure the Cl content in the product using standard AgNO3 solutions (Kealey & Haines, 2002). During the P-ASC synthesis, the dissolution of acetanilide in HSO3 Cl is a strongly exothermic process

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NHCOCH3 HSO3Cl HCl SO3H II

S. Tan et al./Chemical Papers 65 (4) 510518 (2011)

NHCOCH3

A
NHCOCH3 HSO3Cl H2SO4 SO3H II SO2Cl III NHCOCH3

B
NHCOCH3 PCl5 POCl3 SO3H II NHCOCH3

Fig. 2. Scheme of the sulfonation reaction.

Fig. 3. Schemes of the chlorination reaction: using HSO3 Cl (A) as the chlorination agent; using PCl5 (B) as the chlorination agent.

while both the sulfonation and chlorination reactions are weakly exothermic. Since the whole process is accompanied by the generation of HCl gas, a water adsorption device was added to the experimental set to recover HCl gas from the system. Moreover, a H2 O ux condenser was used to recirculate the reactive solvent. The melting point of P-ASC was measured by an XRC21 microscopic melting point apparatus (Sichuan University Scientic Instrument Co. Ltd., Chengdu, China). IR spectrum of P-ASC was recorded on a MAGMAIR550 spectrometer (Nicolet Company, USA) using the KBr pressing pellet method. The product solved in methanol was analyzed using an Agilent 1100 HPLC system (UK), equipped with a Diamonsil C18 (4.6 mm 250 mm, 5 m) column and a UV 254 detector. Operating conditions were: temperature 40 C; injection volume of the sample 25 L; ow phase methanol/water (r = 60 : 40); ow rate of the ow phase 1 mL min1 . Finally, 1 H-NMR spectrum of the product dissolved in CDCl3 was recorded on a Bruker AV500 NMR spectrometer (Switzerland) with Si(CH3 )4 as the internal reference.

as the chlorination agent with the aim to decrease the amount of HSO3 Cl and to increase the chlorination eciency. The comparison of several commonly used chlorination agents, e.g., SOCl2 (Moore, 2003), SO2 Cl2 (Castaner et al., 1991), PCl3 , trichloromethyl benzene, PCl5 , resulted in the selection of PCl5 due to its high chlorination eciency and easy treatment of byproducts (Emerson & Ifalade, 2005). Reaction scheme with PCl5 as the chlorination agent is presented in Fig. 3b, the byproducts being POCl3 and HCl. As with HSO3 Cl, excess POCl3 can be removed by its reaction with water (Eqs. (1) and (2)), generated HCl gas as well as that from the chlorination reaction can be recovered by water scrubbing to produce hydrochloric acid. HSO3 Cl + H2 O H2 SO4 + HCl POCl3 + 3H2 O H3 PO4 + 3HCl (1) (2)

Results and discussion

Reaction mechanism Traditional chlorosulfonation process to synthesize P-ASC from acetanilide actually contains two sequential reactions (Li et al., 2007; Song, 1990; Kong et al., 1998): acetanilide (I ) is sulfonated to pacetamidobenzene sulfonic acid (II ) (Fig. 2) which is then chlorinated to P-ASC (III ) (Fig. 3a). In the traditional process, HSO3 Cl is both the sulfonation and the chlorination agents and it also serves as a diluent maintaining low viscosity of the reaction system. Among the two reactions for P-ASC synthesis, sulfonation is fast and HSO3 Cl has very high sulfonation eciency, consequently, the conversion rate of the sulfonation reaction is close to 100 % (Meier & Tronich, 1992; Xin et al., 2006; Su & Yang, 2002; Su & Hao, 2005). On the other hand, the chlorination reaction is slow and the eciency of HSO3 Cl as the chlorination agent is low. Therefore, a new chlorination agent was employed in this study to partially substitute HSO3 Cl

In the traditional chlorosulfonation process to synthesize P-ASC, HSO3 Cl not only serves as the chlorination and sulfonation agent but also as the diluent maintaining low viscosity of the reaction system. Partial substitution of HSO3 Cl by PCl5 as the chlorination agent in the improved process decreases the amount of HSO3 Cl, which leads to an increase of the reaction systems viscosity and pronounced decrease of the P-ASC yield. An alterative diluent has to be introduced to eectively reduce the viscosity of the reaction system. Owing to the extremely high activity of HSO3 Cl and PCl5 , the candidate diluent has to be very inert. In this work, CCl4 was used as the diluent, however, since CCl4 is to be banned worldwide in the near future due to its damage to the ozone layer, an environmentally friendly diluent is being actively searched for. It has also been found experimentally that the addition of a small amount of NH4 Cl during the chlorination stage increases the product yield signicantly. Although detailed mechanism of NH4 Cl reaction requires further investigation, it is believed that NH4 Cl acts as a phase transfer catalyst which can aect the distribution of reactants and products between the two phases (CCl4 phase and HSO3 Cl phase) due to

lC

SO2Cl III

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513

75

0.5 0.4
Absorbance/a.u. Absorbance /(AU)

60

B A

0.3 0.2 0.1 0

Transmittance /%

45

30

15
0 2 4 t /min 6 8 10

0 4000

3500

3000

2500 2000 1500 -1 Wavenumber /cm-

1000

500

Fig. 4. IR spectra of the standard P-ASC sample (A) and the product (B).

Fig. 5. HPLC chromatogram: void volume (t = 0.977 min), impurities (t = 2.289 min), and P-ASC (t = 3.115 min). Product purity determined using the area normalization method is 98.7 %.

Product characterization Melting point of the synthesized product was determined to be (141.3 1.2) C, while its literature value is between 141 C and 149 C (Pence & Winter, 1939; Smiles & Stewart, 1925; Pouchert, 1970). Since the prepared product is not 100 % pure, the measured value is within a reasonable range conrming thus the prepared product to be P-ASC. Fig. 4 compares the IR spectrum of the standard P-ASC sample (line A) with that of the prepared product (line B). It can be seen that the two spectra are almost identical, which further veries the identication of the product as P-ASC of high purity. In the spectra, the characteristic peaks at 1371.1 cm1 and 1170.3 cm1 can be attributed to the symmetric stretching of OSO. The three intense peaks at 3307.3 cm1 , 3264.5 cm1 , and 1681.8 cm1 correspond to the amide group. The peaks at 3050.6 cm1 , 1495.0 cm1 , 1558.1 cm1 , 1584.7 cm1 , and 1605.7 cm1 correspond to the benzene ring, while the peak at 839.0 cm1 proves that the benzene ring was parasubstituted (Pouchert, 1970; Lin et al., 2009). HPLC chromatogram (Fig. 5) of the product shows three peaks: the rst one at t = 0.977 min was attributed to the ow phase (void volume); the second at t = 2.289 min corresponds to the impurities; while the last one at t = 3.115 min belongs to P-ASC. Quantitative analysis via the peak area normalization method indicated that the product purity is 98.7 %, which conrmed the result of the argentometric method (98.2 %). Fig. 6 shows the 1 H-NMR spectrum of the product, which exhibits three major peaks except three baseline peaks corresponding to the impurities. The

Intensity/a.u. Intensity /(AU)

the salting-out eect and the participation of chloride ions in the surface ion-pairing (Boekman et al., 1992).

1.945

2.963

8.0

7.9

7.8

7.7

16

14

12

10

3.000

-2

-4

Fig. 6. 1 H-NMR spectrum of the product dissolved in CDCl3 with Si(CH3 )4 as the internal reference. The spectrum exhibits three major peaks correnponding to the four types of hydrogen atoms in P-ASC while the three baseline peaks are attributed to impurities.

peak at = 2.189 was attributed to methyl hydrogen atoms. The two double-peaks at = 7.7 and = 7.9 correspond to the four hydrogen atoms in the benzene ring; peaks at = 7.7 contain an overlapping peak corresponding to the hydrogen atom in NH. The 1 H-NMR spectra show that two types of hydrogen atoms exist in the benzene ring of the products, which further conrms that the benzene ring is parasubstituted. If the benzene ring was ortho-substituted, four dierent types of hydrogen atoms would exit in the benzene ring. Aecting factors of synthesis reaction The aim of the improved process is to decrease the consumption of HSO3 Cl by using PCl5 to partially replace HSO3 Cl as the chlorination agent; however, it has been found that the dose of HSO3 Cl cannot be less than a critical range, where the molar ratio of HSO3 Cl and acetanilide is around 2.0; otherwise, the P-ACS yield decreases remarkably (Fig. 7) even at a very high dose of PCl5 . Accordingly, the molar ratio of

514
90 80 70

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80 70 60

Yield /%

60 50 40 30 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 HSO3Cl : acetanilide molar ratio 3.2

Yield /%

50 40 30 20 45 50 55 Ts /C 60 65

Fig. 7. P-ASC yield at dierent amounts of HSO3 Cl. Other operating conditions are: molar ratio of PCl5 , NH4 Cl, and CCl4 to acetanilide 1.40, 0.1, and 4.0, respectively; sulfonation time 1 h; chlorination time 3 h; sulfonation temperature 54 C; chlorination temperature 66 C; stirring intensity medium.

Fig. 9. P-ASC yield at dierent sulfonation temperatures (Ts ). Other operating conditions are: molar ratio of HSO3 Cl, PCl5 , NH4 Cl, and CCl4 to acetanilide 2.0, 1.4, 0.1, and 4.0, respectively; sulfonation time 1 h; chlorination time 3 h; chlorination temperature 66 C; stirring intensity medium.

80 75 70

85 80 75

Yield /%

65 60 55 50 0.9

Yield /%

70 65 60 55

1.1 1.2 1.3 PCl5 : acetanilide molar ratio

1.4

1.5

50 55 60 65 Tc /C 70 75 80

Fig. 8. P-ASC yield at dierent amounts of PCl5 . Other operating conditions are: molar ratio of HSO3 Cl, NH4 Cl, and CCl4 to acetanilide 2.0, 0.1, and 4.0, respectively; sulfonation time 1 h; chlorination time 3 h; sulfonation temperature 54 C; chlorination temperature 66 C; stirring intensity medium.

Fig. 10. Eect of chlorination temperature (Tc ). Other operating conditions are: molar ratio of HSO3 Cl, PCl5 , NH4 Cl, and CCl4 to acetanilide 2.0, 1.4, 0.1, and 4.0, respectively; sulfonation time 1 h; chlorination time 3 h; sulfonation temperature 54 C; stirring intensity medium.

HSO3 Cl and acetanilide was set to 2.0 and the eect of PCl5 and CCl4 dosage, reaction time and temperature on the product yield was investigated. Fig. 8 displays the P-ASC yield versus the molar ratio of PCl5 to acetanilide, the results show that the P-ASC yield increases with an increase in the PCl5 amount until a plateau, when the molar ratio of PCl5 to acetanilide is higher than 1.4, was reached. The eect of the sulfonation and chlorination temperatures on the product yield is shown in Figs. 9 and 10, respectively. Both results show that the P-ASC yield rst increases with an increase of the reaction temperature until a maximum is reached, and then decreases with a further increase of the reaction temperature. Optimum sulfonation temperature is around 58 C and the decrease of the product yield at higher temperatures is believed to be due to the enhancement of side reactions. Optimum chlorination temperature

is around 70 C, the decrease of the product yield at higher temperatures is caused by the enhancement of side reactions, decomposition of HSO3 Cl and the evaporation of the solvent. The chlorosulfonation reaction takes about 4.5 h to be completed in the traditional process, and it was also reported that the chlorination process is slower and requires longer time (Galat, 1944; Li et al., 2007; Song, 1990; Kong et al., 1998; Meier & Tronich, 1992). Figs. 11 and 12 show the eect of the sulfonation and chlorination time on the P-ASC yield. The results indicate that the product yield rst increases with an increase of both sulfonation and chlorination time and decreases with a further increase in the reaction time after reaching a maximum value. Optimum sulfonation and chlorination times are around 1.0 h and 3.0 h, respectively; longer reaction time leads to a decrease of the P-ASC yield,

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75 72

80 77

Yield /%

69 66 63 60 0.4

Yield /%

74 71 68 65

0.6

0.8

ts /h

1.2

1.4

1.6

1.5

2.5

3.5

4.5

tc /h
Fig. 12. P-ASC yield at dierent chlorination times (tc ). Other operating conditions are: molar ratio of HSO3 Cl, PCl5 , NH4 Cl, and CCl4 to acetanilide 2.0, 1.4, 0.1, and 4.0, respectively; sulfonation time 1 h; sulfonation temperature 54 C; chlorination temperature 66 C; stirring intensity medium.

Fig. 11. P-ASC yield at dierent sulfonation times (ts ). Other operating conditions are: molar ratio of HSO3 Cl, PCl5 , NH4 Cl, and CCl4 to acetanilide 2.0, 1.4, 0.1, and 4.0, respectively; chlorination time 3 h; sulfonation temperature 54 C; chlorination temperature 66 C; stirring intensity medium.

which is also due to the enhancement of the side reactions. Orthogonal experiments Based on the single-factor experiments, a group of orthogonal experiments was employed to study the importance of the aecting factors and to obtain the optimum operating conditions. Since there are nine essential aecting factors including the material ratio of HSO3 Cl, PCl5 , CCl4 , and NH4 Cl, the time and temperature of both sulfonation and chlorination reaction, and the stirring intensity (Li, 2005; Montgomery, 2004); and also the interactive eect of sulfonation temperature and time, chlorination temperature and time, material ratio of HSO3 Cl to PCl5 , material ratio of CCl4 to NH4 Cl are interesting, the L27 (313 ) design was selected. Aecting factors and their values in the orthogonal experiments are listed in Table 1, where columns numbers 4, 8, 9, and 11 studies the interactive eects of factors 1 and 2, factors 10 and 12, factors 6 and 12, and factors 3 and 5, respectively. Experimental design and results are shown in Tables 2 and 3, where the range value (R) indicates the affecting degree of each aecting factor. The larger the

range value, the more important the corresponding factor. K is the average product yield corresponding to each level of every aecting factor. From the K values, optimum operating conditions can be determined by choosing the level of each factor corresponding to the largest K value (Table 2). Afterwards, verication experiments were done at the optimum operating conditions to conrm the results of orthogonal experiments and to obtain the highest product yield. The range analysis in Table 2 demonstrates that the HSO3 Cl amount (R = 11.9), sulfonation temperature (R = 8.26) and the chlorination time (R = 6.90) are the major aecting factors while the sulfonation time, amount of CCl4 , PCl5 , and NH4 Cl or the stirring intensity have minor eect on the product yield. The study on the eect of several factors (Table 3) shows that the interaction between the amount of NH4 Cl and CCl4 has the most signicant eect on the product yield (R = 7.10). The addition of NH4 Cl increases the P-ASC yield; however, it also increases the viscosity of the reaction system, which is unfavorable to the chlorination reaction. Sincean increase in the CCl4 amount can reduce the viscosity of the reaction system, the addition of a suitable amount of CCl4 can increase the eect of NH4 Cl. Table 4 (obtained from Table 2)

Table 1. Factors and levers of the L27 (313 ) orthogonal experiments: sulfonation temperature (Ts ), sulfonation time (ts ), chlorination temperature (Tc ), chlorination time (tc ), molar ratio of compound to acetanilide Factor number 1 Ts Level
C

2 ts h 0.5 1.0 1.5

3 Tc
C

4 12

5 tc

8 7 12

9 35

10

11 6 10

12

13

HSO3 Cl h 2.5 3.0 3.5 1.9 2.0 2.1

CCl4 3.0 4.0 5.0

PCl5 1.10 1.25 1.40

NH4 Cl 0 0.1 0.2

Stiring intensity

1 2 3

50 55 60

62 67 72

High Medium Low

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Table 2. Design and results of the L27 (313 ) orthogonal experiment: sulfonation temperature (Ts ), sulfonation time (ts ), chlorination temperature (Tc ), chlorination time (tc ), molar ratio of compound to acetanilide, stirring intensity: 1 low, 2 medium, 3 high Factor number 1 Ts Experiment
C

2 ts h 1 1 1 2 2 2 3 3 3 1 1 1 2 2 2 3 3 3 1 1 1 2 2 2 3 3 3 68.50 71.61 71.0 3.10

3 Tc
C

5 tc

10

12

13 Yield

HSO3 Cl h 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 71.74 73.12 66.23 6.90 1 2 3 1 2 3 1 2 3 2 3 1 2 3 1 2 3 1 3 1 2 3 1 2 3 1 2 63.73 71.70 75.66 11.9

CCl4 1 2 3 1 2 3 1 2 3 3 1 2 3 1 2 3 1 2 2 3 1 2 3 1 2 3 1 69.83 69.26 72.00 2.74

PCl5 1 2 3 2 3 1 3 1 2 3 1 2 1 2 3 2 3 1 1 2 3 3 1 2 2 3 1 70.83 68.22 72.04 3.82

NH4 Cl 1 2 3 3 1 2 2 3 1 2 3 1 1 2 3 3 1 2 3 1 2 2 3 1 1 2 3 68.89 69.51 72.69 3.80

Stiring intensity % 1 2 3 3 1 2 2 3 1 3 1 2 2 3 1 1 2 3 2 3 1 1 2 3 3 1 2 72.16 69.99 68.93 3.23 61.90 62.08 71.74 53.64 73.10 72.90 68.04 74.80 64.72 70.18 74.64 51.50 70.01 78.44 70.59 79.43 76.04 48.85 81.09 69.27 74.14 78.28 77.12 70.42 83.07 72.66 71.17

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 K1 K2 K3 R

1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 66.99 68.85 75.25 8.26

1 1 1 2 2 2 3 3 3 2 2 2 3 3 3 1 1 1 3 3 3 1 1 1 2 2 2 69.54 69.20 72.34 3.14

shows that the combination of the molar ratio of CCl4 to acetanilide of 5.0 and the molar ratio of NH4 Cl to acetanilide of 0.2 results in the highest product yield; verication experiments also showed that the product yield does not increase when the amounts of CCl4 and NH4 Cl are further increased. Optimum operating conditions of the P-ASC synthesis were determined from Table 2 as: sulfonation temperature of 60 C; sulfonation time of 1.0 h; chlorination temperature of 72 C; chlorination time of 3 h; molar ratio of HSO3 Cl to acetanilide of 2.1; molar ratio of CCl4 to acetanilide of 5.0; molar ratio of PCl5 to acetanilide of 1.4; molar ratio of NH4 Cl to acetanilide of 0.2; stirring intensity high. The verication experiments demonstrated that the P-ASC yield can reach 86.3 % under optimum operating conditions, the yield being signicantly higher than that of the traditional process, (82.4 % for lab-scale and 77 % for the industrial process) with the molar ratio of HSO3 Cl to acetanilide as high as 4.96 (Li et al., 2007). Since the orthogonal experiments showed that the molar ratio of PCl5 to acetanilide has a minor eect on the

product yield, the P-ASC yield at the molar ratio of PCl5 to acetanilide of 1.10 (Level 1) and 1.25 (Level 3) was also studied when other conditions were xed, and the P-ASC yield reached 84.3 % and 85.4 %, respectively. Therefore, in the scale production of P-ASC using the alternative process, the molar ratio of PCl5 to acetanilide can be adjusted according to the cost evaluation with little sacrice of the product yield. When the molar ratio of PCl5 to acetanilide was 1.1, the alternative process generated 6.6 mol of HCl, 1.1 mol of H3 PO4 , and 1.1 mol of H2 SO4 for producing a mol of P-ASC. Total amount of H+ was 12.1 mol, by 0.22 mol more than that generated using the traditional process (3.96 mol of HCl and 3.96 mol of H2 SO4 ). However, since most HCl gas can be recovered to hydrochloric acid, the amount of aqueous acid was signicantly decreased in the alternative process, which reduces the amount of the low value byproduct of mixed acid and the waste acidic water generated during the washing of crude product. The experiments show that CHCl3 is also a suitable solvent; the yield of P-ASC can reach as high as

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Table 3. Design and results of the L27 (313 ) orthogonal experiment: interactive eect Factor number Experiment 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 K1 K2 K3 R 4 12 1 1 1 2 2 2 3 3 3 3 3 3 1 1 1 2 2 2 2 2 2 3 3 3 1 1 1 71.30 69.826 69.97 1.47 9 35 1 2 3 2 3 1 3 1 2 2 3 1 3 1 2 1 2 3 3 1 2 1 2 3 2 3 1 70.86 70.20 70.10 0.798 8 7 12 1 2 3 2 3 1 3 1 2 1 2 3 2 3 1 3 1 2 1 2 3 2 3 1 3 1 2 72.29 65.85 72.95 7.10 11 6 10 1 2 3 3 1 2 2 3 1 1 2 3 3 1 2 2 3 1 1 2 3 3 1 2 2 3 1 69.62 72.27 69.20 3.07

alleviate the limitations of the traditional process in generating a large amount of mixed acid byproduct and waste acidic water. In the alternative process, the decrease of the HSO3 Cl amount leads to an increase of the reaction systems viscosity, which can be solved by introducing CCl4 as a diluent. Moreover, the addition of a small amount of NH4 Cl was found to increase the P-ASC yield signicantly. The factors aecting the synthesis reaction include the material ratio of HSO3 Cl, PCl5 , NH4 Cl, and CCl4 , sulfonation temperature and time, and the chlorination temperature and time. These were investigated rst by single-factor experiments and later by orthogonal experiments to determine the optimum operating conditions under which the P-ASC yield can reach up to 86.3 %.
Acknowledgements. This research was supported by the Fundamental Research Funds for the Central Universities (CDJZR10 22 00 10, CDJXS11 22 11 69, CDJXS10 22 11 40).

References
Boekman, F., Bohman, O., & Siegbahn, H. O. G. (1992). ESCA studies of phase transfer catalysts in solution. 2. Surface ion pairing and salting-out eects. The Journal of Physical Chemistry, 96, 22782283. DOI: 10.1021/j100184a047. Castaner, J., Riera, J., Carilla, J., Robert, A, Molins, E., & Miravitlles, C. (1991). A new triuoromethylating agent: synthesis of polychlorinated (triuoromethyl)benzenes and 1,3-bis(triuoromethyl)benzenes and conversion into their trichloromethyl counterparts and molecular structure of highly strained polychloro-m-xylenes. The Journal of the Organic Chemistry, 56, 103110. DOI: 10.1021/jo00001a022. Emerson, D. W., & Ifalade, S. O. (2005). Improved preparation of macroporous, chlorosulfonated poly(styrene-codivinylbenzene) and conversion to sulfonamides and sulfonylhydrazines. Industrial & Engineering Chemistry Research, 44, 70457048. DOI: 10.1021/ie050371u. Fan, X., Wang, J. G., & Wang, J. P. (2005). Optimum semimicro synthesis of P-aminobenzene sulfonamide. Journal of Luoyang Normal Univiversity, 2, 133135. Fidock, D. A., Rosenthal, P. J., Croft, S. L., Brun, R., & Nwaka, S. (2004). Antimalarial drug discovery: ecacy models for compound screening. Nature Reviews Drug Discovery, 3, 509520. DOI: 10.1038/nrd1416. Galat, A. (1944). New processes for sulfanilamide. Industrial & Engineering Chemistry, 36, 192. DOI: 10.1021/ie50410a023. Gao, F., Wang, Y., & Zeng, Y. (2002). New process study on sulfanilamide synthesis by chlorobenzene. Chemical Production and Technology, 9, 46. Huang, Z., Lin, Z., & Huang, J. (2001). A novel kind of antitumour drugs using sulfonamide as parent compound. European Journal of Medicinal Chemistry, 36, 863872. DOI: 10.1016/S0223-5234(01)80002-7. Kealey, D., & Haines, P. J. (2002). BIOS instant notes in analytical chemistry. New York, NY, USA: Taylor & Francis. Kong, X., Teng, Y., & Zhang, T. (1998). Synthesis of pacetamidobenzene sulfone chloride. Journal of Shenyang Institute of Chemical Technology, 12, 117121. Li, G., Liu, J., & Li, J. (2007). Improved synthetic technology for the organic dye intermediate: p-acetamidobenzene sulfonyl chloride. Journal of Henan Normal University (Natural Science), 35, 182184.

Table 4. Product yield under dierent CCl4 : acetanilide and NH4 Cl : acetanilide mole ratios CCl4 NH4 Cl 0 0.1 0.2 3.0 4.0 Yield/% 72.55 67.75 57.3 5.0

68.39 76.68 71.8

75.55 65.55 77.8

86.5 % with an identical synthesis procedure. However, since the boiling point of CHCl3 is only 61.15 C, the sulfonation and chlorination temperatures have to be decreased and the reaction time has to be prolonged.

Conclusions
An alternative chlorosulfonic acid process to synthesize P-ASC was investigated by partially substituting HSO3 Cl with PCl5 as the chlorination agent. Compared with the traditional process, the alternative process uses lower amount of HSO3 Cl, which can

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Li, P. (2002). Treatment of waste acid in chlorosulfonic acid production process. Chemical Intermediates, 17, 1516. Li, Y., & Hu, C. (2005). Experimental design and data analysis. Beijing, China: Chemical Industry Press. Lin, X., Wei, R.-Q., Liu, X.-N., & Zhou, R. (2009). Study on the function group uniformity of polystyrol sulfonyl chloride resins by infrared spectra. Spectroscopy and Spectral Analysis, 29, 18011804. DOI: 10.3964/j.issn.1000-0593(2009)071801-04. Martin, H., Gysin, H., Neracher, O., & Hirt, R. (1943). U.S. Patent No. 243,5974. Washington, D.C.: U.S. Patent and Trademark Oce. Martin. H., & Hirt, R. (1947). U.S. Patent No. 242,9207. Washington, D.C.: U.S. Patent and Trademark Oce. Meier, M., & Tronich, W. (1992). U.S. Patent No. 513,6043. Washington, D.C.: U.S. Patent and Trademark Oce. Meng, G. (1995). Improvement for the synthesis and purication of p-acetate-amino-benzene-sulfonyl chloride. Jounal of Henan Normal University (Medical Science), 14, 179180. Montgomery, D. C. (2004). Design and analysis of experiments (6th Ed.). New York, NY, USA: Wiley. Moore, R. M., Jr. (2003). A convenient synthesis of high-purity 1-chloro-2,6-diuorobenzene. Organic Process Research & Development, 7, 921924. DOI: 10.1021/op0340816. Pence, L. H., & Winter, H. C. (1939). Purication of pacetaminobenzenesulfonyl chloride. Journal of the American Chemical Society, 61, 29772978. DOI: 10.1021/ja01265a509.

Pouchert, C. J. (1970). The Aldrich library of infrared spectra. Milwaukee, WI, USA: Aldrich Chemical Co Inc. Smiles, S., & Stewart, J. (1925). p-Acetaminobenzenesulfonyl chloride. Organic Syntheses, 5, 1. Song, B. (1990). New process for acetanilide chlorosulfonation. Tianjin Chemical Industry, 2, 2429. Su, Y., & Hao, Y. (2005). Improved technology for synthesis of p-acetylsulfanilamide. Journal Hebei Normal University (Natural Science Edition), 29, 5860. Su, Y., & Yang, J. (2002). Improved technology for synthesis of p-acetamidobenzenesulfonyl chloride. Journal Hebei Normal University (Natural Science Edition), 26, 162164. Xin, J.-F., Ma, J.-H., Zhang, S.-F., Chen, S.-R., & Li, H.-Y. (2006). Review of the methods of preparing acyl chlorides. Hebei Chemical Engineering Industry, 29, 1618. Zeng, Z. (1981). Organic chemical experiments. Beijing, China: Peoples Education Press. Zhang, S. (1991). Handbook of ne organic chemical technology. Beijing, China: Science Press. Zhao, Z., Wolkenberg, S. E., Lu, M., Munshi, V., Moyer, G., Feng, M., Carella, A. V., Ecto, L. T., Gabryelski, L. J., Lai, M.-T., Prasad, S. G., Yan, Y., McGaughey, G. B., Miller, M. D., Lindsley, C. W., Hartman, G. D., Vacca, J. P., & Williams, T. M. (2008). Novel indole-3-sulfonamides as potent HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs). Bioorganic & Medicinal Chemistry Letters, 18, 554559. DOI: 10.1016/j.bmcl.2007.11.085.