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

Article abstract of DOI:10.2478/s11696-011-0026-1

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 HSO₃Cl 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 HSO₃Cl by PCl₅ as the chlorination agent. Compared with the traditional process, the molar ratio of HSO₃Cl 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 NH₄Cl was found to significantly increase the P-ASC yield. Operating conditions of the reaction were studied first 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 %.

Full text of DOI:10.2478/s11696-011-0026-1

Chemical Papers 65 (4) 510–518 (2011)
DOI: 10.2478/s11696-011-0026-1
ORIGINAL PAPER
An alternative synthetic process of -acetaminobenzenesulfonyl
chloride through combined chlorosulfonation by HClSO and PCl5
3
a
a,b
a
a
a,b
c
Shiyu Tan, Yang Yang, Ziping Luo, Shuo Zhao, Dafu Huang*, Jun Zhang,
a,b
a
Lichun Dong, Gang Wang
aSchool of Chemistry and Chemical Engineering, Chongqing University, 400044 Chongqing, China
bChongqing Key laboratory of the Three Gorges Reservoir Region’s Eco-Environment, Ministry of Education,
400044 Chongqing, China
cThe Environmental Protection Bureau of Wansheng District, 400800 Chongqing, China
Received 21 July 2010; Revised 8 January 2011; Accepted 27 January 2011
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 HSO Cl has to
3
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 sub-
stituting HSO
molar ratio of HSO
using CCl as the diluent; also, addition of a small amount of NH
3
Cl by PCl
Cl to acetanilide (the main raw material) can be decreased from 4.96 to 2.1
Cl was found to significantly
5
as the chlorination agent. Compared with the traditional process, the
3
4
4
increase the P-ASC yield. Operating conditions of the reaction were studied first 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
3 5
Keywords: p-aminobenzene sulfone chloride, chlorosulfonation process, HSO Cl, PCl , p-amino-
benzene sulfonamide
Introduction
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 Cu2O as the catalyst. This process
has the advantage of generating a lower amount of
waste acid. However, it requires severe operating con-
ditions 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 ac-
etanilide which is first sulfonated and chlorinated to p-
acetaminobenzenesulfonyl chloride (P-ASC) using an
excess of chlorosulfonation acid as a combined chlo-
rination and sulfonation agent. Afterwards, P-ASC is
Sulfonamides are the second most-used antibacte-
rial medicine just after antibiotics. They are sta-
ble, cheap and have a very broad antimicrobial spec-
trum (Fidock et al., 2004; Huang et al., 2001; Zhao
et al., 2008). Among the sulfonamide medicines, p-
aminobenzene sulfonamide (sulfanilamide, SN) has
the simplest molecular structure and the highest an-
nual production. There are two main routines for the
production of SN: chlorobenzene and chlorosulfonic
acid (Martin et al., 1943; Martin & Hirt, 1947; Galat,
1
944). In the chlorobenzene process (Gao et al., 2002),
raw material, chlorobenzene, is first sulfonated and
chlorinated to chlorobenzene sulfonyl chloride using
*Corresponding author, e-mail: lcdong72@gmail.com

S. Tan et al./Chemical Papers 65 (4) 510–518 (2011)
511
Fig. 1. Scheme of the experimental set-up. 1 – heater; 2 – four-neck flask; 3 – water/ice bath; 4 – feed inlet; 5 – thermometer; 6
stirrer; 7 – condenser.
–
ammoniated and hydrolyzed to produce SN. Raw ma-
terials for this process are easy to obtain and the oper-
ating conditions are fairy mild, which is why it is the
most used industrial process for SN production. How-
ever, during the production of P-ASC, an excess of
HSO3Cl with the molar ratio of HSO3Cl to acetanilide
as high as 5.0 has to be used in order to obtain the
required product yield. After the reaction, the reac-
tion mixture is treated with water which reacts with
HSO3Cl to generate mixed H2SO4/HCl acidic solution
and HCl gas. P-ASC is obtained as a crystal precip-
itate. In this process, HCl gas can be recovered by
water-scrubbing producing pure HCl while the mixed
acidic solution, after being filtered to obtain crude
product, can only be sold as a low value byproduct
since it contains a significant amount of impurities.
Finally, the crude product is washed with water to
obtain the final product, which generates a significant
amount of waste acidic water resulting in serious en-
vironment problem (Li, 2002).
HSO3Cl (Industrial Grade) from Changshou Chemi-
cal Co. Ltd. (Chongqing, China); and the standard P-
ASC sample was obtained from Changshou Chemical
Plant (> 99 %, Chongqing, China). All the reagents
were used without further purification.
In a 250 mL four-neck flask (Fig. 1), 7.3 mL of
HSO3Cl were mixed with CCl4 at a volume ratio of
HSO3Cl : CCl4 = 1 : 3.4 at room temperature. Then,
7.00 g of acetanilide were added in seven batches un-
der 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 reac-
tion. After 60 min, when the reaction was close to the
end, 0.277 g of NH4Cl 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 chlo-
With the aim to decrease the amount of HSO3Cl,
an alternative chlorosulfonic acid process for the syn-
thesis of P-ASC, in which PCl5 is used to partially re-
place HSO3Cl as the chlorination agent, is proposed.
A diluent, CCl4, is introduced to reduce the viscosity
of the reaction system, and a small amount of NH4Cl
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 HSO3Cl but
also significantly increases the product yield.
rination reaction proceeded for 3 h. After the synthe-
sis reaction, most CCl4 was removed under vacuum
and ice water was added to remove POCl3, HSO3Cl,
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, ob-
tained by filtration, 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 final product (10.4 g,
Experimental
white crystals). Purity of the P-ASC product was de-
termined 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 ac-
etanilide in HSO3Cl is a strongly exothermic process
−
Acetanilide (Analytical Grade, AR) was purchased
from Sinopharm Chemical Reagent Co. Ltd. (Shang-
hai, China); PCl5 (AR) was from Tingxin Chemical
Reagent Co. Ltd. (Shanghai, China); CCl4 (AR) from
Chuandong Chemical Co. Ltd. (Chongqing, China);

5
12
S. Tan et al./Chemical Papers 65 (4) 510–518 (2011)
NHCOCH3
NHCOCH3
A
B
NHCOCH3
NHCOCH3
NHCOCH
3
NHCOCH
3
HSO Cl
3
−
HCl
HSO
3
Cl
PCl5
−
H SO
2
− POCl
3
4
−
Η
SO H
II
3
SO H
II
SO Cl
III
SO
II
H
3
SO Cl
2
III
3
2
I
Fig. 2. Scheme of the sulfonation reaction.
Fig. 3. Schemes of the chlorination reaction: using HSO3Cl (A)
as the chlorination agent; using PCl5 (B) as the chlori-
nation agent.
while both the sulfonation and chlorination reactions
are weakly exothermic. Since the whole process is ac-
companied by the generation of HCl gas, a water ad-
sorption device was added to the experimental set to
recover HCl gas from the system. Moreover, a H2O
flux condenser was used to recirculate the reactive sol-
vent.
The melting point of P-ASC was measured by an
XRC21 microscopic melting point apparatus (Sichuan
University Scientific Instrument Co. Ltd., Chengdu,
China). IR spectrum of P-ASC was recorded on
a MAGMA–IR550 spectrometer (Nicolet Company,
USA) using the KBr pressing pellet method.
as the chlorination agent with the aim to decrease
the amount of HSO3Cl and to increase the chlorina-
tion efficiency. The comparison of several commonly
used chlorination agents, e.g., SOCl2 (Moore, 2003),
SO2Cl2 (Castaner et al., 1991), PCl3, trichloromethyl
benzene, PCl5, resulted in the selection of PCl5 due
to its high chlorination efficiency and easy treatment
of byproducts (Emerson & Ifalade, 2005). Reaction
scheme with PCl5 as the chlorination agent is pre-
sented in Fig. 3b, the byproducts being POCl3 and
HCl. As with HSO3Cl, excess POCl3 can be removed
by its reaction with water (Eqs. (1) and (2)), gener-
ated HCl gas as well as that from the chlorination
reaction can be recovered by water scrubbing to pro-
duce hydrochloric acid.
The product solved in methanol was analyzed us-
ing an Agilent 1100 HPLC system (UK), equipped
with a Diamonsil C18 (4.6 mm × 250 mm, 5 µm)
column and a UV 254 detector. Operating conditions
◦
were: temperature 40 C; injection volume of the sam-
ple 25 µL; flow phase methanol/water (ϕr = 60 : 40);
HSO3Cl + H2O ⇔ H2SO4 + HCl
POCl3 + 3H2O ⇔ H3PO4 + 3HCl
(1)
(2)
−
1
flow rate of the flow phase 1 mL min
.
1
Finally, H-NMR spectrum of the product dis-
solved in CDCl3 was recorded on a Bruker AV500
NMR spectrometer (Switzerland) with Si(CH3)4 as
the internal reference.
In the traditional chlorosulfonation process to syn-
thesize P-ASC, HSO3Cl not only serves as the chlo-
rination and sulfonation agent but also as the dilu-
ent maintaining low viscosity of the reaction system.
Partial substitution of HSO3Cl by PCl5 as the chlo-
rination agent in the improved process decreases the
amount of HSO3Cl, which leads to an increase of the
reaction system’s viscosity and pronounced decrease
of the P-ASC yield. An alterative diluent has to be
introduced to effectively reduce the viscosity of the
reaction system. Owing to the extremely high activity
of HSO3Cl and PCl5, the candidate diluent has to be
very inert. In this work, CCl4 was used as the dilu-
ent, 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 ad-
dition of a small amount of NH4Cl during the chlori-
nation stage increases the product yield significantly.
Although detailed mechanism of NH4Cl reaction re-
quires further investigation, it is believed that NH4Cl
acts as a phase transfer catalyst which can affect the
distribution of reactants and products between the
two phases (CCl4 phase and HSO3Cl phase) due to
Results and discussion
Reaction mechanism
Traditional chlorosulfonation process to synthe-
size P-ASC from acetanilide actually contains two
sequential reactions (Li et al., 2007; Song, 1990;
Kong et al., 1998): acetanilide (I ) is sulfonated to p-
acetamidobenzene sulfonic acid (II ) (Fig. 2) which is
then chlorinated to P-ASC (III ) (Fig. 3a). In the tra-
ditional process, HSO3Cl 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, sul-
fonation is fast and HSO3Cl has very high sulfonation
efficiency, consequently, the conversion rate of the sul-
fonation reaction is close to 100 % (Meier & Tronich,
1
2
992; Xin et al., 2006; Su & Yang, 2002; Su & Hao,
005). On the other hand, the chlorination reaction is
slow and the efficiency of HSO3Cl as the chlorination
agent is low. Therefore, a new chlorination agent was
employed in this study to partially substitute HSO3Cl

S. Tan et al./Chemical Papers 65 (4) 510–518 (2011)
513
0
0
.5
.4
7
6
5
0
B
0
0
.3
.2
A
4
3
1
5
0
5
0
.1
0
0
2
4
6
8
10
t /min
0
Fig. 5. HPLC chromatogram: void volume (t = 0.977 min), im-
purities (t = 2.289 min), and P-ASC (t = 3.115 min).
Product purity determined using the area normaliza-
tion method is 98.7 %.
4
000
3500
3000 2500
2000
1500 1000
-
500
-1
Wavenumber /cm
Fig. 4. IR spectra of the standard P-ASC sample (A) and the
product (B).
the “salting-out” effect and the participation of chlo-
ride ions in the surface ion-pairing (Boekman et al.,
1
992).
Product characterization
8.0
7
.9
7.8
7.7
Melting point of the synthesized product was de-
◦
termined to be (141.3 ± 1.2) C, while its literature
◦
◦
1
6
14
12
10
8
6
4
2
0
-2
-4
value is between 141 C and 149 C (Pence & Winter,
δ
1
939; Smiles & Stewart, 1925; Pouchert, 1970). Since
the prepared product is not 100 % pure, the measured
value is within a reasonable range confirming thus the
prepared product to be P-ASC.
Fig. 6. 1H-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 base-
line peaks are attributed to impurities.
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 verifies the iden-
tification of the product as P-ASC of high purity. In
peak at δ = 2.189 was attributed to methyl hydrogen
atoms. The two double-peaks at δ = 7.7 and δ = 7.9
correspond to the four hydrogen atoms in the ben-
zene ring; peaks at δ = 7.7 contain an overlapping
peak corresponding to the hydrogen atom in —NH—.
−
1
the spectra, the characteristic peaks at 1371.1 cm
and 1170.3 cm
−
1
can be attributed to the symmet-
ric stretching of O—S—O. The three intense peaks at
−
1
−1
−1
corre-
3
307.3 cm , 3264.5 cm , and 1681.8 cm
−
1
1
spond to the amide group. The peaks at 3050.6 cm
,
The H-NMR spectra show that two types of hydro-
−
1
−1
−1
1
495.0 cm , 1558.1 cm , 1584.7 cm , and 1605.7
gen atoms exist in the benzene ring of the products,
which further confirms that the benzene ring is para-
substituted. If the benzene ring was ortho-substituted,
four different types of hydrogen atoms would exit in
the benzene ring.
−
1
cm correspond to the benzene ring, while the peak
−
1
at 839.0 cm proves that the benzene ring was para-
substituted (Pouchert, 1970; Lin et al., 2009).
HPLC chromatogram (Fig. 5) of the product shows
three peaks: the first one at t = 0.977 min was at-
tributed to the flow 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 normaliza-
tion method indicated that the product purity is 98.7
Affecting factors of synthesis reaction
The aim of the improved process is to decrease the
consumption of HSO3Cl by using PCl5 to partially
replace HSO3Cl as the chlorination agent; however, it
has been found that the dose of HSO3Cl cannot be
less than a critical range, where the molar ratio of
HSO3Cl 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
%, which confirmed the result of the argentometric
method (98.2 %).
1
Fig. 6 shows the H-NMR spectrum of the prod-
uct, which exhibits three major peaks except three
baseline peaks corresponding to the impurities. The

5
14
S. Tan et al./Chemical Papers 65 (4) 510–518 (2011)
9
8
7
6
5
4
3
0
0
0
0
0
0
0
8
0
70
60
50
40
30
20
4
5
50
55
ºC
60
65
1
.6
1.8
2.0
2.2
2.4
2.6
2.8
3.0
3.2
HSO Cl : acetanilide molar ratio
T
s
/
3
Fig. 7. P-ASC yield at different amounts of HSO3Cl. Other
operating conditions are: molar ratio of PCl5, NH4Cl,
and CCl4 to acetanilide – 1.40, 0.1, and 4.0, respec-
tively; sulfonation time – 1 h; chlorination time – 3 h;
Fig. 9. P-ASC yield at different sulfonation temperatures (Ts).
Other operating conditions are: molar ratio of HSO3Cl,
PCl5, NH4Cl, and CCl4 to acetanilide – 2.0, 1.4, 0.1,
and 4.0, respectively; sulfonation time – 1 h; chlori-
nation time – 3 h; chlorination temperature – 66◦C;
stirring intensity – medium.
◦
sulfonation temperature – 54 C; chlorination tempera-
◦
ture – 66 C; stirring intensity – medium.
8
7
7
6
6
5
5
0
5
0
5
0
5
0
85
8
7
7
6
6
5
5
0
5
0
5
0
5
0
0
.9
1
1.1
1.2
1.3
1.4
1.5
5
5
60
65
70
75
80
PCl : acetanilide molar ratio
Tc /ºC
5
Fig. 8. P-ASC yield at different amounts of PCl5. Other op-
erating conditions are: molar ratio of HSO3Cl, NH4Cl,
and CCl4 to acetanilide – 2.0, 0.1, and 4.0, respectively;
sulfonation time – 1 h; chlorination time – 3 h; sulfona-
Fig. 10. Effect of chlorination temperature (Tc). Other oper-
ating conditions are: molar ratio of HSO3Cl, PCl5,
NH Cl, and CCl4 to acetanilide – 2.0, 1.4, 0.1, and
4
4.0, respectively; sulfonation time – 1 h; chlorination
◦
◦
tion temperature – 54 C; chlorination temperature –
time – 3 h; sulfonation temperature – 54 C; stirring
◦
6
6 C; stirring intensity – medium.
intensity – medium.
◦
HSO3Cl and acetanilide was set to 2.0 and the effect
of PCl5 and CCl4 dosage, reaction time and tempera-
ture on the product yield was investigated. Fig. 8 dis-
plays 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.
is around 70 C, the decrease of the product yield at
higher temperatures is caused by the enhancement of
side reactions, decomposition of HSO3Cl and the evap-
oration 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 effect of
the sulfonation and chlorination time on the P-ASC
yield. The results indicate that the product yield first
increases with an increase of both sulfonation and
chlorination time and decreases with a further in-
crease 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 re-
action time leads to a decrease of the P-ASC yield,
The effect of the sulfonation and chlorination tem-
peratures on the product yield is shown in Figs. 9 and
1
0, respectively. Both results show that the P-ASC
yield first increases with an increase of the reaction
temperature until a maximum is reached, and then
decreases with a further increase of the reaction tem-
perature. Optimum sulfonation temperature is around
◦
5
8 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

S. Tan et al./Chemical Papers 65 (4) 510–518 (2011)
515
75
72
69
66
63
60
80
77
74
71
68
65
0.4
0.6
0.8
1
ts /h
1.2
1.4
1.6
1.5
2
2.5
3
tc /h
3.5
4
4.5
Fig. 11. P-ASC yield at different sulfonation times (ts). Other
operating conditions are: molar ratio of HSO3Cl,
PCl5, NH4Cl, and CCl4 to acetanilide – 2.0, 1.4, 0.1,
and 4.0, respectively; chlorination time – 3 h; sulfona-
Fig. 12. P-ASC yield at different chlorination times (tc). Other
operating conditions are: molar ratio of HSO3Cl,
PCl5, NH4Cl, and CCl4 to acetanilide – 2.0, 1.4, 0.1,
and 4.0, respectively; sulfonation time – 1 h; sulfona-
◦
tion temperature – 54◦C; chlorination temperature –
tion temperature – 54 C; chlorination temperature –
◦
66◦C; stirring intensity – medium.
6
6 C; stirring intensity – medium.
which is also due to the enhancement of the side re-
actions.
range value, the more important the corresponding
factor. K is the average product yield corresponding
to each level of every affecting factor. From the K val-
ues, optimum operating conditions can be determined
by choosing the level of each factor corresponding to
the largest K value (Table 2). Afterwards, verifica-
tion experiments were done at the optimum operating
conditions to confirm the results of orthogonal exper-
iments and to obtain the highest product yield.
The range analysis in Table 2 demonstrates that
the HSO3Cl amount (R = 11.9), sulfonation tempera-
ture (R = 8.26) and the chlorination time (R = 6.90)
are the major affecting factors while the sulfonation
time, amount of CCl4, PCl5, and NH4Cl or the stirring
intensity have minor effect on the product yield. The
study on the effect of several factors (Table 3) shows
that the interaction between the amount of NH4Cl and
CCl4 has the most significant effect on the product
yield (R = 7.10). The addition of NH4Cl increases the
P-ASC yield; however, it also increases the viscosity of
the reaction system, which is unfavorable to the chlori-
nation 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 effect of NH4Cl. Table 4 (obtained from Table 2)
Orthogonal experiments
Based on the single-factor experiments, a group
of orthogonal experiments was employed to study the
importance of the affecting factors and to obtain the
optimum operating conditions. Since there are nine
essential affecting factors including the material ra-
tio of HSO3Cl, PCl5, CCl4, and NH4Cl, the time and
temperature of both sulfonation and chlorination reac-
tion, and the stirring intensity (Li, 2005; Montgomery,
2
004); and also the interactive effect of sulfonation
temperature and time, chlorination temperature and
time, material ratio of HSO3Cl to PCl5, material ratio
13
of CCl4 to NH4Cl are interesting, the L27(3 ) design
was selected. Affecting factors and their values in the
orthogonal experiments are listed in Table 1, where
columns numbers 4, 8, 9, and 11 studies the inter-
active effects 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 af-
fecting degree of each affecting factor. The larger the
Table 1. Factors and levers of the L27(313) orthogonal experiments: sulfonation temperature (Ts), sulfonation time (ts), chlorina-
tion temperature (Tc), chlorination time (tc), molar ratio of compound to acetanilide
Factor number
Level
1
2
3
4
5
6
7
8
9
10
11
12
13
Ts
ts
Tc
tc
1 × 2
HSO3Cl CCl4 7 × 12 3 × 5 PCl5 6 × 10 NH4Cl Stiring intensity
◦
◦
C
h
C
h
1
2
3
50 0.5 62
55 1.0 67
60 1.5 72
2.5
3.0
3.5
1.9
2.0
2.1
3.0
4.0
5.0
1.10
1.25
1.40
0
0.1
0.2
High
Medium
Low

5
16
S. Tan et al./Chemical Papers 65 (4) 510–518 (2011)
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
Experiment
1
2
3
5
6
7
10
12
13
Ts
ts
Tc
tc
Yield
%
HSO3Cl
CCl4
PCl5
NH4Cl
Stiring intensity
◦
◦
C
h
C
h
1
2
3
4
5
6
7
8
9
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
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
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
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
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
3
1
2
3
1
2
3
3
1
2
3
1
2
3
1
2
2
3
1
2
3
1
2
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
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
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
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
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
3
3
3
3
2
2
2
3
1
2
3
1
3
1
2
3
1
2
K1
K2
K3
R
66.99
68.85
75.25
8.26
68.50
71.61
71.0
3.10
69.54
69.20
72.34
3.14
71.74
73.12
66.23
6.90
63.73
71.70
75.66
11.9
69.83
69.26
72.00
2.74
70.83
68.22
72.04
3.82
68.89
69.51
72.69
3.80
72.16
69.99
68.93
3.23
–
–
–
shows that the combination of the molar ratio of CCl4
to acetanilide of 5.0 and the molar ratio of NH4Cl to
acetanilide of 0.2 results in the highest product yield;
verification experiments also showed that the product
yield does not increase when the amounts of CCl4 and
NH4Cl are further increased.
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 fixed, and
the P-ASC yield reached 84.3 % and 85.4 %, respec-
tively. 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 sacrifice 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 H3PO4, and 1.1 mol of H2SO4 for produc-
Optimum operating conditions of the P-ASC syn-
thesis were determined from Table 2 as: sulfonation
◦
temperature of 60 C; sulfonation time of 1.0 h; chlo-
◦
rination temperature of 72 C; chlorination time of 3
h; molar ratio of HSO3Cl to acetanilide of 2.1; mo-
lar ratio of CCl4 to acetanilide of 5.0; molar ratio of
PCl5 to acetanilide of 1.4; molar ratio of NH4Cl to ac-
etanilide of 0.2; stirring intensity high. The verification
experiments demonstrated that the P-ASC yield can
reach 86.3 % under optimum operating conditions, the
yield being significantly higher than that of the tradi-
tional process, (82.4 % for lab-scale and 77 % for the
industrial process) with the molar ratio of HSO3Cl
to acetanilide as high as 4.96 (Li et al., 2007). Since
the orthogonal experiments showed that the molar ra-
tio of PCl5 to acetanilide has a minor effect on the
+
ing 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
H2SO4). However, since most HCl gas can be recov-
ered to hydrochloric acid, the amount of aqueous acid
was significantly 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 suit-
able solvent; the yield of P-ASC can reach as high as

S. Tan et al./Chemical Papers 65 (4) 510–518 (2011)
517
Table 3. Design and results of the L27(313) orthogonal exper-
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 HSO3Cl amount leads to an in-
crease of the reaction system’s viscosity, which can
be solved by introducing CCl4 as a diluent. More-
over, the addition of a small amount of NH4Cl was
found to increase the P-ASC yield significantly. The
factors affecting the synthesis reaction include the ma-
terial ratio of HSO Cl, PCl , NH Cl, and CCl , sul-
fonation temperature and time, and the chlorination
temperature and time. These were investigated first
by single-factor experiments and later by orthogonal
experiments to determine the optimum operating con-
ditions under which the P-ASC yield can reach up to
iment: interactive effect
Factor number
Experiment
4
9
8
11
1 × 2
3 × 5
7 × 12
6 × 10
1
2
3
4
5
6
7
8
9
1
1
1
2
2
2
3
3
1
2
3
2
3
1
3
1
1
2
3
2
3
1
3
1
1
2
3
3
1
2
2
3
3
5
4
4
3
2
2
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
3
3
3
1
1
1
2
2
2
2
2
2
3
3
3
1
1
2
3
1
3
1
2
1
2
3
3
1
2
1
2
3
2
3
1
2
3
2
3
1
3
1
2
1
2
3
2
3
1
3
1
1
2
3
3
1
2
2
3
1
1
2
3
3
1
2
2
3
8
6.3 %.
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
0).
(
4
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